Clinical trial NCT03894540
Conditions: Solid Tumor
Sponsor: Ipsen
Start date: 2019-03-22; Completion date: 2020-12-21
Enrollment: 22 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The purpose of the protocol is to determine safety, tolerability, recommended dose (RD), pharmacokinetics (PK), pharmacodynamics (PD) and preliminary anti-tumour activity of IPN60090 as a single agent (Part A) and in combination with pembrolizumab (Part B) or paclitaxel (Part C) in patients with advanced solid tumours and to evaluate food effect (Part D).

Detailed description:

Arms: arm 1: Part 1: Dose escalation of IPN60090, Part 2: Dose expansion

IPN60090 given as a Bis in Die (BID) oral dose administered up to Maximum Tolerated Dose (MTD) over a 21-day cycle arm 2: Part 1: Dose escalation of IPN60090 in combination with pembrolizumab, Part 2: Dose expansion

IPN60090 given as a Bis in Die (BID) oral dose, starting with pharmacologically active dose identified in 1dose escalation of IPN60090 as a single agent, over a 21-day cycle in combination with 200 mg pembrolizumab given every 21 days (Day 1 of every cycle) as IV infusion arm 3: Part 1: Dose escalation of IPN60090 in combination with paclitaxel, Part 2: Dose expansion

IPN60090 given as a BID oral dose, starting with pharmacologically active dose identified in dose escalation of IPN60090 as a single agent over a 21-day cycle in combination with 175 mg/m2 or 135 mg/m2 paclitaxel given every 21 days (Day 1 of every cycle) as IV infusion arm 4: Part 1: Food Effect of IPN60090

IPN60090 given as a single oral dose as a single agent at the recommended dose (RD) under fasting and fed conditions followed by IPN60090 given as a BID oral dose administered at the RD over a 21-day cycle.
Interventions: intervention 1: IPN60090 intervention 2: pembrolizumab intervention 3: paclitaxel intervention 4: IPN60090 single administration
Intervention descriptions: intervention 1: Oral capsules given daily intervention 2: An intravenous solution in single-use vial to be diluted for infusion. intervention 3: An intravenous solution in single-use vial to be diluted for infusion. intervention 4: Oral capsules given once

Protocol documents:
Prot_000.pdf: 
,36(1*5283
'86

&21),'(17,$/
35272&2/),1$/9(56,21'(&(0%(5
3$*(

35272&2/ 7,7/( $ 3+$6( , 23(1 /$%(/ '26( (6&$/$7,21 $1' '26(
(;3$16,21 678'< 72 ,19(67,*$7( 7+( 6$)(7< 3+$50$&2.,1(7,&6
3+$50$&2'<1$0,&6$1'$17,780285$&7,9,7<2),31$66,1*/(
$*(17$1',1&20%,1$7,21,13$7,(176:,7+$'9$1&('62/,'7802856
678'<35272&2/
678'<180%(5'86
,31
(XGUD&7QXPEHU
&OLQLFDO7ULDOVJRYQXPEHU1&7
,1'QXPEHU
9HUVLRQ'HFHPEHULQFRUSRUDWLQJDPHQGPHQW
9HUVLRQ0D\LQFRUSRUDWLQJDPHQGPHQW
9HUVLRQ'HFHPEHU
9HUVLRQ'HFHPEHU
9HUVLRQ2FWREHU

6WXG\6SRQVRU
,36(1%LRVFLHQFH,SVHQ*URXS
(DVW.HQGDOO6WUHHW
&DPEULGJH0$86$
7HO


6SRQVRU6LJQDWRU\0HGLFDO0RQLWRUDQG(PHUJHQF\&RQWDFW

,36(1%LRVFLHQFH
(DVW.HQGDOO6WUHHW
&DPEULGJH0$86$


3KDUPDFRYLJLODQFH&RQWDFW


3DWLHQW6DIHW\,SVHQ,QQRYDWLRQ
=RQH,QGXVWULHOOHGH&RXUWDERHXI$YHQXHGX&DQDGD/HV8OLV)UDQFH





$OOVHULRXVDGYHUVHHYHQWV6$(VDQGSUHJQDQFLHVPXVWEHUHSRUWHGLPPHGLDWHO\XVLQJWKH
HOHFWURQLFGDWDFDSWXUH('&V\VWHP,IWKH('&V\VWHPLVQRWDYDLODEOHWKH6$(IRUPPXVW
EHHPDLOHGWR
LIQRWSRVVLEOH
WRHPDLO

Persons supplied with this information must understand that it is strictly confidential. 
Information contained herein cannot be disclosed, submitted for publication or used for any 
33'
33'
33'
33'
33'
33'


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 2/264 
 
purpose other than that contemplated herein without the sponsor’s prior written 
authorisation. 


,36(1*5283
'86

&21),'(17,$/
35272&2/),1$/9(56,21'(&(0%(5
3$*(

,19(67,*$725¶6$*5((0(17
,QYHVWLJDWRU$JUHHPHQWDQG6LJQDWXUH
, KDYH UHDG DQG DJUHH WR 3URWRFRO '86 HQWLWOHG $ 3KDVH , 2SHQ /DEHO 'RVH
(VFDODWLRQ DQG 'RVH ([SDQVLRQ 6WXG\ WR ,QYHVWLJDWH WKH 6DIHW\ 3KDUPDFRNLQHWLFV
3KDUPDFRG\QDPLFV DQG $QWLWXPRXU $FWLYLW\ RI ,31 DV 6LQJOH $JHQW DQG LQ
&RPELQDWLRQLQ3DWLHQWVZLWK$GYDQFHG6ROLG7XPRXUV,DPDZDUHRIP\UHVSRQVLELOLWLHVDV
DQLQYHVWLJDWRUXQGHUWKHJXLGHOLQHVRI*RRG&OLQLFDO3UDFWLFH*&3ORFDOUHJXODWLRQVDV
DSSOLFDEOHDQGWKHVWXG\SURWRFRO,DJUHHWRFRQGXFWWKHVWXG\DFFRUGLQJWRWKHVHJXLGHOLQHV
DQGWRDSSURSULDWHO\GLUHFWDQGDVVLVWWKHVWDIIXQGHUP\FRQWUROZKRZLOOEHLQYROYHGLQWKH
VWXG\

1$0(

7,7/(
35,1&,3$/
6,*1$785(

,19(67,*$725

'$7(
2)),&(








6SRQVRU¶V5HSUHVHQWDWLYH6LJQDWXUH
1$0(


6,*1$785(

'$7(
2)),&(
,36(1%LRVFLHQFH

(DVW.HQGDOO6WUHHW

&DPEULGJH0$86$
33'
33'
33'


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 4/264 
 
SUMMARY OF CHANGES 
The initial version of the protocol (Version 1.0) was released on 29 October 2018, Version 1.1 
was released on 20 December 2018, Version 1.2 was released on 21 December 2018, and 
Version 2.0 (including Amendment 1.0) was released on 24 May 2019. The current version of 
the protocol (Version 3.0) was released on 10 December 2019 and includes Amendment 2.0. 
The respective protocol amendment forms were prepared and are provided in Appendix 10 
(Table 1). 
Table 1 
List of Protocol Amendments  
Amendment 
Release date 
Amendment form 
Version 1.2 
21 December 2018 
Appendix 10 
Version 2.0 (Amendment 1.0) 
24 May 2019 
Appendix 10 
Version 3.0 (Amendment 2.0) 
10 December 2019 
Appendix 10 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 5/264 
 
SYNOPSIS 
Name of Sponsor/Company: IPSEN Bioscience  
Name of Finished Product: IPN60090 
Name of Active Ingredient(s): IPN60090 
Title of Study: A Phase I, Open Label, Dose Escalation and Dose Expansion Study to 
Investigate the Safety, Pharmacokinetics, Pharmacodynamics and Anti-tumour Activity of 
IPN60090 as Single Agent and in Combination in Patients with Advanced Solid Tumours 
Study Number: D-US-60090-001 
Number of Planned Centres: From one centre in the United States of America to 
approximately 50 sites worldwide over the dose escalation and expansion parts of the study 
Planned Study Period: 
Dose Escalation: Q1 2019 to Q3 2020 
Dose Expansion: Q3 2020 to Q4 2022 
Phase of Development: 
Phase I 
Study Type: Interventional, safety, efficacy, pharmacokinetics (PK), pharmacodynamics 
(PD)  
Objectives:  
This study will evaluate the safety, the PK, PD and anti-tumour activity of IPN60090 as a 
single agent (Part A) and in combination with pembrolizumab (Part B) or paclitaxel (Part C) 
in patients with advanced solid tumours. Part D will evaluate the safety of IPN60090 as a 
single agent and explore the effect of food on the IPN60090 PK profile. Specific objectives 
and corresponding endpoints for the study are outlined below. 
Primary: 
• 
To assess the safety and tolerability of oral IPN60090 as a single agent (Part A and 
Part D) and in combination therapy with pembrolizumab (Part B) or paclitaxel (Part C). 
For Dose Escalation Only: 
• 
To determine the maximum tolerated dose (MTD) if reached, and the recommended 
dose (RD) of IPN60090 as a single agent (Part A) and in combination therapy with 
pembrolizumab (Part B) or paclitaxel (Part C).  
Secondary: 
• 
To assess the preliminary anti-tumour activity of IPN60090 as a single agent (Part A 
and Part D) and in combination with pembrolizumab (Part B) or paclitaxel (Part C) in 
patients with or without biomarker selected specific tumour types. 
• 
To characterise the PK and PD profile of IPN60090 as a single agent (Part A and 
Part D) and in combination with pembrolizumab (Part B) or paclitaxel (Part C).  
• 
To assess the effect of food on the PK profile of a single administration of IPN60090 
(Part D). 
• 
To document the concentrations of pembrolizumab and paclitaxel (Parts B and C). 
• 
To document the potential development of antibodies against pembrolizumab (Part B). 
• 
To evaluate biomarkers of patient stratification and correlate them with clinical 
outcome.  


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 6/264 
 
Exploratory: 
• 
To analyse exploratory biomarkers in archival and fresh biopsy samples, including 
biomarkers of response or resistance to the treatment, and associate them with clinical 
outcome.  
• 
To collect biobank samples for potential future analysis of biomarkers (optional, 
informed consent required). 
Study Hypothesis: IPN60090 will have a manageable safety profile to permit further clinical 
development as a single agent and in combination with pembrolizumab or paclitaxel in 
patients with advanced solid tumours and will demonstrate preliminary efficacy and 
anti-tumour effects as a monotherapy and/or in combination with pembrolizumab or paclitaxel 
across Kelch-like ECH-associated protein 1 (KEAP1)/ nuclear factor erythroid 2-related 
factor 2 (NRF2) mutant solid tumours and in low protein expression level of asparagine 
synthetase (ASNSlow) solid tumours. 
Methodology:  
This is a phase I, first in human, open-label, dose escalation and dose expansion study of 
IPN60090 as a single agent or in combination in patients with advanced solid tumours.  
As summarised in Figure 1, the study will be divided into four parts. 
Figure 1 IPN60090: Summary of Early Clinical Development 
 
PART D 
 
ASNS=asparagine synthetase; BID=bis in die (twice daily); BOIN=Bayesian Optimal Interval; HGSOC= high-grade serous 
ovarian cancer; KEAP1=Kelch-like ECH-associated protein 1; NRF2=nuclear factor erythroid 2–related factor 2; 
NSCLC=non-small cell lung cancer; Ph.=pharmacologically; RD=recommended dose 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 7/264 
 
Part A: The dose escalation will explore the safety profile and establish the MTD (if 
reached), the target engagement or PD levels (glutamate:glutamine (Glu:Gln) ratio in 
peripheral blood mononuclear cells (PBMC)) and the RD of single agent IPN60090 in 
biomarker unselected patient populations. During the dose expansion portion, safety and 
tolerability at the RD will be assessed further, and the preliminary anti-tumour activity of 
IPN60090 will be explored in three different cohorts (non-small cell lung cancer (NSCLC) 
KEAP1 or NRF2 mutant, other KEAP1 or NRF2 mutant tumours and high-grade serous 
ovarian cancer (HGSOC) ASNSlow). 
Part B: The dose escalation will explore the safety profile and establish the MTD (if reached) 
and the RD of IPN60090 in combination with pembrolizumab. During the dose expansion 
portion, safety and tolerability at the RD will be assessed further, and preliminary anti-tumour 
activity of this combination will be explored. 
Part C: The dose escalation will explore the safety profile and establish the MTD (if reached) 
and the RD of IPN60090 in combination with paclitaxel. During the dose expansion portion, 
safety and tolerability at the RD will be assessed further, and preliminary anti-tumour activity 
of this combination will be explored. 
Parts B and C: These dose escalations in combination with pembrolizumab or paclitaxel will 
be initiated at the first dose with pharmacological activity (at least 50% inhibition of Glu:Gln 
ratio in PBMCs at trough plasma concentration (Ctrough; 12 hours postdose) on Day 14 in 66% 
of patients treated at this dose level) and with good tolerability as identified in Part A. 
Part D: This cohort will evaluate the safety of IPN60090 administered as a single agent and 
explore the effect of a moderate fat meal on the PK profile of IPN60090 administered as a 
single dose under fasting and fed conditions at the RD as defined by the Safety Review 
Committee (SRC). 
Part A – Dose Escalation with IPN60090 as a Single Agent 
Dose escalation of IPN60090 will be conducted in patients with biomarker-positive and 
biomarker-negative advanced solid tumours. 
These patients will not be selected for KEAP1/NRF2 mutation status and may be wild-type or 
mutated. Patients may have tumours with any level of asparagine synthetase (ASNS) 
expression. 
Seven dose levels are planned to be tested and the study will follow a Bayesian Optimal 
Interval (BOIN) design for dose escalation, with accelerated titration, using N=1, up to dose 
level (DL) 3 (included). At all dose levels, IPN60090 will be administered as a twice daily 
(BID) oral dose (every 12 hours) during or after a meal, starting from Day 1 of each 21-day 
cycle. The predefined dose escalation plan is described in Table 2. 
Table 2 
Dose Escalation Phase I-Part A 
DL1 
DL2 
DL3 
DL4 
DL5 
DL6 
DL7 
20 mg BID 
40 mg BID 
80 mg BID 
180 mg BID 
320 mg BID 
480 mg BID 
720 mg BID 
BID=bis in die (twice daily); DL=dose level 
Part A monotherapy dose escalation will enrol single-patient cohorts for the first three dose 
levels (if no Grade 2 adverse event (AE) that is at least possibly related to the study drug(s) or 
dose limiting toxicity (DLT) is observed) and then cohorts of three patients each at the 
predefined dose levels. If a Grade 2 AE that is at least possibly related to the study drug(s) or 
DLT is observed in a single-patient cohort (first three dose levels), two additional patients will 
be added at this dose level with the same rules for escalation and de-escalation as the cohorts 
of three patients. At any point, additional patients may be enrolled as required for safety 
assessment and/or biomarker analysis. Following each cohort DLT assessment period, the 
observed DLT data will be used to determine the dose level for the next cohort in accordance 
with the escalation and de-escalation rules for a local BOIN design using a target 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 8/264 
 
toxicity rate of 30% with escalation and de-escalation thresholds of 23.6% and 35.9%, 
respectively. Following the completion of enrolment, the MTD will be estimated at the dose 
level at which the isotonic estimate of the DLT rate is closest to 30%. 
At the end of each part, up to two dose levels may be repeated in order to reach a total of 
18 patients at each dose level to collect more PK/PD information to better define the RD. The 
decision to repeat a dose level will be made by the SRC. Safety data from these additional 
patients will not be included in the BOIN design to determine the MTD but will be evaluated 
by the SRC and ultimately be taken into consideration for RD selection. 
MTD Definition 
The MTD is defined as the maximum dose of IPN60090 that may be administered BID for 
21 days, so that no more than 30% of patients experience a DLT. The MTD will be 
determined by the dose for which the isotonic estimate of DLT rate is closest to 30% of 
patients experiencing a DLT.  
DLT Assessment Period 
The DLT assessment period will consist of the first 21 days of treatment (one cycle). The 
SRC will evaluate safety and available PK and PD data after patients have completed at least 
one cycle of treatment in order to make a decision on dose escalation, and to determine the 
MTD and the RD. The SRC may decide to evaluate an intermediate, not predefined, 
previously evaluated or not previously-evaluated dose or a less frequent dosing schedule that 
will not exceed the MTD level, if evaluation of toxicity at such a dose or schedule is desired. 
More details about the SRC are included in Section 4.3.1 and will be described in the SRC 
charter. 
DLT Criteria 
The DLTs for Part A are defined for the investigational medicinal product (IMP)-related, 
probably related or possibly related AEs according to National Cancer Institute – Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 that occur during the 
defined DLT assessment period (over the 21 days following the first dose of IPN60090). 
Other clinically significant or persistent toxicities may be considered a DLT following review 
by the SRC. Detailed DLT definitions are included in Section 3.1.2.1 of the protocol.  
Patient Eligibility for Dose Escalation Decision 
Any patient who does not complete the DLT assessment period for any reason other than a 
DLT will be considered nonevaluable for dose escalation decisions and MTD assessment and 
will be replaced by an additional patient at that same dose level. Patients will be considered 
eligible for the DLT assessment only if they are able to receive ≥75% of the total planned 
IPN60090 dose over the DLT assessment period. Noncompliant patients will also be replaced. 
The SRC may decide to enrol additional patients based on the safety, PK or PD data.  
Treatment Duration - Additional Cycles 
Patients will be offered IPN60090 treatment beyond Cycle 1 as long as they continue to 
experience clinical benefit, in the opinion of the investigator, until the earlier of disease 
progression, symptomatic deterioration, poor tolerability despite appropriate medical 
management or any of the other reasons for treatment discontinuation. Patients who 
experience a DLT (or other toxicities considered related, probably related or possibly related 
to the study treatment) will be permitted to continue to receive study treatment at a lower dose 
level than the dose at which the DLT was observed, at the discretion of the investigator, and 
will be followed for safety. Biomarker-positive patients who are enrolled and receive study 
treatment at initial dose levels below the pharmacologically active range for at least two 
cycles with good tolerability, and achieve and maintain at least stable disease (SD), may be 
escalated to a higher dose level that has been tested and proven to be well tolerated, at the 
recommendation of the SRC. These patients will be treated outside of the BOIN design. 
Patients who discontinue study treatment for reasons other than disease progression (for 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 9/264 
 
example toxicity) should continue to undergo scheduled tumour assessments approximately 
every 12 weeks until disease progression, initiation of further systemic cancer therapy, death, 
or until the study closes, whichever occurs first.  
Part B – Pembrolizumab Combination Dose Escalation 
The dose escalation portion of Part B is a phase I, open-label, dose escalation study to 
evaluate the safety, tolerability, PK and PD of IPN60090 given as a BID oral dose (every 
12 hours) during or after a meal, in combination with pembrolizumab, over a 21-day cycle.  
Dose escalation of IPN60090 in combination with pembrolizumab will be conducted in 
patients with biomarker-positive and biomarker-negative advanced solid tumours.  
These patients will be unselected for KEAP1/NRF2 mutation status and may be 
KEAP1/NRF2 wild-type or mutated; patients may have tumours with any level of ASNS 
expression. Previous treatment with checkpoint inhibitor therapy is allowed.  
This dose escalation in combination with pembrolizumab will be initiated at a dose level 
showing pharmacological activity (at least 50% inhibition of Glu:Gln ratio in PBMCs at 
Ctrough (12 hours postdose and predose for the following dose) on Day 14 of Cycle 1 in 66% of 
patients treated at this dose level) and with good tolerability as identified in Part A. The 
IPN60090 dose being tested in the dose escalation of Part B will always remain lower than 
that being tested in the dose escalation of Part A (at least one dose level lower than the highest 
dose tested in Part A).  
Three dose levels of IPN60090 are planned to be tested with an additional lower dose level 
(DL-1) if DL1 is not tolerated. The study will follow a BOIN design for dose escalation.  
At all dose levels, IPN60090 will be administered orally BID starting from Day 1 of each 
21-day cycle and pembrolizumab will be administered as one intravenous (i.v.) infusion every 
21 days (±1 day in Cycle 1 and ±3 days in all other cycles) starting from Day 1 of each cycle. 
The predefined dose escalation plan is described in Table 3. 
Table 3 
Dose Escalation Phase I-Part B in Combination with Pembrolizumab 
Dose level 
Dose level -1 
Dose level 1 
Dose level 2 
Dose level 3 
Planned dose of 
IPN60090 [a] 
80 mg BID 
180 mg BID 
320 mg BID 
480 mg BID 
Planned dose of 
pembrolizumab 
200 mg Q3W[b] 200 mg Q3W[b] 
200 mg Q3W[b] 
200 mg Q3W[b] 
BID=bis in die (twice daily); Q3W=every three weeks (21 days) 
a 
dose levels are examples; the actual starting dose will be determined by PD from the Part A dose escalation 
b 
or according to the local approved label for particular tumour types 
Dose finding will begin at DL1. The study will enrol in cohorts of three patients at the 
predefined dose levels until up to six cohorts have been enrolled. Following each cohort, the 
observed DLT data will be used to determine the dose level for the next cohort in accordance 
with the escalation and de-escalation rules for a local BOIN design using a target toxicity rate 
of 30% with escalation and de-escalation thresholds of 23.6% and 35.9%, respectively. 
Following the completion of enrolment, the MTD will be estimated as the dose level at which 
the isotonic estimate of the DLT rate is closest to 30%.  
If the first dose level of IPN60090 in combination with 200 mg pembrolizumab is not well 
tolerated, upon the decision of the SRC, the dose of IPN60090 may be de-escalated and thus a 
new cohort may start with DL-1. 
At the end of each part, up to two dose levels may be repeated in order to reach a total of 
18 patients at each dose level to collect more PK/PD information to better define the RD. The 
decision to repeat a dose level will be made by the SRC. Safety data from these additional 
patients will not be included in the BOIN design to determine the MTD but will be evaluated 
by the SRC and ultimately be taken into consideration for RD selection. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 10/264 
 
MTD Definition 
The MTD is defined as the maximum dose of IPN60090 that may be administered BID for 
21 days, in combination with an i.v. infusion of 200 mg of pembrolizumab (or according to 
the local approved label for particular tumour types), so that no more than 30% of patients 
experience a DLT. The MTD will be determined by the dose for which the isotonic estimate 
of DLT rate is closest to 30% of patients experiencing a DLT.  
DLT Assessment Period 
The DLT assessment period will consist of the first 21 days of treatment (one cycle). The 
SRC will evaluate safety and available PK and PD data in order to make a decision on dose 
escalation, and to determine the MTD and the RD. The safety data reviewed by the SRC will 
include the safety findings and DLTs observed during the DLT assessment period from the 
previous cohort. The SRC may decide to evaluate an intermediate, not predefined, previously 
evaluated or not previously-evaluated dose or a less frequent dosing schedule that will not 
exceed the MTD level if evaluation of toxicity at such a dose or schedule is desired.  
DLT Criteria 
The DLTs are defined for the IMP-related, probably related or possibly related AEs according 
to the NCI-CTCAE version 5.0 that occur during the defined DLT assessment period (over 
the 21 days following the first dose of IPN60090 combined with pembrolizumab).  
Other clinically significant or persistent toxicities may be considered a DLT following review 
by the SRC. 
Detailed DLT definitions are included in Section 3.1.2.2 of the protocol. 
Patient Eligibility for Dose Escalation Decision 
Any patient who does not complete the DLT assessment period for any reason other than a 
DLT will be considered nonevaluable for dose escalation decisions and MTD assessment and 
will be replaced by an additional patient at that same dose level. Moreover, patients will be 
considered eligible for the DLT assessment only if they received ≥75% of the total planned 
IPN60090 dose and one infusion of pembrolizumab over the DLT assessment period. 
Noncompliant patients will also be replaced. The SRC may decide to enrol additional patients 
based on the safety, PK or PD data. 
Treatment Duration - Additional Cycles  
Patients will be offered IPN60090 + pembrolizumab treatment beyond Cycle 1 as long as they 
continue to experience clinical benefit, in the opinion of the investigator, until the earlier of 
confirmed disease progression, symptomatic deterioration, poor tolerability despite 
appropriate medical management or any of the other reasons for treatment discontinuation. 
Patients who experience a DLT (or other toxicities considered related, probably related or 
possibly related to the study treatment) will be permitted to continue to receive study 
treatment at a lower dose level than the dose at which the DLT was observed, at the discretion 
of the investigator and will be followed for safety. Patients who discontinue study treatment 
for reasons other than disease progression (for example toxicity) should continue to undergo 
scheduled tumour assessments approximately every 12 weeks until confirmed disease 
progression, or initiation of further systemic cancer therapy, death, or until the study closes, 
whichever occurs first.  
Part C – Paclitaxel Combination Dose Escalation  
The dose escalation portion of Part C is a phase I, open-label, dose escalation study to 
evaluate the safety, tolerability, PK and PD of IPN60090 given as a BID oral dose (every 
12 hours) during or after a meal, in combination with paclitaxel (IPN60090 to be taken at least 
2.5 hours before the start of the paclitaxel infusion), over a 21-day cycle. 
Dose escalation of IPN60090 in combination with paclitaxel will be conducted in patients 
with biomarker-positive and biomarker-negative advanced solid tumours. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 11/264 
 
These patients will be unselected for KEAP1/NRF2 mutation and may be KEAP1/NRF2 
wild-type or mutated with any level of ASNS expression. Dose escalation in combination 
with paclitaxel will be initiated at a dose level showing pharmacological activity (at least 50% 
inhibition of Glu:Gln ratio in PBMC at Ctrough (12 hours postdose and predose for the 
following dose) on Day 14 of Cycle 1 in 66% of patients treated at this dose level) and good 
tolerability as identified in Part A. The IPN60090 dose being tested in Part C will always 
remain lower than that being tested in Part A (at least one dose level lower than the highest 
dose tested in Part A). 
Three dose levels of IPN60090 are planned to be tested with an additional lower dose level 
(DL-1) if DL1 is not tolerated. The study will follow a BOIN design for dose escalation.  
At all dose levels, IPN60090 will be administered orally BID starting from Day 1 of each 
21-day cycle and paclitaxel will be administered as one i.v. infusion every 21 days (±1 day in 
Cycle 1 and ±3 days in all other cycles) starting from Day 1 of each cycle. The predefined 
dose escalation plan is described in Table 4. 
Table 4 
Dose Escalation Phase I-Part C in Combination with Paclitaxel 
Dose level 
Dose level -1 
Dose level 1 
Dose level 2 
Dose level 3 
Planned dose of 
IPN60090 [a] 
80 mg BID 
180 mg BID 
320 mg BID 
480 mg BID 
Planned dose of 
paclitaxel 
175 or 135 mg/m2 
Q3W [b] 
175 or 135 mg/m² 
Q3W [b] 
175 or 135 mg/m² 
Q3W [b]  
175 or 135 mg/m² 
Q3W [b] 
BID=bis in die (twice daily); Q3W=every three weeks (21 days) 
a 
dose levels are examples; the actual starting dose will be determined by PD from the Part A dose escalation 
b 
or according to the local label for particular tumour types 
Dose finding will begin at DL1. The study will enrol in cohorts of three patients at the 
predefined dose levels until up to six cohorts have been enrolled. Following each cohort, the 
observed DLT data will be used to determine the dose level for the next cohort in accordance 
with the escalation and de-escalation rules for a local BOIN design using target toxicity rate 
of 30% with escalation and de-escalation thresholds of 23.6% and 35.9%, respectively. 
Following the completion of enrolment, the MTD will be estimated as the dose level at which 
the isotonic estimate of the DLT rate is closest to 30%.  
If the first dose level of IPN60090 in combination with paclitaxel 175 or 135 mg/m² (or 
according to the local approved label for particular tumour types) given intravenously is not 
well tolerated, the dose of IPN60090 may be de-escalated and thus a new cohort may start 
with the DL-1.  
At the end of each part, up to two dose levels may be repeated in order to reach a total of 
18 patients at each dose level to collect more PK/PD information to better define the RD. The 
decision to repeat a dose level will be made by the SRC. Safety data from these additional 
patients will not be included in the BOIN design to determine the MTD but will be evaluated 
by the SRC and ultimately be taken into consideration for RD selection. 
MTD Definition 
The MTD is defined as the maximum dose of IPN60090 that may be administered BID for 
21 days, in combination with an i.v. infusion of 175 or 135 mg/m² paclitaxel (or according to 
the local approved label for particular tumour types), so that no more than 30% of patients 
experience a DLT. The MTD will be determined by the dose for which the isotonic estimate 
of DLT rate is closest to 30% of patients experiencing a DLT.  
DLT Assessment Period 
The DLT assessment period will consist of the first 21 days of treatment (one cycle). The 
SRC will evaluate safety and available PK and PD data in order to make a decision on dose 
escalation, and to determine the MTD and the RD. The safety data reviewed by the SRC will 
include the safety findings and DLTs observed during the DLT assessment period from the 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 12/264 
 
previous cohort. The SRC may decide to evaluate an intermediate, not predefined, previously 
evaluated or not previously evaluated dose or a less frequent dosing schedule that will not 
exceed the MTD level, if evaluation of toxicity at such a dose or schedule is desired.  
DLT Criteria 
The DLTs are defined for the IMP-related, probably related or possibly related AEs according 
to the NCI-CTCAE version 5.0 that occur during the defined DLT assessment period (over 
the 21 days following first the dose of IPN60090).  
Other clinically significant or persistent toxicities may be considered a DLT following review 
by the SRC. 
Transient infusion-related AEs that can be controlled with medical management (i.e. flu-like 
symptoms, fever) are not considered DLTs. Detailed DLT definitions are included in 
Section 3.1.2.3 of the protocol. 
Patient Eligibility for Dose Escalation Decision 
Any patient who does not complete the DLT assessment period for any reason other than a 
DLT will be considered nonevaluable for dose escalation decisions and MTD assessment and 
will be replaced by an additional patient at that same dose level. Moreover, patients will be 
considered eligible for the DLT assessment only if they are able to receive ≥75% of the total 
planned IPN60090 dose and one infusion of paclitaxel over the DLT assessment period. The 
SRC may decide to enrol additional patients based on the safety, PK or PD data. 
Treatment Duration - Additional Cycles 
Patients will be offered IPN60090 + paclitaxel treatment beyond Cycle 1 as long as they 
continue to experience clinical benefit, in the opinion of the investigator, until the earlier of 
disease progression, symptomatic deterioration, poor tolerability despite appropriate medical 
management or any of the other reasons for treatment discontinuation. Patients who 
experience a DLT (or other toxicities considered related, probably related or possibly related 
to the study treatment) will be permitted to continue to receive study treatment at a lower dose 
level than the dose at which the DLT was observed, at the discretion of the investigator and 
will be followed for safety. Patients who discontinue study treatment for reasons other than 
disease progression (for example toxicity) should continue to undergo scheduled tumour 
assessments approximately every 12 weeks until disease progression, or initiation of further 
systemic cancer therapy, death, or until the study closes, whichever occurs first.  
Parts A, B and C Dose Escalation 
In Parts A, B and C, when the RD is determined, if a patient is still in the study at a different 
dose, this patient can be moved to the RD at the discretion of the investigator. 
In the event that operational/practical circumstances result in an over-enrolment (i.e. n>3) for 
a BOIN cohort, the next dose level decision would be based on the actual number of patients 
exposed in the cohort and the BOIN criteria.  
Part D – Food Effect Assessment  
Part D will start at the end of the Part A dose escalation. Patients in Part D will not be part of 
the dose escalation and MTD assessment. 
Food effect evaluation will be conducted in patients with biomarker-positive and 
biomarker-negative advanced solid tumours. 
These patients will not be selected for KEAP1/NRF2 mutation status and may be wild-type or 
mutated. Patients may have tumours with any level of ASNS expression. Eligibility criteria 
for Part D will be the same as the criteria for the Part A dose escalation. 
After screening, eight patients will enter a run-in period of 7 days. 
Full PK profiles will be obtained on Day -7 under fasting conditions and Day -3 after a 
moderate fat meal to assess the food effect on the IPN60090 PK profile. 
In Part D, the moderate fat meal is defined as the following: total calories of 500 to 750 kCal 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 13/264 
 
including 30 to 35% fat. 
After the run-in period, patients will receive IPN60090 as a single agent administered orally 
BID (every 12 hours), during or after a meal, starting from Day 1 at the single agent RD. 
Patients in Part D will follow the same schedule of assessments as described for Part A (with 
the exception of the urine sampling for PK).  
Dose Expansion Cohorts 
The multicohort dose expansion part of the study will further explore the safety and 
tolerability of IPN60090 in monotherapy and in combination; assess the preliminary 
anti-tumour activity of IPN60090 as a single agent and in combination with pembrolizumab 
or paclitaxel at the RD in biomarker positive and/or unselected patient population and will 
explore the potential of selected biomarkers as predictors of efficacy (candidate biomarkers 
will include, but will not be limited to, KEAP1/NRF2 mutation status, ASNS expression 
level, and known or new emerging predictive or prognostic markers of efficacy in selected 
tumour types). 
Enrolment into dose expansion cohorts will occur independently of each other. Each cohort 
will follow a sequential 2-stage design and enrol ten patients in Stage 1 and up to a total of 
18 patients (Stage 1 + Stage 2). Further expansion may be initiated in cohorts with observed 
efficacy signals. 
The dose expansion cohorts that will be explored in each part of the study are defined as the 
following: 
• 
Part A- IPN60090 monotherapy 
- 
Dose Expansion Cohort 1: KEAP1 or NRF2 mutant NSCLC  
- 
Dose Expansion Cohort 2: Other KEAP1 or NRF2 mutant tumours 
- 
Dose Expansion Cohort 3: ASNSlow HGSOC 
• 
Part B- IPN60090 + pembrolizumab: 
- 
Dose Expansion Cohort 4: KEAP1 or NRF2 mutant NSCLC  
- 
Dose Expansion Cohort 5: Other KEAP1 or NRF2 mutant tumours  
- 
Dose Expansion Cohort 6: KEAP1 or NRF2 wild-type tumours with any level of 
ASNS expression 
• 
Part C- IPN60090 + paclitaxel: 
- 
Dose Expansion Cohort 7: Other KEAP1 or NRF2 mutant tumours  
- 
Dose Expansion Cohort 8: ASNSlow HGSOC 
- 
Dose Expansion Cohort 9: KEAP1 or NRF2 wild-type tumours with any level of 
ASNS expression 
Dose expansion cohorts (study populations and sample size) may be revised in light of the 
dose escalation data, resulting in a protocol amendment.  
An independent safety assessment committee structured to assess safety in addition to 
efficacy will be established for dose expansion cohorts in order to make recommendations 
regarding protocol modifications to reduce risks to patients enrolled in the study. If 
preliminary clinical evidence in one or several dose expansion cohorts suggests a substantial 
improvement over available therapies on a clinically significant endpoint(s), further efficacy 
expansion cohorts may be initiated in the corresponding populations with the goal of 
assessing the anti-tumour activity of IPN60090 monotherapy or combination. 
Patients enrolled in monotherapy Part A or Part D may receive combination treatment with 
either pembrolizumab or with paclitaxel upon progression on IPN60090 monotherapy at the 
discretion of the investigator and with the approval of the sponsor. These patients will need to 
satisfy eligibility criteria for combination therapy prior to initiating treatment and will be 
followed for safety and efficacy in a separate cohort.  


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 14/264 
 
Number of Patients Planned: 
Dose Escalation 
Part A (single agent): Approximately 30 patients for the dose escalation. 
Part B (combination with pembrolizumab): Approximately 18 patients for the dose 
escalation. 
Part C (combination with paclitaxel): Approximately 18 patients for the dose escalation. 
Food Effect Assessment 
Part D (single agent): Eight patients for preliminary food effect assessment. 
Dose Expansion 
Parts A, B, and C: Approximately 162 patients (90 patients in Stage 1 of dose expansion, 
and 72 patients in Stage 2). 
Diagnosis and Criteria for Inclusion:  
Inclusion Criteria 
General Inclusion Criteria for All Parts 
(1) 
Provision of written informed consent prior to any study related procedures. 
(2) 
Male or female patients ≥18 years of age at the time of study entry who agree to 
participate by giving written informed consent prior to participation in any 
study-related activities. 
(3) 
Histologically or cytologically confirmed advanced solid tumours including tumours 
known to harbour KEAP1 and/or NRF2 mutations or have low ASNS expression 
levels. 
- 
In dose escalations of all parts, patients may be KEAP1 and NRF2 wild-type or 
mutated and have tumours with any level of ASNS expression. For dose 
expansions, see specific inclusion criteria per part below. 
(4) 
Patients must have received at least one line of therapy for advanced stage disease and 
be refractory or ineligible to available existing therapy(ies) known to provide clinical 
benefit for their condition. 
(5) 
Prior treatment with chemotherapy, radiotherapy, immunotherapy or any investigational 
therapies must have been completed at least 3 weeks or at least five half-lives before the 
study drug administration, and all AEs (excluding alopecia and peripheral neuropathy) 
have either returned to baseline or stabilised. 
(6) 
Fresh and/or archival tumour tissue from the biopsy obtained between the completion 
of the most recent line of treatment until study entry must be available for mutation and 
biomarker analysis unless KEAP1/NRF2 mutations were present in any previous 
biopsy, in which case, no further biopsy is required. For ovarian cancer patients, both 
archival biopsies obtained between the completion of the most recent line of treatment 
until study entry and fresh biopsies must be available to evaluate the evolution of ASNS 
levels over time. Patients should not be put at undue risk to obtain fresh tumour biopsy. 
Procedures more invasive than core biopsy should not be used. Procedures to obtain 
biopsy should only be performed if the risk is minimal (no greater than 2% risk of 
serious or severe complications). If available, archival tumour tissue from time of initial 
diagnosis will be collected in addition to the most recent biopsy (archival and/or fresh). 
(7) 
Measurable or non-measurable evaluable disease as defined per the Response 
Evaluation Criteria in Solid Tumors (RECIST) v1.1 (or immune-related RECIST 
(iRECIST) for Part B only). 
(8) 
Eastern Cooperative Oncology Group Performance Status ≤1. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 15/264 
 
(9) 
Adequate organ function as indicated by the following laboratory values: 
(a) 
Absolute neutrophil count ≥1500/mL 
(b) 
Platelets ≥100,000/mL 
(c) 
Haemoglobin ≥9 g/dL or ≥5.6 mmol/L  
(d) 
Serum creatinine ≤1.5×upper limit of normal (ULN) and/or creatinine clearance 
>40 mL/min. Actual body weight should be used for calculating creatinine 
clearance using the Cockroft-Gault equation (except for patients with body mass 
index >30 kg/m2 when the lean body weight should be used). 
(e) 
Serum total bilirubin ≤1.5×ULN (with the exception of patients with known 
Gilbert’s syndrome: serum total bilirubin must be <3×ULN in these patients) 
(f) 
Aspartate aminotransferase (serum glutamic oxaloacetic transaminase) and 
alanine aminotransferase (serum glutamic pyruvic transaminase) ≤2.5×ULN or 
≤5×ULN for patients with liver metastases) 
(10) Adequate cardiac function with a left ventricular ejection fraction ≥50% 
(11) Female patients are eligible to enter and participate in the study if they are of: 
(a) 
Non-childbearing potential (physiologically incapable of becoming pregnant), 
including any female who: 
- 
has had a hysterectomy, OR 
- 
has had a bilateral oophorectomy, OR  
- 
has had a bilateral salpingectomy, OR  
- 
is postmenopausal (total cessation of menses for ≥2 years, or 
follicle-stimulating hormone ≥50 IU/L). 
(b) 
Childbearing potential, but with a negative serum pregnancy test at screening 
(within 7 days of the first IMP administration), is not breastfeeding, and uses 
highly effective contraception at study entry and throughout the study until 
90 days after the last administration. Highly effective contraceptive methods 
include: 
- 
Combined (oestrogen and progestogen containing) hormonal 
contraception associated with inhibition of ovulation (for example oral, 
intravaginal, transdermal) 
- 
Progestogen-only hormonal contraception associated with inhibition of 
ovulation (for example oral, implantable, injectable) 
- 
Intrauterine device 
- 
Intrauterine hormone-releasing system 
- 
Bilateral tubal occlusion 
- 
Male partner has had a vasectomy 
(12) Male patients are eligible to enter and participate in the study if they agree to use 
effective methods of contraception during the study treatment period and for at least 
90 days after the last dose of investigational product. 
Part A Specific Inclusion Criteria 
There are no further inclusion criteria associated with Part A. 
Dose Expansion ONLY:  
(A1) Patients with the following tumour types will be recruited: 
(a) 
NSCLC KEAP1 and/or NRF2 mutant  


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 16/264 
 
(b) 
KEAP1 and/or NRF2 mutant other tumours 
(c) 
HGSOC ASNSlow  
Note: all biomarker mutations/expression levels must be confirmed prior to study treatment. 
Part B Specific Inclusion Criteria 
(B1) 
Patients may have received previous treatment with any programmed cell death 
protein 1 or programmed cell death ligand 1 (PD-L1) inhibitor  
Dose Expansion ONLY:  
(B2) 
Patients may have received previous treatment with any anti-programmed cell death 
protein 1 (PD-1)/PD-L1 monoclonal antibody (mAb) administered either as 
monotherapy, or in combination with other checkpoint inhibitors or other therapies. 
PD-1 treatment progression is defined by meeting all of the following criteria: 
(a) 
Has received at least 2 doses of an approved anti-PD-1/L1 mAb. 
(b) 
Has demonstrated disease progression after PD-1/L1 as defined by iRECIST 
v1.1. The initial evidence of disease progression is to be confirmed by a second 
assessment no less than four weeks from the date of the first documented disease 
progression, in the absence of rapid clinical progression. 
(B3) 
Patients with the following tumour types will be recruited during the dose expansion 
only: 
(a) 
NSCLC KEAP1 and/or NRF2 mutant  
(b) 
Other KEAP1 and/or NRF2 mutant tumours 
(c) 
KEAP1 and NRF2 wild-type tumours with any level of ASNS expression 
Part C Specific Inclusion Criteria 
(C1) 
Patients may have received previous treatment with any platinum- or taxane-based 
chemotherapy.  
Dose Expansion ONLY:  
(C2) 
Patients with the following tumour types will be recruited during dose expansion only: 
(a) 
KEAP1 or NRF2 mutant tumours 
(b) 
HGSOC ASNSlow tumours 
(c) 
KEAP1 or NRF2 wild-type tumours with any level of ASNS expression 
Part D Specific Inclusion Criteria 
(D1) Patients must be able to consume a moderate fat meal.  
Exclusion Criteria 
General Exclusion Criteria for All Parts 
(1) 
Prior malignancy within the previous 2 years except for locally curable cancers that 
have been cured, such as basal or squamous cell skin cancer, or carcinoma in situ of the 
cervix, breast or bladder. 
(2) 
Known primary central malignancy or symptomatic central nervous system 
metastasis(es). 
Note: Patients with stable, previously treated brain metastases may participate if neurologic 
symptoms have resolved, patients have been off steroids for at least 7 days, and there is no 
evidence of disease progression by imaging for at least 2 weeks before the first dose of study 
treatment. 
(3) 
Patients should be excluded if they have a condition requiring systemic treatment with 
either corticosteroids (>10 mg daily prednisone equivalents) or other 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 17/264 
 
immunosuppressive medications within 2 weeks of the first dose of study drug. 
(4) 
Uncontrolled, significant intercurrent or recent illness including, but not limited to, the 
following cardiac conditions: 
(a) 
Any unstable cardiac arrhythmia within 6 months prior to enrolment 
(b) 
Prolongation of the Fridericia corrected QT interval defined as >450 ms for 
males and >470 ms for females 
(c) 
History of any of the following cardiovascular conditions within 6 months of 
enrolment: 
- 
cardiac angioplasty or stenting, myocardial infarction, unstable angina, 
coronary artery 
- 
bypass graft surgery, symptomatic peripheral vascular disease, class III or 
IV congestive heart failure, as defined by the New York Heart 
Association. 
(5) 
Major surgical intervention within 28 days before study drug administration. 
(6) 
Significant acute or chronic infections.  
(7) 
Any psychiatric condition that would prohibit the understanding or rendering of 
informed consent. 
(8) 
Treatment with strong cytochrome P450 (CYP450) subtype 3A4 inducers (including 
St John’s Wort) and inhibitors (including grapefruit juice) within 7 days of the first 
dose of study drug.  
(9) 
Treatment with strong CYP450 subtype 2D6 inhibitors within 7 days of the first dose 
of study drug. 
(10) Radiotherapy within 4 weeks prior to the start of study drug. Palliative radiotherapy for 
symptomatic control is acceptable if completed at least 2 weeks prior to study drug 
administration and no additional radiotherapy for the same lesion is planned. 
(11) Underlying medical conditions that, in the investigator’s opinion, will make the 
administration of study drug hazardous or obscure the interpretation of toxicity 
determination or AEs. 
(12) History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to any of the compounds in the study. 
(13) Known alcohol or drug abuse. 
(14) Legal incapacity or limited legal capacity. 
(15) Inability to swallow oral medications (capsules and tablets) without chewing, breaking, 
crushing, opening or otherwise altering the product formulation. Patients should not 
have gastrointestinal illnesses that would preclude the absorption of IPN60090, which 
is an oral agent. 
(16) Patients unwilling to comply with protocol requirements related to the assigned part. 
Part A Specific Exclusion Criteria 
There are no further exclusion criteria associated with Part A. 
Part B Specific Exclusion Criteria 
(B1) Autoimmune disease that might deteriorate when receiving an immune-stimulatory 
agent, or immunodeficiencies.  
(B2) Known severe hypersensitivity reactions to monoclonal antibodies, any history of 
anaphylaxis, or uncontrolled asthma (that is, three or more features of partially 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 18/264 
 
controlled asthma). 
(B3) Prior organ transplantation, including allogeneic stem cell transplantation. 
(B4) Patient has received a live vaccine within 30 days prior to the first dose of study drug. 
Examples of live vaccines include, but are not limited to, the following: measles, 
mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus 
Calmette-Guérin and typhoid vaccine. Seasonal influenza vaccines for injection are 
generally killed virus vaccines and are allowed; however, intranasal influenza vaccines 
(e.g. FluMist®) are live attenuated vaccines and are not allowed. 
Part C Specific Exclusion Criteria 
(C1) Treatment with strong CYP450 subtype 2C8 inhibitors and inducers within the 7 days 
of the paclitaxel infusion. 
Part D Specific Exclusion Criteria 
(D1) Treatment with drugs that can alter the absorption of IPN60090 by affecting 
gastrointestinal motility or by changing the gastric pH during the run-in period (Day -7 
to Day -3) of Part D.  
(D2) Patients suffering from conditions that are likely to adversely affect gastrointestinal 
motility and/or transit (for example, diarrhoea, vomiting or nausea, gastroparesis, 
irritable bowel syndrome and malabsorption) or patients with gastrointestinal resection 
(e.g. partial or total gastrectomy) likely to interfere with absorption of study treatment. 
Patients with Type 1 diabetes and hypercholesterolaemia are excluded. 
(D3) Patients unable to fast for up to 14 hours. 
Test Product, Dose, Mode of Administration: 
IPN60090 will be administered as oral capsules of either 10, 60 or 240 mg BID during or after 
a meal over 21 days (1 cycle). IPN60090 capsules will be given every 12 hours corresponding 
to a BID regimen. 
Part A dose escalation: tested doses of IPN60090 will range from 20 mg BID (40 mg total 
daily dose) (starting dose) to 720 mg BID (1,440 mg daily dose) (maximum dose). 
Part B dose escalation: the starting dose of IPN60090 will be a dose showing 
pharmacological activity (at least 50% inhibition of Glu:Gln ratio in PBMC at Ctrough 
(12 hours postdose) on Day 14 in 66% of patients at this dose level) and good tolerability as 
identified in Part A. IPN60090 intake should be performed at least 1 hour before the start of 
pembrolizumab infusion. The dose of pembrolizumab will be fixed at 200 mg every 21 days 
(±1 day in Cycle 1 and ±3 days in all other cycles) (or according to the local approved label 
for specific tumour types) as an i.v. infusion. 
Part C dose escalation: the starting dose of IPN60090 will be a dose showing significant 
pharmacological activity (at least 50% inhibition of Glu:Gln ratio in PBMC at Ctrough 
(12 hours postdose) on Day 14 in 66% of patients at this dose level) and good tolerability as 
identified in Part A. When histamine 2 receptor (H2) blockers are administered for paclitaxel 
premedication, they must be administered at least 30 minutes prior to paclitaxel infusion. 
IPN60090 intake should be performed at least 2.5 hours before the start of the paclitaxel 
infusion and at least 2 hours prior to H2 blocker administration. 
The dose of paclitaxel will be fixed at 175 mg/m² or 135 mg/m2 every 21 days (±1 day in 
Cycle 1 and ±3 days in all other cycles) (or according to the local approved label for specific 
tumour types) administered as an i.v. infusion. 
The proposed dose levels may be further modified and additional doses may be considered 
based on the safety, tolerability and efficacy observed during dose escalation. An 
intermediate, not predefined, previously evaluated or not previously evaluated dose or a less 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 19/264 
 
frequent dosing schedule that will not exceed the MTD level may be considered, if evaluation 
of toxicity at such a dose or schedule is desired. 
Part D food effect assessment: single administration of IPN60090 at the RD (morning dose 
only), as defined by the SRC at the end of the Part A dose escalation, will be performed 
during the run-in period at Day -7 and Day -3. On Day -7, IPN60090 will be administered 
following an overnight fast of at least 10 hours. On Day -3, IPN60090 will be administered 
30 minutes after the start of a moderate fat meal. The moderate fat meal should be eaten in 
30 minutes or less. On both days, the patients should not consume any food for at least 
4 hours after the dose. IPN60090 should be taken with 240 mL (i.e. 8 fluid ounces) of water. 
Additional water is permitted ad libitum except for the period 1 hour before to 1 hour after 
administration of the drug product. Substitutions to the test meal can be made after discussion 
with the sponsor. It is understood that some patients may not be able to consume the entire 
meal. Study staff should record the percent of the test meal breakfast and the time it takes to 
be consumed. 
Then starting from Day 1, patients will receive IPN60090 BID (at the RD as defined by the 
SRC at the end of Part A) during or after a meal over 21 days (one cycle) as described in 
Part A. 
Duration of Treatment: Approximately 6 months 
Reference Therapy, Dose and Mode of Administration:  
Not applicable. 
Criteria for Evaluation (Endpoints): 
Primary 
• 
The safety and tolerability of IPN60090 as a single agent (Part A and Part D) and in 
combination with pembrolizumab (Part B) or paclitaxel (Part C) will be assessed by the 
rate of DLTs at each dose level in the dose escalation, and the rate of AEs and the rate 
of Grade 3 and higher AEs in the dose escalation and dose expansion. Continuous 
monitoring of AEs and serious AEs (SAEs), clinical laboratory test results, the 
presence of anti-pembrolizumab antidrug antibodies (ADA; Part B only), vital signs 
measurements, electrocardiogram (ECG) and physical examination results and 
concomitant medication usage will be performed. 
For dose escalation only: 
• 
Define MTD, if reached, as determined by the incidence and nature of DLTs, of: 
- 
single agent IPN60090 (Part A) 
- 
the combination of IPN60090 and pembrolizumab (Part B) or paclitaxel (Part C) 
• 
Define RD, as determined by the PD, PK and safety of: 
- 
single agent IPN60090 (Part A) 
- 
the combination of IPN60090 and pembrolizumab (Part B) or paclitaxel (Part C) 
Secondary 
• 
Anti-tumour activity parameters assessed locally (for dose escalation) and centrally (for 
dose expansion) using RECIST v1.1 for Parts A, C and D and iRECIST for Part B only, 
including:  
- 
Clinical benefit rate (CBR) is defined as the proportion of patients in whom the 
Best Overall Response (BOR) is equal to complete response (CR), partial 
response (PR) or SD lasting at least 12 weeks for Parts A, C and D, and equal to 
immune CR (iCR), immune PR (iPR) or immune SD (iSD) lasting at least 
12 weeks for Part B 
- 
Objective response rate (ORR) is defined as the proportion of patients in whom 
the BOR is equal to CR and PR for Parts A, C and D or iCR and iPR for Part B 
- 
Disease control rate (DCR) is defined as the proportion of patients in whom the 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 20/264 
 
BOR is equal to CR, PR or SD for Parts A, C and D, and equal to iCR, iPR or 
iSD for Part B 
- 
Progression free survival (PFS) is defined as the time from first dose of study 
medication to the first documented objective disease progression (for RECIST) 
or confirmed objective disease progression (for iRECIST) or death due to any 
cause, whichever occurs first (except for Part B where confirmation of 
progression is needed to determine the PFS to exclude pseudoprogression). 
- 
Overall survival is defined as the time from first dose of study medication to 
death due to any cause. 
• 
Pharmacokinetic parameters of IPN60090, including but not limited to maximum 
observed plasma drug concentration (Cmax), time to Cmax (Tmax), Ctrough, area under the 
plasma concentration time curve (AUC), elimination half-life (t1/2), apparent total 
clearance from plasma (CL/F) and apparent volume of distribution (V/F) of IPN60090 
(Parts A to D). 
• 
Describe the PK of a single dose of IPN60090 administered in fed state (Day -3) 
relative to fasted state (Day -7) using the following PK parameters: Cmax, AUC, Tmax, 
t1/2, CL/F and V/F (Part D). 
• 
Assessment of concentrations of the combined product (Parts B and C) 
• 
Assessment of potential ADA for pembrolizumab (Part B) 
• 
Pharmacodynamic parameters and biomarkers evaluation: 
- 
Target engagement: Glu:Gln ratio in PBMC 
- 
Tumour mutation status (for example KEAP1/NRF2, serine/threonine kinase 11, 
Kirsten Rat Sarcoma Viral Oncogene Homolog and other mutations) and 
correlation with clinical outcome 
- 
Tumour ASNS expression  
Exploratory 
• 
Biomarkers of tumour biology evolution under treatment (e.g. immune profiling, 
PD-L1 expression, nuclear antigen Ki67, phosphorylation of histone variant H2AX, 
liver kinase B1, etc) may be evaluated and correlated with clinical outcome. 
• 
Biobank samples will be collected for potential future analysis of biomarkers (optional, 
informed consent required) 
Exploratory IPN60090 concentrations in urine will be assessed only in Part A of dose 
escalation. The following PK parameters will be calculated: the amount of IPN60090 excreted 
in urine and renal clearance. 
Safety  
The safety and tolerability of IPN60090 will be assessed by the rate of DLTs at each dose 
level in the dose escalation, and the rate of AEs and the rate of Grade 3 and higher AEs in the 
dose escalation and dose expansion. Continuous monitoring of AEs and SAEs, clinical 
laboratory test results, the presence of anti-pembrolizumab ADA (Part B only), vital signs 
measurements, ECG and physical examination results, and concomitant medication usage will 
be performed.  
Statistical Methods: 
The following populations will be defined during statistical analyses: 
Screened population: All patients screened (i.e. who signed the informed consent). 
Safety population: All patients who are exposed to (or started receiving) IPN60090 and/or 
the combination agents.  
DLT evaluable population for the escalation phase only: All patients from the safety 
population who are evaluable for DLT (patients who have completed at least one cycle of 
treatment and have received ≥75% of the total planned dose of IPN60090 over the DLT 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 21/264 
 
assessment period). Patients with noncompliance (<75% of total planned dose) due to DLT 
will be included in this population. 
Efficacy population: All patients who receive at least one dose of IPN60090. 
Pharmacokinetic population for noncompartmental analysis: All patients who have no 
major protocol deviation affecting the PK variables and who have a sufficient number of 
IPN60090 plasma concentrations to estimate the main PK parameters (Cmax, Tmax, AUC from 
time 0 to the last time point with quantifiable concentrations (AUC0-last)).  
Pharmacokinetic population for population PK modelling: All patients who receive at 
least one IPN60090 dose and who have at least one plasma IPN60090 concentration and who 
have no major protocol deviation affecting the PK variables. 
Food effect population: All patients in Part D who have received IPN60090 under fasting 
and fed conditions (Day -7 and Day -3), have consumed ≥80% of the moderate fat meal in 
approximately 30 minutes on Day -3, and who have no major protocol deviation affecting the 
PK variables and who have a sufficient number of IPN60090 plasma concentrations to 
estimate the main PK parameters (Cmax, Tmax and AUC0-last). 
Pharmacodynamic population: All patients who have at least one PD endpoint 
measurement. PD endpoints refer to target engagement levels (Glu:Gln ratio in PBMC). 
Data will be listed and summarised by dose level and part in the escalation phase; by cohort 
and part for safety and by cohort for efficacy in the expansion phase. Safety results will be 
presented for all the patients included in the study at the RD (dose escalation and expansion 
phases) by part and RD. Furthermore, all safety and efficacy results could be presented by 
group of patients depending on the interest there may be in these groups. 
Categorical variables will be summarised by frequency distributions (number and percentages 
of patients). The 95% confidence interval (CI) will be calculated following the exact method. 
Continuous variables will be summarised by descriptive statistics (mean, standard deviation, 
median, minimum and maximum). Time-to-event variables will be summarised using the 
Kaplan-Meier method and the 95% CI of the median will be given. 
Food effect assessment – Part D 
The assessment of food effect will be based upon the ratio of the population geometric means 
(fed versus fasted, i.e. Day -3 versus Day -7) for the PK parameters (Cmax and AUC). The data 
will be transformed prior to analysis using a logarithmic transformation. Tmax between fed and 
fasted states will be compared using a non-parametric test such as the Wilcoxon test. 
Descriptive statistics of other PK parameters will be presented both in fasting and fed 
conditions. 
Sample Size: 
Monotherapy Dose Escalation – Part A 
A BOIN design with target toxicity rate of 30% (with escalation and de-escalation thresholds 
of 23.6% and 35.9%, respectively) with maximum number of approximately 30 patients will 
be used to estimate the IPN60090 monotherapy MTD.  
The design will proceed with accelerated titration up to DL3, i.e. cohorts of one will be 
enrolled until either the third dose level is evaluated, a Grade 2 AE that is at least possibly 
related to the study drug(s) occurs, or a DLT is observed (whichever occurs first). If a Grade 2 
AE that is at least possibly related to the study drug(s) or a DLT is observed in a single patient 
cohort (i.e. in one of the first three dose levels), two additional patients will be added at this 
dose level with the same rules for escalation and de-escalation as the cohorts of three patients 
detailed below. 
If the DLT rate within a cohort at a given dose level is less than the escalation boundary of 
23.6% the rule is then to escalate, if the DLT rate is higher than the de-escalation boundary of 
35.9% then the rule is either to de-escalate, or to retain the dose or to stop if the maximum 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 22/264 
 
sample size is reached. Following the requisite follow-up in a cohort, the dose level for the 
next cohort will be determined using the following decision rules where ↑indicates the next 
cohort at one dose level higher, ↓ indicates the next dose level at one dose level lower and 
“Elim” indicates that the dose level (and all higher dose levels) is removed from further 
consideration:  
 
Number of patients at current dose level 
Action 
3 
4 
5 
6 
7 
8 
9 
10 
↑if number of DLT ≤ 
0 
0 
1 
1 
1 
1 
2 
2 
Stay current dose if DLT 
1 
1 
- 
2 
2 
2 
3 
3 
↓ if number of DLT ≥ 
2 
2 
2 
3 
3 
3 
4 
4 
Elim if number of DLT ≥ 
3 
3 
4 
4 
5 
5 
5 
6 
DLT=dose limiting toxicity; Elim=eliminate 
If none of the actions is indicated, then the next cohort is enrolled at the same dose level as 
current. If the current dose level is the lowest dose level and the action indicated is 
de-escalation, then the next cohort is enrolled at the same dose level (i.e. the lowest dose 
level). Similarly, if the current dose level is the highest dose level and the action indicated is 
escalation then the next cohort is treated at the same dose level. When a dose is eliminated, 
the next cohort is enrolled at the next lower dose level. If the lowest dose is eliminated, then 
the study is stopped and none of the dose levels is selected as the MTD.  
The study will continue until one of the following occurs: 
(a) 
the maximum number of patients has been reached (approximately 30) 
(b) 
the decision indicated by the table would result in adding patients to a dose level where 
at least 9 patients have already been treated 
(c) 
the number of patients treated at the lowest dose level is ≥3 and the probability that the 
DLT rate at the lowest dose level exceeds the target is >0.90.  
When (a) or (b) occurs, the MTD of IPN60090 will be estimated as the dose level at which the 
isotonic estimate of the DLT rate is closest to 30%. If there are ties, the MTD is selected as 
the higher dose level when the isotonic estimate is lower than the target toxicity rate and 
selected as the lower dose level when the isotonic estimate is greater than or equal to the 
target toxicity rate.  
Combination Dose Escalation – Parts B and C 
A BOIN design with target toxicity rate of 30% (with escalation and de-escalation thresholds 
of 23.6% and 35.9%, respectively) with maximum number of approximately 18 patients (for 
each combination dose finding) will be used to estimate the IPN60090 combination MTD. 
The design will enrol six cohorts of three patients. Patients in the first cohort will be treated at 
combination DL1. Because the escalation and de-escalation thresholds are the same as those 
used for the monotherapy, the escalation and de-escalation rules as a function of number of 
patients treated are the same as those presented for the monotherapy. 
The study continues until one of the following occurs 
(a) 
the maximum number of patients has been reached (approximately 18): 
(b) 
the decision indicated by the table would result in the number of patients at a dose level 
exceeding nine patients. 
(c) 
the number of patients treated at the lowest dose level is ≥3 and the probability that the 
DLT rate at the lowest dose level exceeds the target is greater than 0.90.  
When (a) or (b) occurs, the MTD of IPN60090 will be estimated as the dose level at which the 
isotonic estimate of the DLT rate is closest to 30%. If there are ties, the MTD is selected as 
the higher dose level when the isotonic estimate is lower than the target toxicity rate and 
selected as the lower dose level when the isotonic estimate is greater than or equal to the 
target toxicity rate.  


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 23/264 
 
Food Effect Assessment - Part D 
The sample size (n=8) is not based on statistical calculation. A sample size of eight patients 
allows for a preliminary assessment of the potential effect of food on the PK of IPN60090. 
Dose Expansion Phase 
Preliminary anti-tumour activity will be evaluated in each dose expansion cohort (each 
regimen and indication combination) according to a sequential two-stage design based on a 
fixed sample size with look at 10 and at 18. The first stage will enrol 10 patients and stop for 
futility if no patients or only one patient achieves the efficacy criterion defined by a BOR of 
CR, PR or SD lasting at least 12 weeks in Parts A and C cohorts; respectively iCR, iPR or iSD 
for 12 weeks for Part B cohorts. If an expansion cohort passes the first stage, then a total of 
18 patients (eight additional patients) would be enrolled. Six or more patients achieving the 
efficacy criterion already defined would suggest promising anti-tumour activity in the 
corresponding expansion cohort. The table below shows the operating characteristics for a 
range of true CBRs. 
True CBR rate 
Pr(find encouraging) 
Pr(stop at stage 1) 
0.10 
0.01 
0.74 
0.20 
0.13 
0.38 
0.30 
0.46 
0.15 
0.35 
0.64 
0.09 
0.40 
0.78 
0.05 
0.45 
0.89 
0.02 
0.50 
0.95 
0.01 
CBR=clinical benefit rate; Pr=probability 
As this is a signal seeking study, no statistical adjustments are considered for the multiple 
comparisons.  
All assumptions for this sequential two-stage design may be revised in light of the dose 
escalation data and will then be described in a protocol amendment. 
Tumour response to treatment will be evaluated using RECIST v1.1 and iRECIST guideline 
(Part B only) per the investigator. ORR, CBR and DCR will be summarised descriptively by 
cohort with two-sided 95% CIs.  
Within each expansion cohort, PFS will be summarised descriptively using the Kaplan-Meier 
method. 
 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 24/264 
 
TABLE OF CONTENTS 
INVESTIGATOR’S AGREEMENT ...................................................................................... 3 
SYNOPSIS ................................................................................................................................ 5 
LIST OF ABBREVIATIONS ................................................................................................ 31 
1 
BACKGROUND INFORMATION ............................................................................ 36 
1.1 
Introduction ................................................................................................................... 36 
1.2 
Study Rationale ............................................................................................................. 37 
1.2.1 
Nonclinical Pharmacology Data ................................................................ 37 
1.2.2 
Unmet Medical Need ................................................................................... 39 
1.2.3 
Current Clinical Data Available on Glutaminase Inhibitors .................... 40 
1.3 
Name and Description of Investigational Medicinal Product ................................... 40 
1.4 
Known and Potential Risks and Benefits to Human Patients ................................... 40 
1.5 
Selection of Investigational Medicinal Products and Dosages .................................. 42 
1.5.1 
Starting Dose ............................................................................................... 42 
1.5.2 
Dosing Regimen .......................................................................................... 43 
1.5.3 
Projections of Pharmacologically Active Range ........................................ 43 
1.5.4 
Proposed Dosing Strategy and Dose Escalation Scheme .......................... 45 
1.5.5 
Food Effect Assessment Rationale ............................................................. 47 
1.6 
Population to be Studied .............................................................................................. 47 
1.7 
Compliance Statement .................................................................................................. 48 
2 
PURPOSE OF THE STUDY AND STUDY OBJECTIVES ..................................... 49 
2.1 
Purpose of the Study ..................................................................................................... 49 
2.2 
Study Objectives ........................................................................................................... 49 
2.2.1 
Primary ........................................................................................................ 49 
2.2.2 
Secondary .................................................................................................... 49 
2.2.3 
Exploratory .................................................................................................. 49 
2.3 
Study Hypothesis ........................................................................................................... 50 
3 
STUDY DESIGN ........................................................................................................... 51 
3.1 
General Design and Study Schema ............................................................................. 51 
3.1.1 
Number of Patients ..................................................................................... 53 
3.1.2 
Dose Escalations ......................................................................................... 53 
3.1.2.1 
Part A – Dose Escalation with IPN60090 as a Single Agent ...................... 53 
3.1.2.2 
Part B – Pembrolizumab Combination Dose Escalation ............................ 56 
3.1.2.3 
Part C – Paclitaxel Combination Dose Escalation ..................................... 59 
3.1.2.4 
Transition to Recommended Dose or Different Regimen ............................ 61 
3.1.3 
Food Effect Assessment – Part D ............................................................... 62 
3.1.4 
Dose Expansion Cohorts ............................................................................ 62 
3.2 
Primary and Secondary Endpoints and Evaluations ................................................ 63 
3.2.1 
Primary ........................................................................................................ 63 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 25/264 
 
3.2.2 
Secondary .................................................................................................... 64 
3.2.3 
Exploratory .................................................................................................. 65 
3.2.4 
Safety Endpoints and Evaluations ............................................................. 65 
3.2.5 
Biobanking .................................................................................................. 65 
3.3 
Randomisation and Blinding ....................................................................................... 65 
3.4 
Maintenance of Randomisation and Blinding ............................................................ 65 
3.5 
Study Treatments and Dosage ..................................................................................... 65 
3.6 
Study Duration .............................................................................................................. 68 
3.7 
Source Data Recorded on the Case Report Form ...................................................... 68 
4 
SELECTION AND WITHDRAWAL OF PATIENTS ............................................. 70 
4.1 
Inclusion Criteria .......................................................................................................... 70 
4.1.1 
General Inclusion Criteria for All Parts .................................................... 70 
4.1.2 
Part A Specific Inclusion Criteria .............................................................. 71 
4.1.3 
Part B Specific Inclusion Criteria .............................................................. 71 
4.1.4 
Part C Specific Inclusion Criteria .............................................................. 72 
4.1.5 
Part D Specific Inclusion Criteria .............................................................. 72 
4.2 
Exclusion Criteria ......................................................................................................... 72 
4.2.1 
General Exclusion Criteria for All Parts ................................................... 72 
4.2.2 
Part A Specific Exclusion Criteria ............................................................. 73 
4.2.3 
Part B Specific Exclusion Criteria ............................................................. 73 
4.2.4 
Part C Specific Exclusion Criteria ............................................................. 74 
4.2.5 
Part D Specific Exclusion Criteria ............................................................. 74 
4.3 
Stopping Rules, Discontinuation and Withdrawal Criteria and Procedures .......... 74 
4.3.1 
Discontinuation of a Cohort ....................................................................... 74 
4.3.2 
Discontinuation of a Site or Study Termination ........................................ 74 
4.3.3 
Individual Discontinuation Rules .............................................................. 75 
5 
STUDY PROCEDURES .............................................................................................. 77 
5.1 
Study Schedule .............................................................................................................. 77 
5.2 
Study Visits .................................................................................................................... 86 
5.2.1 
Procedures for Screening and Enrolment ................................................. 86 
5.3 
Laboratory Assessments ............................................................................................... 86 
5.4 
Disease Evaluation ........................................................................................................ 88 
6 
TREATMENT OF PATIENTS ................................................................................... 90 
6.1 
Investigational Medicinal Product Preparation and Accountability ....................... 90 
6.1.1 
Investigational Medicinal Product Preparation ........................................ 90 
6.1.2 
Investigational Medicinal Product Accountability .................................... 90 
6.2 
Study Drugs Administered ........................................................................................... 90 
6.2.1 
IPN60090 ..................................................................................................... 90 
6.2.1.1 
Dose Expansion ........................................................................................... 91 
6.2.2 
Other Study Drugs ...................................................................................... 91 
6.2.2.1 
Part B: Pembrolizumab ............................................................................... 91 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 26/264 
 
6.2.2.2 
Part C: Paclitaxel ........................................................................................ 92 
6.3 
Concomitant Medication/Therapy .............................................................................. 92 
6.3.1 
List of Prohibited Medications During Study Drug Treatment ................ 92 
6.3.2 
List of Medications to be Used with Caution during Study Drug 
Treatment .................................................................................................... 93 
6.3.3 
Permitted Concomitant Medications .......................................................... 93 
6.4 
Dose Modifications ........................................................................................................ 94 
6.4.1 
Reduction of IPN60090 Monotherapy ....................................................... 94 
6.4.2 
Reduction of IPN60090 + Pembrolizumab ................................................ 94 
6.4.3 
Reduction of IPN60090 + Paclitaxel .......................................................... 95 
6.4.4 
Dose Adjustments and Modifications ......................................................... 95 
6.4.4.1 
Dose Adjustments and Modifications for Nonimmune Related Adverse 
Events ........................................................................................................... 96 
6.4.4.2 
Dose Adjustments and Modifications for Immune-Related Adverse Events 
Associated with Pembrolizumab .................................................................. 98 
6.4.5 
Transition to Recommended Dose or Other Regimen ............................. 103 
6.5 
Procedures for Monitoring Patient Compliance ...................................................... 103 
7 
ASSESSMENT OF ANTI-TUMOUR ACTIVITY .................................................. 104 
7.1 
Efficacy Endpoints and Evaluations ......................................................................... 104 
7.1.1 
Dose Escalation (Part A - Monotherapy and Parts B and 
C - Combinations) and Food Effect Cohort (Part D) .............................. 104 
7.1.2 
Dose Expansion Phases ............................................................................ 104 
7.2 
Methods and Timing of Assessing, Recording and Analysing Efficacy Data ........ 104 
7.2.1 
Tumour Response Using RECIST v1.1 .................................................... 104 
7.2.2 
Tumour Response Using iRECIST (Part B Only) ................................... 105 
8 
ASSESSMENT OF SAFETY ..................................................................................... 108 
8.1 
Adverse Events ............................................................................................................ 108 
8.1.1 
Definition of an Adverse Event ................................................................ 108 
8.1.2 
Categorisation of Adverse Events ............................................................. 108 
8.1.2.1 
Intensity Classification ............................................................................... 108 
8.1.2.2 
Causality Classification ............................................................................. 109 
8.1.2.3 
Assessment of Expectedness ....................................................................... 109 
8.1.2.4 
Laboratory Test Abnormalities .................................................................. 109 
8.1.2.5 
Abnormal Physical Examination Findings ................................................ 109 
8.1.2.6 
Other Investigation Abnormal Findings .................................................... 109 
8.1.3 
Recording and Follow-up of Adverse Events ........................................... 109 
8.1.4 
Reporting of Serious Adverse Events ....................................................... 110 
8.1.5 
Pregnancy .................................................................................................. 112 
8.1.6 
Deaths ........................................................................................................ 112 
8.1.7 
Discontinuation/Withdrawal due to Adverse Events/Serious Adverse 
Events ........................................................................................................ 112 
8.1.8 
Reporting to Competent Authorities/IECs/IRBs/Other Investigators ..... 113 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 27/264 
 
8.2 
Clinical Laboratory Tests .......................................................................................... 113 
8.2.1 
Haematology .............................................................................................. 113 
8.2.2 
Blood Biochemistry ................................................................................... 113 
8.2.3 
Urinalysis ................................................................................................... 114 
8.2.4 
Pregnancy Test .......................................................................................... 114 
8.2.5 
Antipembrolizumab Antibody Testing (Part B Only) .............................. 114 
8.3 
Physical Examination ................................................................................................. 114 
8.4 
Infusion Reactions and Local Tolerance .................................................................. 114 
8.5 
Vital Signs .................................................................................................................... 115 
8.6 
Electrocardiography ................................................................................................... 115 
8.7 
Echocardiogram/multigated acquisition ................................................................... 116 
9 
ASSESSMENTS OF PHARMACOKINETICS/PHARMACODYNAMICS ........ 117 
9.1 
Pharmacokinetics ........................................................................................................ 117 
9.1.1 
Sample Collection ..................................................................................... 117 
9.1.1.1 
Assessment of IPN60090 Plasma Concentrations ..................................... 117 
9.1.1.2 
Assessment of IPN60090 Urine Concentrations ........................................ 118 
9.1.1.3 
Assessment of Pembrolizumab Serum Concentrations .............................. 118 
9.1.1.4 
Assessment of Paclitaxel Plasma Concentrations ..................................... 118 
9.1.2 
Analytical Procedures ............................................................................... 119 
9.1.3 
Data Analysis ............................................................................................. 119 
9.2 
Pharmacodynamic Biomarkers ................................................................................. 120 
9.3 
Pharmacokinetics/Pharmacodynamics Interactions ............................................... 120 
10 
BIOMARKER EVALUATION AND BIOBANKING ............................................ 121 
10.1 Biomarker Evaluation ................................................................................................ 121 
10.1.1 
Collection of Biopsies for Biomarker Analysis ........................................ 121 
10.1.2 
Collection of cfDNA for Biomarker Analysis .......................................... 121 
10.1.3 
Biomarkers of Patient Stratification ........................................................ 121 
10.1.4 
Biomarkers of Disease Evolution Under Treatment ............................... 121 
10.2 Exploratory Biomarkers ............................................................................................ 121 
10.3 Biobanking ................................................................................................................... 121 
10.3.1 
Serum ......................................................................................................... 121 
10.3.2 
Plasma ....................................................................................................... 121 
10.3.3 
Blood for RNA for Biobank ...................................................................... 122 
10.3.4 
Blood for DNA for Biobank...................................................................... 122 
10.3.5 
Blood for CfDNA for Biobank.................................................................. 122 
10.3.6 
Blood for PBMC ........................................................................................ 122 
10.3.7 
Stools .......................................................................................................... 122 
10.3.8 
Leftover Tissue Material and Additional Biopsies for Biobanking ........ 122 
11 
STATISTICS ............................................................................................................... 124 
11.1 Analysis Populations ................................................................................................... 124 
11.1.1 
Populations Analysed ................................................................................ 125 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 28/264 
 
11.1.2 
Reasons for Exclusion from the Analyses ............................................... 125 
11.2 Statistical Methods for Dose Escalation Phase and Food Effect ............................ 125 
11.2.1 
Sample Size Determination ....................................................................... 125 
11.2.1.1 
Monotherapy Dose Escalation – Part A .................................................... 125 
11.2.1.2 
Combination Dose Escalation – Parts B and C ......................................... 128 
11.2.1.3 
Sample Size for Part D ............................................................................... 128 
11.2.2 
Significance Testing and Estimations ...................................................... 129 
11.2.3 
Statistical Methods .................................................................................... 129 
11.2.3.1 
Demographic and Other Baseline Characteristics .................................... 129 
11.2.3.2 
Patient Disposition and Withdrawals ........................................................ 129 
11.2.3.3 
Pharmacokinetic Data ............................................................................... 129 
11.2.3.4 
Anti-tumour Activity Evaluation ................................................................ 129 
11.2.3.5 
Safety Evaluation ....................................................................................... 129 
11.2.3.6 
Food Effect Assessment .............................................................................. 130 
11.2.3.7 
Interim Analyses/Safety Review Committees ............................................. 130 
11.3 Statistical Methods for the Expansion Phase ........................................................... 131 
11.3.1 
Sample Size Determination ....................................................................... 131 
11.3.2 
Significance Testing and Estimation ....................................................... 131 
11.3.3 
Statistical Methods .................................................................................... 131 
11.3.3.1 
Demographics and Other Baseline Characteristics .................................. 131 
11.3.3.2 
Patient Disposition and Withdrawals ........................................................ 131 
11.3.3.3 
Pharmacokinetic Data ............................................................................... 131 
11.3.3.4 
Anti-tumour Activity Evaluation ................................................................ 131 
11.3.3.5 
Safety Evaluation ....................................................................................... 132 
11.3.3.6 
Interim Analyses ......................................................................................... 132 
11.3.4 
Independent Safety Assessment Committee ............................................. 132 
12 
DIRECT ACCESS TO SOURCE DATA AND DOCUMENTS ............................. 134 
13 
QUALITY CONTROL AND QUALITY ASSURANCE ........................................ 135 
13.1 Protocol Amendments and Protocol Deviations ...................................................... 135 
13.1.1 
Protocol Amendments ............................................................................... 135 
13.1.2 
Protocol Deviations and Exceptions......................................................... 135 
13.2 Information to Study Personnel ................................................................................ 136 
13.3 Study Monitoring ........................................................................................................ 136 
13.4 Investigator’s Regulatory Obligations ...................................................................... 137 
13.5 Audit and Inspection .................................................................................................. 137 
13.6 Data Quality Assurance .............................................................................................. 137 
14 
ETHICS ....................................................................................................................... 138 
14.1 Compliance with Good Clinical Practice and Ethical Considerations .................. 138 
14.2 Informed Consent for Participation in the Study .................................................... 138 
14.2.1 
Optional Informed Consent for Biobanking ............................................ 138 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 29/264 
 
14.3 Health Authorities and Independent Ethics Committees/Institutional Review 
Boards .......................................................................................................................... 139 
14.4 Confidentiality Regarding Study Patients ................................................................ 139 
15 
DATA HANDLING AND RECORD KEEPING ..................................................... 140 
15.1 Recording of Study Data ............................................................................................ 140 
15.2 Data Management ....................................................................................................... 140 
15.3 Record Archiving and Retention ............................................................................... 141 
16 
FINANCING AND INSURANCE ............................................................................. 142 
16.1 Contractual and Financial Details ............................................................................. 142 
16.2 Insurance, Indemnity and Compensation ................................................................ 142 
17 
REPORTING AND PUBLICATION OF RESULTS .............................................. 143 
17.1 Publication Policy ....................................................................................................... 143 
17.2 Clinical Study Report ................................................................................................. 144 
18 
REFERENCES ............................................................................................................ 145 
19 
LIST OF APPENDICES ............................................................................................ 147 
 
LIST OF TABLES 
Table 1 
List of Protocol Amendments ............................................................................... 4 
Table 2 
Dose Escalation Phase I-Part A ............................................................................ 7 
Table 3 
Dose Escalation Phase I-Part B in Combination with Pembrolizumab ........... 9 
Table 4 
Dose Escalation Phase I-Part C in Combination with Paclitaxel .................... 11 
Table 5 
Summary Table of Projected Human Doses ..................................................... 46 
Table 6 
Projected Escalation Scheme .............................................................................. 46 
Table 7 
Dose Escalation Phase I-Part A .......................................................................... 54 
Table 8 
Dose Escalation Phase I-Part B in Combination with Pembrolizumab ......... 57 
Table 9 
Dose Escalation Phase I-Part C in Combination with Paclitaxel .................... 59 
Table 10 
IPN60090 Dose Level and Corresponding Number of Capsules to be 
Administered ........................................................................................................ 66 
Table 11 
Pembrolizumab and IPN60090 Dose Level and Corresponding Number of 
Capsules to be Administered .............................................................................. 66 
Table 12 
Paclitaxel and IPN60090 Dose Level and Corresponding Number of 
Capsules to be Administered .............................................................................. 67 
Table 13 
Composition of the Moderate Fat Meal ............................................................ 67 
Table 14 
Study Procedures and Assessments (Parts A to C) .......................................... 78 
Table 15 
Study Procedures and Assessments (Part D) .................................................... 82 
Table 16 
Total Blood Volume for All Evaluations (Parts A to C) .................................. 87 
Table 17 
Total Blood Volume for All Evaluations (Part D) ............................................ 88 
Table 18 
Dose Adjustment for IPN60090 .......................................................................... 94 
Table 19 
Dose Adjustment for IPN60090 + Pembrolizumab .......................................... 95 
Table 20 
Dose Adjustment for IPN60090 + Paclitaxel ..................................................... 95 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 30/264 
 
Table 21 
Dose Adjustment and Management Recommendations for IPN60090 in 
Case of Haematologic Toxicity ........................................................................... 96 
Table 22 
Dose Adjustment and Management Recommendations for IPN60090 in 
Case of Hepatotoxicity ........................................................................................ 97 
Table 23 
Dose Adjustment and Management Recommendations for IPN60090 in 
Case of Cardiac Toxicity ..................................................................................... 97 
Table 24 
Dose Modification and Toxicity Management Guidelines for Immune-
Related AEs Associated with Pembrolizumab .................................................. 99 
Table 25 
Dose Adjustment and Management Recommendations for IPN60090 in 
Case of Immune-Related Reactions: Noninfectious Pneumonitis ................. 102 
Table 26 
Dose Adjustment and Management Recommendations for IPN60090 in 
Case of Other Toxicities .................................................................................... 103 
Table 27 
Efficacy Endpoints and Evaluations During Dose Escalation and Food 
Effect Cohort ...................................................................................................... 104 
Table 28 
Efficacy Endpoints and Evaluations During Dose Expansion ...................... 104 
Table 29 
Imaging and Treatment after First Radiologic Evidence of Progressive 
Disease ................................................................................................................ 107 
Table 30 
Electrocardiogram Timepoints ........................................................................ 115 
Table 31 
Timepoints for IPN60090 PK Blood Sample Determination ......................... 117 
Table 32 
Additional Timepoints for PK Pembrolizumab Blood Sampling of Patients 
in Part B ............................................................................................................. 118 
Table 33 
Additional Timepoints for PK Paclitaxel Blood Sampling of Patients in 
Part C .................................................................................................................. 119 
Table 34 
Collection Time Points for PD evaluation in PBMC ...................................... 120 
Table 35 
Dose Escalation Decision Rules ........................................................................ 125 
Table 36 
Operating Characteristics for Monotherapy BOIN Dose Finding from 
Simulation .......................................................................................................... 127 
Table 37 
Operating Characteristics for Combination BOIN Dose Finding from 
Simulation .......................................................................................................... 128 
Table 38 
Operating Characteristics for True CBRs ...................................................... 131 
 
LIST OF FIGURES 
Figure 1 
IPN60090: Summary of Early Clinical Development ........................................ 6 
Figure 2 
Summary of Nonclinical Pharmacology Results .............................................. 38 
Figure 3 
Effect of IPN60090 Doses (from 10 to 100 mg/kg BID) on Tumour Growth 
Inhibition .............................................................................................................. 43 
Figure 4 
PK/PD/Efficacy Study in a KEAP1 Mutant PDX Model of NSCLC 
(Ru337) ................................................................................................................. 45 
Figure 5 
IPN60090: Summary of Early Clinical Development ...................................... 51 
Figure 6 
Part A-IPN60090 Monotherapy - Predefined Escalation and De-escalation 
Scheme .................................................................................................................. 54 
 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 31/264 
 
LIST OF ABBREVIATIONS 
ABBREVIATION 
Wording Definition  
ADA 
antidrug antibodies 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT  
alanine aminotransferase  
ANC 
absolute neutrophil count  
ASCO 
American Society of Clinical Oncology 
ASNS 
asparagine synthetase 
ASNSlow 
low protein expression level of asparagine synthetase 
AST  
aspartate aminotransferase  
AUC 
area under the plasma concentration time curve 
AUC0-24h 
area under the plasma concentration time curve from time 0 to 
24 hours  
AUC0-last 
area under the plasma concentration time curve from time 0 to the 
last time point with quantifiable concentrations 
BOIN 
Bayesian Optimal Interval  
BOR 
Best Overall Response 
BID 
bis in die (twice daily) 
CA 
Competent Authority 
CBR 
clinical benefit rate  
CD8 
cluster of differentiation 8 
cfDNA 
circulating free deoxyribonucleic acid  
CFR 
Code of Federal Regulations (United States of America) 
CI 
confidence interval 
CL/F 
apparent total clearance from plasma 
Cmax 
maximum observed plasma drug concentration 
Cmin 
minimum observed plasma concentration 
CPI 
checkpoint inhibitor 
CR 
complete response 
CRO 
contract research organisation 
CSR 
clinical study report 
CT 
computed tomography 
Ctrough 
trough plasma concentration 
CYP2C8 
cytochrome P450 subtype 2C8 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 32/264 
 
ABBREVIATION 
Wording Definition  
CYP2D6 
cytochrome P450 subtype 2D6 
CYP3A4 
cytochrome P450 subtype 3A4 
CYP450 
cytochrome P450 
DCR 
disease control rate 
DDI 
drug-drug interactions  
DL 
dose level 
DLT 
dose limiting toxicity 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
ECLA 
ElectroChemiLuminiscence 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EDTA 
ethylenediaminetetraacetic acid 
eGFR 
estimated glomerular filtration rate  
ELISA 
enzyme-linked immunosorbent assay 
EOS 
end of study 
EU 
European Union 
EW 
early withdrawal 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
gamma glutamyl transferase  
GLP 
Good Laboratory Practice 
Glu:Gln 
glutamate:glutamine  
GLS1 
glutaminase-1 
H2 
histamine 2 receptor 
HCC 
hepatocellular carcinoma 
HCG 
human chorionic gonadotrophin 
HED 
human equivalent dose 
HGSOC 
high-grade serous ovarian cancer  
HNSCC 
head and neck squamous cell carcinoma 
HNSTD 
highest non-severely toxic dose 
HSNTD 
highest severely non-toxic dose 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 33/264 
 
ABBREVIATION 
Wording Definition  
IACS 
Institute for Applied Cancer Sciences 
IB 
Investigator’s Brochure  
IC50 
half maximal inhibitory concentration 
IC90 
90% inhibitory concentration 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
iCPD 
immune confirmed progressive disease 
iCR 
immune complete response  
ID 
identification 
IEC 
independent ethics committee 
IMP 
investigational medicinal product 
iPR 
immune partial response 
IRB 
institutional review board 
iRECIST 
immune-related Response Evaluation Criteria in Solid Tumors 
irAE 
immune-related adverse event 
IRT 
Interactive Response Technology 
ISAC 
independent safety assessment committee  
iSD 
immune stable disease  
iUPD 
immune unconfirmed progressive disease 
i.v. 
intravenous 
KEAP1 
Kelch-like ECH-associated protein 1 
Ki67 
nuclear antigen Ki67 
KRAS 
Kirsten Rat Sarcoma Viral Oncogene Homolog 
LC 
liquid chromatography 
LKB1 
liver kinase B1 
LVEF 
left ventricular ejection fraction 
mAb 
monoclonal antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MS 
mass spectrometry 
MTD 
maximum tolerated dose 
NCI-CTCAE 
National Cancer Institute – Common Terminology Criteria for 
Adverse Events 
NOAEL 
no-observed-adverse-effect-level 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 34/264 
 
ABBREVIATION 
Wording Definition  
NOS 
not otherwise specified 
NRF2 
nuclear factor erythroid 2–related factor 2 
NSCLC 
non-small cell lung cancer 
ORR 
objective response rate 
PBMC 
peripheral blood mononuclear cells  
PD 
pharmacodynamics 
PD-1 
programmed cell death protein 1 
PD-L1 
programmed death-ligand 1 
PFS 
progression free survival 
PK 
pharmacokinetics 
PR 
partial response 
PT 
preferred term 
Q3W 
every 3 weeks 
QD 
once daily 
QTcF 
Fridericia corrected QT interval 
R & D 
research and development 
RCC 
renal cell carcinoma 
RD 
recommended dose 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
stable disease 
SmPC 
Summary of Product Characteristics 
SoC 
standard of care 
SOC 
system organ class 
SOP 
Standard Operating Procedure 
SRC 
Safety Review Committee 
STK11 
serine/threonine kinase 11 
t½ 
elimination half-life 
TEAE 
treatment-emergent adverse event 
TGI 
tumour growth inhibition  
Tmax 
time to maximum observed drug concentration 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 35/264 
 
ABBREVIATION 
Wording Definition  
TNBC 
triple-negative breast cancer  
Treg 
regulatory T-cell 
ULN 
upper limit of normal  
US 
United States  
USA 
United States of America 
V/F 
apparent volume of distribution 
WHO-DD 
World Health Organization drug dictionary 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 36/264 
 
1 
BACKGROUND INFORMATION 
1.1 
Introduction 
Altered metabolism is one of the main hallmarks of tumour biology, forming the conceptual 
basis for the development of metabolic therapies in cancer. Many tumour cells depend on 
glutamine for their growth and survival. Indeed, glutamine provides a main source of key 
bioenergetics and biosynthetic buildings blocks. The enzyme glutaminase-1 (GLS1) catalyses 
the conversion of glutamine into glutamate. This directly impacts on a number of other 
nutrients and cellular building blocks including nucleotides and glutathione. Glutaminase-1 
inhibition has been shown to deprive tumour cells of their fuel, thus leading to tumour stasis. 
This inhibition was also associated with a decrease in the glutathione levels and an increase in 
the reactive oxygen species resulting in deoxyribonucleic acid (DNA) damage. 
IPN60090 (also coded as IACS-06274) is a novel oral and potent selective GLS1 inhibitor 
developed by the MD Anderson Cancer Centre (part of the University of Texas), Institute for 
Applied Cancer Sciences (IACS). In May 2018, IACS and Ipsen entered into a research and 
development collaboration agreement to co-develop IPN60090. 
Preclinical investigations have demonstrated a strong link between the Kelch-like 
ECH-associated protein 1 (KEAP1)/nuclear factor erythroid 2–related factor 2 (NRF2) 
mutation status in tumour cells and glutaminase dependency, as well as a synthetic lethal 
interaction between glutaminase inhibition and low protein expression levels of asparagine 
synthetase (ASNSlow i.e. immunohistochemistry 0-1), an alternative source of glutamate. 
These data provide a rationale for the development plan described herein that is focused on 
biomarker-based selection of patients whose tumours have a high dependency on glutaminase.  
IPN60090 is currently in clinical development and the first treatment in humans took place on 
04 April 2019. Another GLS1 inhibitor developed by Calithera, CB-839, is currently in the 
phase II stage of clinical development. However, no biomarker strategy is currently 
established or being pursued with CB-839 in clinical studies. With the current 
biomarker-driven strategy (KEAP1/NRF2 mutant tumours or ASNSlow tumours) defined for 
the novel GLS1 inhibitor IPN60090, it is thought that better anti-tumour activity may be 
expected in monotherapy. 
The alterations in the metabolic networks necessary to fuel and sustain cellular growth have 
been linked to therapeutic resistance, which is frequently correlated with a very poor patient 
outcome. By targeting these sources of energy using a GLS1 inhibitor, resistant tumour cells 
can often be resensitised to anticancer therapies. Indeed, early compelling clinical activity was 
reported with CB-839 in combinatorial regimens, such as nivolumab, paclitaxel or 
cabozantinib in patients with aggressive tumour types, including triple-negative breast cancer 
(TNBC) and renal cell carcinoma (RCC) [1, 2]. These preliminary results suggest that GLS1 
inhibitors, when combined with targeted therapies, immunotherapy or chemotherapy, present 
a pathway to overcome resistance within tumours that no longer respond to current standards 
of care (SoC). 
This is a first in human study of IPN60090. The phase I study will generate safety, 
tolerability, and preliminary anti-tumour activity data in biomarker-selected and -unselected 
patients with advanced solid tumours. This study is also expected to provide a better 
understanding of the mechanism of action of IPN60090 and of the potential of selected 
biomarkers to predict the clinical outcome in monotherapy as well as in combination with 
other cancer therapies. The dose escalation part of the study will generate the first 
pharmacokinetic (PK), pharmacodynamic (PD) and safety data in humans, and will support 
the choice of the recommended dose (RD) for expansion. Dose expansion cohorts at the RD 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 37/264 
 
will further define the safety and tolerability, and anti-tumour activity of IPN60090 
monotherapy and combination therapy. The results observed in terms of anti-tumour activity 
during dose escalation and dose expansion will determine whether efficacy expansion cohorts 
will be conducted to further investigate the efficacy of IPN60090 in biomarker-selected or 
unselected populations and in combination with other anticancer agents. 
1.2 
Study Rationale 
1.2.1 
Nonclinical Pharmacology Data 
Preclinical data have shown that human non-small cell lung cancer (NSCLC) cells harbouring 
KEAP1/NRF2 mutations or high-grade serous ovarian cancer (HGSOC) cells with low 
expression levels of asparagine synthetase (ASNS) are highly sensitive to GLS1 inhibition. 
IPN60090 has shown a strong anti-proliferative activity in vitro across multiple NSCLC cell 
lines harbouring KEAP1 mutations (Figure 2, Panel A; Report IACS-6274-Pharm-001) and 
HGSOC cell lines with low levels of ASNS with half maximal inhibitory concentrations 
(IC50) ranging from 45 nM to <1 μM (Figure 2, Panel B; Report IACS-6274-Pharm-002). In 
vivo investigations also confirm that IPN60090 exhibits significant tumour growth inhibition 
(TGI) in KEAP1 mutant NSCLC (Figure 2, Panel C; Report IACS-6274-Pharm-003) and 
ASNSlow HGSOC (Figure 2, Panel D; Report IACS-6274-Pharm-003). These data provide 
strong evidence that in the context of these mutations/alterations in tumour cells, glutaminase 
dependence is observed.  
It is known that within the tumour microenvironment, competition between tumour cells and 
immune cells for glutamine can lead to poor T-cell activation. IPN60090 synergises with 
anti-programmed cell death protein 1 (PD-1) in preclinical tumour models (Figure 2, Panel E). 
This 
synergy 
can 
be 
explained 
by 
the 
significant 
increase 
of 
cluster 
of 
differentiation 8 (CD8)/regulatory T-cells (Tregs) ratio in treated tumours (Figure 2, Panel F). 
These data highlight the ability of IPN60090 to modulate oncogenic pathways through actions 
on both tumour cells and T-cells within the tumour microenvironment.  


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 38/264 
 
Figure 2 Summary of Nonclinical Pharmacology Results 
 
ASNShigh=high protein expression level of asparagine synthetase; ASNSlow=low protein expression level of asparagine 
synthetase; BID=bis in die (twice daily); CD8=cluster of differentiation 8; GLSi=glutaminase 1 inhibition; 
HGSOC=high-grade serous ovarian cancer; IACS-06274=IPN60090; IC50=half maximal inhibitory concentration; 
KEAP1=Kelch-like ECH associated protein 1; KP=K-rasLSL-G12D/+;p53fl/fl; MUT=mutant; NRF2=nuclear factor erythroid 
2-related factor 2; NSCLC=non-small cell lung cancer; OVCAR=ovarian cancer; PD-1=programmed cell death protein-1; 
Treg=regulatory T-cells; WT=wild-type 
***=p<0.001, ****=p<0.0001 
Panel A: IC50 for the anti-proliferative activity of IPN60090 across multiple NSCLC cell lines over 72 hours 
Panel B: IC50 for the anti-proliferative activity of IPN60090 across multiple HGSOC cell lines over 72 hours 
Panel C: Anti-tumour activity in a subcutaneous KEAP1mut NSCLC model (H2122) treated with IPN60090 at 100 mg/kg BID 
for 21 days 
Panel D: Anti-tumour activity in an orthototopic model of ASNSlow HGSOC treated with IPN60090 at 100 mg/kg BID for 
27 days 
Panel E: Anti-tumour activity of IPN60090 (100 mg/kg BID) in monotherapy or in combination with anti-PD-1 in a 
syngeneic model of NSCLC model (KRAS/P53mut)  
Panel F: The ratio of infiltrating CD8+/Tregs in tumours of mice treated with IPN60090 (100 mg/kg BID), anti-PD-1 or the 
combination of both drugs 
*** 
*** 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 39/264 
 
IPN60090 was also shown to synergise with paclitaxel in ASNSlow tumours, potentially due to 
its capacity for decreasing glutathione pool levels and for increasing oxidative stress inside 
the tumours, thus, leading to tumour cell death. 
These data all together provide strong evidence for evaluating IPN60090 in tumours 
harbouring KEAP1/NRF2 mutations or ASNS low levels in monotherapy. Preclinical data 
supporting anti-tumour activity in combination with anti-PD-1 and taxanes provide the 
rationale for exploring a combination therapy approach across a broad range of tumour types. 
1.2.2 
Unmet Medical Need 
Lung cancer is the leading cause of cancer-related mortality world-wide. GLOBOCAN 
estimated worldwide incidence of lung cancer tumours in 2012 to be 1.8 million (12.9% of all 
cancers) with an age standardised rate of 23.1 per 100,000. Non-small cell lung cancer 
(NSCLC) accounts for 85% to 90% of all lung cancer cases [3]. When feasible, surgical 
resection remains the single most consistent and successful option for cure. However, close to 
70% of patients with lung cancer present with locally advanced or metastatic disease at the 
time of diagnosis [4]. Combination chemotherapy modestly improves overall survival from 
approximately 6 months without chemotherapy to 10 to 12 months with chemotherapy. 
Molecular targeted therapy for a biomarker selected population with metastatic NSCLC 
allows long duration of disease control with acceptable toxicity for a subset of patients, 
extending median overall survival beyond 2 to 3 years [5, 6]. Given the global burden of 
NSCLC and despite a number of new therapies to treat advanced stage tumours, there is still a 
high unmet medical need for patients with NSCLC, especially for those harbouring these 
KEAP1 and NRF2 mutations. Expression of KEAP1/NRF2 mutations in NCSLC, and several 
advanced solid tumours, is indeed associated with higher malignant biological behaviour and 
poor prognosis [7]. NSCLC is the most common tumour type expressing these mutations with 
approximately 20% and 10% of patients expressing KEAP1/NRF2 mutations, respectively. 
Additionally, these mutations can commonly be found in head and neck squamous cell 
carcinoma (HNSCC) (5% and 13%), urothelial carcinoma (7% and 3%) and hepatocellular 
carcinoma (HCC) (5% and 4%), among others.  
It has been demonstrated that KEAP1/NRF2 mutations drive increased dependency on 
glutamine in human lung adenocarcinoma [7]. A significant increased sensitivity to IPN60090 
was also demonstrated across multiple KEAP1/NRF2 mutant cell lines as well as in in vivo 
tumour models harbouring these alterations, making tumours harbouring KEAP1/NRF2 
mutation good candidates for treatment with IPN60090. 
Significant unmet medical need exists for subsets of NSCLC like those with co-occurring 
genomic alterations in Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) and 
serine/threonine kinase 11 (STK11)/liver kinase B1 (LKB1) (KL cluster) representing about 
30% of KRAS-mutant NSCLC. These genomic alterations are associated with a “cold” 
tumour immune microenvironment with reduced density of infiltrating CD8+ T lymphocytes 
but also lower levels of programmed death-ligand 1 (PD-L1) expression and thus very poor 
response to checkpoint inhibitor (CPI) alone (objective response rate (ORR): 0%; 0/6 in 
CheckMate-057 study) [8]. A significant co-occurrence of KEAP1 mutation was reported in 
this KL cluster making this subset good candidate for treatment with IPN60090 [9]. The 
combination of IPN60090 with CPI may thus be a way to revert CPI resistance in this subset 
of NSCLC since IPN60090 was shown to synergize with CPI (see Section 1.2.1).  
Preclinical activity of IPN60090 was observed in ASNSlow HGSOC cell lines and xenograft 
models. Acquired or de-novo resistance to platinum-based chemotherapy represents a 
significant challenge in the treatment of advanced ovarian cancer. Platinum-resistant tumours 
have been shown to have a significant dependency on glutamine, with an upregulated 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 40/264 
 
expression of glutamine transporter ASCT2 and glutaminase [10]. Targeting a subset of 
ASNSlow HGSOC with a GLS1 inhibitor such as IPN60090 may provide a way to overcome 
resistance to platinum-based therapies.  
Therefore, for these patients, a biomarker-driven approach with IPN60090 in monotherapy 
may provide previously unseen benefit in the second or later line setting. Preclinical data also 
supports studying IPN60090 in combination with SoC anticancer therapies (anti PD-1 and 
taxanes). 
1.2.3 
Current Clinical Data Available on Glutaminase Inhibitors 
A GLS1 inhibitor, CB-839 developed by Calithera, is currently in the phase II stage of 
development. To date, CB-839 monotherapy demonstrated one partial response (PR) and 
eight stable disease (SD) among 15 patients with RCC (ORR=7%) [11]. This would suggest 
the need for identification of the patient subpopulation carrying specific mutations or genetic 
alterations that render cancers glutaminase-dependent to potentiate anti-tumour efficacy in 
monotherapy.  
CB-839 was also tested in combination with different standard therapies, such as nivolumab, 
paclitaxel and cabozantinib. Early phase I efficacy results were reported with these 
combinatorial regimens: 
• 
combination with nivolumab: 44% disease control rate (DCR) and 19% ORR in 
16 patients with melanoma previously treated with a CPI,  
• 
combination with paclitaxel: 80% DCR and 40% ORR in TNBC patients at the RD of 
600 mg twice daily (BID) of CB-839 [1], 
• 
combination with cabozantinib: 100% DCR and 33% of ORR in 12 patients with clear 
cell and papillary advanced or metastatic RCC at a dose of 800 mg BID of CB-839 [2]. 
These preliminary results suggest that GLS1 inhibitors, when combined with other therapies, 
may present a pathway to overcome resistance within cancers that no longer respond to 
current SoC. 
1.3 
Name and Description of Investigational Medicinal Product 
IPN60090 is an oral potent and selective small molecule inhibitor of GLS1. IPN60090 will be 
supplied as hard capsules containing either 10 mg, 60 mg or 240 mg of active substance. A 
more detailed description of the product is provided in Section 3.5. 
1.4 
Known and Potential Risks and Benefits to Human Patients 
Anti-tumour efficacy of IPN60090 in monotherapy may be potentiated by identifying and 
selecting patients with specific mutational profiles that render cancer glutaminase dependent. 
Indeed, preclinical investigations have shown that IPN60090 inhibits glutamine metabolism in 
NSCLC and HGSOC cell lines in vitro and shows anti-proliferative effects on 
biomarker-defined subsets of KEAP1/NRF2 mutant NSCLC cells and ASNSlow HGSOC cells 
in vitro. In animal models using KEAP1/NRF2 mutant NSCLC and ASNSlow HGSOC human 
tumour cell lines, IPN60090 inhibited tumour growth, with TGI of 38% to 55%. Upon 
orthotopic implantation of an ASNSlow model of HGSOC in the intraperitoneal cavity, 
IPN60090 caused an even more significant inhibition of tumour growth (TGI=67%). 
Combinatorial regimens of CB-839 with standard therapies such as nivolumab or paclitaxel 
showed preliminary clinical efficacy results in different types of tumours. Nonclinical 
investigations have shown that IPN60090 sensitises taxane-resistant KEAP1/NRF2 mutant 
NSCLC and ASNSlow HGSOC models to taxane-based therapies. These data suggest that for 
indications in which taxane-based chemotherapy is the front-line SoC, IPN60090 has the 
potential to enhance clinical response, especially in patients with NSCLC whose tumours 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 41/264 
 
have mutations in KEAP1/NRF2 and patients with HGSOC whose tumours are characterised 
as ASNSlow. In addition, glutamine metabolism has been shown to play important roles within 
the immune system, including roles in T-cell activation and T-cell effector functions. In a 
syngeneic model of KRASmut, TP53mut NSCLC, co-administration of IPN60090 and αPD-1 
monoclonal antibodies (mAb) induced an overall TGI of 65% whereas neither agent alone 
showed anti-tumour activity. The mechanism of how IPN60090 treatment enhances 
checkpoint blockade is likely due to the statistically significant increase in CD8+ T-cells and 
concurrent reduction in Tregs present in tumours treated with IPN60090 in combination with 
an anti-PD-1 mAb. These findings demonstrate that IPN60090 treatment enhances the activity 
of checkpoint blockade agents through actions both on tumour cells and on T-cells within the 
tumour microenvironment. 
Based on the clinical data generated with a related compound and based on the nonclinical 
data generated with IPN60090, evaluating the investigational new drug in the selected 
populations is justified. 
The known and potential risks in humans from nonclinical toxicology studies are 
haematotoxicity observed in dog and hepatotoxicity observed in both rat and dog. IPN60090 
was well tolerated in male rats up to 300 mg/kg/day but reversible increases in alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transferase 
(GGT), total bilirubin, total cholesterol, and triglycerides were observed in two female rats 
administered 300 mg/kg/day. These changes correlated with mild bile duct hyperplasia (also 
present in one recovery female animal), minimal focal necrosis of the liver, necrosis of the 
pancreatic duct and/or mild to moderate lymphoid necrosis of the thymus. The dog was the 
more sensitive species in the 4-week Good Laboratory Practice (GLP) toxicology studies. 
Both male and female dogs in the high dose group (100 mg/kg/day) were terminated early 
after only 8 days of dosing due to adverse clinical signs of inappetence, prostration, salivation, 
thinness, decreased activities, vomitus, dilated pupils, yellowish eye discolouration and 
significantly decreased body weight and food consumption. Treatment-related findings in this 
group included: reversible decreased reticulocyte count that correlated with reversible bone 
marrow hypocellularity and/or decreased erythropoiesis in bone marrow; increased ALT, 
AST, total bilirubin, alkaline phosphatase (ALP), total cholesterol, triglyceride, creatine 
kinase, and GGT that were correlated with bile duct hyperplasia, periportal fibrosis, periportal 
mixed cell infiltration, canalicular cholestasis, Kupffer cell pigmentation, hepatocellular 
necrosis and/or hepatocellular vacuolation. These adverse liver findings were partially 
reversible at the end of the 28-day recovery period. Consequently, biochemistry and 
haematology parameters will be carefully monitored during the phase I study with laboratory 
assessments performed on Days 1, 2, 8, 14, 22, 29 and then every 21 days. 
The target GLS1 is also known to be expressed in organs such as the brain, kidney, cardiac 
muscle and pancreas [12, 13]. Regarding the brain, there were no treatment-related effects on 
neurobehavioral functional observational battery tests in rats. Potential central effects in 
humans will be carefully monitored by neurological examination. Monitoring of kidney 
function is part of the biochemistry assessments with creatinine serum levels and estimated 
glomerular filtration rate (eGFR) calculation. Regarding cardiac function, in both the 
non-GLP and GLP human ether-a-go-go-related gene assays, the IC50 was >30 μM indicating 
negligible risk for corrected QT interval prolongation and there were no treatment-related 
effects on cardiovascular parameters in dogs (based on the electrocardiogram (ECG) 
measurements in the GLP 4-week toxicology studies). Repeated ECG measurements will 
nevertheless be performed during the first days of treatment in this study. Pancreatic function 
will be monitored as part of the regular laboratory assessments. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 42/264 
 
The starting dose has been selected using a conservative approach as approximately 1/8.4 (or 
0.12) of the human equivalent dose (HED) associated with the highest severely non-toxic 
dose (HSNTD) in the most sensitive species with consideration of the Food and Drug 
Administration (FDA) Guidance for estimating the maximum safe starting dose in initial 
clinical studies for therapeutics in adult healthy volunteers [14, 15]. Moreover, the dose of 
IPN60090 will be carefully escalated using a Bayesian Optimal Interval (BOIN) design [16, 
17] with target dose limiting toxicity (DLT) rate of 30% in monotherapy and combination 
dose escalations. 
Based on all the available data, the sponsor believes that the potential benefits of IPN60090 
will outweigh the potential risks in this phase I study conducted in patients with serious and 
advanced diseases for which no curative therapies are available. In addition, patients enrolled 
in this study will be closely monitored for potential safety risks. The sponsor will ensure that a 
safety surveillance plan is put into place to disseminate new safety information to 
investigators, institutional review boards (IRBs) and regulatory authorities in a timely manner. 
1.5 
Selection of Investigational Medicinal Products and Dosages 
1.5.1 
Starting Dose 
Nonclinical efficacy, toxicology and PK data were used to define a starting dose in humans 
and to support preliminary projections of potentially pharmacologically active doses. The 
estimations of HEDs for the starting dose and the projected pharmacologically active doses 
were based on the methods proposed in the International Council for Harmonisation (ICH) 
Guidance for Industry S9 [ICH 2009] and in the FDA Guidance for Industry “Estimating the 
Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy 
Volunteers” [14]. 
A no-observed-adverse-effect-level (NOAEL) was determined for rats and dogs in the pivotal 
28-day oral toxicity studies. The NOAEL in rats was 300 mg/kg/day in males and 
100 mg/kg/day in females. Associated exposure to IPN60090 in female rats was 142 μg/mL 
(maximum observed plasma drug concentration (Cmax)) and 2280 μg*h/mL (area under the 
plasma concentration time curve (AUC) from time 0 to 24 hours (AUC0-24h)). In dogs, the 
NOAEL was 30 mg/kg/day in males and 10 mg/kg/day in females. The lower NOAEL for 
female dogs was mainly due to one animal in the 30 mg/kg/day group that had test 
article-related adverse findings in the liver (for example increased liver enzymes, bile duct 
hyperplasia, hepatocellular necrosis) and bone marrow (for example decreased erythropoiesis 
and hypocellularity of the bone marrow) like those observed in the 100 mg/kg/day group. This 
one female dog exhibited much higher exposures to the drug than the other animals in the 
group. Consequently, the highest non-severely toxic dose (HNSTD) in this study (for the 
female dog) was equivalent to the NOAEL (i.e. 10mg/kg/day). Associated exposure to 
IPN60090 at the HNSTD was 11.6 μg/mL (Cmax) and 138 μg*h/mL (AUC0-24h). Using the 
HNSTD for the female dog (the more sensitive species), the calculated HED for a 60 kg 
human is 5.4 mg/kg. Based on this calculated HED and after applying a safety factor of 6, the 
starting dose in the clinic is estimated to be approximately 54 mg/day (i.e. 27 mg BID). 
However, because of limited capsule strengths availability (10 mg, 60 mg and 240 mg), a 
starting dose in humans of 40 mg/day (0.67 mg/kg/day for a 60 kg human patient), dosed as 
20 mg every 12 hours (i.e. 20 mg BID), was selected. This proposed starting dose provides 
about 8.4-fold safety margins below the HED associated with the HNSTD in the dog GLP 
toxicology studies. 
The dose escalation studies in combination with pembrolizumab and paclitaxel (Parts B and 
C, respectively) will start at the first dose level showing pharmacological activity (i.e. at least 
50% inhibition of glutamate:glutamine (Glu:Gln) ratio in peripheral blood mononuclear cells 


,36(1*5283
'86

&21),'(17,$/
35272&2/),1$/9(56,21'(&(0%(5
3$*(

3%0&VDWWURXJKSODVPDFRQFHQWUDWLRQ&WURXJKLHKRXUVSRVWGRVHRQ'D\LQRI
SDWLHQWVWUHDWHGDWWKLVGRVHOHYHOZLWKJRRGWROHUDELOLW\LGHQWLILHGLQ3DUW$7KLVWKUHVKROGRI
LQKLELWLRQRIWKH3'PDUNHUDWKRXUVZDVVHOHFWHGVLQFHGDWDIURPDPRXVHPRGHORI
16&/& + VXJJHVW WKDW PDLQWDLQLQJ DW OHDVW  LQKLELWLRQ RI WKH *OX*OQ UDWLR LQ
3%0& RYHU D GRVLQJ LQWHUYDO LH  KRXUV IRU %,' GRVLQJ LV FRUUHODWHG ZLWK 7*,
5HSRUW,$&63KDUP VHH )LJXUH WKDW LV H[SHFWHG WR EH IXUWKHU SRWHQWLDWHG LQ
FRPELQDWLRQ ZLWK RWKHU DJHQWV ,QGHHG WKH WZR GRVHV WKDW VKRZHG DQWLWXPRXU HIILFDF\ LQ
WHUPVRI7*,DQGPJNJ%,'ZHUHDEOHWRPDLQWDLQIURPXSWRLQKLELWLRQ
RI*OX*OQUDWLRLQ3%0&XSWRWKHHQGRIWKHGRVLQJLQWHUYDO
)LJXUH (IIHFWRI,31'RVHVIURPWRPJNJ%,'RQ7XPRXU*URZWK,QKLELWLRQ

%,' ELVLQGLHWZLFHGDLO\*/8*/1 JOXWDPDWHJOXWDPLQH3%0& SHULSKHUDOEORRGPRQRQXFOHDUFHOO
 S S
(IIHFWRIGLIIHUHQW,31GRVHVIURPWRPJNJ%,'RQWXPRXUJURZWKLQKLELWLRQLQ+PRXVHPRGHOOHIW
SDQHODQGFRUUHVSRQGLQJQRUPDOLVHG*OX*OQUDWLRLQ3%0&DWDQGKRXUVRQ'D\ULJKWSDQHO
1.5.2 
Dosing Regimen 
0RVWQRQFOLQLFDOSKDUPDFRORJ\H[SHULPHQWVRQZKLFKGRVHH[WUDSRODWLRQVZHUHEDVHGZHUH
SHUIRUPHGZLWKD%,'UHJLPHQ0RUHRYHUDWWKHVDPHGDLO\GRVHD%,'UHJLPHQDOORZVD
UHGXFWLRQLQ&PD[FRPSDUHGWRDRQFHGDLO\4'UHJLPHQWKXVGHFUHDVLQJWKHULVNRISRWHQWLDO
&PD[UHODWHG DGYHUVH HIIHFWV ,Q DGGLWLRQ QRQFOLQLFDO SKDUPDFRORJ\ H[SHULPHQWV VHHPHG WR
VKRZWKDWVLJQLILFDQWDQWLWXPRXUDFWLYLW\LVUHDFKHGZKHQPLQLPXP,31FRQFHQWUDWLRQ
DQGWKXV3'PDUNHULQKLELWLRQ*OX*OQUDWLRLQKLELWLRQDUHPDLQWDLQHGRYHUDGRVLQJLQWHUYDO
5HSRUW,$&63KDUP$%,'UHJLPHQDOORZVPDLQWHQDQFHRIDKLJKHUPLQLPXP
REVHUYHGSODVPDFRQFHQWUDWLRQ&PLQRYHUDGRVLQJLQWHUYDOFRPSDUHGWRD4'UHJLPHQDWWKH
VDPHGDLO\GRVH)RUWKHVHUHDVRQVD%,'UHJLPHQKDVEHHQVHOHFWHG
1.5.3 
Projections of Pharmacologically Active Range 
,Q LQ YLWUR SKDUPDFRORJ\ VWXGLHV ,31 LQKLELWHG WKH FRQYHUVLRQ RI JOXWDPLQH WR
JOXWDPDWHLQDQ$OXQJFDQFHUFHOOOLQHZLWKDQ,&RIDSSUR[LPDWHO\Q0,QDGGLWLRQ
,31 GHPRQVWUDWHG D SRWHQW DQWLSUROLIHUDWLYH HIIHFW DFURVV D SDQHO RI 16&/& DQG
+*62& KXPDQ WXPRXU FHOO OLQHV ZLWK  LQKLELWRU\ FRQFHQWUDWLRQV ,&V UDQJLQJ IURP
0WR0,31WUHDWPHQWZDVDOVRDVVRFLDWHGZLWKDUHGXFWLRQLQJOXWDWKLRQH
OHYHOVDQGDQLQFUHDVHLQUHDFWLYHR[\JHQVSHFLHVSURGXFWLRQDQG'1$GDPDJHDFFXPXODWLRQ
LQ WXPRXU FHOOV DW  0 D GRVH WKDW LV FRQVLVWHQW ZLWK WKH DIRUHPHQWLRQHG UDQJH RI ,&
UHTXLUHGIRULQKLELWLRQ RIWXPRXUFHOOSUROLIHUDWLRQ ,QDGGLWLRQ WKHDELOLW\RI ,31WR
LQKLELW*/6DFWLYLW\PHDVXUHGDVWKHFRQYHUVLRQRI&*/1WR&*/8ZDVHYDOXDWHG
LQ3%0&VIURPKXPDQGRQRUVLQYLWUR,QWKHVHVWXGLHV,31KDGDQ,&RI0
JP/FRQVLVWHQWZLWKWKHFRQFHQWUDWLRQVUHTXLUHGWRLQKLELWWXPRXUFHOOSUROLIHUDWLRQ


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 44/264 
 
(0.4 μM to 6.8 μM; i.e. 0.213 μg/mL to 3.62 μg/mL). Thus, the in vitro activity of IPN60090 
in both mechanistic glutaminase inhibition and tumour cell proliferation assays supports target 
trough plasma levels in the range of approximately 1 μg/mL to 4 μg/mL.  
In in vivo pharmacology studies, IPN60090 inhibited the growth of biomarker-defined subsets 
of both NSCLC and HGSOC in monotherapy and enhanced anti-tumour response to taxanes 
and immune CPIs in several tumour models. A potent anti-tumour effect was achieved with 
an oral dosing of IPN60090 at 100 mg/kg BID or 200 mg/kg QD in a NSCLC model. The 
dose of 100 mg/kg BID was selected for multiple preclinical in vivo studies. This dose 
achieves the maximal potent target engagement of GLS1, as measured both in vitro and ex 
vivo and is associated with a Cmax of 52.7 μg/mL, an AUC0-24h of 319 μg*h/mL and a Ctrough 
of 11.34±3.60 μM (6.03 μg/mL) in the mouse.  
The minimally effective dose of IPN60090 was explored in a dose-ranging study 
(Report IACS-6274-Pharm-005). IPN60090 inhibited tumour growth in a KEAP1 mutant 
patient derived xenograft model of NSCLC (Ru337 model). The effect on tumour growth was 
similar at doses ranging from 25 mg/kg BID to 100 mg/kg BID (see Figure 5) suggesting that 
doses less than 100 mg/kg BID may be potentially associated with a clinical benefit. Indeed, 
the maximal potent target engagement in tumours (Glu:Gln ratio inhibition) was already 
achieved at the dose of 25 mg/kg BID and was similar across the different doses tested up to 
100 mg/kg BID. In addition, the concentrations of IPN60090 that were achieved in plasma 
and the tumours of treated animals (Day 28, 4 hours post-treatment) were between 1 μM and 
10 μM at 25 mg/kg BID. These values are consistent with the IC90 of anti-proliferative effect 
of IPN60090 in vitro (0.4 μM to 6.8 μM) and with the IC90 of the compound observed in 
human PBMC assay (2.56 μM). In addition, the inhibition of Glu:Gln ratio evaluated in 
mouse PBMCs at 2 hours post-treatment with IPN60090 reached a plateau at the doses 
between 10 mg/kg and 30 mg/kg. These doses corresponded to more than 90% of inhibition 
of GLS1 activity with a 90% effective concentration around 1.4 μM.  


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 45/264 
 
Figure 4 PK/PD/Efficacy Study in a KEAP1 Mutant PDX Model of NSCLC (Ru337) 
 
BID=bis in die (twice daily); GLU:GLN=glutamate:glutamine; IACS-6274=IPN60090; KEAP1=Kelch-like ECH-associated 
protein 
1; 
NSCLC=non-small 
cell 
lung 
cancer; 
PD=pharmacodynamic; 
PDX=patient 
derived 
xenograft; 
PK=pharmacokinetic 
*=p<0.05, **=p<0.01 
Panel A: Anti-tumour efficacy of IPN60090 in Ru337 model by oral BID dosing at 25, 50 and 100 mg/kg. Panels B and C: 
Concentrations levels of IPN60090 achieved in plasma (panel B) and in tumours (Panel C) of animals treated with IPN60090 
at the different doses tested (4 hours post-treatment on Day 28). Panel D: The ratio of Glu:Gln in tumours of treated animals 
at Day 4 and Day 28. 
All together, these data strongly support the consideration of the dose of 25 mg/kg BID as the 
minimal active dose in mice. Thus, the projected HED associated with the range of 
pharmacologically active doses in mice models (25 to 100 mg/kg BID) is 230 mg BID to 
900 mg BID, when corrected by the unbound fraction being different across species (0.9% in 
human and 1.7% in mouse). 
1.5.4 
Proposed Dosing Strategy and Dose Escalation Scheme 
Table 5 summarises the projected human starting dose and potentially pharmacologically 
active doses. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 46/264 
 
Table 5 
Summary Table of Projected Human Doses 
Projected human dose 
Extrapolated from 
Human equivalent dose (HED)[a]  
 
 
Total 
Corrected by unbound 
fraction[b] 
Dose associated with 
HNSTD 
HNSTD in female dog: 
10 mg/kg/day (5 mg/kg 
BID) 
336 mg/day  
(168 mg BID)[c]  
~860 mg/day (430 mg BID) 
Starting dose in human 
HNSTD in female dog: 
10 mg/kg/day (5 mg/kg 
BID) 
Starting dose of 40 mg/day 
(20 mg BID) corresponding 
to a safety factor of 8.4 in 
dog 
~100 mg/day (50 mg BID) 
Projected range of 
pharmacologically active 
doses in human 
25 mg/kg BID in mouse 
model 
120 mg BID 
230 mg BID[d] 
BID=bis in die (twice daily); HED=human equivalent dose; HNSTD=highest non-severely toxic dose 
a 
assuming a 60 kg human 
b 
dose yielding similar unbound concentration in human and animal 
c 
the low HNSTD (10 mg/kg/day) is due to one single animal with high exposure. If 30 mg/kg/day had been selected as the 
HNSTD, the dose associated with the HNSTD and the corresponding starting dose would be 972 mg/day (486 mg BID) 
and about 160 mg/day (80 mg BID), respectively. 
d 
computed using HED conversion factor and correction by fu (0.9 % in human, 1.7 % in mouse, 2.3% in dog) 
The proposal in dose escalation Part A (monotherapy) is to use an accelerated titration with 
single-patient cohorts and 100% dose increments up to 80 mg BID. Single-patient cohorts will 
only be used for doses projected to be below the dose associated with the HNSTD and thus 
expected to produce low or no toxicity (20, 40 and 80 mg BID with safety factors of 8.4, 4.2 
and 2.1, respectively). Then, from 180 mg BID (human dose associated with the HNSTD), the 
number of patients in each cohort will be increased to three. The dose escalation will continue 
with 100% increments until the range of projected pharmacologically active doses is reached 
(i.e. 320 mg BID) then dose increments will be decreased to 50%.  
Table 6 
Projected Escalation Scheme 
Dose level 1 
Dose level 2 
Dose level 3 
Dose level 4 
Dose level 5 
Dose level 6 
Dose level 7 
20 mg BID 
40 mg BID 
80 mg BID 
180 mg BID[a] 320 mg BID 
480 mg BID 
720 mg BID 
N=1 patient 
N=1 
N=1 
N=3 
N=3 
N=3 
N=3 
2×10 mg 
capsules 
4×10 mg 
1×60 mg + 
2×10 mg 
3×60 mg 
1×240 mg + 
1×60 mg + 
2×10 mg 
2×240 mg 
3×240 mg 
BID=bis in die (twice daily) 
a 
180 mg BID was selected instead of 160 mg BID to reduce the number of capsules and therefore reduce the burden for 
patients. The dose of 160 mg BID would correspond to six capsules BID (2×60 mg+4×10 mg) whereas the dose of 
180 mg corresponds to three capsules BID (3x60 mg). 
This is a projected escalation scheme that may be revised on an ongoing basis since the 
escalation will be guided by a BOIN design using a target DLT rate of 30%. 
Beside the safety data (DLTs), other parameters, such as PK and PD parameters, will be 
looked at during the escalation to evaluate the levels of target engagement and compound 
exposure. The Glu:Gln ratio in PBMCs will be the PD parameter used to analyse the target 
engagement potency at each dose level. In addition to DLT considerations, the PK and PD 
parameters will also help to refine the escalation levels if needed. 
Further details on study treatments are presented in Section 6.2. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 47/264 
 
1.5.5 
Food Effect Assessment Rationale 
Part D will explore the effect of food on a single administration of IPN60090 (patients will 
receive the treatment under fed and fasted conditions). A moderate fat meal has been selected 
since patients with late stage cancer may have difficulties eating a high-fat meal as described 
in the FDA Guidance for Industry Assessing the Effects of Food on Drugs in INDs and NDAs 
— Clinical Pharmacology Considerations. For ethical reasons, after the run-in period 
designed to evaluate the effect of food on the IPN60090 PK profile, patients will be allowed 
to receive IPN60090 BID as described in Part A. 
1.6 
Population to be Studied 
Emerging studies highlight the determinant role of the metabolic heterogeneity and plasticity 
to potentially influence the clinical outcome of molecules targeting cancer metabolism. Thus, 
patients whose tumours are highly dependent on glutamine catabolism should be in principle 
more susceptible to glutaminase inhibition, both in monotherapy and in combination. Thus, 
the clinical development strategy for IPN60090 will be focusing on a biomarker driven 
approach in monotherapy to select glutamine-dependent tumours harbouring a high frequency 
of either KEAP1/NRF2 mutations or low level of ASNS such as: 
• 
NSCLC: ~20% and 10% KEAP1 and NRF2 mutations respectively. NSCLC patient 
selection will also allow exploring the predictive role of co-occurring mutations such as 
KRAS and LKB1 status (mutant versus wild-type) 
• 
Other tumour types that express KEAP1/NRF2 mutations including, but not limited to: 
HNSCC (approximately 5% of KEAP1 mutations and 12% to 14% of NRF2 
mutations), urothelial cancer (7% and 3% KEAP1 and NRF2 mutations respectively), 
and HCC (approximately 5% of KEAP1 mutations and 4 % of NRF2 mutations) 
• 
HGSOC with low expression levels of ASNS (approximatively 15% of HGSOC 
tumours). Tumours will be classified as ASNS low using a qualitative analysis of 
ASNS staining in tumour biopsies with a score of 0 or 1+ depending on the intensity 
(negative or weak) and pervasiveness of staining [18]. A quantitative method of ASNS 
staining using H-SCORE may also be explored to evaluate the optimal range of 
H-SCORE that would be associated with a clinical benefit. 
The dose escalation study and the food assessment study will be performed in biomarker 
unselected patients with solid tumours to establish the RD of IPN60090. Patients will be 
actively screened for putative predictive biomarkers of response to IPN60090, for example 
KEAP1 and NRF2 mutations, and low ASNS expression levels for this study. A retrospective 
analysis of the correlation between KEAP1/NRF2 mutations versus wild-type or ASNSlow 
versus ASNShigh tumours and the sensitivity to IPN60090 will be performed. Patients will be 
enrolled in four separate parts either: 
• 
Part A: IPN60090 monotherapy, or  
• 
Part B: IPN60090 + pembrolizumab, or 
• 
Part C: IPN60090 + paclitaxel, or 
• 
Part D: IPN60090 monotherapy, food effect part 
The dose expansion portions will aim to further assess safety and tolerability, and preliminary 
anti-tumour activity of IPN60090 in monotherapy and the combination of IPN60090 with 
pembrolizumab or paclitaxel.  
Patients must have received at least one line of therapy for advanced stage disease and be 
refractory or ineligible to available existing therapy(ies) known to provide clinical benefit for 
their condition.  


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 48/264 
 
Patients in Part A (IPN60090 monotherapy) dose expansion must be KEAP1/NRF2 mutation 
carriers or have ASNSlow levels.  
Patients enrolled in the Part B expansion portion may have received previous treatment with 
any PD-1 or PD-L1 inhibitor, to evaluate if adding IPN60090 can increase response rate or 
reverse resistance to CPI.  
Patients enrolled in the Part C expansion portion must have received at least one line of 
therapy for metastatic disease (including platinum- or taxane-based chemotherapy) and may 
be refractory or resistant to platinum and/or -taxane chemotherapies (for example HGSOC, 
TNBC).  
Patients enrolled in Parts B (IPN60090 + pembrolizumab) and C (IPN60090 + paclitaxel) 
dose expansion portions may be KEAP1/NRF2 mutant or KEAP1/NRF2 wild-type, or may 
have different levels of ASNS. 
Further details on administration procedures and dosage are provided in Section 6.2. 
1.7 
Compliance Statement 
The study will adhere to all local regulatory requirements and relevant company policies. The 
sponsor will ensure that the countries where the data are transferred provide an adequate level 
of protection to the data. 
In case of data transfer outside the European Union (EU), the sponsor will either ensure that 
the countries where the data are transferred provide an adequate level of data protection or 
that the company receiving the data has joined the EU-United States (US) of America (USA) 
Privacy Shield Framework or will put in place a contract including standard contractual 
clauses adopted by the European Commission to ensure that the transfer of study information 
complies with applicable data protection legislation. Such a contract can be made available 
upon request. 
Before initiating the study, the investigator/institution will have: written and dated 
approval/favourable opinion from the independent ethics committee (IEC)/IRB for the study 
protocol/amendment(s), written informed consent form, any consent form updates, patient 
emergency study contact cards, patient recruitment procedures (for example advertisements), 
any written information to be provided to patients and a statement from the IEC/IRB that they 
comply with Good Clinical Practice (GCP) requirements. The IEC/IRB approval must 
identify the protocol version as well as the documents reviewed. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 49/264 
 
2 
PURPOSE OF THE STUDY AND STUDY OBJECTIVES 
2.1 
Purpose of the Study 
Preclinical studies provide strong evidence for evaluating IPN60090 in tumours harbouring 
KEAP1/NRF2 mutations or ASNS low levels in monotherapy, and in combination with 
different therapeutic agents, including anti-PD-1 and taxanes across a variety of tumour types 
(see Section 1.2.1). 
This is a phase I, first in human, dose escalation study with multiple expansion cohorts of 
IPN60090. The dose escalation part will investigate the safety and tolerability and provide a 
better understanding of the mechanism of action of IPN60090 and of the potential of selected 
biomarkers to predict the clinical outcome in monotherapy as well as in combination with 
other cancer therapies. This study will also generate the first PK data in humans and PK/PD 
correlation data that will support the choice of the RD. An additional cohort will explore the 
effect of food on the IPN60090 PK profile. The dose expansion part will further define the 
safety and tolerability of IPN60090 alone and in combination and investigate the preliminary 
anti-tumour activity. 
2.2 
Study Objectives 
This study will evaluate the safety, PK, PD and anti-tumour activity of IPN60090 as a single 
agent (Part A) and in combination with pembrolizumab (Part B) or paclitaxel (Part C) in 
patients with advanced solid tumours. Part D will evaluate the safety of IPN60090 as a single 
agent and explore the effect of food on the IPN60090 PK profile. Specific objectives and 
corresponding endpoints for the study are outlined below.  
2.2.1 
Primary 
• 
To assess the safety and tolerability of oral IPN60090 as a single agent (Part A and 
Part D) and in combination therapy with pembrolizumab (Part B) or paclitaxel (Part C).  
For Dose Escalation Only:  
• 
To determine the maximum tolerated dose (MTD), if reached, and the RD of IPN60090 
as a single agent (Part A) and in combination therapy with pembrolizumab (Part B) or 
paclitaxel (Part C).  
2.2.2 
Secondary 
• 
To assess the preliminary anti-tumour activity of IPN60090 as a single agent (Part A 
and Part D) and in combination with pembrolizumab (Part B) or paclitaxel (Part C) in 
patients with or without biomarker selected specific tumour types. 
• 
To characterise the PK and PD profile of IPN60090 as a single agent (Part A and 
Part D) and in combination with pembrolizumab (Part B) or paclitaxel (Part C). 
• 
To assess the effect of food on the PK profile of a single administration of IPN60090 
(Part D). 
• 
To document the concentrations of pembrolizumab and paclitaxel (Parts B and C). 
• 
To document the potential development of antibodies against pembrolizumab (Part B) 
• 
To evaluate biomarkers of patient stratification and correlate them with clinical 
outcome. 
2.2.3 
Exploratory 
• 
To analyse exploratory biomarkers in archival and fresh biopsy samples, including 
biomarkers of response or resistance to the treatment, and associate them with clinical 
outcome.  


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 50/264 
 
• 
To collect biobank samples for potential future analysis of biomarkers (optional, 
informed consent required). 
2.3 
Study Hypothesis 
IPN60090 will have a manageable safety profile to permit further clinical development as a 
single agent or in combination with pembrolizumab or paclitaxel in patients with advanced 
solid tumours and will demonstrate preliminary efficacy and anti-tumour effects as a 
monotherapy and/or in combination with pembrolizumab or paclitaxel across KEAP1/NRF2 
mutant solid tumours and in ASNSlow solid tumours. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 51/264 
 
3 
STUDY DESIGN 
3.1 
General Design and Study Schema 
This is a phase I, first in human, open-label, dose escalation and dose expansion study of 
IPN60090 as a single agent or in combination in patients with advanced solid tumours. The 
study will be conducted from one centre in the USA to approximately 50 sites worldwide over 
the dose escalation and expansion parts of the study.  
As summarised in Figure 5, the study will be divided into four parts. 
Figure 5 IPN60090: Summary of Early Clinical Development 
 
PART D 
 
ASNS=asparagine synthetase; BID=bis in die (twice daily); BOIN=Bayesian Optimal Interval; HGSOC=high-grade serous 
ovarian cancer; KEAP1=Kelch-like ECH-associated protein 1; NRF2=nuclear factor erythroid 2-related factor 2; 
NSCLC=non-small cell lung cancer; Ph.=pharmacologically; RD=recommended dose 
Part A: The dose escalation will explore the safety profile and establish the MTD (if 
reached), the target engagement or PD levels (Glu:Gln ratio in PBMC) and the RD of single 
agent IPN60090 in biomarker unselected patient populations. During the dose expansion 
portion, safety and tolerability at the RD will be assessed further, and the preliminary 
anti-tumour activity of IPN60090 will be explored in three different cohorts (NSCLC KEAP1 
or NRF2 mutant, other KEAP1 or NRF2 mutant tumours and HGSOC ASNSlow). The 
scientific rationale for conducting these cohorts is provided in Section 1.2.1 and described 
below:  


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 52/264 
 
Dose Expansion Cohort 1: NSCLC KEAP1 or NRF2 Mutant: Due to the inherent 
heterogeneity of NSCLC and despite recent advances in targeted and combination treatment 
approaches, management of advanced NSCLC in the absence of targetable mutation, such as 
epidermal growth factor receptor, anaplastic lymphoma kinase, or BRAF, represents an unmet 
medical need as these patients inevitably relapse post each subsequent line of chemotherapy 
and have limited response to CPI blockade. KEAP1 and NRF2 mutations may represent novel 
markers of GLS1 inhibition. These mutations are present in about 20% of NSCLC, and often 
co-occur with KRAS mutations, for which no available targeted treatment option exists.  
Dose Expansion Cohort 2: Other KEAP1 or NRF2 Mutant Tumours: KEAP1 and NRF2 
mutations are present in about 6% of HNSCC, 5% of HCC and 3% to 5% of urothelial 
carcinomas, respectively, and convey tumour dependence on glutaminase and sensitivity to 
GLS1 inhibition, which warrants further exploration as there may be a potential to induce 
sensitivity to conventional therapy by including a tumour metabolism altering agent in the 
treatment paradigm.  
Dose Expansion Cohort 3: HGSOC ASNSlow: Treatment of advanced recurrent HGSOC 
represents a highly unmet medical need, especially in the platinum resistant/refractory setting. 
By the time patients are determined to be platinum resistant or refractory, treatment options 
available to them become extremely limited. Targeting a specific subset of patients with low 
ASNS expression and sensitivity to GLS1 inhibition will explore the therapeutic potential of 
IPN60090 in this highly unmet medical need population. 
Part B: The dose escalation will explore the safety profile and establish the MTD (if reached) 
and the RD of IPN60090 in combination with pembrolizumab. During the dose expansion 
portion, safety and tolerability at the RD will be assessed further, and preliminary anti-tumour 
activity of this combination will be explored. 
In general, response to CPI blockade monotherapy is limited; however, those responses are 
durable. There is a need to explore treatment strategies that will increase response or 
overcome resistance to PD-1 inhibition.  
Dose Expansion Cohort 4: KEAP1 or NRF2 Mutant NSCLC: Preclinical data indicates that 
adding a GLS1 inhibitor to anti-PD-1 therapy has the potential to boost response via an 
increase in the CD8/Treg ratio. Dose expansion Cohort 4 will focus on KEAP1/NRF2 mutant 
NSCLC. Within that patient population, patients with co-occurring KRAS/KEAP1/LKB1 
mutations are of particular interest, as presence of this cluster mutation may convey resistance 
to CPI therapy.  
Dose Expansion Cohort 5: Other KEAP1 or NRF2 Mutant Tumours: A similar approach is 
applied in Cohort 5 in additional biomarker positive KEAP1/NRF2 mutant tumour types for 
which pembrolizumab is approved as SoC to explore if addition of IPN60090 would prevent 
or reverse resistance to CPI.  
Dose Expansion Cohort 6: KEAP1 or NRF2 Wild-type Tumours with any level of ASNS 
Expression: In addition, the combination of IPN60090 and pembrolizumab will be explored 
in KEAP1/NRF2 wild-type tumours, as there are early clinical data from CB-839 that indicate 
preliminary anti-tumour activity of the combination in the biomarker-unselected patient 
population. 
Part C: The dose escalation will explore the safety profile and establish the MTD (if reached) 
and the RD of IPN60090 in combination with paclitaxel. During the dose expansion portion, 
safety and tolerability at the RD will be assessed further, and preliminary anti-tumour activity 
of this combination will be explored. 
Dose Expansion Cohort 7: KEAP1 or NRF2 Mutant Tumours and Dose Expansion 
Cohort 8: ASNSlow HGSOC: Preclinical data for the combination of IPN60090 and paclitaxel 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 53/264 
 
provides rationale for the synergistic activity of the combination in HGSOC and NSCLC 
models. Given the high unmet medical need in treatment of these tumour types, dose 
expansion Cohorts 7 and 8 will look into this combination in KEAP1/NRF2 mutant tumours 
and ASNSlow HGSOC, respectively, to explore if adding a glutaminase inhibitor may enhance 
response to treatment.  
Dose Expansion Cohort 9: KEAP1 or NRF2 Wild-type Tumours with any level of ASNS 
Expression: In addition, Cohort 9 will explore the combination of IPN60090 and paclitaxel in 
the biomarker-unselected patient population across approved tumour types, based on early 
clinical data from CB-839 that indicate the potential synergy of IPN60090 and paclitaxel. 
Parts B and C: These dose escalations in combination with pembrolizumab or paclitaxel will 
be initiated at the first dose with pharmacological activity (at least 50% inhibition of Glu:Gln 
ratio in PBMCs at Ctrough (12 hours postdose) on Day 14 in 66% of patients treated at this dose 
level) and with good tolerability as identified in Part A. The threshold of 50% inhibition of the 
PD marker has been selected since in a mouse model of NSCLC (H2122), maximum TGI (at 
50 and 100 mg/kg BID) was observed when at least 50% up to 96% inhibition of the PD 
marker in PBMC was maintained over a dosing interval (i.e. 12 hours). 
Part D: This cohort will evaluate the safety of IPN60090 administered as a single agent and 
explore the effect of a moderate fat meal on the PK profile of IPN60090 administered as a 
single dose under fasting and fed conditions at the RD as defined by the Safety Review 
Committee (SRC). 
3.1.1 
Number of Patients 
Number of Patients Planned:  
Dose Escalation 
Part A (single agent): Approximately 30 patients for the dose escalation. 
Part B (combination with pembrolizumab): Approximately 18 patients for the dose 
escalation. 
Part C (combination with paclitaxel): Approximately 18 patients for the dose escalation. 
Food Effect Assessment 
Part D: Eight patients for preliminary food effect assessment. 
Dose Expansion 
Parts A, B and C: Approximately 162 patients (90 patients in Stage 1 of dose expansion and 
72 patients in Stage 2). 
3.1.2 
Dose Escalations 
3.1.2.1 
Part A – Dose Escalation with IPN60090 as a Single Agent 
The dose escalation portion of Part A is to evaluate the safety, tolerability, PK and PD of 
IPN60090 given as a BID oral dose (every 12 hours), during or after a meal, over a 21-day 
cycle.  
Dose escalation of IPN60090 will be conducted in patients with biomarker-positive and 
biomarker-negative advanced solid tumours. 
These patients will not be selected for KEAP1/NRF2 mutation status and may be wild-type or 
mutated. Patients may have tumours with any level of ASNS expression. 
Seven dose levels are planned to be tested (as presented in Figure 6). The study will follow a 
BOIN design for dose escalation [16, 17]. Dose levels provided are examples and after the 
starting dose, the dose level will be determined by the SRC. After each SRC meeting, the 
tested dose level can be escalated, de-escalated or extended as indicated per the BOIN design. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 54/264 
 
Figure 6 Part A-IPN60090 Monotherapy - Predefined Escalation and De-escalation Scheme 
 
BOIN=Bayesian Optimal Interval; DL=dose level; MTD=maximum tolerated dose; SRC=Safety Review Committee 
At all dose levels, IPN60090 will be administered orally BID starting from Day 1 of each 
21-day cycle. The predefined dose escalation plan is described in Table 7. 
Table 7 
Dose Escalation Phase I-Part A 
DL1 
DL2 
DL3 
DL4 
DL5 
DL6 
DL7 
20 mg BID 
40 mg BID 
80 mg BID 
180 mg BID[a] 
320 mg BID 
480 mg BID 
720 mg BID 
BID=bis in die (twice daily); DL=dose level 
a 
180 mg BID was selected instead of 160 mg BID to reduce the number of capsules and therefore reduce the burden for 
patients. The dose of 160 mg BID would correspond to six capsules BID (2×60 mg+4×10 mg) whereas the dose of 
180 mg corresponds to three capsules BID (3×60 mg). 
The Part A monotherapy dose escalation will enrol single-patient cohorts for the first three 
dose levels (if no Grade 2 adverse event (AE) that is at least possibly related to the study 
drug(s) or DLT is observed) and then cohorts of three patients each at the predefined dose 
levels. If a Grade 2 AE that is at least possibly related to the study drug(s) or a DLT is 
observed in a single patient cohort (first three dose levels), two additional patients will be 
added at this dose level with the same rules for escalation and de-escalation as the cohorts of 
three patients. At any point, additional patients may be enrolled as required for safety 
assessment and/or biomarker analysis. Following each cohort DLT assessment period, the 
observed DLT data will be used to determine the dose level for the next cohort in accordance 
with the escalation and de-escalation rules for a local BOIN design using a target toxicity rate 
of 30% with escalation and de-escalation thresholds of 23.6% and 35.9%, respectively. 
Following the completion of enrolment, the MTD will be estimated at the dose level at which 
the isotonic estimate of the DLT rate is closest to 30%.  
At the end of each part, up to two dose levels may be repeated in order to reach a total of 
18 patients at each dose level to collect more PK/PD information to better define the RD. The 
decision to repeat a dose level will be made by the SRC. Safety data from these additional 
patients will not be included in the BOIN design to determine the MTD but will be evaluated 
by the SRC and ultimately be taken into consideration for RD selection. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 55/264 
 
MTD Definition 
The MTD is defined as the maximum dose of IPN60090 that may be administered BID for 
21 days, so that no more than 30% of patients experience a DLT. The MTD will be 
determined by the dose for which the isotonic estimate of DLT rate is closest to 30% of 
patients experiencing a DLT.  
DLT Assessment Period 
The DLT assessment period will consist of the first 21 days of treatment (one cycle). The 
SRC will evaluate safety and available PK and PD data after patients have completed at least 
one cycle of treatment in order to make a decision on dose escalation, and to determine the 
MTD and the RD. The SRC may decide to evaluate an intermediate, not predefined, 
previously evaluated or not previously-evaluated dose or a less frequent dosing schedule that 
will not exceed the MTD level, if evaluation of toxicity at such a dose or schedule is desired. 
More details about the SRC are included in Section 4.3.1 and will be described in the SRC 
charter. 
DLT Criteria 
The DLTs for Part A are defined for any of the following investigational medicinal product 
(IMP)-related, probably related or possibly related AEs according to National Cancer Institute 
– Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 that occur 
during the defined DLT assessment period (over the 21 days following the first dose of 
IPN60090): 
• 
Grade 4 neutropenia lasting >7 days 
• 
Febrile neutropenia of any grade (absolute neutrophil count (ANC) <1000/mm3 with a 
single temperature episode of 38.3°C or a sustained temperature of 38°C for >1 hour). 
• 
Grade 3 or 4 neutropenia with infection. 
• 
Grade 3 thrombocytopenia with bleeding and Grade 4 thrombocytopenia. 
• 
Grade 4 life threatening anaemia. 
• 
ALT/AST ≥3×upper limit of normal (ULN) with total bilirubin ≥2×ULN without 
elevation of ALP and no other reasonable explanation for the abnormality (Hy’s law 
criteria). 
• 
Grade 3 lasting more than 7 days or Grade 4 laboratory abnormalities of ALT/AST 
and/or bilirubin, with the following exceptions: 
- 
for patients with Grade 1 ALT/AST at baseline (>ULN to 3×ULN), an ALT/AST 
value of >7.5×ULN will be considered a DLT. 
- 
for patients with Grade 2 ALT/AST at baseline (>3×ULN to 5×ULN), an 
ALT/AST value >10×ULN will be considered a DLT. 
• 
Grade 3 or higher non-haematological toxicity excluding: 
- 
Grade 3 nausea, vomiting or diarrhoea for less than 72 hours with adequate 
supportive care. 
- 
Grade 3 fatigue lasting less than a week. 
- 
Grade 3 or higher electrolyte abnormality that lasts for less than 72 hours, that is 
not clinically complicated and resolves spontaneously or with conventional 
medical interventions. 
- 
Grade 3 or higher amylase or lipase lasting less than 72 hours and not associated 
with clinical manifestations of pancreatitis. 
• 
Grade 5 (death). 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 56/264 
 
Other clinically significant or persistent toxicities may be considered a DLT following review 
by the SRC.  
Patient Eligibility for Dose Escalation Decision 
Any patient who does not complete the DLT assessment period for any reason other than a 
DLT will be considered nonevaluable for dose escalation decisions and MTD assessment and 
will be replaced by an additional patient at that same dose level. Patients will be considered 
eligible for the DLT assessment only if they are able to receive ≥75% of the total planned 
IPN60090 dose over the DLT assessment period. Noncompliant patients will also be replaced. 
The SRC may decide to enrol additional patients based on the safety, PK or PD data. 
Treatment Duration - Additional Cycles 
Patients will be offered IPN60090 treatment beyond Cycle 1 as long as they continue to 
experience clinical benefit, in the opinion of the investigator, until the earlier of disease 
progression, symptomatic deterioration, poor tolerability despite appropriate medical 
management or any of the other reasons for treatment discontinuation. Patients who 
experience a DLT (or other toxicities considered related, probably related or possibly related 
to the study treatment) will be permitted to continue to receive study treatment at a lower dose 
level than the dose at which the DLT was observed, at the discretion of the investigator (see 
Section 6.4.4) and will be followed for safety. Biomarker-positive patients who are enrolled 
and receive study treatment at initial dose levels below the pharmacologically active range for 
at least two cycles with good tolerability, and achieve and maintain at least SD, may be 
escalated to a higher dose level that has been tested and proven to be well tolerated, at the 
recommendation of the SRC. These patients will be treated outside of the BOIN design. 
Patients who discontinue study treatment for reasons other than disease progression (for 
example toxicity) should continue to undergo scheduled tumour assessments approximately 
every 12 weeks until disease progression, initiation of further systemic cancer therapy, death, 
or until the study closes, whichever occurs first.  
3.1.2.2 
Part B – Pembrolizumab Combination Dose Escalation 
The dose escalation portion of Part B is to evaluate the safety, tolerability, PK and PD of 
IPN60090 given as a BID oral dose (every 12 hours) during or after a meal in combination 
with pembrolizumab, over a 21-day cycle. The intake of IPN60090 will be made before the 
start of the pembrolizumab infusion.  
Dose escalation of IPN60090 in combination with pembrolizumab will be conducted in 
patients with biomarker-positive and biomarker-negative advanced solid tumours.  
These patients will be unselected for KEAP1/NRF2 mutation status and may be 
KEAP1/NRF2 wild-type or mutated. The same applies for ASNS expression levels; patients 
may have tumours with any level of ASNS expression. Previous treatment with CPI therapy is 
allowed.  
This dose escalation in combination with pembrolizumab will be initiated at a dose level 
showing pharmacological activity (at least 50% inhibition of Glu:Gln ratio in PBMCs at 
Ctrough (12 hours postdose and predose for the following dose) on Day 14 of Cycle 1 in 66% of 
patients treated at this dose level) and with good tolerability as identified in Part A. The 
IPN60090 dose being tested in the dose escalation of Part B will always remain lower than 
that being tested in the dose escalation of Part A (at least one dose level lower than the highest 
dose tested in Part A).  
Three dose levels of IPN60090 are planned to be tested with an additional lower dose level 
(DL-1) if DL1 is not tolerated. The study will follow a BOIN design for dose escalation.  


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 57/264 
 
At all dose levels, IPN60090 will be administered orally BID starting from Day 1 of each 
21-day cycle and pembrolizumab will be administered as one intravenous (i.v.) infusion every 
21 days (±1 day in Cycle 1 and ±3 days in all other cycles) starting from Day 1 of each cycle. 
The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W). Based on 
the totality of data generated in the Keytruda development program, 200 mg Q3W is the 
appropriate dose of pembrolizumab for adults across all indications and regardless of tumour 
type. The predefined dose escalation plan is described in Table 8.  
Table 8 
Dose Escalation Phase I-Part B in Combination with Pembrolizumab 
Dose level 
Dose level -1 
Dose level 1 
Dose level 2 
Dose level 3 
Planned dose of 
IPN60090 [a] 
80 mg BID 
180 mg BID 
320 mg BID 
480 mg BID 
Planned dose of 
pembrolizumab 
200 mg Q3W [b] 200 mg Q3W [b] 
200 mg Q3W [b] 
200 mg Q3W [b] 
BID=bis in die (twice daily); Q3W=every 3 weeks (21 days) 
a 
dose levels are examples; the actual starting dose will be determined by PD from the Part A dose escalation 
b 
or according to the local approved label for particular tumour types 
Dose finding will begin at DL1. The study will enrol in cohorts of three patients at the 
predefined dose levels until up to six cohorts have been enrolled. Following each cohort, the 
observed DLT data will be used to determine the dose level for the next cohort in accordance 
with the escalation and de-escalation rules for a local BOIN design using a target toxicity rate 
of 30% with escalation and de-escalation thresholds of 23.6% and 35.9%, respectively. 
Following the completion of enrolment, the MTD will be estimated as the dose level at which 
the isotonic estimate of the DLT rate is closest to 30%.  
If the first dose level of IPN60090 in combination with 200 mg pembrolizumab is not well 
tolerated, upon the decision of the SRC, the dose of IPN60090 may be de-escalated and thus a 
new cohort may start with DL-1. 
At the end of each part, up to two dose levels may be repeated in order to reach a total of 
18 patients at each dose level to collect more PK/PD information to better define the RD. The 
decision to repeat a dose level will be made by the SRC. Safety data from these additional 
patients will not be included in the BOIN design to determine the MTD but will be evaluated 
by the SRC and ultimately be taken into consideration for RD selection. 
MTD Definition 
The MTD is defined as the maximum dose of IPN60090 that may be administered BID for 
21 days in combination with an i.v. infusion of 200 mg pembrolizumab (or according to the 
local approved label for particular tumour types), so that no more than 30% of patients 
experience a DLT. The MTD will be determined by the dose for which the isotonic estimate 
of DLT rate is closest to 30% of patients experiencing a DLT.  
DLT Assessment Period 
The DLT assessment period for IPN60090 in combination with pembrolizumab (Part B) will 
consist of the first 21 days of treatment (one cycle). An additional safety assessment for 
delayed onset AEs will be performed at 6 weeks (42 days), and at 12 weeks (84 days). The 
SRC will evaluate safety and available PK and PD data in order to make a decision on dose 
escalation, and to determine the MTD and the RD. The safety data reviewed by the SRC will 
include the safety findings and DLTs observed during the DLT assessment period from the 
previous cohort. The SRC may decide to evaluate an intermediate, not predefined, previously 
evaluated or not previously-evaluated dose of IPN60090 or a less frequent dosing schedule 
that will not exceed the MTD level if evaluation of toxicity at such a dose or schedule is 
desired.  


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 58/264 
 
DLT Criteria 
The DLTs for Part B are defined for any of the following IMP-related, probably related or 
possibly related AEs according to NCI-CTCAE version 5.0 that occur during the defined DLT 
assessment period (over the 21 days following the first dose of IPN60090 combined with 
pembrolizumab): 
• 
Grade 4 neutropenia lasting >7 days 
• 
Febrile neutropenia of any grade (ANC <1000/mm3 with a single temperature episode 
of 38.3°C or a sustained temperature of 38°C for >1 hour) 
• 
Grade 3 or 4 neutropenia with infection. 
• 
Grade 3 thrombocytopenia with bleeding and Grade 4 thrombocytopenia. 
• 
Grade 4 life threatening anaemia. 
• 
ALT/AST ≥3×ULN with total bilirubin ≥2×ULN without elevation of ALP and no 
other reasonable explanation for the abnormality (Hy’s law criteria). 
• 
Grade 3 lasting more than 7 days or Grade 4 laboratory abnormalities of ALT/AST 
and/or bilirubin, with the following exceptions: 
- 
for patients with Grade 1 ALT/AST at baseline (>ULN to 3×ULN, an ALT/AST 
value of >7.5×ULN will be considered a DLT. 
- 
for patients with Grade 2 ALT/AST at baseline (>3×ULN to 5×ULN), an 
ALT/AST value >10×ULN will be considered a DLT. 
• 
Grade 3 or Grade 4 pneumonitis, hepatitis, colitis, nephritis, encephalitis, etc 
• 
Grade 3 or Grade 4 rash lasting more than 72 hours with adequate supportive care. 
• 
Grade 3 or higher non-haematological toxicity excluding: 
- 
Grade 3 nausea, vomiting or diarrhoea lasting less than 72 hours with adequate 
supportive care. 
- 
Grade 3 fatigue lasting less than a week. 
- 
Grade 3 or higher electrolyte abnormality that lasts for less than 72 hours, that is 
not clinically complicated and resolves spontaneously or with conventional 
medical interventions. 
- 
Grade 3 or higher amylase or lipase lasting less than 72 hours and not associated 
with clinical manifestations of pancreatitis. 
• 
Grade 5 (death) 
Other clinically significant or persistent toxicities may be considered a DLT following review 
by the SRC. 
Transient infusion-related AEs that can be controlled with medical management (i.e. flu-like 
symptoms, fever) are not considered DLTs. 
Patient Eligibility for Dose Escalation Decision 
Any patient who does not complete the DLT assessment period for any reason other than a 
DLT will be considered nonevaluable for dose escalation decisions and MTD assessment and 
will be replaced by an additional patient at that same dose level. Moreover, patients will be 
considered eligible for the DLT assessment only if they received ≥75% of the total planned 
IPN60090 dose and one infusion of pembrolizumab over the DLT assessment period. 
Noncompliant patients will also be replaced. The SRC may decide to enrol additional patients 
based on the safety, PK or PD data. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 59/264 
 
Treatment Duration - Additional Cycles 
Patients will be offered IPN60090 + pembrolizumab treatment beyond Cycle 1 as long as they 
continue to experience clinical benefit, in the opinion of the investigator, until the earlier of 
confirmed disease progression, symptomatic deterioration, poor tolerability despite 
appropriate medical management or any of the other reasons for treatment discontinuation. 
Patients who experience a DLT (or other toxicities considered related, probably related or 
possibly related to the study treatment) will be permitted to continue to receive study 
treatment at a lower dose level than the dose at which the DLT was observed, at the discretion 
of the investigator (see Section 6.4.4) and will be followed for safety. Patients who 
discontinue study treatment for reasons other than disease progression (for example toxicity) 
should continue to undergo scheduled tumour assessments approximately every 12 weeks 
until confirmed disease progression, or initiation of further systemic cancer therapy, death, or 
until the study closes, whichever occurs first. 
3.1.2.3 
Part C – Paclitaxel Combination Dose Escalation 
The dose escalation portion of Part C is to evaluate the safety, tolerability, PK and PD of 
IPN60090 given as a BID oral dose (every 12 hours) in combination with paclitaxel, during or 
after a meal, over a 21-day cycle. The intake of IPN60090 will be made before the paclitaxel 
infusion. 
Dose escalation of IPN60090 in combination with paclitaxel will be conducted in patients 
with biomarker-positive and biomarker-negative advanced solid tumours. 
These patients will be unselected for KEAP1/NRF2 mutation and may be KEAP1/NRF2 
wild-type or mutated. The same applies for ASNS expression levels, patients may have 
tumours with any level of ASNS expression. Dose escalation in combination with paclitaxel 
will be initiated at a dose level showing pharmacological activity (at least 50% inhibition of 
Glu:Gln ratio in PBMC at Ctrough (12 hours postdose and predose for the following dose) on 
Day 14 of Cycle 1 in 66% of patients treated at this dose level) and good tolerability as 
identified in Part A. The IPN60090 dose being tested in Part C will always remain lower than 
that being tested in Part A (at least one dose level lower than the highest dose tested in 
Part A). 
Three dose levels of IPN60090 are planned to be tested with an additional lower dose level 
(DL-1) if DL1 is not tolerated. The study will follow a BOIN design for dose escalation. 
At all dose levels, IPN60090 will be administered orally BID starting from Day 1 of each 
21-day cycle and paclitaxel will be administered as one i.v. infusion every 21 days (±1 day in 
Cycle 1 and ±3 days in all other cycles) starting from Day 1 of each cycle. The predefined 
dose escalation plan is described in Table 9. 
Table 9 
Dose Escalation Phase I-Part C in Combination with Paclitaxel 
Dose level 
DL-1 
DL1 
DL2 
DL3 
Planned dose of 
IPN60090 [a] 
80 mg BID 
180 mg BID 
320 mg BID 
480 mg BID 
Planned dose of 
paclitaxel 
175 or 135 mg/m2 
Q3W [b] 
175 or 135 mg/m² 
Q3W [b] 
175 or 135 mg/m² 
Q3W [b] 
175 or 135 mg/m² 
Q3W [b] 
BID=bis in die (twice daily); DL=dose level; Q3W=every 3 weeks (21 days) 
a 
dose levels are examples; the actual starting dose will be determined by PD from the Part A dose escalation 
b 
or according to the local approved label for particular tumour types 
Dose finding will begin at DL1. The study will enrol in cohorts of three patients at the 
predefined dose levels until up to six cohorts have been enrolled. Following each cohort, the 
observed DLT data will be used to determine the dose level for the next cohort in accordance 
with the escalation and de-escalation rules for a local BOIN design using a target toxicity rate 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 60/264 
 
of 30% with escalation and de-escalation thresholds of 23.6% and 35.9%, respectively. 
Following the completion of enrolment, the MTD will be estimated as the dose level at which 
the isotonic estimate of the DLT rate is closest to 30%.  
If the first dose level of IPN60090 in combination with paclitaxel 175 or 135 mg/m² (or 
according to the local approved label for particular tumour types) given intravenously is not 
well tolerated, the dose of IPN60090 may be de-escalated and thus a new cohort may start 
with the DL-1.  
At the end of each part, up to two dose levels may be repeated in order to reach a total of 
18 patients at each dose level to collect more PK/PD information to better define the RD. The 
decision to repeat a dose level will be made by the SRC. Safety data from these additional 
patients will not be included in the BOIN design to determine the MTD but will be evaluated 
by the SRC and ultimately be taken into consideration for RD selection. 
MTD Definition 
The MTD is defined as the maximum dose of IPN60090 that may be administered BID for 
21 days in combination with an i.v. infusion of 175 or 135 mg/m² paclitaxel (or according to 
the local approved label for particular tumour types), so that no more than 30% of patients 
experience a DLT. The MTD will be determined by the dose for which the isotonic estimate 
of DLT rate is closest to 30% of patients experiencing a DLT.  
DLT Assessment Period 
The DLT assessment period will consist of the first 21 days of treatment (one cycle). The 
SRC will evaluate safety and available PK and PD data in order to make a decision on dose 
escalation, and to determine the MTD and the RD. The safety data reviewed by the SRC will 
include the safety findings and DLTs observed during the DLT assessment period from the 
previous cohort. The SRC may decide to evaluate an intermediate, not predefined, previously 
evaluated or not previously evaluated dose or a less frequent dosing schedule that will not 
exceed the MTD level, if evaluation of toxicity at such a dose or schedule is desired.  
DLT Criteria 
The DLTs for Part C are defined for any of the following IMP-related, probably related or 
possibly related AEs according to NCI-CTCAE version 5.0 that occur during the defined DLT 
assessment period (over the 21 days following the first dose of IPN60090 combined with 
paclitaxel): 
• 
Grade 4 neutropenia lasting >7 days 
• 
Febrile neutropenia of any grade (ANC <1000/mm3 with a single temperature episode 
of 38.3°C or a sustained temperature of 38°C for >1 hour. 
• 
Grade 3 or 4 neutropenia with infection. 
• 
Grade 3 thrombocytopenia with bleeding and Grade 4 thrombocytopenia. 
• 
Grade 4 life threatening anaemia. 
• 
ALT/AST ≥3×ULN with total bilirubin ≥2×ULN without elevation of ALP and no 
other reasonable explanation for the abnormality (Hy’s law criteria). 
• 
Grade 3 lasting more than 7 days or Grade 4 laboratory abnormalities of ALT/AST 
and/or bilirubin, with the following exceptions: 
- 
for patients with Grade 1 ALT/AST at baseline >ULN to 3×ULN, an ALT/AST 
value of >7.5×ULN will be considered a DLT. 
- 
for patients with Grade 2 ALT/AST at baseline (>3×ULN to 5×ULN), an 
ALT/AST value >10×ULN will be considered a DLT. 
• 
Grade 3 or Grade 4 rash lasting more than 72 hours with adequate supportive care. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 61/264 
 
• 
Grade 3 or higher non-haematological toxicity excluding: 
- 
Grade 3 nausea, vomiting or diarrhoea for less than 72 hours with adequate 
supportive care. 
- 
Grade 3 fatigue lasting less than 1 week. 
- 
Grade 3 or higher electrolyte abnormality that lasts for less than 72 hours, that is 
not clinically complicated and resolves spontaneously or with conventional 
medical interventions. 
- 
Grade 3 or higher amylase or lipase lasting less than 72 hours and not associated 
with clinical manifestations of pancreatitis. 
• 
Grade 5 (death). 
Other clinically significant or persistent toxicities may be considered a DLT following review 
by the SRC. 
Transient infusion-related AEs that can be controlled with medical management (i.e. flu-like 
symptoms, fever) are not considered DLTs. 
Patient Eligibility for Dose Escalation Decision 
Any patient who does not complete the DLT assessment period for any reason other than a 
DLT will be considered nonevaluable for dose escalation decisions and MTD assessment and 
will be replaced by an additional patient at that same dose level. Moreover, patients will be 
considered eligible for the DLT assessment only if they are able to receive ≥75% of the total 
planned IPN60090 dose and one infusion of paclitaxel over the DLT assessment period. 
Noncompliant patients will also be replaced. The SRC may decide to enrol additional patients 
based on the safety, PK or PD data. 
Treatment Duration - Additional Cycles 
Patients will be offered IPN60090 + paclitaxel treatment beyond Cycle 1 as long as they 
continue to experience clinical benefit, in the opinion of the investigator, until the earlier of 
disease progression, symptomatic deterioration, poor tolerability despite appropriate medical 
management or any of the other reasons for treatment discontinuation. Patients who 
experience a DLT (or other toxicities considered related, probably related or possibly related 
to the study treatment) will be permitted to continue to receive study treatment at a lower dose 
level than the dose at which the DLT was observed, at the discretion of the investigator (see 
Section 6.4.4) and will be followed for safety. Patients who discontinue study treatment for 
reasons other than disease progression (for example toxicity) should continue to undergo 
scheduled tumour assessments approximately every 12 weeks until disease progression, or 
initiation of further systemic cancer therapy, death, or until the study closes, whichever occurs 
first. 
3.1.2.4 
Transition to Recommended Dose or Different Regimen 
In Parts A, B and C, when the RD is determined, if a patient is still in the study at a different 
dose, this patient can be moved to the RD, at the discretion of the investigator. 
In Part A, biomarker-positive patients who are enrolled and receive study treatment at initial 
dose levels below the pharmacologically active range for at least two cycles with good 
tolerability, and achieve and maintain at least SD, may be escalated to a higher dose level that 
has been tested and proven to be well tolerated at the recommendation of the SRC. These 
patients will be treated outside of the BOIN design. 
Patients enrolled in monotherapy Part A may receive combination treatment with either 
pembrolizumab or with paclitaxel upon progression on IPN60090 monotherapy, at the 
discretion of the investigator, and with the approval of the sponsor, once the safe dose level 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 62/264 
 
for the combination is determined. These patients will need to satisfy the eligibility criteria for 
combination therapy prior to initiating treatment (see Section 4.1) and will be followed for 
safety and efficacy in a separate cohort. 
3.1.3 
Food Effect Assessment – Part D 
Part D will start at the end of the Part A dose escalation. Patients in Part D will not be part of 
the dose escalation and MTD assessment. 
Food effect evaluation will be conducted in patients with biomarker-positive and 
biomarker-negative advanced solid tumours. 
These patients will not be selected for KEAP1/NRF2 mutation status and may be wild-type or 
mutated. Patients may have tumours with any level of ASNS expression. Eligibility criteria 
for Part D will be the same as the criteria for the Part A dose escalation. 
After screening, eight patients will enter a run-in period of 7 days: 
x At Day -7, patients will receive a single administration of IPN60090 at the RD (as 
defined by the SRC at the end of the Part A dose escalation) following an overnight 
fast of at least 10 hours. The patients should not consume any food for at least 4 hours 
after the dose. IPN60090 should be taken with 240 mL (i.e. 8 fluid ounces) of water. 
Additional water is permitted ad libitum except for the period 1 hour before to 1 hour 
after administration of the drug product. 
x At Day -3, patients will receive a single administration of IPN60090 at the RD 
(morning dose only, as defined by the SRC at the end of the Part A dose escalation) 
30 minutes after the start of a moderate fat meal. The moderate fat meal should be 
eaten in 30 minutes or less. The patients should not consume any food for at least 
4 hours after the dose. IPN60090 should be taken with 240 mL (i.e. 8 fluid ounces) of 
water. Additional water is permitted ad libitum except for the period 1 hour before to 
1 hour after administration of the drug product. Substitutions to the test meal can be 
made after discussion with the sponsor. It is understood that some patients may not be 
able to consume the entire meal. Study staff should record the percent of the test meal 
breakfast and the time it takes to be consumed. 
Full PK profiles will be obtained on Day -7 and Day -3 to assess the effect of a moderate fat 
meal on the IPN60090 PK profile. Blood samples will be collected on Day -7 and Day -3 for 
the evaluation of haematology and serum chemistry, and AEs will be reported. 
In Part D, the moderate fat meal is defined as the following: total calories of 500 to 750 kCal 
including 30 to 35% fat (see Table 13). 
After the run-in period, patients will receive IPN60090 as a single agent administered orally 
BID (every 12 hours), during or after a meal, starting from Day 1 at the single agent RD. 
Patients in Part D will follow the same schedule of assessments as described for Part A (with 
the exception of the urine sampling for PK). 
Patients enrolled in monotherapy Part D may receive combination treatment with either 
pembrolizumab or with paclitaxel upon progression on IPN60090 monotherapy, at the 
discretion of the investigator, and with the approval of the sponsor, once the safe dose level 
for the combination is determined. These patients will need to satisfy the eligibility criteria for 
combination therapy prior to initiating treatment (see Section 4.1), and will be followed for 
safety and efficacy in a separate cohort. 
3.1.4 
Dose Expansion Cohorts 
The multicohort dose expansion part of the study will further explore the safety and 
tolerability of IPN60090 in monotherapy and in combination; assess the preliminary 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 63/264 
 
anti-tumour activity of IPN60090 as a single agent and in combination with pembrolizumab 
or paclitaxel at the RD in biomarker positive and/or unselected patient population and will 
explore the potential of selected biomarkers as predictors of efficacy (candidate biomarkers 
will include, but will not be limited to, KEAP1/NRF2 mutation status, ASNS expression level 
and known or new emerging predictive or prognostic markers of efficacy in selected tumour 
types). 
Enrolment into dose expansion cohorts will occur independently of each other. Each cohort 
will follow a sequential 2-stage design and enrol ten patients in Stage 1 and up to a total of 
18 patients (Stage 1 + Stage 2).  
The dose expansion cohorts that will be explored in each part of the study are defined as the 
following (which may be further expanded if an efficacy signal is observed): 
• 
Part A- IPN60090 monotherapy 
- 
Dose Expansion Cohort 1: KEAP1 or NRF2 mutant NSCLC  
- 
Dose Expansion Cohort 2: Other KEAP1 or NRF2 mutant tumours 
- 
Dose Expansion Cohort 3: ASNSlow HGSOC 
• 
Part B- IPN60090 + pembrolizumab: 
- 
Dose Expansion Cohort 4: KEAP1 or NRF2 mutant NSCLC  
- 
Dose Expansion Cohort 5: Other KEAP1 or NRF2 mutant tumours  
- 
Dose Expansion Cohort 6: KEAP1 or NRF2 wild-type tumours with any level of 
ASNS expression 
• 
Part C- IPN60090 + paclitaxel: 
- 
Dose Expansion Cohort 7: KEAP1 or NRF2 mutant tumours  
- 
Dose Expansion Cohort 8: ASNSlow HGSOC 
- 
Dose Expansion Cohort 9: KEAP1 or NRF2 wild-type tumours with any level of 
ASNS expression 
Dose expansion cohorts (study populations and sample size) may be revised in light of the 
dose escalation data and would then be described in a protocol amendment.  
An independent safety assessment committee (ISAC) structured to assess safety in addition to 
efficacy will be established for dose expansion cohorts in order to make recommendations 
regarding protocol modifications to reduce risks to patients enrolled in the study. If 
preliminary clinical evidence in one or several dose expansion cohorts suggests a substantial 
improvement over available therapies on a clinically significant endpoint(s), further efficacy 
expansion cohorts may be initiated in the corresponding populations with the goal of 
assessing the anti-tumour activity of IPN60090 monotherapy or combination. 
Patients enrolled in monotherapy Part A may receive combination treatment with either 
pembrolizumab or with paclitaxel upon progression on IPN60090 monotherapy, at the 
discretion of the investigator, and with the approval of the sponsor. These patients will need to 
satisfy the eligibility criteria for combination therapy prior to initiating treatment, and will be 
followed for safety and efficacy in a separate cohort. 
3.2 
Primary and Secondary Endpoints and Evaluations 
3.2.1 
Primary 
• 
The safety and tolerability of IPN60090 as a single agent (Part A and Part D) and in 
combination with pembrolizumab (Part B) or paclitaxel (Part C) will be assessed by the 
rate of DLTs at each dose level in the dose escalation, and the rate of AEs and the rate 
of Grade 3 and higher AEs in the dose escalation and dose expansion. Continuous 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 64/264 
 
monitoring of AEs and serious AEs (SAEs), clinical laboratory test results, the 
presence of anti-pembrolizumab antidrug antibodies (ADA; Part B only), vital signs 
measurements, ECG and physical examination results and concomitant medication 
usage will be performed. 
For dose escalation only: 
• 
Define MTD, if reached, as determined by the incidence and nature of DLTs, of: 
- 
single agent IPN60090 (Part A) 
- 
the combination of IPN60090 and pembrolizumab (Part B) or paclitaxel (Part C). 
• 
Define RD, as determined by the PD, PK and safety of: 
- 
single agent IPN60090 (Part A) 
- 
the combination of IPN60090 and pembrolizumab (Part B) or paclitaxel (Part C). 
3.2.2 
Secondary 
• 
Anti-tumour activity parameters assessed locally (for dose escalation) and centrally (for 
dose expansion) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 
for Parts A, C and D and immune-related RECIST (iRECIST) for Part B only, 
including:  
- 
Clinical benefit rate (CBR) is defined as the proportion of patients in whom the 
Best Overall Response (BOR) is equal to complete response (CR), PR or SD 
lasting at least 12 weeks for Parts A, C and D, and equal to immune CR (iCR), 
immune PR (iPR) or immune SD (iSD) lasting at least 12 weeks for Part B 
- 
ORR is defined as the proportion of patients in whom the BOR is equal to CR 
and PR for Parts A, C and D or iCR and iPR for Part B 
- 
DCR is defined as the proportion of patients in whom the BOR is equal to CR, 
PR or SD for Parts A, C and D, and equal to iCR, iPR or iSD for Part B 
- 
Progression free survival (PFS) is defined as the time from first dose of study 
medication to the first documented objective disease progression (for RECIST) 
or confirmed objective disease progression (for iRECIST) or death due to any 
cause, whichever occurs first (except for Part B where confirmation of 
progression is needed to determine the PFS to exclude pseudoprogression). 
- 
Overall survival (OS) is defined as the time from first dose of study medication 
to death due to any cause. 
• 
Pharmacokinetic parameters of IPN60090, including but not limited to Cmax, time to 
Cmax (Tmax), Ctrough, area under the plasma concentration-time curve (AUC), elimination 
half-life (t1/2), apparent total clearance from plasma (CL/F) and apparent volume of 
distribution (V/F) of IPN60090 (Parts A to D). 
• 
Describe the PK of a single dose of IPN60090 administered in fed state (Day -3) 
relative to fasted state (Day -7) using the following PK parameters: Cmax, AUC, Tmax, 
t1/2, CL/F and V/F (Part D). 
• 
Assessment of concentrations of the combined product (Parts B and C). 
• 
Assessment of potential ADA for pembrolizumab (Part B) 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 65/264 
 
• 
Pharmacodynamic parameters and biomarkers evaluation: 
- 
Target engagement: Glu:Gln ratio in PBMC 
- 
Tumour mutation status (for example KEAP1/NRF2, STK11, KRAS and other 
mutations) and correlation with clinical outcome 
- 
Tumour ASNS expression  
3.2.3 
Exploratory 
• 
Biomarkers of tumour biology evolution under treatment (e.g. immune profiling, 
PD-L1 expression, nuclear antigen Ki67 (Ki67), phosphorylation of histone variant 
H2AX (γH2AX), LKB1, etc) may be evaluated and correlated with clinical outcome. 
• 
Biobank samples will be collected for potential future analysis of biomarkers (optional, 
informed consent required) 
Exploratory IPN60090 concentrations in urine will be assessed only in Part A of dose 
escalation. The following PK parameters will be calculated: the amount of IPN60090 excreted 
in urine and renal clearance. 
3.2.4 
Safety Endpoints and Evaluations 
The safety and tolerability of IPN60090 will be assessed by the rate of DLTs at each dose 
level in the dose escalation, and the rate of AEs and the rate of Grade 3 and higher AEs in the 
dose escalation and dose expansion. Continuous monitoring of AEs and SAEs, clinical 
laboratory test results, the presence of anti-pembrolizumab ADA (Part B only), vital signs 
measurements, ECG and physical examination results, and concomitant medication usage will 
be performed. 
3.2.5 
Biobanking 
For patients participating in the optional research biobanking program, who consent to 
optional informed consent form (ICF) procedures, the samples listed below will be biobanked 
for potential future exploratory biomarkers evaluation: 
PBMC, plasma, serum, circulating free DNA (cfDNA), paxgene DNA, paxgene ribonucleic 
acid (RNA), stools and remaining material from tumour biopsies.  
Analysis of biobank samples will be performed outside the scope of the main study and 
reported separately. 
Instructions for collection, processing, handling and shipment of the biobanking samples will 
be outlined in the laboratory manual. 
3.3 
Randomisation and Blinding 
This is a nonrandomised, open-label study. 
3.4 
Maintenance of Randomisation and Blinding 
Not applicable. 
3.5 
Study Treatments and Dosage 
IPN60090 will be administered as oral capsules of either 10, 60 or 240 mg BID during or after 
a meal over 21 days (1 cycle). IPN600900 capsules will be taken every 12 hours 
corresponding to a BID regimen. Table 10 outlines the defined dose levels and the number of 
capsules in the dose escalation portion of the study. The RD for dose expansion, and number 
of capsules, will be determined at the completion of the dose escalation. 
Patients will be instructed to swallow IPN60090 capsules with a glass of water without biting, 
breaking or opening the capsules, or attempting to dissolve the content in water prior to taking 
them. For patients in Part B, on the days of infusion, patients should take the capsules before 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 66/264 
 
the start of the pembrolizumab infusion. For patients in Part C, on the days of infusion, when 
histamine 2 receptor (H2) blockers are administered for paclitaxel premedication, they must 
be administered at least 30 minutes prior to paclitaxel infusion. IPN60090 intake should be 
performed at least 2.5 hours before the start of the paclitaxel infusion and at least 2 hours 
prior to H2 blocker administration. 
Table 10 IPN60090 Dose Level and Corresponding Number of Capsules to be Administered 
DL 
DL1 
DL2 
DL3 
DL4 
DL5 
DL6 
DL7 
Dose 
20 mg BID 
40 mg BID 
80 mg BID 
180 mg 
BID[a] 
320 mg BID 480 mg BID 720 mg BID 
Number of 
capsules 
2×10 mg  
4×10 mg  
1×60 mg + 
2×10 mg  
3×60 mg  
1×240 mg + 
1×60 mg + 
2×10 mg  
2×240 mg  
3×240 mg  
BID=bis in die (twice daily); DL=dose level 
a 
180 mg BID was selected instead of 160 mg BID to reduce the number of capsules and therefore reduce the burden for 
patients. The dose of 160 mg BID would correspond to six capsules BID (2×60 mg+4×10 mg) whereas the dose of 
180 mg corresponds to three capsules BID (3×60 mg). 
In Part B, the dose of pembrolizumab will be fixed at 200 mg administered as an i.v. infusion 
over 30 minutes every 21 days (±1 day in Cycle 1 and ±3 days in all other cycles) (Day 1 of 
every cycle), consistent with the pembrolizumab prescribing information. Premedication with 
an antipyretic and antihistamine should be considered. The table below outlines the defined 
dose levels and the number of capsules in the dose escalation portion of the study. The RD for 
dose expansion, and number of capsules, will be determined at the completion of the dose 
escalation. 
Table 11 Pembrolizumab and IPN60090 Dose Level and Corresponding Number of Capsules to be 
Administered 
Dose level 
Dose level -1 
Dose level 1 
Dose level 2 
Dose level 3 
Planned dose of 
IPN60090 
80 mg BID 
180 mg BID 
320 mg BID 
480 mg BID 
Number of 
IPN60090 capsules 
1×60 mg + 2×10 mg 3×60 mg 
1×240 mg + 1×60 mg 
+ 2×10 mg 
2×240 mg 
Planned dose of 
pembrolizumab 
200 mg [a] i.v. Q3W 200 mg [a] i.v.Q3W 
200 mg [a] i.v.Q3W 
200 mg [a] i.v.Q3W 
BID=bis in die (twice daily); i.v.=intravenous; Q3W=every three weeks (21 days) 
a 
or according to the local approved label for particular tumour types 
In Part C, the dose of paclitaxel will be fixed at 175 or 135 mg/m² (or according to the local 
approved label for particular tumour types) administered as an i.v. infusion as per standard 
practice or at the approved RD per indication every 21 days (±1 day in Cycle 1 and ±3 days in 
all other cycles) (Day 1 of each cycle), consistent with the paclitaxel prescribing information. 
Premedication (e.g. dexamethasone, diphenhydramine, histamine H2 blockers) to prevent 
hypersensitivity reactions should be considered. H2 blockers may decrease absorption of the 
drugs given orally, such as IPN60090, therefore decreasing the exposure. When H2 blockers 
are administered for paclitaxel premedication, they must be administered at least 30 minutes 
prior to paclitaxel infusion. IPN60090 intake should be performed at least 2.5 hours before the 
start of the paclitaxel infusion and at least 2 hours prior to H2 blocker administration. 
Table 12 outlines the defined dose levels and the number of capsules in the dose escalation 
portion of the study. The RD for dose expansion, and number of capsules, will be determined 
at the completion of the dose escalation. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 67/264 
 
Table 12 Paclitaxel and IPN60090 Dose Level and Corresponding Number of Capsules to be 
Administered 
Dose level 
Dose level -1 
Dose level 1 
Dose level 2 
Dose level 3 
Planned dose of 
IPN60090 
80 mg BID 
180 mg BID 
320 mg BID 
480 mg BID 
Number of 
IPN60090 
capsules 
1×60 mg + 2×10 mg 
3 × 60 mg 
1×240 mg + 1×60 mg 
+ 2×10 mg 
2×240 mg 
Planned dose of 
paclitaxel 
175 or 135 mg/m2[a] 
i.v. 
175 or 135 mg/m2[a] 
i.v. 
175 or 135 mg/m2[a] 
i.v. 
175 or 135 mg/m2 [a] 
i.v. 
BID=bis in die (twice daily); i.v.=intravenous 
a 
or according to the local approved label for particular tumour types 
The proposed dose levels may be further modified and additional doses may be considered 
based on the safety, tolerability and efficacy observed during dose escalation. An 
intermediate, not predefined, previously evaluated or not previously evaluated dose or a less 
frequent dosing schedule that will not exceed the MTD level may be considered, if evaluation 
of toxicity at such a dose or schedule is desired. 
In Part D, single administration of IPN60090 at the RD (morning dose only), as defined by 
the SRC at the end of the Part A dose escalation, will be performed during the run-in period at 
Day -7 and Day -3. On Day -7, IPN60090 will be administered following an overnight fast of 
at least 10 hours. On Day -3, IPN60090 will be administered 30 minutes after the start of a 
moderate fat meal (see Table 13). The moderate fat meal should be eaten in 30 minutes or 
less. On both days, the patients should not consume any food for at least 4 hours after the 
dose. IPN60090 should be taken with 240 mL (i.e. 8 fluid ounces) of water. Additional water 
is permitted ad libitum except for the period 1 hour before to 1 hour after administration of the 
drug product. Substitutions to the test meal can be made after discussion with the sponsor. It 
is understood that some patients may not be able to consume the entire meal. Study staff 
should record the percent of the test meal breakfast eaten and the time it takes to be 
consumed.  
Table 13 Composition of the Moderate Fat Meal 
Type of meal 
Total calories (Kcal) Calories from fat 
(%) 
Calories from 
carbohydrates (%) 
Calories from proteins 
(%) 
Moderate fat 
500-750 
30-35 
≥55% 
≥12-14 
Then, starting from Day 1, patients will receive IPN60090 BID (at the RD as defined by the 
SRC at the end of Part A) during or after a meal over 21 days (one cycle) as described in 
Part A. 
Investigational Product 
The IPN60090 capsules will be manufactured, packaged and labelled by WuXi AppTec 
(Shanghai, China) and delivered to an interim storage facility. A sufficient quantity of IMP 
will be supplied with an acknowledgement of receipt form. 
The sponsor’s representative will receive a Certificate of Analysis for which batch of IMP has 
been used under their study, Material Data Safety Sheets for IMP and a Packaging Order that 
reflects the product release statement. 
The core label texts for all packaging units will be translated and/or adjusted, to be in 
compliance with applicable regulatory requirements (for example Good Manufacturing 
Practice guidelines (Volume 4 Annex 13)), national laws in force and in accordance with the 
local languages.  
The investigator or designee will only dispense IMPs to patients included in this study. Each 
patient will only be given the IMP carrying his/her number. An Interactive Response 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 68/264 
 
Technology (IRT) system will be used to track and allocate IMP to the patients. Dispensation 
will be documented in the electronic case report form (eCRF). 
The treatment kits will be allocated by IRT each time drug is dispensed, according to the 
cohort. The IRT will also manage all the logistical aspects of treatments (for example drug 
supplies and replacement of lost, damaged, quarantined, expiring and expired kits). 
This service provides investigators, site coordinators and project team members with a 
24-hour per day, 7-day per week service. In case of medical or technical dispensation queries, 
a 24-hour helpline is available. See supporting information in the IRT reference manual 
3.6 
Study Duration 
During dose escalation, for each patient the study duration will consist of an up to 28-day 
screening period (up to 21 days in Part D), followed by the DLT assessment period, which 
will consist of the first 21 days of treatment (one cycle). Patients will be offered IPN60090 
and combination treatment (as defined in Parts B and C) beyond Cycle 1 as long as they 
continue to experience clinical benefit, in the opinion of the investigator, until the earlier of 
disease progression, symptomatic deterioration, poor tolerability despite appropriate medical 
management or any of the other reasons for treatment discontinuation. Patients will then be 
followed up for safety and survival during follow-up visits as per the schedule of assessments 
(Table 14). Patients who experience a DLT (or other toxicities considered related, probably 
related or possibly related to the study treatment) will be permitted to continue to receive 
study treatment at a lower dose level than the dose at which the DLT was observed, at the 
discretion of the investigator (see Section 6.4.4), and will be followed for safety. 
During dose expansion, for each patient the study duration will consist of an up to 28-day 
screening period, followed by a treatment period of 21 days per cycle. Patients will be offered 
IPN60090 and combination treatment (as defined in Parts B and C) as long as they continue to 
experience clinical benefit, in the opinion of the investigator, until the earlier of unacceptable 
toxicity, symptomatic deterioration attributed to disease progression, or any of the other 
reasons for treatment discontinuation. Patients will then be followed up for safety and survival 
during follow-up visits as per the schedule of assessments (Table 14). 
Any patient in this study who continues to demonstrate objective clinical benefit at the end of 
a 2-year treatment duration may continue study treatment after agreement between the 
sponsor and treating investigator.  
All patients will then be followed post end of treatment at 30 days ±3 days (for Parts A, C and 
D) and 90±3 days (for Part B) for the end of treatment visit, at 180 days ±14 days for the 
safety follow-up visit and then every 3 months ±14 days for survival until the end of the 
study. 
The overall duration of the study will be approximately 3 years. The study will be considered 
to have started when the first patient has provided signed informed consent.  
The study will be considered to have ended after the last patient has completed the last 
follow-up period in the study. 
3.7 
Source Data Recorded on the Case Report Form 
Data will be collected in the eCRF in compliance with FDA 21 Code of Federal Regulations 
(CFR) Part 11. As required by GCP guidelines, the sponsor assigned monitor will verify, by 
direct reference to the source documents, that the data required by the protocol are accurately 
reported on the eCRF.  
The source documents must, at a minimum, contain a statement that the patient is included in 
a clinical study, the date that informed consent was obtained prior to participation in the 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 69/264 
 
study, the identity of the study, diagnosis and eligibility criteria, visit dates, IMP 
administration and any AEs and associated concomitant medication. 
As required by ICH-E6, if some items are recorded directly on the eCRF and are considered 
as source data, the identification of these data must be documented and agreed between the 
investigator and the sponsor. 
Definition for source data and source documents are given below: 
• 
Source data: All original records and certified copies of original records of clinical 
findings, observations, or other activities necessary for the reconstruction and 
evaluation of the study. Source data are contained in source documents (original 
records or certified copies). 
• 
Source documents: Original documents, data and records (for example hospital 
records, clinical and office charts, laboratory notes, memoranda, patients’ diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate 
copies, microfiches, photographic negatives, microfilm or magnetic media, X-rays, 
patient files and records kept at the pharmacy, at the laboratories and at 
medicotechnical departments involved in the clinical study). 
The patient must have consented to their medical records being viewed by the sponsor’s 
authorised personnel and by local and possibly foreign, Competent Authorities (CAs). This 
information is included in the informed consent. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 70/264 
 
4 
SELECTION AND WITHDRAWAL OF PATIENTS 
4.1 
Inclusion Criteria 
4.1.1 
General Inclusion Criteria for All Parts 
(1) 
Provision of written informed consent prior to any study related procedures. 
(2) 
Male or female patients ≥18 years of age at the time of study entry who agree to 
participate by giving written informed consent prior to participation in any 
study-related activities. 
(3) 
Histologically or cytologically confirmed advanced solid tumours including tumours 
known to harbour KEAP1 and/or NRF2 mutations or have low ASNS expression 
levels. 
- 
In dose escalations of all parts, patients may be KEAP1 and NRF2 wild-type or 
mutated and have tumours with any level of ASNS expression. For dose 
expansions, see specific inclusion criteria per part below. 
(4) 
Patients must have received at least one line of therapy for advanced stage disease and 
be refractory or ineligible to available existing therapy(ies) known to provide clinical 
benefit for their condition. 
(5) 
Prior 
treatment 
with 
chemotherapy, 
radiotherapy, 
immunotherapy 
or 
any 
investigational therapies must have been completed at least 3 weeks or at least 
five half-lives before the study drug administration, and all AEs (excluding alopecia 
and peripheral neuropathy) have either returned to baseline or stabilised.  
(6) 
Fresh and/or archival tumour tissue from the biopsy obtained between the completion 
of the most recent line of treatment until study entry must be available for mutation and 
biomarker analysis unless KEAP1/NRF2 mutations were present in any previous 
biopsy, in which case, no further biopsy is required. For ovarian cancer patients, both 
archival biopsies obtained between the completion of the most recent line of treatment 
until study entry and fresh biopsies must be available to evaluate the evolution of 
ASNS levels over time. Patients should not be put at undue risk to obtain fresh tumour 
biopsy. Procedures more invasive than core biopsy should not be used. Procedures to 
obtain biopsy should only be performed if the risk is minimal (no greater than 2% risk 
of serious or severe complications). If available, archival tumour tissue from time of 
initial diagnosis will be collected in addition to the most recent biopsy (archival and/or 
fresh). 
(7) 
Measurable or non-measurable evaluable disease as defined per the RECIST v1.1 (or 
iRECIST for Part B only). 
(8) 
Eastern Cooperative Oncology Group (ECOG) Performance Status ≤1. 
(9) 
Adequate organ function as indicated by the following laboratory values: 
(a) 
ANC ≥1500/mL 
(b) 
Platelets ≥100,000/mL 
(c) 
Haemoglobin ≥9 g/dL or ≥5.6 mmol/L  
(d) 
Serum creatinine ≤1.5×ULN and/or creatinine clearance >40 mL/min. Actual 
body weight should be used for calculating creatinine clearance using the 
Cockroft-Gault equation (except for patients with body mass index >30 kg/m2 
when the lean body weight should be used). 
(e) 
Serum total bilirubin ≤1.5×ULN (with the exception of patients with known 
Gilbert’s syndrome: serum total bilirubin must be <3×ULN in these patients). 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 71/264 
 
(f) 
AST (serum glutamic oxaloacetic transaminase) and ALT (serum glutamic 
pyruvic transaminase) ≤2.5×ULN or ≤5×ULN for patients with liver metastases) 
(10) Adequate cardiac function with a left ventricular ejection fraction (LVEF) ≥50% 
(11) Female patients are eligible to enter and participate in the study if they are of: 
(a) 
Non-childbearing potential (physiologically incapable of becoming pregnant), 
including any female who: 
- 
has had a hysterectomy, OR 
- 
has had a bilateral oophorectomy, OR  
- 
has had a bilateral salpingectomy, OR  
- 
is postmenopausal (total cessation of menses for ≥2 years, or 
follicle-stimulating hormone ≥50 IU/L) 
(b) 
Childbearing potential, but with a negative serum pregnancy test at screening 
(within 7 days of the first IMP administration), is not breastfeeding, and uses 
highly effective contraception at study entry and throughout the study until 
90 days after the last administration. Highly effective contraceptive methods 
include: 
- 
Combined 
(oestrogen 
and 
progestogen 
containing) 
hormonal 
contraception associated with inhibition of ovulation (for example oral, 
intravaginal, transdermal) 
- 
Progestogen-only hormonal contraception associated with inhibition of 
ovulation (for example oral, implantable, injectable) 
- 
Intrauterine device 
- 
Intrauterine hormone-releasing system 
- 
Bilateral tubal occlusion 
- 
Male partner has had a vasectomy 
(12) Male patients are eligible to enter and participate in the study if they agree to use 
effective methods of contraception during the study treatment period and for at least 
90 days after the last dose of investigational product. 
4.1.2 
Part A Specific Inclusion Criteria 
There are no further inclusion criteria associated with Part A. 
Dose Expansion ONLY:  
(A2) Patients with the following tumour types will be recruited: 
(a) 
NSCLC KEAP1 and/or NRF2 mutant  
(b) 
KEAP1 and/or NRF2 mutant other tumours 
(c) 
HGSOC ASNSlow  
Note: all biomarker mutations/expression levels must be confirmed prior to study treatment. 
4.1.3 
Part B Specific Inclusion Criteria 
(B1) Patients may have received previous treatment with any PD-1 or PD-L1 inhibitor. 
Dose Expansion ONLY:  
(B2) Patients may have received previous treatment with any anti-PD-1/PD-L1 mAb 
administered either as monotherapy, or in combination with other checkpoint inhibitors 
or other therapies. PD-1 treatment progression is defined by meeting all of the 
following criteria: 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 72/264 
 
(a) 
Has received at least 2 doses of an approved anti-PD-1/L1 mAb. 
(b) 
Has demonstrated disease progression after PD-1/L1 as defined by iRECIST 
v1.1. The initial evidence of disease progression is to be confirmed by a second 
assessment no less than four weeks from the date of the first documented disease 
progression, in the absence of rapid clinical progression. 
(B3) Patients with the following tumour types will be recruited during the dose expansion 
only: 
(a) 
NSCLC KEAP1 and/or NRF2 mutant  
(b) 
Other KEAP1 and/or NRF2 mutant tumours 
(c) 
KEAP1 and NRF2 wild-type tumours with any level of ASNS expression 
4.1.4 
Part C Specific Inclusion Criteria 
(C1) 
Patients may have received previous treatment with any platinum- or taxane-based 
chemotherapy.  
Dose Expansion ONLY:  
(C2) 
Patients with the following tumour types will be recruited during the dose expansion 
only: 
(a) 
KEAP1 or NRF2 mutant tumours 
(b) 
HGSOC ASNSlow tumours  
(c) 
KEAP1 or NRF2 wild-type tumours with any level of ASNS expression 
4.1.5 
Part D Specific Inclusion Criteria 
(D1) Patients must be able to consume a moderate fat meal.  
4.2 
Exclusion Criteria 
4.2.1 
General Exclusion Criteria for All Parts 
(1) 
Prior malignancy within the previous 2 years except for locally curable cancers that 
have been cured, such as basal or squamous cell skin cancer, or carcinoma in situ of the 
cervix, breast or bladder. 
(2) 
Known primary central malignancy or symptomatic central nervous system 
metastasis(es). 
Note: Patients with stable, previously treated brain metastases may participate if neurologic 
symptoms have resolved, patients have been off steroids for at least 7 days, and there is no 
evidence of disease progression by imaging for at least 2 weeks before the first dose of study 
treatment. 
(3) 
Patients should be excluded if they have a condition requiring systemic treatment with 
either corticosteroids (>10 mg daily prednisone equivalents) or other 
immunosuppressive medications within 2 weeks of the first dose of study drug. 
(4) 
Uncontrolled, significant intercurrent or recent illness including, but not limited to, the 
following cardiac conditions: 
(a) 
Any unstable cardiac arrhythmia within 6 months prior to enrolment 
(b) 
Prolongation of the Fridericia corrected QT (QTcF) interval defined as >450 ms 
for males and >470 ms for females 
(c) 
History of any of the following cardiovascular conditions within 6 months of 
enrolment: 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 73/264 
 
- 
cardiac angioplasty or stenting, myocardial infarction, unstable angina, 
coronary artery 
- 
bypass graft surgery, symptomatic peripheral vascular disease, class III or 
IV congestive heart failure, as defined by the New York Heart 
Association. 
(5) 
Major surgical intervention within 28 days before study drug administration. 
(6) 
Significant acute or chronic infections.  
(7) 
Any psychiatric condition that would prohibit the understanding or rendering of 
informed consent. 
(8) 
Treatment with strong cytochrome P450 (CYP450) subtype 3A4 (CYP3A4) inducers 
(including St John’s Wort) and inhibitors (including grapefruit juice) within 7 days of 
the first dose of study drug.  
(9) 
Treatment with strong CYP450 subtype 2D6 (CYP2D6) inhibitors within 7 days of the 
first dose of study drug. 
(10) Radiotherapy within 4 weeks prior to the start of study drug. Palliative radiotherapy for 
symptomatic control is acceptable if completed at least 2 weeks prior to study drug 
administration and no additional radiotherapy for the same lesion is planned. 
(11) Underlying medical conditions that, in the investigator’s opinion, will make the 
administration of study drug hazardous or obscure the interpretation of toxicity 
determination or AEs. 
(12) History of allergic reactions attributed to compounds of similar chemical or biological 
composition to any of the compounds in the study. 
(13) Known alcohol or drug abuse. 
(14) Legal incapacity or limited legal capacity. 
(15) Inability to swallow oral medications (capsules and tablets) without chewing, breaking, 
crushing, opening or otherwise altering the product formulation. Patients should not 
have gastrointestinal illnesses that would preclude the absorption of IPN60090, which 
is an oral agent. 
(16) Patients unwilling to comply with protocol requirements related to the assigned part. 
4.2.2 
Part A Specific Exclusion Criteria 
There are no further exclusion criteria associated with Part A 
4.2.3 
Part B Specific Exclusion Criteria 
(B1) Autoimmune disease that might deteriorate when receiving an immune-stimulatory 
agent, or immunodeficiencies.  
(B2) Known severe hypersensitivity reactions to monoclonal antibodies, any history of 
anaphylaxis, or uncontrolled asthma (that is, three or more features of partially 
controlled asthma). 
(B3) Prior organ transplantation, including allogeneic stem cell transplantation. 
(B4) Patient has received a live vaccine within 30 days prior to the first dose of study drug. 
Examples of live vaccines include, but are not limited to, the following: measles, 
mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–
Guérin and typhoid vaccine. Seasonal influenza vaccines for injection are generally 
killed virus vaccines and are allowed; however, intranasal influenza vaccines 
(e.g. FluMist®) are live attenuated vaccines and are not allowed. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 74/264 
 
4.2.4 
Part C Specific Exclusion Criteria 
(C1) Treatment with strong CYP450 subtype 2C8 (CYP2C8) inhibitors and inducers within 
the 7 days of the paclitaxel infusion. 
4.2.5 
Part D Specific Exclusion Criteria 
(D1) Treatment with drugs that can alter the absorption of IPN60090 by affecting 
gastrointestinal motility or by changing the gastric pH during the run-in period (Day -7 
to Day -3) of Part D.  
(D2) Patients suffering from conditions that are likely to adversely affect gastrointestinal 
motility and/or transit (for example, diarrhoea, vomiting or nausea, gastroparesis, 
irritable bowel syndrome and malabsorption) or patients with gastrointestinal resection 
(e.g. partial or total gastrectomy) likely to interfere with absorption of study treatment. 
Patients with Type 1 diabetes and hypercholesterolaemia are excluded. 
(D3) Patients unable to fast for up to 14 hours. 
4.3 
Stopping Rules, Discontinuation and Withdrawal Criteria and Procedures 
4.3.1 
Discontinuation of a Cohort 
The safety and preliminary anti-tumour activity profile of IPN60090 will be explored in the 
dose escalation portion of the study and will inform the decisions for the dose expansion.  
In the dose escalation, safety will be monitored on an ongoing basis by the SRC, which will 
be comprised of participating investigators and medical monitors of the sponsor. Cohort 
stopping rules are defined by the DLT criteria outlined in Section 3.1.2.1 for Part A, 
Section 3.1.2.2 for Part B, and Section 3.1.2.3 for Part C, and the DLT rate described in 
Section 11.2.1. 
The decision to halt enrolment at a specific dose level, or to discontinue a cohort may be 
made by the SRC at any point if a safety signal or unacceptable toxicity is observed.  
The dose escalations will be stopped once the MTD has been established. The SRC may also 
decide to stop the escalation before the MTD is reached if no safety signals (DLTs) are seen 
but consecutive escalating doses (covering a 2- and 3-fold dose range) showed significant PD 
effect (90% inhibition of Glu:Gln ratio in PBMCs in 66% of patients). 
Both the safety and anti-tumour activity of IPN60090 in patients in the dose expansion 
cohorts, as well as of patients from the dose escalation receiving additional cycles of 
IPN60090 treatment, will continue to be monitored by the SRC, and by the ISAC on an 
ongoing basis. The ISAC will meet 1 year after the start of the study or at the end of the dose 
escalation, whichever occurs first. The decision to halt enrolment or to discontinue a patient 
or a cohort may be made by the SRC and ISAC at any point if a safety signal or unacceptable 
toxicity is observed. The anti-tumour activity of IPN60090 will be assessed by the SRC and 
ISAC after Stage I of the sequential two-stage design, and if the study treatment does not 
demonstrate sufficient anti-tumour activity in any given cohort(s) as defined in Section 11.3.1 
(CBR at 12 weeks in at least one patient out of 10), then the cohort(s) will be discontinued. 
4.3.2 
Discontinuation of a Site or Study Termination 
A specific site or a given cohort can be discontinued or the entire study may be terminated at 
any time, if the sponsor judges it necessary for any reason. In such a case, all scheduled 
procedures and assessments for patients who are still in the study will be performed. Some 
possible reasons for the closure of a study site may include: 
• 
failure of the investigator staff to comply with the protocol or with the GCP guidelines; 
• 
safety concerns; 


,36(1*5283
'86

&21),'(17,$/
35272&2/),1$/9(56,21'(&(0%(5
3$*(


LQDGHTXDWHSDWLHQWUHFUXLWPHQW
,QWKHFDVHRISUHPDWXUHGLVFRQWLQXDWLRQRIDVLWHRUHDUO\WHUPLQDWLRQRIWKHVWXG\GHSHQGLQJ
RQ WKH UHDVRQV IRU WKH GLVFRQWLQXDWLRQ RU WHUPLQDWLRQ WKH VSRQVRU ZLOO QRWLI\ WKH
LQYHVWLJDWRUV DIIHFWHG LQ ZULWLQJ DV WR ZKHWKHU WKH RQJRLQJ SDWLHQWV VKRXOG FRQWLQXH WKH
UHPDLQLQJ,03GRVHDGPLQLVWUDWLRQV
4.3.3 
Individual Discontinuation Rules 
$ SDWLHQW PD\ GLVFRQWLQXH SDUWLFLSDWLRQ LQ WKH VWXG\ DW DQ\ WLPH IRU DQ\ UHDVRQ IRU
H[DPSOHODFNRIHIILFDF\ZLWKGUDZDORIFRQVHQW$(7KHLQYHVWLJDWRUDQGRUVSRQVRUFDQ
ZLWKGUDZDSDWLHQWIURPWKHVWXG\DWDQ\WLPHIRUDQ\UHDVRQIRUH[DPSOHSURWRFROYLRODWLRQ
RU GHYLDWLRQ DV GHILQHG LQ 6HFWLRQ QRQFRPSOLDQFH ZLWK WKH SURWRFRO FRQGLWLRQV RU
$(V$OOFDVHVRIGLVFRQWLQXDWLRQZLOOEHGLVFXVVHGEHWZHHQWKHLQYHVWLJDWRUDQGWKHVSRQVRU 
,IDVWRSSLQJUXOHLVPHWDWDQ\GRVHOHYHOWKHVDIHW\GDWDZLOOEHUHYLHZHGE\WKH65&DQGRQ
WKHEDVLVRIWKHHYDOXDWLRQRIWKHVDIHW\GDWDDUHFRPPHQGDWLRQZLOOEHPDGH'HWHUPLQLQJDQ
$(WREHDSRWHQWLDO'/7LVLQGHSHQGHQWRIWKHLQYHVWLJDWRU¶VFDXVDOLW\DVVHVVPHQWEXWWKH
HYHQWPXVWEHDWOHDVWSRVVLEO\UHODWHGWR,03DGPLQLVWUDWLRQLHDIWHU,03DGPLQLVWUDWLRQ
WKURXJKWKHIROORZXSYLVLWFOLQLFDOO\VLJQLILFDQWLQWKHRSLQLRQRIWKHLQYHVWLJDWRUDQGRIDW
OHDVWPRGHUDWHVHYHULW\,QDGGLWLRQDPHGLFDOO\SODXVLEOHDOWHUQDWLYHH[SODQDWLRQIRUWKH$(
VKRXOGQRWEHDSSDUHQW
(DFKSDWLHQWZLOOEHDOORZHGDPD[LPXPRIWZRGRVHUHGXFWLRQVIRU,31WRPDQDJH
VHYHUHDGYHUVHUHDFWLRQV
3DWLHQWVZKRH[SHULHQFHD'/7ZLOOEHDOORZHGWRFRQWLQXHWRUHFHLYHVWXG\WUHDWPHQWDWD
ORZHUGRVHOHYHODWWKHGLVFUHWLRQRIWKHLQYHVWLJDWRUDQGZLOOEHFORVHO\PRQLWRUHGIRUVDIHW\
7KH65&PD\FRQVLGHUDGGLWLRQDOVSDUVH3.VDPSOHVIRU'/7DVVHVVPHQW7KHFULWHULDIRU
'/7V DUH GHVFULEHG LQ 6HFWLRQ  IRU 3DUW $ 6HFWLRQ  IRU 3DUW% DQG
6HFWLRQIRU3DUW&
,IDSDWLHQWGHFLGHVWR ZLWKGUDZIURPWKHVWXG\DIWHUDGPLQLVWUDWLRQRI,03RUVKRXOGWKH
LQYHVWLJDWRUGHFLGHWRZLWKGUDZWKHSDWLHQWDOOHIIRUWVZLOOEHPDGHWRFRPSOHWHDQGUHSRUWWKH
REVHUYDWLRQV XS WR WKH WLPH RI ZLWKGUDZDO DV WKRURXJKO\ DV SRVVLEOH $ FRPSOHWH ILQDO
HYDOXDWLRQDWWKHWLPHRIWKHSDWLHQW¶VZLWKGUDZDOVKRXOGEHPDGHDQGDQH[SODQDWLRQJLYHQ
IRUZK\WKHSDWLHQWLVZLWKGUDZLQJRUEHLQJZLWKGUDZQIURPWKHVWXG\ 
7KHUHDVRQIRUDQGGDWHRIZLWKGUDZDOIURPWKHVWXG\PXVWEHUHFRUGHGRQWKHH&5),ID
SDWLHQWZLWKGUDZVFRQVHQWHYHU\DWWHPSWZLOOEHPDGHWRGHWHUPLQHWKHUHDVRQ,IWKHUHDVRQ
IRUZLWKGUDZDOLVDQ$(RUDFOLQLFDOO\VLJQLILFDQWODERUDWRU\WHVWDEQRUPDOLW\PRQLWRULQJZLOO
FRQWLQXHXQWLOWKHHYHQWKDVUHVROYHGRUVWDELOLVHGXQWLOWKHSDWLHQWLVUHIHUUHGWRWKHFDUHRID
ORFDOKHDOWKFDUHSURIHVVLRQDORUXQWLOGHWHUPLQDWLRQRIDFDXVHXQUHODWHGWRWKH,03RUVWXG\
SURFHGXUH LV PDGH 7KH VSHFLILF $( RU WHVW UHVXOWV PXVW EH UHFRUGHG RQ WKH H&5) $OO
HYDOXDWLRQV VKRXOG EH SHUIRUPHG DFFRUGLQJ WR WKH SURWRFRO RQ WKH ODVW GD\ WKH SDWLHQW
UHFHLYHV,03RUDVVRRQDVSRVVLEOHWKHUHDIWHU
3DWLHQWV SDUWLFLSDWLQJ LQ WKH RSWLRQDO UHVHDUFK ELREDQNLQJ SURJUDPPH KDYH WKH ULJKW WR
ZLWKGUDZWKHLUFRQVHQWDWDQ\WLPHDQGIRUDQ\UHDVRQGXULQJWKHVWXG\RUGXULQJWKHSHULRGRI
VDPSOHVWRUDJHLHWKHHQWLUH\HDUVGXULQJZKLFKVDPSOHVDUHNHSW,IDSDWLHQWZLVKHVWR
ZLWKGUDZWKHLUFRQVHQWIRUELREDQNLQJDQGWKHVDPSOHVDUHVWLOODWWKHLQYHVWLJDWRUVLWHRUDWWKH
FHQWUDOODERUDWRU\DWWKHWLPHWKHLQYHVWLJDWRUPXVWLQIRUPWKHVWXG\PRQLWRULQZULWLQJRIWKH
SDWLHQW¶V GHFLVLRQ DQG GHVWUR\ WKH VDPSOHV ,I WKH VDPSOHV DUH DW WKH VSRQVRU¶V FHQWUDO
ELRUHSRVLWRU\ WKH LQYHVWLJDWRU PXVW LQIRUP WKH VSRQVRU GLUHFWO\ XVLQJ WKH HPDLO DGGUHVV
PHQWLRQLQJRQO\WKHSDWLHQWLGHQWLILFDWLRQ,'LQWKLVHPDLO
7KHVSRQVRUZLOOHQVXUHGHVWUXFWLRQRIWKHVDPSOHVDQGDOOFRUUHVSRQGLQJDOLTXRWVDQGLVVXH
&&,


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 76/264 
 
confirmation of the destruction, which will be forwarded to the investigator. Analyses 
conducted before the withdrawal will not be affected. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 77/264 
 
5 
STUDY PROCEDURES 
5.1 
Study Schedule 
The schedule of procedures and assessments during the study is summarised in Table 14 
(Parts A to C) and Table 15 (Part D). 
 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 78/264 
 
Table 14 Study Procedures and Assessments (Parts A to C) 
Procedures and assessments 
Protocol section 
Screening 
Treatment 
Follow-up 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
All Cycles after 
Cycle 4 
EOS/EW Safety FU Survival 
FU 
D -28 to -1 
D1 
D2 D8 D14 
D15 
D1 
D8 D15 D1 
D8 D15 D1 
D8 D15 D1 D8 D15 
30 days 
(Parts A 
and C) or 
90 days 
(Part B) 
after last 
dose 
Up to 
180 days 
after last 
dose 
Every 
3 months 
after safety 
FU 
D1 
D2 D8 D14 
D15 
D22 D29 D36 D43 D50 D57 D64 D71 D78 Dx Dx Dx 
Visit window (days) 
 
N/A 
N/A 
±1 
±3 
±3 
±3 
±3 
±3 
±14 
±14 
Baseline documentation and physical examination 
Informed consent  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and disease history 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and height  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
 
X 
X[a] 
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Body weight  
 
X 
X[a] 
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Vital signs 
 
X 
X[a] 
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
ECOG performance status 
 
X 
X[a] 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Ophthalmological examination 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enrolment 
Inclusion/exclusion criteria  
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
End of phase disposition 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Safety/Laboratory assessments 
Haematology 
 
X 
X[a] 
X 
X 
X 
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Chemistry (including liver 
function tests) 
 
X 
X[a] 
X 
X 
X 
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
INR 
 
X 
X[a] 
 
 
 
 
 
 
 
Day 1 of every 3rd cycle starting with Day 1 (i.e. 
Day 1, Cycle 6 Day 1, etc.) 
X 
 
 
TSH (Part B only) 
 
X 
X[a] 
 
 
 
 
 
 
 
Day 1 of every 3rd cycle starting with Day 1 (i.e. 
Day 1, Cycle 6 Day 1, etc.) 
X 
 
 
Urinalysis 
 
X 
X[a] 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Serum pregnancy test  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
ECHO/MUGA 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Triplicate ECG (12-lead)  
 
X 
X[b] 
 
 
 
 
X [b] 
[c] 
 
 
X[c] 
 
 
X[c] 
 
 
As clinically 
indicated 
X 
 
 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 79/264 
 
Procedures and assessments 
Protocol section 
Screening 
Treatment 
Follow-up 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
All Cycles after 
Cycle 4 
EOS/EW Safety FU Survival 
FU 
D -28 to -1 
D1 
D2 D8 D14 
D15 
D1 
D8 D15 D1 
D8 D15 D1 
D8 D15 D1 D8 D15 
30 days 
(Parts A 
and C) or 
90 days 
(Part B) 
after last 
dose 
Up to 
180 days 
after last 
dose 
Every 
3 months 
after safety 
FU 
D1 
D2 D8 D14 
D15 
D22 D29 D36 D43 D50 D57 D64 D71 D78 Dx Dx Dx 
Visit window (days) 
 
N/A 
N/A 
±1 
±3 
±3 
±3 
±3 
±3 
±14 
±14 
PK/Biomarkers 
Blood sampling for PK of 
IPN60090 
 
 
X[d] 
X[c] 
 
X[d] 
X[e] 
X[f] 
 
 
X[f] 
 
 
X[f] 
 
 
X[f] 
 
 
X 
 
 
Blood sampling for PK of 
combined drug: pembrolizumab 
(Part B only) 
 
 
X[c] 
 
 
 
 
X[c] 
 
 
X[c] 
 
 
X[c] 
 
 
X[c] 
 
 
 
 
 
Blood sampling for PK of 
combined drug: paclitaxel 
(Part C only) 
 
 
X[g] 
 
 
 
 
X[g] 
 
 
X[g] 
 
 
 
 
 
 
 
 
 
 
 
Urine sampling for PK (Part A 
dose escalation only) 
 
 
X[h] 
 
 
X[h] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood/PBMC samples for PD 
biomarker[i] 
 
 
X[j] 
 
 
X[j] 
X[e] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Ca-125 
 
 
X[k] 
 
 
 
 
 
 
 
X[k] 
 
 
 
 
 
X[k] 
 
 
 
 
 
cfDNA 
 
X[c] 
 
 
 
 
X[c] 
 
 
 
X[c] 
 
 
 
 
 
X[c] 
[l] 
 
 
X 
 
 
Fresh tumour biopsy[m] 
 
X[n][o] 
 
 
 
 
X[n][p] 
 
 
 
 
 
 
 
 
 
 
 
 
X[n][q] 
 
 
Archival tumour biopsies[r] 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ADA samples for 
pembrolizumab (binding and 
neutralising) (Part B only) 
 
X 
 
 
 
 
 
 
 
 
X[c] 
 
 
 
 
 
X[c] 
 
 
X 
 
 
Biobanking (optional) 
Biobanking serum[s]  
 
 
X[t] 
 
 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Biobanking PBMC[s] 
 
 
Remaining and not used PBMC for PD biomarker should be biobanked 
 
 
Biobanking plasma[s]  
 
 
X[t] 
 
 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Biobanking paxgene RNA[s]  
 
 
X[t] 
 
 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Biobanking paxgene DNA[s] 
 
 
X[c] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biobanking stools[s]  
 
 
X[c] 
 
 
 
X[c] 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 80/264 
 
Procedures and assessments 
Protocol section 
Screening 
Treatment 
Follow-up 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
All Cycles after 
Cycle 4 
EOS/EW Safety FU Survival 
FU 
D -28 to -1 
D1 
D2 D8 D14 
D15 
D1 
D8 D15 D1 
D8 D15 D1 
D8 D15 D1 D8 D15 
30 days 
(Parts A 
and C) or 
90 days 
(Part B) 
after last 
dose 
Up to 
180 days 
after last 
dose 
Every 
3 months 
after safety 
FU 
D1 
D2 D8 D14 
D15 
D22 D29 D36 D43 D50 D57 D64 D71 D78 Dx Dx Dx 
Visit window (days) 
 
N/A 
N/A 
±1 
±3 
±3 
±3 
±3 
±3 
±14 
±14 
Biobanking cfDNA[s]  
 
 
X[c] 
 
 
 
X[c] Blood collection for cfDNA should occur at the same time as efficacy 
assessments. 
Every 6 weeks from Cycle 1 Day 1[c]. 
X[c] 
 
 
Biobanking leftover tissue 
material and additional biopsies 
obtained from fresh frozen 
biopsies[s] 
 
Remaining biopsies from biomarkers collection should be biobanked along with any additional tumour material collected at these 
visits (archival and/or fresh). 
 
 
Tumour assessments 
CT/MRI chest, abdomen, pelvis, 
or other (if clinically indicated) 
 
X 
Images required every 6 weeks (±1 week) from Cycle 1 Day 1 for the first 24 weeks of treatment, and 
every 12 weeks (±2 weeks) thereafter. 
To ensure image consistency, the same imaging modalities and acquisition protocols used at screening are 
to be used for subsequent tumour assessments. 
X 
X 
 
CT/MRI brain 
 
 
Required in patients with documented, treated brain metastasis. As clinically indicated for patients with 
suspected brain metastasis.  
Images required every 6 weeks (±1 week) from Cycle 1 Day 1 for the first 24 weeks of treatment, and 
every 12 weeks (±2 weeks) thereafter. 
To ensure image consistency, the same imaging modalities and acquisition protocols used at screening are 
to be used for subsequent tumour assessments. 
X (if 
applicable) 
X 
 
Other clinical assessments 
Adverse events 
 
 
Document new or worsening AEs from informed consent through 30 days after the date of the decision to permanently 
discontinue study treatment. AE information will be collected at study visits and may also be collected at any time over 
the phone or by spontaneous patient report. Certain AEs and all SAEs that are ongoing 30 days after of the date of the 
decision to permanently discontinue study treatment are to be followed until resolution or determination by the 
investigator that the event is stable or irreversible. 
 
Prior and concomitant 
medication/procedures/non-drug 
therapies  
 
 
Document prior and concomitant medication taken from 28 days before first dose of study treatment 
through 30 days after the date of the decision to discontinue study treatment. 
 
 
 
Further anti-tumour treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
IPN60090 
 
 
Daily BID starting on Cycle 1 Day 1. Dose will be determined by phase and cohort. 
 
 
 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 81/264 
 
Procedures and assessments 
Protocol section 
Screening 
Treatment 
Follow-up 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
All Cycles after 
Cycle 4 
EOS/EW Safety FU Survival 
FU 
D -28 to -1 
D1 
D2 D8 D14 
D15 
D1 
D8 D15 D1 
D8 D15 D1 
D8 D15 D1 D8 D15 
30 days 
(Parts A 
and C) or 
90 days 
(Part B) 
after last 
dose 
Up to 
180 days 
after last 
dose 
Every 
3 months 
after safety 
FU 
D1 
D2 D8 D14 
D15 
D22 D29 D36 D43 D50 D57 D64 D71 D78 Dx Dx Dx 
Visit window (days) 
 
N/A 
N/A 
±1 
±3 
±3 
±3 
±3 
±3 
±14 
±14 
Pembrolizumab 
 
 
200 mg (or per approved label) every 21 days (Day 1 of every cycle) as i.v. infusion. 
 
 
 
Paclitaxel 
 
 
175 mg/m2 or 135 mg/m2 (or per approved label) every 21 days (Day 1 of every cycle) i.v. infusion. 
 
 
 
ADA=antidrug antibodies; AE=adverse event; BID=bis in die (twice daily); cfDNA=circulating free DNA; CT=computed tomography; D=day; DNA=deoxyribonucleic acid; 
ECG=electrocardiogram; ECHO=echocardiogram; ECOG=Eastern Cooperative Oncology Group; EOS=end of study; EW=early withdrawal; FU=follow-up; HGSOC=high-grade serous ovarian 
cancer; INR=international normalised ratio; i.v.=intravenous; MRI=magnetic resonance imaging; MUGA=multigated acquisition; N/A=not applicable; PBMC=peripheral blood mononuclear 
cells; PD=pharmacodynamics; PK=pharmacokinetics; RNA=ribonucleic acid; SAE=serious adverse event; TSH=thyroid stimulating hormone 
a 
assessment does not need to be repeated if done within 3 days of first dose. 
b 
30 minutes (±15 minutes), 1 hour (±15 minutes), 2 hours (±15 minutes), 4 hours (±15 minutes), 8 hours (±15 minutes) and 12 hours (±15 minutes) postdose. 
c 
predose. 
d 
predose, 30 minutes (±5 minutes), 1 hour (±5 minutes), 2 hours (±5 minutes), 4 hours (±10 minutes), 8 hours (±30 minutes) and 12 hours (±1 hour) postdose. 
e 
predose, and between 2 to 4 hours postdose. 
f 
predose, 2 hours (±5 minutes) postdose. 
g 
two time points: immediately before paclitaxel infusion and at the end of the paclitaxel infusion i.e. 3 hours after the start of the infusion. 
h 0-12 h urine time collection interval (only performed for Part A Dose Escalation). 
i 
see Table 34 for more details on collection timepoints and volumes. 
j 
predose, 2 and 12 hours postdose. 
k 
serum Ca-125 assessments will be performed at baseline, on Day 1 of Cycle 3 and then on Day 1 of every other cycle. This assessment will be performed in patients with HGSOC only. 
l 
cfDNA sample on Day 1 of every other cycle after Cycle 3. 
m remaining tumour materials should be biobanked. 
n 
cfDNA should be collected at the same day of biopsy, if feasible. 
o fresh tumour must be available for mutation and biomarker analysis unless KEAP1/NRF2 mutations were present in any previous biopsy, in which case, no further biopsy is required. For 
ovarian cancer patients, fresh biopsies must be collected in addition to the archival biopsies. Procedures to obtain biopsy should only be performed if the risk is minimal (no greater than 2% 
risk of serious or severe complications). 
p 
performed 2 to 4 hours postdose. 
q 
the EOS fresh biopsy is optional. 
r 
archival biopsies collected after the completion of the last line of treatment until study entry and archival biopsies from initial diagnosis if available. 
s 
biobanking samples will only be collected for patients who have signed the optional biobanking informed consent form. 
t 
predose and 12 hours postdose. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 82/264 
 
Table 15 Study Procedures and Assessments (Part D) 
Procedures and assessments 
Protocol section 
Screening 
Run-in 
Treatment 
Follow-up 
 
 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
All cycles after 
Cycle 4 
 
 
 
D -28 to 
D -8 
D -7 D -3 D1 
D2 
D8 D14 D15 D1 
D8 D15 D1 
D8 D15 D1 
D8 D15 D1 
D8 D15 EOS/EW Safety 
FU 
Survival 
FU 
 
D1 
D2 
D8 D14 D15 D22 D29 D36 D43 D50 D57 D64 D71 D78 Dx 
Dx 
Dx 
30 days 
after last 
dose 
Up to 
180 days
after 
last dose 
Every 
3 months 
after 
safety 
FU 
Visit windows (days) 
 
N/A 
N/A N/A 
N/A 
±1 
±3 
±3 
±3 
±3 
±3 
±14 
±14 
Baseline documentation and physical examination 
Informed consent  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and disease history 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and height  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
 
X 
 
 
X[a]  
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Body weight  
 
X 
 
 
X[a]  
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Vital signs 
 
X 
 
 
X[a] 
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
ECOG performance status 
 
X 
 
 
X[a] 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Ophthalmological examination 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enrolment 
Inclusion/exclusion criteria  
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
End of phase disposition 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Safety/Laboratory assessments 
Haematology 
 
X 
X 
X 
X[a] 
X 
X 
X 
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Chemistry (including liver 
function tests) 
 
X 
X 
X 
X[a] 
X 
X 
X 
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
INR 
 
X 
 
 
X[a] 
 
 
 
 
 
 
 
Day 1 of every 3rd cycle starting with Day 1 (i.e. Day 
1, Cycle 6 Day 1, etc.) 
X 
 
 
Urinalysis 
 
X 
 
 
X[a] 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Serum pregnancy test  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
ECHO/MUGA 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Triplicate ECG (12-lead)  
 
X 
X[b] X[b] X[c] 
 
 
 
 
 
X[c] 
[d] 
 
 
X[d] 
 
 
X[d] 
 
 
As clinically 
indicated 
X 
 
 
PK/Biomarkers 
Blood sampling for PK of 
IPN60090 
 
 
X[e] X[e] X[f] X[d] 
 
X[f] X[g]  X[h] 
 
 
X[h] 
 
 
X[h]  
 
 
X[h] 
 
 
X 
 
 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 83/264 
 
Procedures and assessments 
Protocol section 
Screening 
Run-in 
Treatment 
Follow-up 
 
 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
All cycles after 
Cycle 4 
 
 
 
D -28 to 
D -8 
D -7 D -3 D1 
D2 
D8 D14 D15 D1 
D8 D15 D1 
D8 D15 D1 
D8 D15 D1 
D8 D15 EOS/EW Safety 
FU 
Survival 
FU 
 
D1 
D2 
D8 D14 D15 D22 D29 D36 D43 D50 D57 D64 D71 D78 Dx 
Dx 
Dx 
30 days 
after last 
dose 
Up to 
180 days
after 
last dose 
Every 
3 months 
after 
safety 
FU 
Visit windows (days) 
 
N/A 
N/A N/A 
N/A 
±1 
±3 
±3 
±3 
±3 
±3 
±14 
±14 
Blood/PBMC samples for PD 
biomarker[i] 
 
 
 
 
X[j] 
 
 
X[j]  X[g] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Ca-125 
 
 
 
 
X[k] 
 
 
 
 
 
 
 
X[k]  
 
 
 
 
 
X[k] 
 
 
 
 
 
cfDNA 
 
X[d] 
 
 
 
 
 
 
X[d] 
 
 
 
X[d] 
 
 
 
 
 
X[d] 
[l] 
 
 
X 
 
 
Fresh tumour biopsy[m] 
 
X[n][o]  
 
 
 
 
 
 
X[n] 
[p] 
 
 
 
 
 
 
 
 
 
 
 
 
X[n][q]  
 
 
Archival tumour biopsies[r] 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biobanking (optional) 
Biobanking serum[s] 
 
 
 
 
X[t] 
 
 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Biobanking PBMC[s] 
 
 
 
 
Remaining and not used PBMC for PD biomarker should be biobanked 
 
 
Biobanking plasma[s] 
 
 
 
 
X[t] 
 
 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Biobanking paxgene RNA[s] 
 
 
 
 
X[t]  
 
 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Biobanking paxgene DNA[s] 
 
 
 
 
X[d] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biobanking stools[s] 
 
 
 
 
X[d] 
 
 
 
X[d] 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Biobanking cfDNA[s] 
 
 
 
 
X[d] 
 
 
 
X[d]  Blood collection for cfDNA should occur at the same time as efficacy 
assessments.  
Every 6 weeks from Cycle 1 Day 1[d]. 
X[d] 
 
 
Biobanking leftover material 
and additional biopsies obtained 
from fresh frozen biopsies[s] 
 
Remaining biopsies from biomarkers collection should be biobanked along with any additional tumour material collected at these visits 
(archival and/or fresh) 
 
 
Tumour assessments 
CT/MRI chest, abdomen, pelvis, 
or other (if clinically indicated) 
 
X 
 
 
Images required every 6 weeks (±1 week) from Cycle 1 Day 1 for the first 24 weeks of treatment, and 
every 12 weeks (±2 weeks) thereafter. 
To ensure image consistency, the same imaging modalities and acquisition protocols used at screening 
are to be used for subsequent tumour assessments. 
X 
X 
 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 84/264 
 
Procedures and assessments 
Protocol section 
Screening 
Run-in 
Treatment 
Follow-up 
 
 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
All cycles after 
Cycle 4 
 
 
 
D -28 to 
D -8 
D -7 D -3 D1 
D2 
D8 D14 D15 D1 
D8 D15 D1 
D8 D15 D1 
D8 D15 D1 
D8 D15 EOS/EW Safety 
FU 
Survival 
FU 
 
D1 
D2 
D8 D14 D15 D22 D29 D36 D43 D50 D57 D64 D71 D78 Dx 
Dx 
Dx 
30 days 
after last 
dose 
Up to 
180 days
after 
last dose 
Every 
3 months 
after 
safety 
FU 
Visit windows (days) 
 
N/A 
N/A N/A 
N/A 
±1 
±3 
±3 
±3 
±3 
±3 
±14 
±14 
CT/MRI brain 
 
 
 
 
Required in patients with documented, treated brain metastasis. As clinically indicated for patients 
with suspected brain metastasis.  
Images required every 6 weeks (±1 week) from Cycle 1 Day 1 for the first 24 weeks of treatment, and 
every 12 weeks (±2 weeks) thereafter. 
To ensure image consistency, the same imaging modalities and acquisition protocols used at screening 
are to be used for subsequent tumour assessments. 
X (if 
applicable) 
X 
 
Other clinical assessments 
Adverse events 
 
 
Document new or worsening AEs from informed consent through 30 days after the date of the decision to permanently 
discontinue study treatment. AE information will be collected at study visits and may also be collected at any time over the 
phone or by spontaneous patient report. Certain AEs and all SAEs that are ongoing 30 days after of the date of the decision to 
permanently discontinue study treatment are to be followed until resolution or determination by the investigator that the event 
is stable or irreversible. 
 
 
Prior and concomitant 
medication/procedures/non-drug 
therapies  
 
 
 
 
Document prior and concomitant medication taken from 28 days before first dose of study treatment 
through 30 days after the date of the decision to discontinue study treatment. 
 
 
 
Further anti-tumour treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
IPN60090 
 
 
X[u] X[u] Daily BID starting on Cycle 1 Day 1. Dose will be at the RD (as defined by the SRC at the end of the 
Part A dose escalation) 
 
 
 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 85/264 
 
Procedures and assessments 
Protocol section 
Screening 
Run-in 
Treatment 
Follow-up 
 
 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
All cycles after 
Cycle 4 
 
 
 
D -28 to 
D -8 
D -7 D -3 D1 
D2 
D8 D14 D15 D1 
D8 D15 D1 
D8 D15 D1 
D8 D15 D1 
D8 D15 EOS/EW Safety 
FU 
Survival 
FU 
 
D1 
D2 
D8 D14 D15 D22 D29 D36 D43 D50 D57 D64 D71 D78 Dx 
Dx 
Dx 
30 days 
after last 
dose 
Up to 
180 days
after 
last dose 
Every 
3 months 
after 
safety 
FU 
Visit windows (days) 
 
N/A 
N/A N/A 
N/A 
±1 
±3 
±3 
±3 
±3 
±3 
±14 
±14 
Pembrolizumab 
 
 
 
 
200 mg (or per approved label) every 21 days (Day 1 of every cycle) as i.v. infusion. 
 
 
 
Paclitaxel 
 
 
 
 
175 mg/m2 or 135 mg/m2 (or per approved label) every 21 days (Day 1 of every cycle) i.v. infusion. 
 
 
 
AE=adverse event; BID=bis in die (twice daily); cfDNA=circulating free DNA; CT=computed tomography; D=day; DNA=deoxyribonucleic acid; ECG=electrocardiogram; 
ECHO=echocardiogram; ECOG=Eastern Cooperative Oncology Group; EOS=end of study; EW=early withdrawal; FU=follow-up; HGSOC=high-grade serous ovarian cancer; INR=international 
normalised ratio; i.v.=intravenous; MRI=magnetic resonance imaging; MUGA=multigated acquisition; N/A=not applicable; PBMC=peripheral blood mononuclear cells; PD=pharmacodynamics; 
PK=pharmacokinetics; RNA=ribonucleic acid; SAE=serious adverse event 
a 
assessment does not need to be repeated if done within 3 days of first dose. 
b 
1 hour (±15 minutes), 2 hours (±15 minutes) and 4 hours (±15 minutes) postdose. 
c 
30 minutes (±15 minutes), 1 hour (±15 minutes), 2 hours (±15 minutes), 4 hours (±15 minutes), 8 hours (±15 minutes) and 12 hours (±15 minutes) postdose. 
d 
predose. 
e 
predose, 30 minutes (±5 minutes), 1 hour (±5 minutes), 2 hours (±5 minutes), 4 hours (±10 minutes), 8 hours (±30 minutes), 12 hours (±1 hour), 24 hours (±2 hours), 48 hours (±2 hours) and 
72 hours (±2 hours) postdose. 
f 
predose, 30 minutes (±5 minutes), 1 hour (±5 minutes), 2 hours (±5 minutes), 4 hours (±10 minutes), 8 hours (±30 minutes) and 12 hours (±1 hour) postdose. 
g 
predose, and between 2 to 4 hours postdose. 
h 
predose, 2 hours (±5 minutes) postdose. 
i 
see Table 34 for more details on collection timepoints and volumes. 
j 
predose, 2 and 12 hours postdose. 
k 
serum Ca-125 assessments will be performed at baseline, on Day 1 of Cycle 3 and then on Day 1 of every other cycle. This assessment will be performed in patients with HGSOC only. 
l 
cfDNA sample on Day 1 of every other cycle after Cycle 3. 
m remaining tumour materials should be biobanked. 
n 
cfDNA should be collected at the same day of biopsy, if feasible. 
o 
fresh tumour must be available for mutation and biomarker analysis unless KEAP1/NRF2 mutations were present in any previous biopsy, in which case, no further biopsy is required. For 
ovarian cancer patients, fresh biopsies must be collected in addition to the archival biopsies. Procedures to obtain biopsy should only be performed if the risk is minimal (no greater than 2% 
risk of serious or severe complications). 
p 
performed 2 to 4 hours postdose. 
q 
the EOS fresh biopsy is optional. 
r 
archival biopsies collected after the completion of the last line of treatment until study entry and archival biopsies from initial diagnosis if available. 
s 
biobanking samples will only be collected for patients who have signed the optional biobanking informed consent form. 
t 
predose and 12 hours postdose. 
u 
morning dose only. 
 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 86/264 
 
5.2 
Study Visits 
The schedule of visits and main procedures at each visit are summarised in Table 14 (Parts A 
to C) and Table 15 (Part D). 
5.2.1 
Procedures for Screening and Enrolment 
A signed and dated ICF will be obtained from each patient before any screening procedures 
are conducted. Evaluations obtained as part of routine medical care and performed during the 
screening period may be used in place of the study specific evaluations as long as they are 
consistent with the protocol requirements. Patients will acknowledge and agree to the possible 
use of this information for the study by giving informed consent. Computed tomography 
(CT)/magnetic resonance imaging (MRI) scans performed within 28 days prior the start of 
study treatment are acceptable. Otherwise they are to be repeated. 
Patients will be offered to participate in an optional research biobanking programme. Patients 
who agree to participate will be requested to sign a separate ICF. 
After informed consent is obtained, patients who are screened will be allocated a patient 
number. All screened patients must be identifiable throughout the study. The investigator will 
maintain a list of patient numbers and names to enable records to be found at a later date, if 
required. 
Patients may be re-screened once. The reason for prior screening failure will be recorded in 
the eCRF. 
Following confirmation of eligibility for the study, patients will be allocated to one of the 
dosing groups specified in Section 6.1. 
Each investigator will also maintain a record of all patients screened in the study (i.e. who 
signed the ICF). In the event that the patient was not receiving IMP, the primary reason will 
be recorded in the eCRF. 
5.3 
Laboratory Assessments 
Blood samples will be tested locally for safety clinical laboratory evaluations. During dose 
expansion, blood samples will also be tested centrally.  
The total volume of blood collected for all evaluations throughout this study varies depending 
on the study part, and will reach a maximum of approximately 278.0 mL per month for any 
one patient (in Part D) (Table 16 and Table 17). An additional 60.5 mL of blood will be 
collected from patients who have signed the optional biobanking ICF. 
Therefore, the maximum total blood volume collected per month from any one patient will 
not reach more than 338.5 mL per patient over the study duration. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 87/264 
 
Table 16 Total Blood Volume for All Evaluations (Parts A to C) 
Assessments 
Volume per sample  
(mL) 
Max number of 
samples/month 
Total max 
volume/month (mL) 
Laboratory assessments 
Haematology 
2 
6 
12 
Chemistry (including liver function tests) 
5 
6 
30 
INR 
2 
2 
4 
TSH (Part B only) 
2 
2 
4 
Serum pregnancy test 
2 
1 
2 
PK and Biomarkers 
Blood sampling for PK of IPN60090 
2 
17 
34 
Blood sampling for PK of paclitaxel (Part C 
only) 
2 
2 
4 
Blood sampling for PK of pembrolizumab 
(Part B only) 
2 
1 
2 
Blood sampling for ADA against 
pembrolizumab (Part B only) 
6 
1 
6 
Blood sampling for Ca-125 (HGSOC only) 
2 
2 
4 
Blood/PBMC samples 
6 
18 
108 
cfDNA 
10 
3 
30 
Total volume Part A 
 
 
224 
Total volume Part B 
 
 
236 
Total volume Part C 
 
 
228 
Biobanking (optional) 
Biobanking serum 
2.5 
4 
10 
Biobanking plasma 
2 
4 
8 
Biobanking paxgene RNA 
2.5 
4 
10 
Biobanking paxgene DNA 
2.5 
1 
2.5 
Biobanking cfDNA 
10 
3 
30 
Total biobanking 
 
 
60.5 
Maximum Total 
 
 
296.5 
ADA=antidrug antibody; cfDNA=circulating free deoxyribonucleic acid; DNA=deoxyribonucleic acid; HGSOC=high-grade 
serous ovarian cancer; INR=international normalised ratio; max=maximum; PBMC=peripheral blood mononuclear cells; 
PK=pharmacokinetic; RNA=ribonucleic acid; TSH=thyroid stimulating hormone 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 88/264 
 
Table 17 Total Blood Volume for All Evaluations (Part D) 
Assessments 
Volume per sample  
(mL) 
Max number of 
samples/month 
Total max 
volume/month (mL) 
Laboratory assessments 
Haematology 
2 
8 
16 
Chemistry (including liver function tests) 
5 
8 
40 
INR 
2 
2 
4 
Serum pregnancy test 
2 
1 
2 
PK and Biomarkers 
Blood sampling for PK of IPN60090 
2 
37 
74 
Blood sampling for Ca-125 (HGSOC only) 
2 
2 
4 
Blood/PBMC samples 
6 
18 
108 
cfDNA 
10 
3 
30 
Total volume Part D 
 
 
278 
Biobanking (optional) 
Biobanking serum 
2.5 
4 
10 
Biobanking plasma 
2 
4 
8 
Biobanking paxgene RNA 
2.5 
4 
10 
Biobanking paxgene DNA 
2.5 
1 
2.5 
Biobanking cfDNA 
10 
3 
30 
Total biobanking 
 
 
60.5 
Maximum Total 
 
 
338.5 
cfDNA=circulating free deoxyribonucleic acid; DNA=deoxyribonucleic acid; HGSOC=high-grade serous ovarian cancer; 
INR=international normalised ratio; max=maximum; PBMC=peripheral blood mononuclear cells; PK=pharmacokinetic; 
RNA=ribonucleic acid 
Technical instructions will be provided in a separate laboratory manual. During dose 
escalation (Parts A to C) and during Part D, all samples will be analysed locally, except PK 
samples for pembrolizumab and paclitaxel analyses and anti-pembrolizumab ADA samples. 
During the dose expansion, all samples will be sent for central analysis (with the exception of 
laboratory safety tests for clinical decision making, which will be analysed locally). 
5.4 
Disease Evaluation 
Tumour assessments will be performed at screening and every 6 weeks (±1 week) from 
Cycle 1, Day 1 using the RECIST v1.1 or iRECIST (Part B only). 
Tumour evaluations will be assessed locally during the dose escalation and centrally during 
the dose expansion phase. Additionally, during the dose expansion part of the study, safety 
and supportive efficacy data will be reviewed and evaluated by an Independent Radiology 
Review Committee and ISAC to ensure that the continuation of the study is appropriate and to 
make recommendations to the sponsor. A specific scope of work and procedures will be 
described in an ISAC Charter and ISAC statistical analysis plan (SAP), to be established prior 
to the start of recruitment of the dose expansion phase.  
The tumour assessments at screening are: 
• 
CT/MRI (chest/abdomen and pelvis if indicated), 
• 
brain MRI if clinically indicated. 
Baseline tumour assessments performed per SoC within 28 days of enrolment are acceptable 
as long they are consistent with protocol requirements, and imaging data are available to 
transmit for central review (for the dose expansion only). 
The tumour assessment will be conducted every 6 weeks (±1 week) from Cycle 1, Day 1, for 
the first 6 months, then every 12 weeks. Patients who discontinue study treatment for reasons 
other than progressive disease should continue tumour evaluations per the visit schedule until 
progression. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 89/264 
 
For patients who are allergic to i.v. contrast or cannot tolerate i.v. contrast due to impaired 
renal function or other issues, a regular CT or MRI is acceptable. Each follow-up tumour 
assessment should use the same assessment method as performed at screening, unless 
medically contraindicated. The sponsor will collect and store all tumour measurement images 
on all patients throughout the study. A review of the scans may be performed by the sponsor 
for an independent analysis of anti-tumour activity. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 90/264 
 
6 
TREATMENT OF PATIENTS 
6.1 
Investigational Medicinal Product Preparation and Accountability 
6.1.1 
Investigational Medicinal Product Preparation 
The investigator or an approved representative (for example pharmacist), will ensure that all 
IMP and any other study related material is stored in a secured area, under recommended 
temperature monitored storage conditions, in accordance with applicable regulatory 
requirements. 
IPN60090 capsules do not require any special storage conditions but should not be 
refrigerated or frozen. 
6.1.2 
Investigational Medicinal Product Accountability 
All IMP and any other study related material are to be accounted for on the IMP 
accountability log provided by the sponsor. It is essential that all used and unused supplies are 
retained for verification (by the sponsor or sponsor’s representative). The investigator should 
ensure adequate records are maintained in the IMP accountability log. 
6.2 
Study Drugs Administered 
6.2.1 
IPN60090 
The sponsor will provide the site with adequate supplies of IPN60090, which will be supplied 
as 10 mg, 60 mg and 240 mg capsules.  
Patients in Part D will receive IPN60090 as a single dose in the morning on Day -7 and 
Day -3 as described in Section 3.1.3. Patients in all parts (Parts A, B, C and D [from Day 1]) 
should take IPN60090 BID (every 12 hours), during or after a meal. IPN60090 will be 
administered in the clinic on the first treatment day so that each patient can be observed for 
initial tolerability. Subsequent doses will be self-administered at home by taking IPN60090 
BID at the same time each day until the next visit. Patients will be given a medication diary to 
record the day and time of administration, missed administration, if any, with related reasons, 
if available, or retake medication in case of rejection, if applicable. Any unused study 
treatment must be returned to the study site for drug accountability and disposal. 
The assigned dose of IPN60090 will vary from cohort to cohort and will be defined by each 
SRC meeting, except for the starting dose for each part that is defined in the protocol. Patients 
should maintain their assigned dose in the absence of treatment-emergent toxicity. 
If patients experience emesis, they should be instructed not to take additional doses of study 
medication and to maintain the planned dosing schedule. Patients should not make up for 
missed doses if more than 6 hours have elapsed after the time the patient would usually take 
IPN60090. In the event of missed doses, patients should not take 2 doses to make up for the 
one the patient missed.  
During the Part A dose escalation, doses of IPN60090 will range from 20 mg BID (40 mg 
total daily dose) (starting dose) to 720 mg BID (1440 mg daily dose) (maximum dose).  
During the Part B dose escalation, the starting dose of IPN60090 will be a dose showing 
pharmacological activity (at least 50% inhibition of Glu:Gln ratio in PBMC at Ctrough 
(12 hours postdose) on Day 14 in 66% of patients at this dose level) and good tolerability as 
identified in Part A. Details of the dose of pembrolizumab are provided in Section 6.2.2.  
During the Part C dose escalation, the starting dose of IPN60090 will be a dose showing 
pharmacological activity (at least 50% inhibition of Glu:Gln ratio in PBMC at Ctrough 
(12 hours postdose) on Day 14 in 66% of patients at this dose level) and good tolerability as 
identified in Part A. Details of the dose of paclitaxel are provided in Section 6.2.2. When 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 91/264 
 
H2 blockers are administered for paclitaxel premedication, they must be administered at least 
30 minutes prior to paclitaxel infusion. IPN60090 intake should be performed at least 
2.5 hours before the start of the paclitaxel infusion and at least 2 hours prior to H2 blocker 
administration. 
The administration date and time of IPN60090 and pembrolizumab or paclitaxel should be 
recorded in the eCRF for days with PK/PD and ADA sampling. Administered doses, date and 
time of other concomitant medications (H2 blockers, or any other drugs) should be recorded 
in the eCRF for days when PK sampling is performed. 
During Part D, the administered dose during the run-in period (Day -7 and Day -3) will be the 
RD (morning dose only) as defined by the SRC at the end of the Part A dose escalation. Then, 
starting from Day 1, IPN60090 will be administered at the RD BID during or after a meal. 
The highest dose is also unknown. The proposed dose levels may be further modified and 
additional doses may be considered based on the safety, tolerability and efficacy observed 
during dose escalation. An intermediate, not predefined, previously evaluated or not 
previously evaluated dose or a less frequent dosing schedule that will not exceed the MTD 
level may be considered, if evaluation of toxicity at such a dose or schedule is desired. 
6.2.1.1 
Dose Expansion 
In the expansion phases, the dose tested will be the RD determined in the dose escalation part. 
6.2.2 
Other Study Drugs 
The sponsor will also provide the other study drugs to site (although locally supplied study 
drug may be used if needed or if required per local regulations and upon sponsor approval). 
Patients will be dosed with IPN60090 before being dosed with pembrolizumab or paclitaxel. 
6.2.2.1 
Part B: Pembrolizumab 
Pembrolizumab will be supplied as a 100 mg/4 mL (25 mg/mL) solution in single-use vials to 
be diluted for infusion. It is a sterile, preservative-free, clear to slightly opalescent, colourless 
to slightly yellow solution that requires dilution for i.v. infusion. Each vial contains 100 mg of 
pembrolizumab in 4 mL of solution. Each 1 mL of solution contains 25 mg of pembrolizumab 
and is formulated in L-histidine (1.55 mg), polysorbate 80 (0.2 mg), sucrose (70 mg) and 
water for injection, USP. 
(a) 
Dosage and administration: 
IPN60090 capsules should be taken at least 1 hour before the pembrolizumab infusion. The 
predose, 30-minute (±5 minutes) and 1-hour (±5 minutes) blood samples for PK analysis 
should be drawn before initiating the pembrolizumab infusion. 
The pembrolizumab dose will be fixed at 200 mg (or according to the approved local label for 
particular tumour types) administered as an i.v. infusion over 30 minutes every 21 days 
(±1 day in Cycle 1 and ±3 days in all other cycles) (Day 1 of every cycle) through an i.v. line 
containing a sterile, non-pyrogenic, low-protein binding 0.2 μm to 5 μm in-line or add-on 
filter. Premedication with antipyretic and antihistamine may be considered. Reconstitution 
and preparation of pembrolizumab solution for infusion should be done as per the 
locally-approved product information. Sites should make every effort to target infusion timing 
to be as close to 30 minutes as possible. However, given the variability of infusion pumps 
from site to site, a window between -5 minutes and +10 minutes is permitted (i.e. infusion 
time is 30 minutes (-5 minutes/+10 minutes). 
(b) 
Storage (per pembrolizumab prescribing information): 
Unopened vials must be stored under refrigeration between 2°C and 8°C.  


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 92/264 
 
At room temperature for no more than 6 hours from the time of dilution. This includes room 
temperature storage of the infusion solution in the i.v. bag, and the duration of infusion. 
Under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from the time of 
dilution. If refrigerated, allow the diluted solution to come to room temperature prior to 
administration. Pembrolizumab should not be frozen. 
6.2.2.2 
Part C: Paclitaxel 
For reconstitution and preparation of paclitaxel, please refer to the local label.  
(a) 
Dosage and administration: 
When H2 blockers are administered for paclitaxel premedication, they must be administered 
at least 30 minutes prior to paclitaxel infusion. IPN60090 intake should be performed at least 
2.5 hours before the start of the paclitaxel infusion and at least 2 hours prior to H2 blocker 
administration. 
The dose of paclitaxel will be fixed at 175 mg/m² or 135 mg/m² (or according to the local 
approved label for particular tumour types) administered as an i.v. infusion every 21 days 
(±1 day in Cycle 1 and ±3 days in all other cycles). 
All patients should be premedicated prior to paclitaxel administration in order to prevent 
severe hypersensitivity reactions. Such premedication may consist of dexamethasone 20 mg 
administered approximately 12 and 6 hours before paclitaxel, diphenhydramine (or its 
equivalent) 50 mg i.v. 30 to 60 minutes prior to paclitaxel, and cimetidine (300 mg) or 
ranitidine (50 mg) i.v. 30 to 60 minutes before paclitaxel. 
Paclitaxel infusion must be diluted prior to infusion. Paclitaxel should be diluted in 0.9% 
sodium chloride injection, USP; 5% dextrose injection, USP; 5% reference ID: 2939751 47 
dextrose and 0.9% sodium chloride injection, USP; or 5% dextrose in Ringer’s injection to a 
final concentration of 0.3 mg/mL to 1.2 mg/mL. The solutions are physically and chemically 
stable for up to 27 hours at ambient temperature (approximately 25°C) and room lighting 
conditions. Parenteral drug products should be inspected visually for particulate matter and 
discoloration prior to administration whenever solution and container permit.  
(b) 
Storage (per paclitaxel prescribing information): 
Unopened vials of paclitaxel infusion are stable until the date indicated on the package when 
stored between 20°C and 25°C (68°F to 77°F), in the original package. Neither freezing nor 
refrigeration adversely affects the stability of the product. Upon refrigeration, components in 
the paclitaxel vial may precipitate, but will redissolve upon reaching room temperature with 
little or no agitation. There is no impact on product quality under these circumstances [19]. 
6.3 
Concomitant Medication/Therapy 
Any prior or concomitant therapy or medication given to a patient within 28 days before, 
during, and up to 30 days after IMP administration will be indicated on the eCRF. The dose 
and generic name or trade name will be indicated. 
6.3.1 
List of Prohibited Medications During Study Drug Treatment 
In general, the use of any concomitant medication deemed necessary for the care of the 
patient is permitted in this study, except as specifically prohibited. Concomitant 
administration of study drug could result in drug-drug interactions (DDI) that could 
potentially lead to reduced activity or enhanced toxicity of the concomitant medication and/or 
of IPN60090. Before any intake of a new concomitant treatment during the study treatment 
period, the investigator should assess the potential DDIs with IPN60090 using the Summary 
of Product Characteristics (SmPC) of the new concomitant treatment. The sponsor should be 
contacted in case of any doubt.  


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 93/264 
 
The prohibited drugs are reported in the exclusion criteria. In-vitro CYP mediated metabolism 
of IPN60090 might be catalysed by CYP3A4 and CYP2D6; for Parts A, B and C, drugs 
which are strong CYP3A4 and CYP2D6 inhibitors and strong CYP3A4 inducers are 
prohibited. In addition, since paclitaxel is a CYP2C8 substrate, for Part C only, drugs that are 
strong CYP2C8 inhibitors and inducers are prohibited. 
The lists of strong inhibitors and inducers of CYP3A4, of strong inhibitors of CYP2D6 and of 
strong inhibitors and inducers of CYP2C8 are provided in Appendix 2, Appendix 3, Appendix 
4 and Appendix 5. 
Grapefruit (listed in Appendix 2), star fruit and Seville oranges may also increase plasma 
concentrations of IPN60090 by inhibition of CYP3A4 and therefore are prohibited. 
St John’s Wort (listed in Appendix 2) may decrease plasma concentrations of IPN60090 by 
induction of CYP3A4 and therefore is prohibited. 
H2 blockers, proton pump inhibitors and antacids are prohibited during the run-in period 
(Day -7 to Day -3) of Part D. 
In-vitro data show that IPN60090 does not induce CYP3A4, CYP2B6 and CYP1A2 and that 
IPN60090 does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and 
CYP3A4 (Report P18-142-73, Report PK-15 and Report PK-17). Therefore, no DDI is 
anticipated in clinical settings regarding the induction of the CYP3A4, CYP2B6 and CYP1A2 
by IPN60090. Similarly, no DDI is anticipated in clinical settings regarding the inhibition of 
CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 by IPN60090.  
6.3.2 
List of Medications to be Used with Caution during Study Drug Treatment 
Concomitant administration of study drug could result in DDIs that could potentially lead to 
reduced activity or enhanced toxicity of the concomitant medication and/or IPN60090. 
Before any intake of a new concomitant treatment during the study treatment period, the 
investigator should assess the potential DDIs with IPN60090 using the SmPC of the new 
concomitant treatment. The sponsor should be contacted in case of any doubt.  
Caution should be exercised when administering IPN60090 concomitantly with medicines 
known to be moderate inhibitors of CYP3A4 or CYP2D6. Administering IPN60090 
concomitantly with medicines known to be moderate inducers of CYP3A4 is not 
recommended. Moreover, moderate inhibitors/inducers of CYP2C8 should also be used with 
caution for Part C as well as immunosuppressive agents for Part B. 
The lists of moderate inhibitors of CYP3A4 and of CYP2D6 are provided in Appendix 3 and 
Appendix 4, respectively. The list of moderate inducers of CYP3A4 is provided in Appendix 
3. The lists of moderate inhibitors/inducers of CYP2C8 are provided in Appendix 6. The list 
of immunosuppressive agents is provided in Appendix 7.  
In-vitro data show that IPN60090 is an inhibitor of the human OATP1B3, OCT1, OCT2, 
MATE2-K, MATE1 and OATP1B1 uptake transporters. Based on the % of maximal 
inhibition in vitro, caution should be exercised when administering IPN60090 concomitantly 
with medicines known to be substrates of OATP1B3, OCT1 and OCT2 transporters 
(Report MD Anderson-05-08Nov2017). 
The lists of drugs known to be substrates of OATP1B3, OCT1 and OCT2 transporters are 
provided in Appendix 8. 
6.3.3 
Permitted Concomitant Medications 
The following concomitant medications are permitted during this study but they must be 
monitored closely and every effort should be made to keep their dose and dose regimen 
constant throughout the course of the study:  


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 94/264 
 
• 
Antiemetics and antidiarrheal medications are allowed prophylactically according to 
standard clinical practice if clinically indicated. 
• 
Granulocyte colony-stimulating factors are allowed if used per clinical guidelines (for 
example American Society of Clinical Oncology (ASCO) or European Society for 
Medical Oncology guidelines). 
• 
Drugs used to control bone loss (e.g. bisphosphonates and denosumab) are allowed if 
started prior to screening. If indicated to be initiated or exchanged during the course of 
the study, sponsor’s approval is required. 
• 
Antacids, H2 blockers. Specific attention should be paid to these medications as they 
may have an impact on IPN60090 absorption. IPN60090 should be taken at least 
2 hours before an antacid or H2 blocker intake.  
• 
Any medication required for the safety of the patient. 
• 
In Part B, premedication with antipyretic and antihistamine may be considered before 
pembrolizumab infusion. 
• 
In Part C, the following premedications are allowed to prevent severe hypersensitivity 
reactions to paclitaxel: dexamethasone, diphenhydramine (or its equivalent) and 
cimetidine or ranitidine (see Section 6.2.2.2 for more details on dosage and 
administration). 
The name, posology, date and time of any concomitant medication intake will be recorded in 
the eCRF. 
6.4 
Dose Modifications 
6.4.1 
Reduction of IPN60090 Monotherapy 
Management of severe or intolerable adverse reactions requires dose reduction, temporary 
interruption, and/or discontinuation of IPN60090 therapy. Each patient is allowed a maximum 
of two dose reductions for IPN60090. After this, the patient will be discontinued from the 
study treatment.  
If a dose reduction is required, reduce the current dose by one dose level from the current 
dose. 
Table 18 Dose Adjustment for IPN60090 
 
DL1 
DL2 
DL3 
DL4 
DL5 
DL6 
DL7 
Starting 
dose level 
20 mg BID 
40 mg BID 
80 mg BID 180 mg BID 320 mg BID 480 mg BID 720 mg BID 
First dose 
reduction 
N/A 
20 mg BID 
40 mg BID 
80 mg BID 180 mg BID 320 mg BID 480 mg BID 
Second dose 
reduction 
N/A 
N/A 
20 mg BID 
40 mg BID 
80 mg BID 180 mg BID 320 mg BID 
BID=bis in die (twice daily); DL=dose level; N/A=not applicable 
6.4.2 
Reduction of IPN60090 + Pembrolizumab  
Management of severe or intolerable adverse reactions requires dose reduction, temporary 
interruption, and/or discontinuation of IPN60090 therapy. Each patient is allowed a maximum 
of two dose reductions for IPN60090. Pembrolizumab will be at a fixed dose and the dose 
cannot be reduced; however, treatment with pembrolizumab can be delayed >6 weeks 
(2 cycles) for any reason. In this case, the patient must be permanently discontinued from 
study therapy, except in cases where permission to resume treatment is granted by the Ipsen 
Medical Monitor or designee. If a patient discontinues IPN60090, they may remain on study 
on pembrolizumab monotherapy.  


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 95/264 
 
If a dose reduction is required, the current dose should be reduced by one dose level from the 
current dose. This can be done up to two times before a patient must discontinue study 
treatment. 
Table 19 Dose Adjustment for IPN60090 + Pembrolizumab 
DL1 
DL2 
DL3 
IPN60090 Pembrolizumab 
IPN60090 Pembrolizumab IPN60090 Pembrolizumab 
Starting dose 
level 
180 mg BID In accordance with 
approved label 
320 mg BID In accordance with 
approved label 
480 mg BID In accordance with 
approved label 
First dose 
reduction 
80 mg BID 
180 mg BID 
320 mg BID 
Second dose 
reduction 
40 mg BID 
80 mg BID 
180 mg BID 
BID=bis in die (twice daily); DL=dose level 
6.4.3 
Reduction of IPN60090 + Paclitaxel  
Management of severe or intolerable adverse reactions requires dose reduction, temporary 
interruption, and/or discontinuation of IPN60090 therapy. Each patient is allowed a maximum 
of two dose reductions for IPN60090; paclitaxel is a fixed dose and the dose cannot be 
reduced. If treatment with paclitaxel is delayed >6 weeks (2 cycles) for any reason, the patient 
must be permanently discontinued from study therapy, except in cases where permission to 
resume treatment is granted by the Ipsen Medical Monitor or designee. If a patient 
discontinues IPN60090 they may remain on study on paclitaxel monotherapy.  
If a dose reduction is required, reduce the current dose by one dose level from the current 
dose. This can be done up to two times before a patient must discontinue study treatment.  
Table 20 Dose Adjustment for IPN60090 + Paclitaxel 
 
DL1 
DL2 
DL3 
IPN60090 
Paclitaxel 
IPN60090 
Paclitaxel 
IPN60090 
Paclitaxel 
Starting dose 
level 
180 mg BID 
In accordance 
with approved 
label 
320 mg BID 
In accordance 
with approved 
label 
480 mg BID 
In accordance 
with approved 
label 
First dose 
reduction 
80 mg BID 
180 mg BID 
320 mg BID 
Second dose 
reduction 
40 mg BID 
80 mg BID 
180 mg BID 
BID=bis in die (twice daily); DL=dose level 
6.4.4 
Dose Adjustments and Modifications 
The management of all study drugs, and any dose adjustments should be in line with the best 
clinical practice for individual patients and is ultimately left to the discretion of the 
investigator or treating physician. 
Dose management of pembrolizumab and paclitaxel should be done according to the 
approved product information.  
The following tables are recommended adjustments and modifications of IPN60090 in case of 
haematologic toxicity (Table 21), hepatotoxicity (Table 22), cardiac toxicity (Table 23), 
immune-related reactions: non-infectious pneumonitis (Table 24) and other toxicities 
(Table 26). 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 96/264 
 
6.4.4.1 
Dose Adjustments and Modifications for Nonimmune Related Adverse Events 
Table 21 Dose Adjustment and Management Recommendations for IPN60090 in Case of Haematologic 
Toxicity 
Toxicity/grade 
Dose adjustment and management recommendations for IPN60090 
Thrombocytopenia 
Grade 1(≥75x109/L) 
No dose adjustment required. 
Grade 2 (≥50x109/L to <75x109/L) -Dose interruption until recovery to Grade ≤1. 
-Re-initiate at the same dose. 
Grade 3 (≥25x109/L to <50x109/L) -Dose interruption until recovery to Grade ≤1. 
-Re-initiate at the same dose level. 
-If toxicity recurs at Grade 3: temporary dose interruption until recovery to 
Grade ≤1 and reduce to the next lower dose level. 
Grade 4 (<25x109/L) 
-Dose interruption until recovery to Grade ≤1. 
-Re-initiate at the next lower dose level.  
-If toxicity recurs at Grade 4: discontinue IPN60090 
Absolute neutrophil count (ANC) 
Grade 1 (≥1.5x109/L) 
No dose adjustment required. 
Grade 2 (≥1.0 to <1.5x109/L) 
No dose adjustment required. 
Grade 3 (≥0.5 to <1.0x109/L) 
-Dose interruption of IPN60090 until recovery to ≥1.0x109/L.  
-Re-initiate IPN60090 at the same dose level.  
-If toxicity recurs at Grade 3: temporary dose interruption until recovery to 
≥1.0x109/L.  
-If resolved in ≤7 days, then maintain dose level.  
-If resolved in >7 days, then reduce IPN60090 dose to the next lower dose 
level. 
Grade 4 (<0.5x109/L) 
-Dose interruption of IPN60090 and pembrolizumab (if applicable) until 
recovery to ≥1.0x109/L.  
-Re-initiate IPN60090 at the next lower dose level. 
-If toxicity recurs at Grade 4: discontinue IPN60090. 
Febrile neutropenia 
Grade 3 
ANC <1.0x109/L with a single 
temperature of >38.3ºC (101 ºF) or a 
sustained temperature of ≥38ºC 
(100.4ºF) for more than one hour 
-Dose interruption of IPN60090 and pembrolizumab (if applicable) until 
improvement of ANC ≥1.0x109/L and no fever. Restart at the next lower 
dose level. 
-If febrile neutropenia recurs, discontinue IPN60090. 
Grade 4 
Life threatening consequences; 
urgent intervention indicated 
-Discontinue IPN60090. 
Anaemia (haemoglobin) 
Grade 1 (≥10.0 to LLN g/dL) 
No dose adjustment required. 
Grade 2 (≥8.0 to <10.0 g/dL) 
No dose adjustment required. 
Grade 3 (<8.0 g/dL) 
-Dose interruption until recovery to Grade ≤2. 
-Re-initiate IPN60090 at the same dose. 
Grade 4 
Life threatening consequences; 
urgent intervention indicated 
-Discontinue IPN60090. 
LLN=lower limit of normal 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 97/264 
 
Table 22 Dose Adjustment and Management Recommendations for IPN60090 in Case of Hepatotoxicity 
Toxicity/grade 
Dose adjustment and management recommendations for IPN60090 
Total bilirubin without ALT/AST increase above baseline value 
Grade 1 (>ULN to 1.5xULN) 
(confirmed 48 to 72 hours later) 
Maintain dose level with LFTs monitored biweekly. 
Grade 2 (>1.5 to 3.0xULN) 
-Dose interruption of IPN60090. 
-If resolved to ≤Grade 1 in ≤14 days, then maintain dose level. 
-If resolved to ≤Grade 1 in >14 days or toxicity recurs, then reduce 
IPN60090 by one dose level. 
-Repeat liver enzymes and bilirubin tests weekly for 2 weeks after dose 
resumption. 
-If toxicity recurs after two dose reductions, discontinue study treatment. 
Grade 3 (>3.0 to 10.0xULN) 
-Dose interruption of IPN60090.  
-If resolved to ≤Grade 1 in ≤14 days, lower one dose level of IPN60090. 
-Repeat liver enzymes and bilirubin tests weekly for 2 weeks after dose 
resumption. 
-If resolved to ≤Grade 1 in >14 days or toxicity recurs, discontinue 
IPN60090. 
Grade 4 (>10.0xULN) 
Discontinue IPN60090 
Confounding factors and/or alternative causes for increase of total bilirubin should be excluded before dose 
interruption/reduction. They include but are not limited to: evidence of obstruction, such as elevated ALP and 
GGT typical of gallbladder or bile duct disease, hyperbilirubinaemia due to the indirect component only 
(i.e. direct bilirubin component ≤1xULN) due to haemolysis or Gilbert’s syndrome, pharmacologic treatment, 
viral hepatitis, alcoholic or autoimmune hepatitis, other hepatotoxic drugs. For patients with Gilbert’s syndrome, 
these dose modifications apply to changes in direct bilirubin only. Bilirubin will be fractionated if elevated. 
ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; GGT=gamma glutamyl 
transferase; LFTs=liver function tests; ULN=upper limit of normal 
Table 23 Dose Adjustment and Management Recommendations for IPN60090 in Case of Cardiac 
Toxicity 
Adverse drug 
reaction 
Severity 
Dose adjustment and management recommendations 
QTcF 
prolongation 
For all grades 
-Check the quality of the ECG and the QT value and repeat if needed. 
-Perform analysis of serum electrolytes (potassium, calcium, 
phosphate, magnesium). If outside of normal range, hold IPN60090, 
correct with supplements or appropriate therapy as soon as possible, 
and repeat electrolytes until documented as normal. 
-Review concomitant medication usage for the potential to prolong the 
QT interval. 
-Check compliance with correct dose and administration of IPN60090. 
-Consider collecting a time matched PK sample; record date and time 
of last study drug intake. 
Grade 1 
QTc 450 to 480 ms 
No dose adjustment required. 
Grade 2 
QTc 481 to 500 ms 
-Hold IPN60090. 
-Perform repeat triplicate ECGs one hour after the first QTcF of 
≥481 ms. 
-If QTcF <481 ms, restart IPN60090 at the same dose. No dose 
adjustment required for first occurrence. If QTcF remains ≥481 ms, 
repeat ECG as clinically indicated until the QTcF returns to <481 ms. 
Restart IPN60090 and pembrolizumab (if applicable) at the same dose. 
No dose adjustment required for first occurrence. 
-If QTcF ≥481 ms recurs, IPN60090 should be reduced by one dose 
level 
-Repeat ECGs 7 days and 14 days after dose resumption (then as 
clinically indicated) for any patients who had therapy interrupted due to 
QTcF ≥481 ms. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 98/264 
 
Adverse drug 
reaction 
Severity 
Dose adjustment and management recommendations 
Grade 3 
QTc ≥501 ms on at 
least two separate 
ECGs 
-Hold IPN60090. 
-Perform repeat triplicate ECGs within one hour of the first QTcF of 
≥501 ms. 
-If QTcF remains ≥501 ms, consult with a cardiologist (or qualified 
specialist) and repeat cardiac monitoring as indicated until the QTcF 
returns to <481 ms. 
-If QTcF returns to <481 ms, IPN60090 will be reduced by one dose 
level. 
-Repeat ECGs 7 days and 14 days after dose resumption (then as 
clinically indicated) for any patients who had therapy interrupted due to 
QTcF ≥501 ms. 
-If QTcF of ≥501 ms recurs, discontinue study treatment.  
-Hold IPN60090 and perform frequent ECGs until the QTcF is 
<500 ms. Address electrolyte, calcium and magnesium abnormalities. 
Restart IPN60090 at a lower dose. 
-If findings recur on the lower dose, hold study treatment until resolve 
to ≤Grade 1, and restart at the next lower dose level. 
If findings recur, discontinue IPN60090. 
Grade 4 QT/QTc 
≥501 or >60 ms 
change from baseline 
and Torsades de 
pointes or 
polymorphic 
ventricular 
tachycardia, or 
signs/symptoms of 
serious arrhythmia 
-Discontinue IPN60090. 
-Obtain local cardiologist (or qualified specialist) consultation and 
repeat cardiac monitoring as indicated until the QTcF returns to 
<481 ms. 
-Stop study treatment, institute emergency care, address electrolyte, 
calcium and magnesium abnormalities and perform frequent ECGs 
until the QTcF is <500 ms. 
-Discontinue the patient from the study. 
Cardiac - Left 
Ventricular 
Systolic 
Dysfunction 
Asymptomatic, 
resting ejection 
fraction 40% to 50%; 
or 10% to 20% drop 
from baseline 
-Maintain dose level and continue study treatment with caution. 
-Repeat LVEF within 4 weeks or as clinically appropriate. 
Symptomatic, 
responsive to 
intervention, ejection 
fraction 20% to 39% 
or >20% drop from 
baseline 
-Hold study treatment until resolved, then reduce one dose level. 
-LVEF measurement to be repeated, if not resolved, within 28 days. 
Refractory or poorly 
controlled, ejection 
fraction <20% 
Discontinue IPN60090. 
ECG=electrocardiogram; LVEF=left ventricular ejection fraction; QTc=corrected QT interval; QTcF=Fridericia corrected 
QT interval 
6.4.4.2 
Dose Adjustments and Modifications for Immune-Related Adverse Events 
Associated with Pembrolizumab 
Adverse events associated with pembrolizumab exposure may represent an immune-related 
response. These immune-related AEs (irAEs) may occur shortly after the first dose or several 
months after the last dose of pembrolizumab treatment and may affect more than one body 
system simultaneously. Therefore, early recognition and initiation of treatment is critical to 
reduce complications. Based on existing clinical study data, most irAEs were reversible and 
could be managed with interruptions of pembrolizumab, administration of corticosteroids 
and/or other supportive care. For suspected irAEs, ensure adequate evaluation to confirm 
aetiology or exclude other causes. Additional procedures or tests such as bronchoscopy, 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 99/264 
 
endoscopy, skin biopsy may be included as part of the evaluation. Dose modification and 
toxicity management guidelines for irAEs associated with pembrolizumab are provided in 
Table 24. 
Table 24 Dose Modification and Toxicity Management Guidelines for Immune-Related AEs Associated 
with Pembrolizumab 
irAEs 
Toxicity grade 
(CTCAE v5.0) 
Action with 
pembrolizumab 
Corticosteroid 
and/or other 
therapies  
Monitoring and 
follow-up  
Pneumonitis  
Grade 2 
Withhold  
x Administer 
corticosteroids 
(initial dose of 
1 to 2 mg/kg 
prednisone or 
equivalent) 
followed by taper 
x Add prophylactic 
antibiotics for 
opportunistic 
infections 
x Monitor 
participants for 
signs and 
symptoms of 
pneumonitis 
x Evaluate 
participants with 
suspected 
pneumonitis with 
radiographic 
imaging and 
initiate 
corticosteroid 
treatment 
Recurrent 
Grade 2, Grade 3 
or 4  
Permanently 
discontinue 
Diarrhoea/colitis  
Grade 2 or 3 
Withhold 
x Administer 
corticosteroids 
(initial dose of 
1 to 2 mg/kg 
prednisone or 
equivalent) 
followed by taper 
x Monitor 
participants for 
signs and 
symptoms of 
enterocolitis (i.e. 
diarrhoea, 
abdominal pain, 
blood or mucus in 
stool with or 
without fever) and 
of bowel 
perforation (i.e. 
peritoneal signs 
and ileus) 
x Participants with 
≥Grade 2 
diarrhoea 
suspecting colitis 
should consider GI 
consultation and 
performing 
endoscopy to rule 
out colitis 
x Participants with 
diarrhoea/colitis 
should be advised 
to drink liberal 
quantities of clear 
fluids. If sufficient 
oral fluid intake is 
not feasible, fluid 
and electrolytes 
should be 
substituted via i.v. 
infusion 
Recurrent Grade 3 
or Grade 4 
Permanently 
discontinue 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 100/264 
 
irAEs 
Toxicity grade 
(CTCAE v5.0) 
Action with 
pembrolizumab 
Corticosteroid 
and/or other 
therapies  
Monitoring and 
follow-up  
AST or ALT 
elevation or 
increased 
bilirubin 
Grade 2a 
Withhold 
x Administer 
corticosteroids 
(initial dose of 
0.5 to 1 mg/kg 
prednisone or 
equivalent) 
followed by taper 
x Monitor with liver 
function tests 
(consider weekly 
or more frequently 
until liver enzyme 
value returned to 
baseline or is 
stable) 
Grade 3b or 4 c 
Permanently 
discontinue 
x Administer 
corticosteroids 
(initial dose of 
1 to 2 mg/kg 
prednisone or 
equivalent) 
followed by taper 
T1DM or 
hyperglycaemia 
New onset T1DM 
or Grade 3 or 4 
hyperglycaemia 
associated with 
evidence of E-cell 
failure 
Withholdd 
x Initiate insulin 
replacement 
therapy for 
participants with 
T1DM 
x Administer 
antihyperglycaemic 
in participants with 
hyperglycaemia 
x Monitor 
participants for 
hyperglycaemia or 
other signs and 
symptoms of 
diabetes 
Hypophysitis 
Grade 2 
Withhold 
x Administer 
corticosteroids and 
initiate hormonal 
replacements as 
clinically indicated 
x Monitor for signs 
and symptoms of 
hypophysitis 
(including 
hypopituitarism 
and adrenal 
insufficiency) 
Grade 3 or 4 
Withhold or 
permanently 
discontinue d 
Hyperthyroidism  
Grade 2 
Continue 
x Treat with 
nonselective 
beta-blockers (e.g. 
propranolol) or 
thionamides as 
appropriate 
x Monitor for signs 
and symptoms of 
thyroid disorders 
Grade 3 or 4 
Withhold or 
permanently 
discontinue d 
Hypothyroidism 
Grade 2, 3, 4 
Continue 
x Initiate thyroid 
replacement 
hormones (e.g. 
levothyroxine or 
liothyronine) per 
standard of care 
x Monitor for signs 
and symptoms of 
thyroid disorders 
Nephritis: grading 
according to 
increased 
creatinine or acute 
kidney injury 
Grade 2 
Withhold 
x Administer 
corticosteroids 
(prednisone 
1 to 2 mg/kg or 
equivalent) 
followed by taper 
x Monitor changes 
of renal function 
Grade 3 or 4 
Permanently 
discontinue 
Myocarditis 
Grade 1 or 2 
Withhold 
x Based on severity 
of AE administer 
corticosteroids 
x Ensure adequate 
evaluation to 
confirm aetiology 
and/or exclude 
other causes 
Grade 3 or 4 
Permanently 
discontinue 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 101/264 
 
irAEs 
Toxicity grade 
(CTCAE v5.0) 
Action with 
pembrolizumab 
Corticosteroid 
and/or other 
therapies  
Monitoring and 
follow-up  
All other irAEs 
Persistent Grade 2 
Withhold 
x Based on severity 
of AE administer 
corticosteroids 
x Ensure adequate 
evaluation to 
confirm aetiology 
or exclude other 
causes 
Grade 3 
Withhold or 
discontinue 
based on the 
evente  
Recurrent Grade 3 
or 4  
Permanently 
discontinue 
AE=adverse event; ALT=alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology 
Criteria for Adverse Events; GI=gastrointestinal; irAE=immune-related adverse event; i.v.=intravenous; T1DM=Type 1 
diabetes mellitus; ULN=upper limit of normal 
a AST/ALT: >3.0 to 5.0 × ULN if baseline normal; >3.0 to 5.0 × baseline, if baseline abnormal; 
bilirubin:>1.5 to 3.0 × ULN if baseline normal; >1.5 to 3.0 × baseline, if baseline abnormal 
b AST/ALT: >5.0 to 20.0 × ULN if baseline normal; >5.0 to 20.0 × baseline, if baseline abnormal; 
bilirubin:>3.0 to 10.0 × ULN if baseline normal; >3.0 to 10.0 × baseline, if baseline abnormal 
c AST/ALT: >20.0 × ULN if baseline normal; >20.0 × baseline, if baseline abnormal; bilirubin: >10.0 × ULN if baseline 
normal; >10.0 × baseline, if baseline abnormal 
d The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating 
physician. If control achieved or ≤ Grade 2, pembrolizumab may be resumed. 
e Events that require discontinuation include but are not limited to: Guillain-Barre Syndrome, encephalitis, 
Stevens-Johnson Syndrome and toxic epidermal necrolysis. 
General instructions: 
(1) 
Severe and life-threatening irAEs should be treated with i.v. corticosteroids followed 
by oral steroids. Other immunosuppressive treatment should begin if the irAEs are not 
controlled by corticosteroids.  
(2) 
Pembrolizumab must be permanently discontinued if the irAE does not resolve or the 
corticosteroid dose is not ≤10 mg/day within 12 weeks of the last pembrolizumab 
treatment. 
(3) 
The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue for at 
least 4 weeks. 
(4) 
If pembrolizumab has been withheld, pembrolizumab may resume after the irAE 
decreased to ≤ Grade 1 after the corticosteroid taper. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 102/264 
 
Table 25 Dose Adjustment and Management Recommendations for IPN60090 in Case of 
Immune-Related Reactions: Noninfectious Pneumonitis 
Worst grade 
pneumonitis 
Required investigations Management of 
pneumonitis 
Dose adjustment 
Grade 1 
Asymptomatic, 
radiographic 
findings only 
CT scans with lung 
windows. 
Repeat at least every 
12 weeks until return to 
within normal limits. 
No specific therapy is 
required. 
-Administer 100% of study treatment. 
-Consider patient referral to pulmonary 
specialist. 
-for recurrent pneumonitis, treat as 
Grade 3 or 4 event. 
Grade 2 
Symptomatic, not 
interfering 
with ADL 
CT scan with lung 
windows. 
Consider pulmonary 
function testing includes: 
spirometry, DLCO, and 
room air O2 saturation at 
rest. 
Repeat at least every 
12 weeks until return to 
within normal limits. 
Consider a bronchoscopy 
with biopsy and/or BAL. 
Symptomatic only. 
Initial dose of 1 to 
2 mg/kg/day prednisone 
or equivalent followed 
by a taper. 
-Hold pembrolizumab (if applicable) 
until recovery to ≤Grade 1. 
-Resume pembrolizumab if event 
resolves to Grade 1 or better within 
12 weeks. 
-Permanently discontinue 
pembrolizumab and contact the sponsor 
if event does not resolve to Grade 1 or 
better within 12 weeks. 
-Reduce IPN60090 dose by one dose 
level until recovery to ≤Grade 1. Study 
treatment may also be interrupted if 
symptoms are troublesome. 
-Patients will discontinue IPN60090 and 
pembrolizumab (if applicable) if they 
fail to recover to ≤Grade 1 within 
12 weeks. 
-If Grade 2 recurs discontinue study 
treatment. 
Grade 3 
Symptomatic, 
interfering with 
ADL; O2 indicated 
CT scan with lung 
windows and pulmonary 
function testing includes: 
spirometry, DLCO, and 
room air O2 saturation at 
rest. 
Repeat at least every 
6 weeks until return to 
within normal limits. 
Bronchoscopy with biopsy 
and/or BAL is 
recommended. 
Initial dose of 1 to 
2 mg/kg/day prednisone 
or equivalent followed 
by a taper. 
Discontinue IPN60090 and 
pembrolizumab (if applicable). 
Grade 4 
Life threatening; 
ventilatory support 
indicated 
CT scan with lung 
windows and required 
pulmonary function 
testing, if possible, 
includes: spirometry, 
DLCO, and room air O2 
saturation at rest. 
Repeat at least every 
6 weeks until return to 
within normal limits. 
Bronchoscopy with biopsy 
and / or BAL is 
recommended if possible. 
Initial dose of 1 to 
2 mg/kg/day prednisone 
or equivalent followed 
by a taper. 
Discontinue IPN60090 and 
pembrolizumab (if applicable). 
ADL=activity of daily living; BAL=bronchoalveolar lavage; CT=computed tomography; DLCO=diffusing capacity of the 
lungs for carbon monoxide; O2=oxygen 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 103/264 
 
Table 26 Dose Adjustment and Management Recommendations for IPN60090 in Case of Other 
Toxicities 
Toxicity 
Action 
Hyperlipidaemia and/or hypertriglyceridaemia Any grade: 
Treat according to best clinical practice. No specific dose 
reductions are needed. 
Hyperglycaemia 
Any grade: 
Treat according to best clinical practice. No specific dose 
reductions are needed. 
All other toxicities 
Any grade: 
Treat according to best clinical practice. No specific dose 
reductions are needed. 
6.4.5 
Transition to Recommended Dose or Other Regimen 
In Parts A, B and C, when the RD is defined, if a patient is still in the study at a different 
dose, this patient can be moved to the RD, at the discretion of the investigator. 
In Part A, biomarker-positive patients who are enrolled and receive study treatment at initial 
dose levels below the pharmacologically active range for at least two cycles with good 
tolerability, and achieve and maintain at least SD, may be escalated to a higher dose level that 
has been tested and proven to be well tolerated at the recommendation of the SRC. These 
patients will be treated outside of the BOIN design. 
Patients enrolled in monotherapy Part A and Part D may receive combination treatment with 
either pembrolizumab or with paclitaxel upon progression on IPN60090 monotherapy, at the 
discretion of the investigator, and with the approval of the sponsor, once the safe dose level 
for the combination is determined. These patients will need to satisfy the eligibility criteria for 
combination therapy prior to initiating treatment, and will be followed for safety and efficacy 
in a separate cohort. 
6.5 
Procedures for Monitoring Patient Compliance 
The investigator will be responsible for monitoring patient compliance. Patients may be 
withdrawn from the study at any time if the investigator or the sponsor determines that the 
patient is not in compliance with the study protocol. 
Administration compliance will be assessed by a capsule count at each visit. Deviations of 
>25% of the scheduled amount of IMP intake will be regarded as a major protocol deviation 
unless the dose is reduced due to toxicity. 
If a patient is consistently noncompliant with IMP intake they should be discontinued from 
IMP/withdrawn from the study, at the discretion of the investigator. Please refer to Section 4.3 
for the criteria for discontinuing the patient from IMP. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 104/264 
 
7 
ASSESSMENT OF ANTI-TUMOUR ACTIVITY 
For the timing of assessments in this study, refer to the schedule in Table 14. 
7.1 
Efficacy Endpoints and Evaluations 
7.1.1 
Dose Escalation (Part A - Monotherapy and Parts B and C - Combinations) and 
Food Effect Cohort (Part D) 
Secondary tumour activity endpoints and evaluations planned during the dose escalation 
phase and food effect cohort are summarised in Table 27. All tumour endpoints will be 
assessed locally. 
Table 27 Efficacy Endpoints and Evaluations During Dose Escalation and Food Effect Cohort 
Measure 
Timepoint 
Variable  
Endpoint 
Tumour size (longest 
diameter) 
Parts A, C and D: Baseline 
and every 6 weeks 
Tumour response according to 
RECIST v1.1 
CBR 
ORR 
PFS 
DCR 
OS 
Part B: Baseline and every 
6 weeks  
Tumour response according to 
iRECIST  
CBR 
ORR 
DCR 
iPFS 
OS 
CBR=clinical benefit rate; DCR=disease control rate; iPFS=immune progression-free survival; ORR=objective response rate; 
OS=overall survival; PFS=progression free survival  
7.1.2 
Dose Expansion Phases 
Secondary tumour activity endpoints and evaluations planned in the dose expansions are 
summarised in Table 28. All tumour endpoints will be assessed centrally. 
Table 28 Efficacy Endpoints and Evaluations During Dose Expansion 
Measure 
Timepoint 
Variable  
Endpoint 
Tumour size (longest 
diameter) 
Parts A and C: Baseline and 
every 6 weeks 
Tumour response according to 
RECIST v1.1 
CBR 
ORR 
PFS 
DCR 
OS 
Part B: Baseline and every 
6 weeks  
Tumour response according to 
iRECIST  
CBR 
ORR 
DCR 
iPFS 
OS 
CBR=clinical benefit rate; DCR=disease control rate; iPFS=immune progression-free survival; ORR=objective response rate; 
OS=overall survival; PFS=progression free survival  
7.2 
Methods and Timing of Assessing, Recording and Analysing Efficacy Data 
The methods for assessing efficacy data are described below. The timing of efficacy 
assessments is discussed in Section 5. The procedures for recording efficacy data are 
discussed in Section 15.1 and the methods of analyses are discussed in Section 11. 
Radiographic response and disease progression will be determined using RECIST v1.1 
(CT/MRI) and iRECIST (Part B only). 
7.2.1 
Tumour Response Using RECIST v1.1 
For this study, tumour response will be evaluated using the revised RECIST guideline v1.1. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 105/264 
 
All measurable lesions up to a maximum of two lesions per organ and five lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline. 
The tumour response of each patient will be graded as CR, PR, SD, progressive disease, or 
unevaluable according to RECIST v1.1. Based on this classification, the following endpoints 
will be calculated as defined by RECIST v1.1: 
• 
ORR: proportion of patients with a BOR characterised as either CR or PR relative to 
the total number of evaluable patients. 
• 
CBR: proportion of patients with BOR of CR, PR and SD lasting ≥12 weeks. 
• 
DCR: proportion of patients with a BOR characterised as CR, PR or SD relative to the 
total number of evaluable patients. 
• 
PFS: time from first dose of study medication to the first documented objective disease 
progression or death due to any cause, whichever occurs first. 
• 
OS: time from the date of first dose of study drug to death due to any cause. 
7.2.2 
Tumour Response Using iRECIST (Part B Only) 
For patients in Part B, tumour response will be evaluated using the iRECIST guideline (see 
[20]). Only patients who have received at least one dose of IPN60090 treatment will be 
considered evaluable for response.  
All measurable lesions up to a maximum of two lesions per organ and five lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline. 
The tumour response of each patient will be graded as iCR, iPR, iSD, immune unconfirmed 
progressive disease (iUPD) or immune confirmed progressive disease (iCPD) and 
unevaluable according to iRECIST. Based on this classification, the following endpoints will 
be calculated: 
• 
ORR: proportion of patients with a BOR characterised as either iCR or iPR relative to 
the total number of evaluable patients. 
• 
CBR: proportion of patients with BOR of iCR, iPR and iSD lasting ≥12 weeks. 
• 
DCR: proportion of patients with a BOR characterised as iCR, iPR or iSD relative to 
the total number of evaluable patients. 
• 
immune PFS: time from first dose of study medication to the first documented 
objective disease progression (time of iUPD if followed by iCPD) or death due to any 
cause, whichever occurs first. 
• 
OS: time from the date of first dose of study drug to death due to any cause. 
iRECIST is adapted to account for the unique tumour response seen with immunotherapeutic 
drugs. When clinically stable, patients should not be discontinued until progression is 
confirmed by the investigator. Some patients can have initial radiographic progressive disease 
due to a transient tumour flare in the first few months after the start of immunotherapy, and 
then experience subsequent disease response.  
Clinical stability is defined as the following:  
• 
absence of symptoms and signs indicating clinically significant progression of disease 
• 
no decline in ECOG performance status  
• 
no requirements for intensified management, including increased analgesia, radiation or 
other palliative care 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 106/264 
 
Any patient deemed clinically unstable should be discontinued from study treatment at first 
radiologic evidence of progressive disease and will not be required to have repeat tumour 
imaging for confirmation of progressive disease by iRECIST. 
Patients who are clinically stable and exhibit initial radiographic progressive disease may 
continue to receive study treatment and the tumour assessment should be repeated 4 to 
6 weeks later to confirm progressive disease by iRECIST, per investigator assessment. If 
repeated imaging does not confirm progressive disease per iRECIST, as assessed by the 
investigator, and the patient continues to be clinically stable, study treatment may continue 
and follow the regular imaging schedule. If progressive disease is confirmed, patients will be 
discontinued from study treatment. 
If a patient has confirmed radiographic progression as defined in Appendix 9, study treatment 
should be discontinued; however, if the patient is achieving a clinically meaningful benefit, an 
exception to continue study treatment may be considered following consultation with the 
sponsor. In this case, if study treatment is continued, tumour imaging should follow the 
6-week tumour assessment schedule.  
A summary of imaging and treatment requirements after first radiologic evidence of 
progression is provided in Table 29. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 107/264 
 
Table 29 Imaging and Treatment after First Radiologic Evidence of Progressive Disease 
 
Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
First radiologic 
evidence of PD by 
RECIST v1.1  
Repeat imaging at 
4 to 8 weeks to 
confirm PD 
May continue study 
treatment at the 
investigator’s 
discretion while 
awaiting confirmatory 
tumour imaging by 
site by iRECIST 
Repeat imaging at 
4 to 8 weeks to 
confirm PD per 
investigator’s 
discretion only 
Discontinue treatment 
Repeat tumour 
imaging confirms 
PD (iCPD) by 
iRECIST per 
investigator 
assessment 
No additional 
imaging required 
Discontinue treatment 
(exception is possible 
upon consultation 
with sponsor) 
No additional 
imaging required 
Not applicable 
Repeat tumour 
imaging shows 
iUPD by iRECIST 
per investigator 
assessment 
Repeat imaging at 
4 to 8 weeks to 
confirm PD.  May 
occur at next 
regularly 
scheduled 
imaging visit. 
Continue study 
treatment at the 
investigator’s 
discretion 
Repeat imaging at 
4 to 8 weeks to 
confirm PD per 
investigator’s 
discretion only 
Discontinue treatment 
Repeat tumour 
imaging shows 
iSD, iPR or iCR 
by iRECIST per 
investigator 
assessment. 
Continue 
regularly 
scheduled 
imaging 
assessments 
Continue study 
treatment at the 
investigator’s 
discretion 
Continue 
regularly 
scheduled 
imaging 
assessments 
May restart study 
treatment if condition 
has improved and/or 
clinically stable per 
investigator’s 
discretion. Next tumour 
imaging should occur 
according to the regular 
imaging schedule. 
BICR=Blinded Independent Central Review; iCPD=iRECIST confirmed progressive disease; iCR=iRECIST complete 
response; iRECIST=modified Response Evaluation Criteria in Solid Tumors for immune-based therapeutics; iSD=iRECIST 
stable disease; iUPD=iRECIST unconfirmed progressive disease; PD=progressive disease; RECIST=Response Evaluation 
Criteria in Solid Tumors; VOP=verification of progression 
 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 108/264 
 
8 
ASSESSMENT OF SAFETY 
8.1 
Adverse Events 
Adverse events will be monitored from the time that the patient gives informed consent and 
throughout the study (see Section 3.6 for a definition of the study duration) and will be 
elicited by direct, nonleading questioning. Further details of AE reporting can be found in 
Section 8.1.2. 
8.1.1 
Definition of an Adverse Event 
An AE is the development of an undesirable medical condition or the deterioration of a 
pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product. An undesirable medical condition 
can be symptoms (for example nausea, chest pain), signs (for example tachycardia, enlarged 
liver) or the abnormal results of an investigation (for example laboratory findings, ECG). In 
clinical studies an AE can include an undesirable medical condition occurring at any time, 
including run in or washout periods, even if no IMP has been administered.  
This definition includes events occurring from the time of the patient giving informed consent 
until the end of the study (as defined in Section 3.6). 
Natural progression or deterioration of the malignancy under study will be recorded as part of 
the efficacy evaluation and should not be recorded as an AE/SAE. 
Death due to disease progression will be recorded as part of the efficacy evaluation and will 
not be regarded as an SAE. 
Signs and symptoms should not be reported as AEs/SAEs if they are clearly related to a 
relapse or an expected change or progression of the baseline malignancy. 
These signs and symptoms should only be reported as AEs/SAEs (depending on the 
investigator’s judgement) if they are: 
• 
Judged by the investigator to be unusually severe or an accelerated malignancy, or 
• 
If the investigator considers the deterioration of malignancy signs and symptoms to be 
caused directly by the IMP. 
If there is any uncertainty about an AE being due solely to the malignancy under study, it 
should be reported as an AE/SAE as appropriate. 
The following events must be reported to the sponsor within 24 hours of the site’s awareness, 
irrespective of causality: serum aminotransferases ALT/AST >3×ULN, with increase in total 
serum bilirubin >2×ULN. 
8.1.2 
Categorisation of Adverse Events 
8.1.2.1 
Intensity Classification 
Adverse events will be recorded and graded according to the current version of the 
NCI-CTCAE v5.0. In view of meta-analyses and for conversion purposes, the following 
conversion mapping will apply if the NCI-CTCAE scale is not available for a given AE: 
• 
NCI-CTCAE Grade 1 corresponds to mild, 
• 
NCI-CTCAE Grade 2 corresponds to moderate, 
• 
NCI-CTCAE Grade 3 corresponds to severe, 
• 
NCI-CTCAE Grade 4 corresponds to life threatening/disabling, 
• 
NCI-CTCAE Grade 5 corresponds to death (related to AE). 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 109/264 
 
Where:  
• 
Mild: symptoms do not alter the patient’s normal functioning 
• 
Moderate: symptoms produce some degree of impairment to function, but are not 
hazardous, uncomfortable or embarrassing to the patient 
• 
Severe: symptoms definitely hazardous to wellbeing or causing significant impairment 
of function or incapacitation. 
• 
Life threatening: any event that places the patient at immediate risk of death from the 
event as it occurred, i.e. it does not include a reaction that, had it occurred in a more 
severe form, might have caused death (also see Section 8.1.4). 
8.1.2.2 
Causality Classification 
The relationship of an AE to IMP administration will be classified according to the following: 
• 
Related: 
reports 
including 
good 
reasons 
and 
sufficient 
information 
(for 
example plausible time sequence, dose response relationship, pharmacology, positive 
dechallenge and/or rechallenge) to assume a causal relationship with IMP 
administration in the sense that it is plausible, conceivable or likely. Since attribution of 
an observed toxicity to a new drug can be uncertain, related events should include any 
toxicities considered related, probably related or possibly related to the drug. 
• 
Not related: reports including good reasons and sufficient information (for 
example implausible time sequence and/or attributable to concurrent disease or other 
drugs) to rule out a causal relationship with IMP administration. 
8.1.2.3 
Assessment of Expectedness 
The reference document for assessing expectedness of AEs/event in this study will be the 
current Investigator’s Brochure (IB) for IPN60090, the EU SmPC (for EU centres) or US 
Prescribing Information (for US centres). 
8.1.2.4 
Laboratory Test Abnormalities 
Abnormalities in laboratory test values should only be reported as AEs if any of the following 
apply:  
• 
They result in a change in IMP schedule of administration (change in dosage, delay in 
administration, IMP discontinuation), 
• 
They require intervention or a diagnosis evaluation to assess the risk to the patient, 
• 
They are considered as clinically significant by the investigator. 
8.1.2.5 
Abnormal Physical Examination Findings 
Clinically significant changes, in the judgement of the investigator, in physical examination 
findings (abnormalities) will be recorded as AEs.  
8.1.2.6 
Other Investigation Abnormal Findings 
Abnormal test findings judged by the investigator as clinically significant (for example ECG 
changes, thyroid function disturbances) that result in a change in study drug dosage or 
administration schedule, or in discontinuation of the study drug, or require intervention or 
diagnostic evaluation to assess the risk to the patient, should be recorded as AEs.  
8.1.3 
Recording and Follow-up of Adverse Events 
At each visit, the patient should be asked a nonleading question such as: “How have you felt 
since starting the last assessment?” 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 110/264 
 
All observed or volunteered AEs, regardless of treatment group or suspected causal 
relationship to IMP, will be recorded on the AE page(s) of the eCRF. Events involving drug 
reactions, accidents, illnesses with onset during the treatment phase of the study, or 
exacerbations of pre-existing illnesses should be recorded according to the National Cancer 
Institute terminology if applicable.  
Any AEs already recorded and designated as ‘continuing’ should be reviewed at each 
subsequent assessment. 
For all AEs, the investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as an SAE 
requiring immediate notification to the sponsor or its designated representative. For all AEs, 
sufficient information should be obtained by the investigator to determine the causality of the 
AE (i.e. IMP or other illness). The investigator is required to assess causality and record that 
assessment on the eCRF. Follow-up of the AE, after the date of IMP discontinuation, is 
required if the AE or its sequelae persist. Follow-up is required until the event or its sequelae 
resolve or stabilise at a level acceptable to the investigator and the sponsor’s clinical monitor 
or his/her designated representative. 
All SAEs that are ongoing 30 days after the last dose of study treatment, and AEs assessed 
Grade 3 or 4 that led to study treatment discontinuation that are ongoing 30 days after the date 
of the decision to discontinue study treatment, are to be followed until either: 
• 
the AE has resolved  
• 
the AE has improved to CTCAE Grade 2 or lower  
• 
the investigator determines that the event has become stable or irreversible. 
This follow-up requirement also applies to related SAEs that occur >30 days after the date of 
the decision to discontinue study treatment.  
The status of all other AEs that are ongoing 30 days after the date of the decision to 
discontinue study treatment will be documented as of the Post-Treatment Follow-Up Visit. 
8.1.4 
Reporting of Serious Adverse Events 
All SAEs (as defined below), regardless of treatment group or suspected relationship to IMP, 
must be reported immediately (within 24 hours of the investigator’s knowledge of the event) 
using the electronic data capture (EDC) system. In instances where the EDC system is not 
available, the SAE form must be completed and sent to the email address or fax number (if 
not possible to email) specified at the beginning of this protocol. If the immediate report is 
submitted by telephone, or if the EDC was not available at initial reporting, this must be 
followed by the reporting of this SAE using the EDC system as soon as it becomes available. 
An SAE is any AE that: 
(1) 
Results in death; 
(2) 
Is life threatening, that is any event that places the patient at immediate risk of death 
from the event as it occurred. It does not include an event that, had it occurred in a 
more severe form, might have caused death; 
(3) 
Results in in-patient hospitalisation or prolongation of existing hospitalisation, 
excluding admission for social or administrative reasons (see below); 
(4) 
Results in a persistent or significant disability/incapacity, where disability is a 
substantial disruption of a person's ability to conduct normal life functions; 
(5) 
Results in congenital anomaly/birth defect in the offspring of a patient who received the 
IMP; 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 111/264 
 
(6) 
Is an important medical event that may not result in death, be life threatening, or 
require hospitalisation when, based upon appropriate medical judgement, it may 
jeopardise the patient and may require medical or surgical intervention to prevent one 
of the outcomes listed in this definition. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions that do not result in in-patient hospitalisation, or the 
development of drug dependency or drug abuse. 
In addition to the above criteria, the following events must be reported to the sponsor 
within 24 hours of the site’s awareness, irrespective of causality: serum 
aminotransferases ALT/AST >3×ULN, with increase in total serum bilirubin >2×ULN. 
• 
Hospitalisation is defined as any in-patient admission (even if less than 24 hours). For 
chronic or long-term in-patients, in-patient admission also includes transfer within the 
hospital to an acute/intensive care in-patient unit. 
• 
Prolongation of hospitalisation is defined as any extension of an in-patient 
hospitalisation beyond the stay anticipated/required in relation to the original reason for 
the initial admission, as determined by the investigator or treating physician. For 
protocol-specified hospitalisation in clinical studies, prolongation is defined as any 
extension beyond the length of stay described in the protocol. Prolongation in the 
absence of a precipitating, treatment-emergent, clinical AE (i.e. not associated with the 
development of a new AE or worsening of a pre-existing condition) may meet the 
criteria for "seriousness" but is not an adverse experience and thus is not subject to 
immediate reporting to the sponsor.  
• 
Preplanned or elective treatments/surgical procedures should be noted in the patient’s 
screening 
documentation. 
Hospitalisation 
for 
a 
preplanned 
or 
elective 
treatment/surgical procedure should not be reported as an SAE unless there are 
complications or sequelae that meet the criteria for seriousness described above. 
Any SAE must be reported immediately (within 24 hours) using the EDC system or email 
address or fax number (if not possible to email) specified at the beginning of this protocol in 
case the EDC system is not available, independent of the circumstances or suspected cause, if 
it occurs or comes to the attention of the investigator at any time during the study period. 
Any AE/SAE with a suspected causal relationship to IMP administration occurring at any 
other time after completion of the study must be reported promptly, within 24 hours. 
The following information is the minimum that must be provided to the sponsor within 
24 hours for each SAE: 
• 
study number 
• 
centre number 
• 
patient number 
• 
AE 
• 
investigator's name and contact details. 
The additional information included in the SAE form must be collected on the eCRF as soon 
as it is available. The investigator should always provide an assessment of causality for each 
event reported to the sponsor. Upon receipt of the initial report, the sponsor will ask for the 
investigator's causality assessment if it was not provided initially. 
The investigator should report a diagnosis or a syndrome rather than individual signs or 
symptoms. The investigator should also try to separate a primary AE considered as the 
foremost untoward medical occurrence from secondary AEs that occurred as complications. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 112/264 
 
All AEs meeting serious criteria, from the time of treatment/allocation through 90 days 
following cessation of study treatment, or 30 days following cessation of study treatment if 
the participant initiates new anticancer therapy, whichever occurs first, must be reported by 
the investigator. 
Additionally, any SAE brought to the attention of an investigator at any time outside of the 
time period specified above must be reported immediately to the sponsor if the event is 
considered to be drug-related. 
8.1.5 
Pregnancy 
If pregnancy occurs during the study, the study treatments (IPN60090, pembrolizumab and 
paclitaxel) should be discontinued immediately. The outcome of the pregnancy will be 
collected following completion of the study.  
Information regarding pregnancies must be collected on the AE/SAE page of the eCRF and 
reported to the sponsor as an SAE via the EDC system. The sponsor will request further 
information from the investigator as to the course and outcome of the pregnancy using the 
standard Pregnancy Outcome Report Form.  
The investigator must instruct all female patients to inform them immediately should they 
become pregnant during the study. The investigator should counsel the patient, discuss the 
risks of continuing with the pregnancy and the possible effects on the foetus. Monitoring of 
the patient should continue until conclusion of the pregnancy, which may involve follow-up 
after the patient’s involvement in the study has ended. 
All pregnancies, from the time of treatment/allocation through 120 days following cessation 
of study treatment, or 30 days following cessation of study treatment if the participant initiates 
new anticancer therapy, must be reported by the investigator. 
If the investigator becomes aware of a pregnancy occurring in the partner of a patient 
participating in the study, this should be reported to the sponsor. After the partner has given 
written consent, she should be counselled and followed as described above. Monitoring of the 
partner should continue until conclusion of the pregnancy 
8.1.6 
Deaths 
For AEs leading to death, NCI-CTCAE Grade 5 is the only appropriate grade (see 
Section 8.1.2.1). Deaths that cannot be attributed to an NCI-CTCAE term associated with 
Grade 5 or that cannot be reported within an NCI-CTCAE category as ‘Other’ have to be 
reported as one of these four AE options: 
• 
death not otherwise specified (NOS) 
• 
disease progression NOS 
• 
multi-organ failure 
• 
sudden death. 
8.1.7 
Discontinuation/Withdrawal due to Adverse Events/Serious Adverse Events 
Discontinuation/withdrawal 
due 
to 
AEs 
should 
be 
distinguished 
from 
discontinuation/withdrawal due to insufficient response to the IMP (see Section 4.3). 
If the IMP is discontinued due to an SAE, it must be reported immediately to the sponsor’s 
designated representative (see Section 8.1.4). 
In all cases, the investigator must ensure that the patient receives appropriate medical 
follow-up (see Section 8.1.3). 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 113/264 
 
8.1.8 
Reporting to Competent Authorities/IECs/IRBs/Other Investigators 
The sponsor will ensure that processes are in place for the submission of reports of suspected 
unexpected serious adverse reactions occurring during the study to the CAs, IECs and other 
investigators concerned by the IMP. Reporting will be in accordance with the applicable 
regulatory requirements. 
For study centres in the USA, investigational new drug application safety reports will be 
submitted directly to the investigators. It is the investigators’ responsibility to notify their IRB 
in a timely manner. 
8.2 
Clinical Laboratory Tests 
During the dose escalation part, all clinical safety laboratory tests listed below will be 
performed at local laboratories (except anti-pembrolizumab antibodies). A list of laboratory 
normal ranges should be provided to the sponsor. Any change in laboratory normal ranges 
during the study will be forwarded to the sponsor. During the dose expansion part, safety 
blood samples will also be analysed centrally. 
Blood and urine samples will be collected as per the visit evaluation schedule in Table 14 for 
the evaluation of haematology, serum chemistry and urinalysis. 
The investigator will review the safety laboratory test results, document the review and record 
any clinically relevant changes occurring or observed during the study in the AE section of 
the eCRF (see Section 8.1.2.4 for abnormal laboratory tests that should be recorded as AEs). 
All clinically relevant abnormal laboratory tests occurring during the study will be repeated at 
appropriate intervals until they return to baseline or to a level deemed acceptable by the 
investigator and the sponsor’s clinical monitor (or his/her designated representative) or until 
the abnormality is explained by an appropriate diagnosis.  
8.2.1 
Haematology 
Blood samples (2 mL) (Table 16) will be collected to assess the following variables: red blood 
cell count, haemoglobin, haematocrit, mean corpuscular volume, mean corpuscular 
haemoglobin, mean corpuscular haemoglobin concentration, white blood cell count with 
differential (neutrophils, lymphocytes, monocytes, eosinophils, basophils and others) and 
platelet count. 
8.2.2 
Blood Biochemistry 
Blood samples (5 mL) (Table 16) will be collected to assess the following parameters: 
• 
urea, creatinine, total bilirubin, conjugated bilirubin 
• 
chloride, bicarbonate, sodium, potassium, calcium, phosphate 
• 
ALP, AST, ALT, GGT 
• 
albumin, total protein, total cholesterol, triglycerides, fasting glucose. 
Creatine clearance will be calculated using the Cockcroft-Gault equation and eGFR will be 
calculated based on serum creatinine levels using the modification of diet in renal disease 
formula as follows:  
eGFR 
(mL/min/1.73 m2) 
= 
175 
(serum 
creatinine 
in 
μmol/L×0.011312)−1.154× 
(age)−0.203×(0.742 if female) × (1.212 if African American/black) 
Blood (2mL) (Table 16) will be collected to assess the following coagulation parameters: 
activated partial thromboplastin time, prothrombin time and its derived measures of 
prothrombin ratio and international normalised ratio.  
At screening, patients will have tests for thyroid stimulating hormone. Thyroid stimulating 
hormone assessment will be repeated on Day 1 every three cycles. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 114/264 
 
8.2.3 
Urinalysis 
Fresh urine samples (at least 10 mL) will be collected to assess the following variables: pH, 
protein, ketones, bilirubin, blood, urobilinogen, nitrites, leukocytes, glucose and specific 
gravity by dipstick.  
Microscopy will be performed, if indicated, but results will not be collected on the eCRF. If, 
in the opinion of the investigator, there are any clinically significant abnormalities in 
microscopy, they will be recorded as an AE on the eCRF. 
8.2.4 
Pregnancy Test 
A beta human chorionic gonadotrophin (HCG) serum test will be performed for all female 
patients of childbearing potential at screening (Visit 1). Then an HCG urine test will be 
conducted on Day 1 every three cycles. Any patient becoming pregnant during the study will 
be withdrawn. All pregnancies that occur during the study are to be reported as described in 
Section 8.1.5. 
8.2.5 
Antipembrolizumab Antibody Testing (Part B Only) 
Blood samples (6 mL) should be collected at each time point (Table 14) with serum clot 
activator for the determination of putative binding/neutralising antibodies against 
pembrolizumab. The tubes should be inverted eight times and left for 30 minutes (for a 
maximum of 60 minutes) at ambient temperature and then centrifuged for 10 minutes at 
1300g at 4°C. The resulting serum will be transferred into three aliquots into 2.0 mL 
cryovials: 1 mL for binding antibody samples, 1 mL for neutralising antibody samples, and 
<1 mL for backup samples. Samples should be stored at ≤-20°C. 
Full details regarding required the processing, labelling and shipment processes for these 
samples are provided in the study manual. 
The determination of putative antibodies against pembrolizumab will be evaluated using 
validated methods: ElectroChemiLuminiscence Assay (ECLA) electrochemiluminescent 
bridging assay for binding antibodies and cell-based assay for neutralising antibodies. 
8.3 
Physical Examination 
Physical examinations consisting of: general appearance, dermatological, head/neck, 
pulmonary, cardiovascular, gastrointestinal, genitourinary, lymphatic, musculoskeletal 
system, extremities, eyes, nose, throat, and neurologic status, including body weight, will be 
conducted at baseline (Visit 2), Cycle 1, Day 1, Cycle 1, Day 3, Cycle 1, Day 5, Cycle 1, 
Day 8, Cycle 1, Day 15, then Day 1 of every cycle, and at the End of Study/Early Withdrawal 
visit. Height will be measured at screening. 
Any clinically significant physical examination findings (abnormalities) observed during the 
study will be reported as AEs. Any physical examination findings (abnormalities) persisting at 
the end of the study will be followed by the investigator until resolution or until reaching a 
clinically stable endpoint. 
8.4 
Infusion Reactions and Local Tolerance 
For Parts B and C, local tolerance of pembrolizumab or paclitaxel infusions will be checked. 
The infusion site will be examined by a physician or Medical Research Associate and 
assessed for characteristics such as tenderness, erythema, swelling, rash, pain, itching, 
induration, haematoma, ulceration or necrosis. If present, the extent of erythema, haematoma, 
rash, ulceration or necrosis will be described and assessed quantitatively; this will at least 
include measurement of maximum length and maximum width.  
Infusion related reactions such as hypersensitivity reactions or cytokine release syndromes 
with symptoms including flushing, alternation in heart rate and blood pressure, dyspnoea, 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 115/264 
 
bronchospasm, back pain, fever, urticaria, oedema, nausea and all types of rashes must be 
recorded as AEs on the eCRF. Transient infusion related reactions that can be controlled by 
medication should not be recorded as a DLT if occurring during the DLT observation period. 
8.5 
Vital Signs 
Blood pressure and heart rate will be assessed with an automated device so that measurements 
are independent of the observer. Blood pressure and heart rate will be recorded after 
5 minutes’ rest in a sitting position. Absolute values and change from baseline will be 
analysed. 
Respiratory rate and temperature will be recorded. 
8.6 
Electrocardiography 
At screening and during the study, triplicate ECG assessments will be performed with 
standard 12-lead ECG equipment according to standard procedures to determine the QTcF. 
For eligibility, a QTcF ≤470 ms for females, and ≤450 ms for males within 28 days before the 
first dose of study treatment is required. ECGs should be performed approximately 2 minutes 
apart when in triplicate, and should always be done just before any blood draw.  
ECGs will be performed at the time points indicated in Table 14 and as clinically indicated. A 
more detailed ECG assessment schedule is listed in Table 30.  
Table 30 Electrocardiogram Timepoints 
Visit 
Timepoint 
Method  
Screening 
Day (D) -28 to D -1 (Parts A to C) 
and D -28 to D -8 (Part D) 
Triplicate 
Run-in, Day -7 and Day -3  
(Part D only) 
1 hours postdose 
Triplicate 
2 hours postdose 
Triplicate 
4 hours postdose 
Triplicate 
Cycle 1, Day 1 
30 minutes postdose 
Triplicate 
1 hours postdose 
Triplicate 
2 hours postdose 
Triplicate 
4 hours postdose 
Triplicate 
8 hours postdose 
Triplicate 
12 hours postdose 
Triplicate 
Cycle 2, Day 1 
Predose 
Triplicate 
30 minutes postdose 
Triplicate 
1 hours postdose 
Triplicate 
2 hours postdose 
Triplicate 
4 hours postdose 
Triplicate 
8 hours postdose 
Triplicate 
12 hours postdose 
Triplicate 
Cycle 3, Day 1 
Predose 
Triplicate 
Cycle 4, Day 1 
Predose 
Triplicate 
End of treatment 
30 days after last dose 
Triplicate 
Abnormalities in the ECG that lead to a change in patient management (such as dose 
reduction or interruption, discontinuation of treatment, or requirement for additional 
medication or monitoring) or results in clinical signs and symptoms that are considered 
clinically significant for the purposes of this study, will be deemed AEs. If the values meet the 
criteria defining them as serious, they must be reported as SAEs. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 116/264 
 
The Fridericia formula is depicted below for calculation of QTcF. 
 
QT=measured QT interval in milliseconds; RR=measured R to R interval (which can be derived from the heart rate as 
60/heart rate). 
8.7 
Echocardiogram/multigated acquisition 
Echocardiogram or multigated acquisition assessment will be performed at screening and at 
the end of study (EOS), or at any point if clinically indicated. For eligibility, LVEF of >50% 
at screening is required. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 117/264 
 
9 
ASSESSMENTS OF PHARMACOKINETICS/PHARMACODYNAMICS 
9.1 
Pharmacokinetics 
9.1.1 
Sample Collection 
9.1.1.1 
Assessment of IPN60090 Plasma Concentrations 
Blood samples for the determination of IPN60090 are described in Table 31.  
Table 31 Timepoints for IPN60090 PK Blood Sample Determination 
Visit 
Timepoint 
Volume  
Run-in phase Day -7 
(Part D only) 
Predose 
2.0 mL 
30 minutes postdose 
2.0 mL 
1 hour postdose 
2.0 mL 
2 hours postdose 
2.0 mL 
4 hours postdose 
2.0 mL 
8 hours postdose 
2.0 mL 
12 hours postdose 
2.0 mL 
24 hours postdose 
2.0 mL 
48 hours postdose 
2.0 mL 
72 hours postdose 
2.0 mL 
Run-in phase Day -3 
(Part D only) 
Predose 
2.0 mL 
30 minutes postdose 
2.0 mL 
1 hour postdose 
2.0 mL 
2 hours postdose 
2.0 mL 
4 hours postdose 
2.0 mL 
8 hours postdose 
2.0 mL 
12 hours postdose 
2.0 mL 
24 hours postdose 
2.0 mL 
48 hours postdose 
2.0 mL 
72 hours postdose 
2.0 mL 
Cycle 1, Day 1 
Predose 
2.0 mL 
30 minutes postdose 
2.0 mL 
1 hour postdose 
2.0 mL 
2 hours postdose 
2.0 mL 
4 hours postdose 
2.0 mL 
8 hours postdose 
2.0 mL 
12 hours postdose 
2.0 mL 
Cycle 1, Day 2 
Predose 
2.0 mL 
Cycle 1, Day 14 
Predose 
2.0 mL 
30 minutes postdose 
2.0 mL 
1 hour postdose 
2.0 mL 
2 hours postdose 
2.0 mL 
4 hours postdose 
2.0 mL 
8 hours postdose 
2.0 mL 
12 hours postdose 
2.0 mL 
Cycle 1, Day 15 
Predose 
2.0 mL 
2 to 4 hours postdose 
2.0 mL 
Cycle 2, Day 1 
Predose 
2.0 mL 
2 hours postdose 
2.0 mL 
Cycle 3, Day 1 
Predose 
2.0 mL 
2 hours postdose 
2.0 mL 
Cycle 4, Day 1 
Predose 
2.0 mL 
2 hours postdose 
2.0 mL 
All cycles after Cycle 4 
Predose 
2.0 mL 
2 hours postdose 
2.0 mL 
End of study 
 
2.0 mL 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 118/264 
 
During the study, the nominal sample collection times may be changed, but the total number 
of samples will not increase. The exact dates and times of blood sample collection, study drug 
administration and vomiting events within 2 hours of administration must be recorded on the 
eCRF.  
Blood samples (2.0 mL) should be collected in a K2-ethylenediaminetetraacetic acid (EDTA) 
tube at each time point and gently inverted eight times. The tubes will be centrifuged at 4ºC 
for 10 minutes. The resulting plasma will be stored at -80°C ±10°C in polypropylene tubes, as 
two 500 μL aliquots, prior to shipment to the analysis laboratory: MD Anderson Cancer 
Centre, USA for IPN60090 during the dose escalation and Kymos Pharma Services, Spain for 
IPN60090 during the dose expansion. Each tube should be labelled in accordance with the 
sponsor’s requirements. Aliquots will be shipped on dry ice. 
9.1.1.2 
Assessment of IPN60090 Urine Concentrations 
Assessment of IPN60090 urine concentrations are part of the exploratory endpoint and will be 
performed for the Part A dose escalation only. Assessment of IPN60090 urine concentrations 
will be performed at the MD Anderson Cancer Centre, USA. 
The urine collection intervals are indicated in the study schedule of assessments (Table 14). 
Urine collection will start after a request to the patient to empty his or her bladder following 
the morning dose. All urine voided during the collection interval will be retained.  
9.1.1.3 
Assessment of Pembrolizumab Serum Concentrations 
The time points for blood sampling for pembrolizumab determination are indicated in 
Table 14 and Table 32. Blood samples (2.0 mL) should be collected at each time point with 
serum clot activator for the determination of serum pembrolizumab levels. Blood samples 
should be collected from the contralateral arm used for the study drug infusion, or from 
another anatomical site. After blood collection, the tubes should be inverted eight times and 
left for 30 minutes (for a maximum of 60 minutes) at ambient temperature and then 
centrifuged for 10 minutes at 1300g at 4°C. The resulting serum should be transferred into 
two aliquots in 2.0 mL cryovials (0.5 mL for the determination of the PK of pembrolizumab 
and <0.5 mL for backup samples). Samples should be stored at ≤̻20°C prior to shipment to 
the analysis laboratory for pembrolizumab level determination. 
Table 32 Additional Timepoints for PK Pembrolizumab Blood Sampling of Patients in Part B 
Visit 
Timepoint 
Volume  
Cycle 1, Day 1 
Pre-pembrolizumab infusion 
2.0 mL 
Cycle 2, Day 1 
Pre-pembrolizumab infusion 
2.0 mL 
Cycle 3, Day 1 
Pre-pembrolizumab infusion 
2.0 mL 
Cycle 4, Day 1 
Pre-pembrolizumab infusion 
2.0 mL 
Full details regarding processing, labelling and shipment processes for these samples are 
provided in the study manual. 
Pembrolizumab blood levels will be determined using a validated, specific and sensitive solid 
phase enzyme-linked immunosorbent assay (ELISA) based on the sandwich principle. 
9.1.1.4 
Assessment of Paclitaxel Plasma Concentrations 
Blood samples for the determination of paclitaxel are described in Table 33.  


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 119/264 
 
Table 33 Additional Timepoints for PK Paclitaxel Blood Sampling of Patients in Part C 
Visit 
Timepoint 
Volume  
Cycle 1, Day 1 
Pre-paclitaxel infusion 
2.0 mL 
Post-paclitaxel infusion[a] 
2.0 mL 
Cycle 2, Day 1 
Pre-paclitaxel infusion 
2.0 mL 
Post-paclitaxel infusion[a] 
2.0 mL 
Cycle 3, Day 1 
Pre-paclitaxel infusion 
2.0 mL 
Post-paclitaxel infusion[a] 
2.0 mL 
a 
i.e. 3 hours after the start of the infusion 
Blood samples (2.0 mL) should be collected from the uninfused arm, in a K2-EDTA tube at 
each time point and gently inverted eight times. The samples should be centrifuged at 2000g 
at 4°C for 10 minutes. The resulting plasma will be stored at -80°C ±10°C in polypropylene 
tubes as two 500 μL aliquots (primary and back-up) prior to shipment to the analysis 
laboratory for paclitaxel level determination. 
9.1.2 
Analytical Procedures 
Plasma samples will be analysed to determine concentrations of IPN60090 during dose 
escalation using a validated, specific and sensitive liquid chromatography (LC)-mass 
spectrometry (MS)/MS method at MD Anderson Cancer Centre, USA.  
Plasma samples will be analysed to determine concentrations of IPN60090 (dose expansion) 
and paclitaxel (dose escalation and dose expansion) using a validated, specific and sensitive 
LC-MS/MS method. 
Urine samples will be analysed to determine urine IPN60090 concentrations. Assessment of 
IPN60090 urine concentrations will be performed at MD Anderson Cancer Centre, USA. 
Serum samples will be analysed to determine concentrations of pembrolizumab using a 
validated, specific and sensitive solid phase ELISA based on the sandwich principle.  
An analytical method for the determination of the presence of binding antibodies to 
pembrolizumab in human serum by ECLA in a bridging format will be developed and 
validated. 
For neutralising anti-pembrolizumab antibodies, a cell-based assay consisting in coculture of 
PD-1 effector cells and PD-L1 expressing cells and induction of T-cell receptor-mediated 
luminescence by blockade of PD-1/PD-L1 interaction with pembrolizumab will be developed 
and validated. 
9.1.3 
Data Analysis 
Individual plasma concentrations of IPN60090 will be listed and summarised by timepoint 
and dose level using descriptive statistics for continuous variables (number of available 
observations, mean, median, standard deviation, minimum, maximum, geometric mean and 
geometric coefficient of variation assuming log-normally distributed data). Linear and 
semilogarithmic plots of individual and mean plasma concentration-time profiles as well as 
spaghetti plots will be reported. 
The PK of IPN600900 plasma concentrations will be performed using noncompartmental 
analysis. The following PK parameters will be calculated:  
• 
Cmax 
• 
Tmax 
• 
Ctrough  
• 
AUC  
• 
t1/2 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 120/264 
 
• 
CL/F 
• 
V/F 
Additional PK parameters may be calculated. Dose proportionality of IPN60090 will be 
assessed over the dose ranges tested. 
Descriptive statistics of PK parameters will be provided. 
Urine IPN60090 concentrations are part of the exploratory endpoints. The amount excreted in 
urine and the renal clearance will be calculated if feasible. 
The noncompartmental analysis plan will be detailed in a separate Data Analysis Plan and 
reported as a stand-alone report. 
Population PK modelling will be performed to describe the PK profile of IPN60090 in 
patients by quantifying the degree of interpatient variability on the PK parameters of 
IPN60090 and the residual unexplained variability in the data and identifying the individual 
patient characteristics (covariates) that can have an impact on the PK parameters explaining 
part of their interpatient variability. 
The population PK plan will be detailed in a separate Data Analysis Plan and reported as a 
stand-alone report. 
For pembrolizumab and paclitaxel, Cmin concentrations and descriptive statistics will be 
reported. For paclitaxel, Cmax and Cmin concentrations and descriptive statistics will be 
reported. 
In Part B, the percentage of patients developing antibodies against pembrolizumab will be 
calculated at each time point. The potential impact of the antibodies against pembrolizumab 
on the concentrations of pembrolizumab will be explored. 
9.2 
Pharmacodynamic Biomarkers 
Pharmacodynamic endpoints with the evaluation of Glu:Gln ratio will be assessed in PBMC 
at the timepoints shown in Table 34. 
Table 34 Collection Time Points for PD evaluation in PBMC 
Visit 
Timepoint 
Volume 
Cycle 1, Day 1 
Predose  
4 tubes x 6 mL for PBMC isolation 
2 hours postdose 
2 tubes x 6 mL for PBMC isolation 
12 hours postdose 
2 tubes x 6 mL for PBMC isolation 
Cycle 1, Day 14 
Predose 
2 tubes x 6 mL for PBMC isolation 
2 hours postdose 
2 tubes x 6 mL for PBMC isolation 
12 hours postdose 
2 tubes x 6 mL for PBMC isolation 
Cycle 1, Day 15  
Predose 
2 tubes x 6 mL for PBMC isolation 
2 to 4 hours postdose 
2 tubes x 6 mL for PBMC isolation 
Two tubes of 6 mL collections per timepoint are needed to ensure the possibility of running 
the assay by purifying a sufficient number of PBMCs for analysis and procuring a back-up 
pellet for biobanking. At Cycle 1, Day 1 predose only, two additional tubes of 6 mL blood are 
needed to be used as quality control samples. In this case, a total of four tubes of 6 mL of 
blood are required at Cycle 1, Day 1 predose. At Cycle 1, Day 14 and Cycle 1, Day 15, two 
tubes of 6 mL will be collected at each time point. 
9.3 
Pharmacokinetics/Pharmacodynamics Interactions 
Pharmacokinetic/PD modelling will be performed, if feasible, to describe the relationship 
between relevant selected biomarkers and/or efficacy parameters and/or adverse effects and 
PK descriptors. A PK/PD modelling plan will be described in a separate Data Analysis Plan 
and results will be reported in a standalone report. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 121/264 
 
10 
BIOMARKER EVALUATION AND BIOBANKING 
10.1 
Biomarker Evaluation  
10.1.1 
Collection of Biopsies for Biomarker Analysis 
Fresh and/or archival tumour tissue from the biopsy obtained between the completion of the 
most recent line of treatment until study entry must be available for mutation and biomarker 
analysis unless KEAP1/NRF2 mutations were present in any previous biopsy, in which case, 
no further biopsy is required. For ovarian cancer patients, both archival biopsies obtained 
between the completion of the most recent line of treatment until study entry and fresh 
biopsies must be available to evaluate the evolution of ASNS levels over time. A fresh tumour 
biopsy is performed at the screening visit, Cycle 1, Day 15, and the EOS/early 
withdrawal (EOS/EW [separate consent is required]). The EOS fresh biopsy is optional and 
requires an additional informed consent for collection. If available, a biopsy at initial 
diagnosis will be also collected for biomarker analysis. 
10.1.2 
Collection of cfDNA for Biomarker Analysis 
Blood samples (10 mL) will be collected in cfDNA (Streck tubes) for plasma isolation and 
will be used for biomarker analysis. Sampling is done at screening, on Cycle 1, Day 15 
(predose), Cycle 3, Day 1 (predose), then on Day 1 of every other cycle after Cycle 3 
(predose) and at EOS/EW.  
10.1.3 
Biomarkers of Patient Stratification 
KEAP1/NRF2 mutations and ASNS levels will be evaluated in fresh and/or archival biopsies 
and will be correlated with clinical outcome. 
10.1.4 
Biomarkers of Disease Evolution Under Treatment 
In HGSOC patients, blood samples (2 mL) will also be collected for serum Ca-125 
assessment at baseline, on Day 1 of Cycle 3 and then on Day 1 of every other cycle. 
10.2 
Exploratory Biomarkers 
Biomarkers of tumour biology evolution under treatment (e.g. immune profiling, PD-L1 
expression, Ki67, phosphorylation of histone variant H2AX (γH2AX), LKB1, etc) may be 
evaluated and correlated with clinical outcome. 
10.3 
Biobanking 
Instructions for collection, processing, handling and shipment of the biobanking samples will 
be outlined in the laboratory manual. 
Samples to be used for biobanking storage will be taken for those individuals who have 
signed a specific consent for the biobank samples at a different visit depending on sampling 
type as described below. 
10.3.1 
Serum 
Blood samples (2.5 mL) will be collected in specific dry tubes for serum isolation and frozen 
for storage. 
Sampling is done on Cycle 1, Day 1 (predose and postdose), Cycle 1, Day 15, Day 1 of each 
following cycle and EOS/EW. 
10.3.2 
Plasma 
Blood samples (2 mL) will be collected in specific EDTA tubes for plasma isolation and 
frozen for storage. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 122/264 
 
Sampling is done on Cycle 1, Day 1 (predose and postdose), Cycle 1, Day 15, Day 1 of each 
following cycle and EOS/EW. 
10.3.3 
Blood for RNA for Biobank 
Blood samples (2.5 mL) will be collected in PAXgene RNA tubes and frozen for storage. 
Sampling is done on Cycle 1, Day 1 (predose and postdose), Cycle 1, Day 15, Day 1 of each 
following cycle and EOS/EW. 
10.3.4 
Blood for DNA for Biobank 
Blood samples (2.5 mL) will be collected in PAXgene DNA tubes and frozen for storage. 
Sampling is done on Cycle 1, Day 1 (predose only). 
10.3.5 
Blood for CfDNA for Biobank 
Blood samples (10 mL) will be collected in CfDNA (Streck tubes) for plasma isolation and 
frozen for storage. 
Sampling is done on Cycle 1, Day 1, Cycle 1, Day 15, Cycle 3, Day 1, then on Day 1 of every 
other cycle after Cycle 3 and at EOS/EW. 
10.3.6 
Blood for PBMC 
Remaining and not used PBMC for PD biomarker evaluation (see Section 9.2) should be 
biobanked.  
Sampling is done on Cycle 1, Day 1 (predose, and 2 and 12 hours postdose), Cycle 1, Day 14 
(predose, and 2 and 12 hours postdose) and Cycle 1, Day 15 (predose, and 2 to 4 hours 
postdose). 
10.3.7 
Stools 
The sampling procedure will be outlined in a laboratory manual. 
Sampling is done on Cycle 1, Day 1 (predose), Cycle 1, Day 15 (predose) and EOS/EW. 
10.3.8 
Leftover Tissue Material and Additional Biopsies for Biobanking 
Leftover tissue material from mandatory biopsies used for biomarker analysis (e.g. remaining 
formalin-fixed paraffin-embedded blocks) and additional fresh biopsies (fine-needle 
aspiration and/or core biopsies) collected will be used for biobanking (if patient consent is on 
the check box for the biobanking in the ICF). 
Samples will be biobanked for future analysis of intratumour or circulating biomarkers, 
including proteins, pharmacogenetic and pharmacogenomic biomarkers and will only be 
collected for those patients who have agreed to it by signing the specific ICF for the 
exploratory part of the study (see Section 14.2.1). 
The biobanked samples will be stored for up to 15 years from the end of the study, to be made 
available for future research towards further understanding of (i) treatment response 
including, but not limited to, the safety profile, (ii) drug treatment mode of actions and 
(iii) disease understanding. 
Samples will be archived in a central biorepository designated by the sponsor and according 
to local administration regulations and/or the European Medicines Agency and will not carry 
personal identification (for example social security number or name). Analysis of additional 
biomarkers (including potential genetic research) from the biobank samples will be performed 
outside the scope of the main study and reported separately. 
Only people designated by the sponsor will be allowed access to the samples. All information 
collected will be kept strictly confidential and all clinical information will be de-identified. 
This means that no personally identifiable information will be retained with the results of the 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 123/264 
 
exploratory analyses, so that no individual or collective results will be linked to the individual 
patient whose sample was taken in the study. No individual genetic results will be 
communicated to the investigator or patient unless required by local regulations. 
The sponsor will comply with all local regulations related to the establishment, management 
and application of a human blood samples biobank. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 124/264 
 
11 
STATISTICS 
Statistical analyses will be performed by an external contract research organisation (CRO), 
managed by the sponsor’s biometry department. 
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a SAP. The SAP may modify the plans outlined in the protocol; 
however, any major modifications of the primary or secondary endpoints and/or their analysis 
will also be reflected in a protocol amendment. 
Statistical evaluation will be performed using SAS® (version 9 or higher). 
Data will be listed and summarised by dose level and part in the dose escalation phase; by 
cohort and part for safety and by cohort for efficacy in the dose expansion phase. Safety 
results will be presented for all the patients included in the study at the RD (dose escalation 
and dose expansion phases) by part and RD. Furthermore, all safety and efficacy results could 
be presented by group of patients depending on the interest there may be in these groups. 
Categorical variables will be summarised by frequency distributions (number and percentages 
of patients). The 95% confidence interval (CI) will be calculated following the exact method. 
Continuous variables will be summarised by descriptive statistics (mean, standard deviation, 
median, minimum and maximum).  
Time-to-event variables will be summarised using the Kaplan-Meier method and the 95% CI 
of the median will be given. 
11.1 
Analysis Populations 
The following populations will be defined during statistical analyses: 
• 
Screened population: All patients screened (i.e. who signed the informed consent). 
• 
Safety population: All patients who are exposed to (or started receiving) IPN60090 
and/or the combination agents.  
• 
DLT evaluable population for the escalation phase only: All patients from the safety 
population who are evaluable for DLT (patients who have completed at least one cycle 
of treatment and have received ≥75% of the total planned dose of IPN60090 over the 
DLT assessment period). Patients with noncompliance (<75% of total planned dose) 
due to DLT will be included in this population). 
• 
Efficacy population: All patients who receive at least one dose of IPN60090. 
• 
Pharmacokinetic population for noncompartmental analysis: All patients who have 
no major protocol deviation affecting the PK variables and who have a sufficient 
number of IPN60090 plasma concentrations to estimate the main PK parameters (Cmax, 
Tmax, area under the plasma concentration time curve from time 0 to the last time point 
with quantifiable concentrations (AUC0-last)).  
• 
Pharmacokinetic population for population PK modelling: All patients who receive 
at least one IPN60090 dose and who have at least one plasma IPN60090 concentration 
and who have no major protocol deviation affecting the PK variables. 
• 
Food effect population: All patients in Part D who have received IPN60090 under 
fasting and fed conditions (Day -7 and Day -3), have consumed ≥80% of the moderate 
fat meal in approximately 30 minutes on Day -3, and who have no major protocol 
deviation affecting the PK variables and who have a sufficient number of IPN60090 
plasma concentrations to estimate the main PK parameters (Cmax, Tmax and AUC0-last). 
• 
Pharmacodynamic population: All patients who have at least one PD endpoint 
measurement. PD endpoints refer to target engagement levels (Glu:Gln ratio in PBMC). 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 125/264 
 
11.1.1 
Populations Analysed 
The analyses of safety data will be performed on the safety population and DLT evaluable 
population when applicable. 
The analyses of PK data will be performed on the PK population. 
The analyses of anti-tumour activity will be performed on the efficacy population. 
The analyses of PD parameters will be performed on the PD population. 
The analyses of food effect PK parameters will be performed on the food effect population. 
11.1.2 
Reasons for Exclusion from the Analyses 
Any major protocol deviation (see Section 13.1.2 for definition) will be described and its 
impact on inclusion in each analysis population (efficacy, PK and safety populations) for any 
patient will be specified. The final list of protocol deviations impacting the populations will 
be reviewed prior to database lock. 
11.2 
Statistical Methods for Dose Escalation Phase and Food Effect 
11.2.1 
Sample Size Determination 
11.2.1.1 Monotherapy Dose Escalation – Part A 
A BOIN design with target toxicity rate of 30% (with escalation and de-escalation thresholds 
of 23.6% and 35.9%, respectively) with maximum number of approximately 30 patients will 
be used to estimate the IPN60090 monotherapy MTD.  
The design will proceed with accelerated titration up to DL3, i.e. cohorts of one will be 
enrolled until either the third dose level is evaluated, a Grade 2 AE that is at least possibly 
related to the study drug(s) occurs, or a DLT is observed (whichever occurs first). If a Grade 2 
AE that is at least possibly related to the study drug(s) or a DLT is observed in a single patient 
cohort (i.e. in one of the first three dose levels), two additional patients will be added at this 
dose level with the same rules for escalation and de-escalation as the cohorts of three patients 
detailed below. 
If the DLT rate within a cohort at a given dose level is less than the escalation boundary of 
23.6% the rule is then to escalate, if the DLT rate is higher than the de-escalation boundary of 
35.9% then the rule is either to de-escalate, or to retain the dose or to stop if the maximum 
sample size is reached. Following the requisite follow-up in a cohort, the dose level for the 
next cohort will be determined using the decision rules in Table 35, where ↑indicates the next 
cohort at one dose level higher, ↓ indicates the next dose level at one dose level lower and 
“Elim” indicates that the dose level (and all higher dose levels) is removed from further 
consideration. 
Table 35 Dose Escalation Decision Rules 
 
Number of patients at current dose level 
Action 
3 
4 
5 
6 
7 
8 
9 
10 
↑ if number of DLT ≤ 
0 
0 
1 
1 
1 
1 
2 
2 
Stay current dose if DLT 
1 
1 
- 
2 
2 
2 
3 
3 
↓ if number of DLT ≥ 
2 
2 
2 
3 
3 
3 
4 
4 
Elim if number of DLT ≥ 
3 
3 
4 
4 
5 
5 
5 
6 
DLT=dose limiting toxicity; Elim=eliminate 
In the event that operational/practical circumstances result in an over-enrolment (i.e. n>3) for 
a BOIN cohort, the next dose level decision would be based on the actual number of patients 
exposed in the cohort and the BOIN criteria. 
If none of the actions is indicated, then the next cohort is enrolled at the same dose level as 
the current dose level. If the current dose level is the lowest dose level and the action 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 126/264 
 
indicated is de-escalation, then the next cohort is enrolled at the same dose level (i.e. the 
lowest dose level). Similarly, if the current dose level is the highest dose level and the action 
indicated is escalation then the next cohort is treated at the same dose level. When a dose is 
eliminated, the next cohort is enrolled at the next lower dose level. If the lowest dose is 
eliminated, then the study is stopped and none of the dose levels is selected as the MTD.  
The study will continue until one of the following occurs: 
(a) 
the maximum number of patients has been reached (approximately 30) 
(b) 
the decision indicated by the table would result in adding patients to a dose level where 
at least nine patients have already been treated 
(c) 
the number of patients treated at the lowest dose level is ≥3 and the probability that the 
DLT rate at the lowest dose level exceeds the target is >0.90.  
When (a) or (b) occurs, the MTD of IPN60090 will be estimated as the dose level at which the 
isotonic estimate of the DLT rate is closest to 30%. If there are ties, the MTD is selected as 
the higher dose level when the isotonic estimate is lower than the target toxicity rate and 
selected as the lower dose level when the isotonic estimate is greater than or equal to the 
target toxicity rate. The operating characteristics for the MTD dose selected for the planned 
design for seven true DLT rate scenarios were estimated by simulation of 2000 studies per 
scenario.  
 


IPSEN GROUP 
D-US-60090-001 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 127/264 
 
Table 36 Operating Characteristics for Monotherapy BOIN Dose Finding from Simulation 
Scenario 
True DLT rate 
for DL1 
%MTD is DL1 
(avg n ) 
True DLT rate 
for DL2 
%MTD is DL2 
(avg n) 
True DLT rate 
for DL3 
%MTD is DL3 
(avg n) 
True DLT rate 
for DL4 
%MTD is DL4 
(avg n) 
True DLT rate 
for DL5 
%MTD is DL5 
(avg n) 
True DLT rate 
for DL6 
%MTD is DL6 
(avg n) 
True DLT rate 
for DL7 
%MTD is DL7 
(avg n) 
Average 
number of 
patients to be 
enrolled 
% early stop 
1 
0.025 
<1 
(1.1) 
0.05 
<1 
(1.4) 
0.075 
1 
(1.7) 
0.10 
4 
(4.4) 
0.15 
13  
(5.0) 
0.20 
20  
(5.2) 
0.25 
61 
(5.9) 
24.7 
<1 
2 
0.025 
<1 
(1.1) 
0.05 
<1  
(1.4) 
0.075 
2  
(1.9) 
0.125 
10 
(4.9) 
0.20 
23 
(5.6) 
0.25 
26 
(5.0) 
0.30 
39  
(4.1) 
24.0 
<1 
3 
0.025 
<1 
(1.1) 
0.05 
<1 
(1.5) 
0.10 
4  
(2.2) 
0.15 
17  
(5.5) 
0.25 
33  
(6.1) 
0.30 
32  
(4.6) 
0.45 
14  
(2.3) 
23.3 
<1 
4 
0.025 
<1  
(1.1) 
0.05 
<1  
(1.5) 
0.10 
6  
(2.7) 
0.20 
30  
(6.3) 
0.30 
45  
(6.3) 
0.45 
16  
(3.4) 
0.55 
2  
(0.7) 
22.0 
<1 
5 
0.05 
<1  
(1.4) 
0.10 
5 
(2.6) 
0.20 
27 
(4.9) 
0.30 
47  
(6.8) 
0.45 
17  
(3.9) 
0.55 
3  
(0.9) 
0.65 
<1  
(0.1) 
20.5 
<1 
6 
0.075 
2  
(1.8) 
0.15 
22  
(4.8) 
0.30 
55 
(7.4) 
0.50 
20  
(4.9) 
0.70 
<1 
(0.9) 
0.80 
0 
(<0.1) 
0.85 
0  
(<0.1) 
19.8 
1 
7 
0.15 
20 
(4.7) 
0.30 
58  
(7.7) 
0.50 
17 
(5.0) 
0.70 
1  
(1.6) 
0.80 
0 
(0.1) 
0.85 
0 
(<0.1) 
0.90 
0  
( 0) 
19.1 
5 
8 
0.30 
50 
(7.0) 
0.45 
23  
(5.5) 
0.60 
3 
(2.3) 
0.75 
0  
(0.6) 
0.85 
0  
(<0.1) 
0.90 
0  
( 0) 
0.95 
0  
( 0) 
10.4 
24 
avg n=the average number of patients treated at each dose level; BOIN=Bayesian Optimal Interval; DL=dose level; DLT=dose limiting toxicity; MTD=maximum tolerated dose 
% early stop is the percentage of times the study would stop early due to case (c) 
% MTD is DLx means selection percentage at dose level x 
 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 128/264 
 
 
11.2.1.2 Combination Dose Escalation – Parts B and C 
A BOIN design with target toxicity rate of 30% (with escalation and de-escalation thresholds 
of 23.6% and 35.9%, respectively) with maximum number of approximately 18 patients (for 
each combination dose finding) will be used to estimate the IPN60090 combination MTD. 
The design will enrol up to six cohorts of three patients. Patients in the first cohort will be 
treated at combination DL1. Because the escalation and de-escalation thresholds are the same 
as those used for the monotherapy, the escalation and de-escalation rules as a function of 
number of patients treated are the same as those presented for the monotherapy.  
The study will continue until one of the following occurs: 
(a) 
the maximum number of patients has been reached (approximately18) 
(b) 
the decision indicated by the table would result in the number of patients at a dose level 
exceeding nine patients 
(c) 
the number of patients treated at the lowest dose level is ≥3 and the probability that the 
DLT rate at the lowest dose level exceeds the target is greater than 0.90. 
In the event that operational/practical circumstances result in an over-enrolment (i.e. n>3) for 
a BOIN cohort, the next dose level decision would be based on the actual number of patients 
exposed in the cohort and the BOIN criteria. 
When (a) or (b) occurs, the MTD of IPN60090 will be estimated as the dose level at which the 
isotonic estimate of the DLT rate is closest to 30%. If there are ties, the MTD is selected as 
the higher dose level when the isotonic estimate is lower than the target toxicity rate and 
selected as the lower dose level when the isotonic estimate is greater than or equal to the 
target toxicity rate. The operating characteristics for the MTD dose selected for the planned 
design for the following true DLT rate scenarios were estimated by simulation (R package 
BOIN) of 2000 studies per scenario. 
Table 37 Operating Characteristics for Combination BOIN Dose Finding from Simulation  
Scenario  
True DLT rate 
for DL1 
 
%MTD is DL1 
 
(avg n DL1) 
True DLT rate 
for DL2 
 
%MTD is DL2 
 
(avg n DL2) 
True DLT rate 
for DL3 
%MTD is DL3 
(avg n DL3) 
Average/expected 
number of 
patients to be 
enrolled 
% early stop 
1 
0.10 
12 
(4.3) 
0.20 
35 
(5.4) 
0.30 
50 
(5.2) 
14.9 
3 
2 
0.20 
29 
(5.3) 
0.30 
44 
(5.6) 
0.40 
21  
(2.9) 
13.8 
6 
3 
0.30 
49 
(6.4) 
0.40 
22 
(3.4) 
0.50 
5 
(1.0) 
10.7 
24 
avg n=the average number of patients treated at each dose level; BOIN=Bayesian Optimal Interval; DL=dose level; 
DLT=dose limiting toxicity; MTD=maximum tolerated dose 
% early stop is the percentage of times the study would stop early due to case (c) 
% MTD is DLx means selection percentage at dose level x 
11.2.1.3 Sample Size for Part D 
The sample size (n=8) is not based on statistical calculation. A sample size of eight patients 
allows for a preliminary assessment of the potential effect of food on the PK of IPN60090. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 129/264 
 
 
11.2.2 
Significance Testing and Estimations 
As this is a descriptive safety and tolerability/efficacy dose escalation phase, no formal 
statistical testing will be carried out. 
11.2.3 
Statistical Methods 
11.2.3.1 Demographic and Other Baseline Characteristics 
Descriptive summary statistics (n, mean, standard deviation, median, minimum, maximum) 
and frequency counts of demographic and baseline data including disease characteristics at 
diagnosis, medical history, prior and concomitant medications, and tumour assessment at 
baseline will be presented for the safety population and per dose level. 
Medical and surgical history findings will be summarised using Medical Dictionary for 
Regulatory Activities (MedDRA) terms. 
Unless prohibited by local regulation, race and ethnicity will be collected to ensure data 
robustness for safety and efficacy evaluation and to prevent adverse reactions or improve 
benefits in the target population. 
11.2.3.2 Patient Disposition and Withdrawals 
The numbers and percentages of patients enrolled and included in each population will be 
tabulated by dose level and overall. The reasons for patient exclusions from each of the 
populations will also be tabulated. Primary reasons for discontinuation of study treatments 
(IPN60090, pembrolizumab or paclitaxel) will be tabulated 
11.2.3.3 Pharmacokinetic Data 
For methodology, please refer Section 9.1.3. 
11.2.3.4 Anti-tumour Activity Evaluation 
Tumour response will be assessed locally by investigators. Response and progression will be 
evaluated using the revised RECIST guideline v1.1 or iRECIST guideline (Part B only). 
The analyses will be carried out on patients in the efficacy population by dose level and 
overall for each part of the dose escalation phase. 
The efficacy proportions CBR, ORR and DCR will be summarised using descriptive statistics 
and will be graphically displayed, if appropriate. The corresponding exact binomial 95% CI 
will be provided. 
Time-to-event variables (PFS and OS) will be analysed using survival methods 
(Kaplan-Meier). The results will be presented both in summary tables and graphically in 
Kaplan-Meier plots. In addition, the 95% CI for median duration will be provided. 
11.2.3.5 Safety Evaluation 
Unless otherwise specified, the safety analyses will be carried out on patients in the safety 
population by dose level and overall for each part. 
Physical examination findings, vital signs, 12-lead ECG and clinical laboratory parameters 
will be summarised descriptively. Actual and change from baseline at each assessment will be 
calculated and summarised, where data are available. The investigator’s interpretation of 
12-lead ECGs will be listed. For laboratory data, abnormal values will be flagged in the data 
listings, and a list of clinically significant abnormal values will be presented. Haematological 
and biochemistry toxicities will be graded and presented according to the NCI-CTCAE 
criteria. 
Concomitant medications will be coded using the latest version of the World Health 
Organization drug dictionary (WHO-DD) and will be summarised with the number and 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 130/264 
 
 
percentage of patients receiving concomitant medication by drug class and preferred drug 
name. 
All AEs will be coded according to the latest version of MedDRA and NCI-CTCAE 
version 5.0. 
Study drug treatment-emergent AE (TEAE) summaries will include the overall incidence (by 
system organ class (SOC) and preferred term (PT)), events by maximum intensity, events by 
relationship to study drug, events leading to discontinuation of study treatments and SAEs. 
Maximum grade or severity will be tabulated by patient for each MedDRA SOC and PT. 
Analyses of AEs and SAEs will be performed in two different ways: regardless of the 
relationship to the study drug and related to the study drug.  
For haematological and biochemical toxicities, the worst NCI-CTCAE grade by patient and 
by cycle will be tabulated and listed. For white blood cells, neutrophils, platelets and 
haemoglobin with associated Grade 3 or 4 toxicities, nadir and day to nadir will be calculated. 
A TEAE is defined as any AE that occurs during the study if:  
• 
It was not present prior to receiving the first administration of study drugs; or  
• 
It was present prior to receiving the first administration of study drugs but the intensity 
increased during the active phase of the study; or  
• 
It was present prior to receiving the first administration of one of the study drugs, the 
intensity is the same but the drug relationship became related during the active phase of 
the study. 
11.2.3.6 Food Effect Assessment 
The assessment of food effect will be based upon the ratio of the population geometric means 
(fed versus fasted, i.e. Day -3 versus Day -7) for the PK parameters (Cmax and AUC). The data 
will be transformed prior to analysis using a logarithmic transformation. Tmax between fed and 
fasted states will be compared using a non-parametric test such as the Wilcoxon test. 
Descriptive statistics of other PK parameters will be presented both for fasting and fed 
conditions. 
11.2.3.7 Interim Analyses/Safety Review Committees 
Safety, in particular DLT occurrence, as well as PK and PD data will be reviewed on an 
ongoing basis during the dose escalation phases. An SRC will be set up at the end of each 
dose escalation cohort to review DLTs and overall safety data and judge the relevance of 
events to the dose escalation scheme. At the time of the SRC meeting, all cumulative 
available information will be reviewed. In case of emerging safety issues, the SRC will 
immediately be informed and an ad hoc SRC meeting may be organised. The composition of 
the SRC and its specific working procedures will be described in a separate SRC charter, 
which will be established prior to the screening of the first patient. 
Bayesian optimal interval modelling of DLT rates will be performed before the planned 
review meetings in order to generate additional relevant information for the adaptive dose 
selection decisions. The SRC will review all available data and make the final decision as to 
dose escalation, de-escalation, or cohort expansion during the adaptive dose escalation. This 
group will also determine when to implement predefined stopping rules. 
An interim analysis will be performed at the end of the dose escalation to characterise the 
safety and define the RD but also to investigate preliminary anti-tumour activity in biomarker 
selected and unselected patients. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 131/264 
 
 
Full analysis will be performed on the entire dataset at the EOS/EW and at the end of the 
follow-up. 
11.3 
Statistical Methods for the Expansion Phase 
11.3.1 
Sample Size Determination 
Preliminary anti-tumour activity will be evaluated in each dose expansion cohort (each 
regimen and indication combination) according to a sequential two-stage design based on a 
fixed sample size with look at 10 and at 18. The first stage will enrol 10 patients and stop for 
futility if no patients or only one patient achieves the efficacy criterion defined by a BOR of 
CR, PR or SD lasting at least 12 weeks for Parts A and C cohorts (respectively iCR, iPR or 
iSD for 12 weeks for Part B cohorts). If an expansion cohort passes the first stage, then a total 
of 18 patients (eight additional patients) would be enrolled. Six or more patients achieving the 
efficacy criterion already defined would suggest promising anti-tumour activity in the 
corresponding expansion cohort. Table 38 shows the operating characteristics for a range of 
true CBRs.  
Table 38 Operating Characteristics for True CBRs 
True CBR rate 
Pr(find encouraging) 
Pr(stop at stage 1) 
0.10 
0.01 
0.74 
0.20 
0.13 
0.38 
0.30 
0.46 
0.15 
0.35 
0.64 
0.09 
0.40 
0.78 
0.05 
0.45 
0.89 
0.02 
0.50 
0.95 
0.01 
CBR=clinical benefit rate; Pr=probability 
As this is a signal seeking study, no statistical adjustments are considered for the multiple 
comparisons.  
The design and its characteristics (uninteresting and target CBRs, type I error, power and the 
sample size to have a sequential 2-stage design for example) may be updated in a protocol 
amendment based on results from the dose escalation phase. 
11.3.2 
Significance Testing and Estimation 
As this is a descriptive expansion phase, no formal statistical testing will be done to compare 
the cohorts presented. 
11.3.3 
Statistical Methods 
11.3.3.1 Demographics and Other Baseline Characteristics 
The statistical methodology and data presentation will be the same as that for the dose 
escalation phase (presentation by cohort and by part (if applicable)). Please see Section 
11.2.3.1. 
11.3.3.2 Patient Disposition and Withdrawals 
The statistical methodology and data presentation will be the same as that for the dose 
escalation phase. Please see Section 11.2.3.2. 
11.3.3.3 Pharmacokinetic Data 
Please refer to the PK sections (Section 9.1.3). 
11.3.3.4 Anti-tumour Activity Evaluation 
Tumour response in the expansion phase will be assessed centrally every 6 weeks. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 132/264 
 
 
Response and progression will be evaluated using the revised RECIST guideline v1.1 or 
iRECIST guideline (Part B cohorts only). 
The planned 2-stage procedure has an unadjusted type 1 error rate of less than 0.15 within 
each dose expansion cohort for a null hypothesis that the true CBR is 20%. 
The CBR will be analysed at the end of Stage 1 for each cohort separately after the inclusion 
of 10 patients by cohort. If no patients or only one patient is responding at the second 
scheduled tumour assessment i.e. with a BOR of CR, PR or SD lasting at least 12-weeks 
(iCR, iPR or iSD for 12 weeks for part B) the respective study cohort will be stopped for 
futility. Otherwise, eight additional patients will be treated to complete the planned enrolment. 
At the end of Stage 2, the null hypothesis will be rejected suggesting promising anti-tumour 
activity in the corresponding cohort if six patients or more are responding. The CBR will be 
calculated along with its CI for each cohort. 
The other efficacy proportions, ORR and DCR, will be summarised using descriptive 
statistics by cohort and will be graphically displayed if appropriate at the end of the dose 
expansion phase for each cohort whenever it comes (after the first stage when the expansion 
phase is stopped for futility and after the second one otherwise). The corresponding exact 
binomial 95% CIs will be provided. 
Time-to-event variables (PFS and OS) will be analysed using survival methods 
(Kaplan-Meier). The results will be presented both in summary tables and graphically in 
Kaplan-Meier plots. In addition, 95% CIs for median durations will be provided. 
11.3.3.5 Safety Evaluation 
The statistical methodology and data presentation will be the same as that for the dose 
escalation phase (presentation by cohort and by part (if applicable)). Please see 
Section 11.2.3.7. 
11.3.3.6 Interim Analyses 
Please see Section 11.3.3.4. 
11.3.4 
Independent Safety Assessment Committee 
An ISAC will be established to monitor the safety and progress of the study on a regular 
basis. The committee will operate independently from the sponsor and the clinical 
investigators. To minimize the potential introduction of bias, these individuals will not have 
any direct contact with the study site personnel or patients. ISAC members will be selected 
for their expertise in oncology.  
The ISAC will meet and evaluate all available data once all patients in Stage 1 (n=10) of each 
respective cohort have either been on treatment for 12 weeks or have discontinued study 
treatment for any reason. Evaluation may be done sooner if enough CBR events at 12 weeks 
have occurred (based on the SAP) to inform a decision on moving to Stage 2, prior to all 
patients being enrolled. Upon evaluation, the ISAC will make the recommendation to the 
sponsor based on the results of the analyses over continuation to Stage 2, or stoppage of the 
cohort. This decision will be made based on, but not limited to: safety events, any available 
results of PK, PD and tumour assessments (local and/or central). 
The ISAC will meet and evaluate all available data again once all patients in Stage 2 (n=18) 
of each respective cohort have either been on treatment for 12 weeks or have discontinued 
study treatment for any reason. Upon evaluation, the ISAC will give a recommendation to 
further peruse the given drug combination and patient population in the clinical development 
plan, or to stop any further investigation. This decision will be made based on, but not limited 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 133/264 
 
 
to: safety events, any available results of PK, PD and tumour assessments (local and/or 
central). 
The ISAC will meet 1 year after the start of the study or at the end of the dose escalation, 
whichever occurs first. 
The ISAC will also be responsible for any adhoc assessments of safety and futility for each 
cohort, and can meet as needed to recommend protocol modifications, or any other actions 
including but not limited to:  
• 
Changing the eligibility criteria if the risks of the intervention seem to be higher in a 
subgroup;  
• 
Altering the drug product dosage and/or schedule if the AEs observed appear likely to 
be reduced by such changes;  
• 
Identifying information needed to inform current and future study patients of newly 
identified risks via changes in the ICF and, in some cases, obtaining reconsent of 
current patients for continued study participation.  
Further details regarding the ISAC and their requirements will be outlined in the ISAC 
charter. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 134/264 
 
 
12 
DIRECT ACCESS TO SOURCE DATA AND DOCUMENTS 
Authorised personnel from external CAs and sponsor authorised Quality Assurance personnel 
may carry out inspections and audits. The purpose of an audit is to ensure that ethical, 
regulatory and quality requirements are fulfilled in all studies performed by the sponsor. 
Auditors and inspectors must have direct access to study documents and site facilities as 
specified in Section 13.4 and to any other locations used for the purpose of the study in 
question (for example laboratories). 
In the event of the site being notified directly of a regulatory inspection, the investigator must 
notify the sponsor’s representative as soon as possible, to assist with preparations for the 
inspection. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 135/264 
 
 
13 
QUALITY CONTROL AND QUALITY ASSURANCE 
13.1 
Protocol Amendments and Protocol Deviations 
13.1.1 
Protocol Amendments 
No changes from the final approved (signed) protocol will be initiated without the prior 
written approval or favourable opinion by the IEC/IRB, except when necessary to eliminate 
immediate safety concerns to the patients or when the change involves only logistics or 
administration.  
In the event that an amendment to this protocol is required, it will be classified into one of the 
following three categories: 
• 
Nonsubstantial amendments are those that are not considered ‘substantial’ (for 
example administrative changes) and as such only need to be notified to the IECs or 
regulatory authorities for information purposes. 
• 
Substantial amendments are those considered ‘substantial’ to the conduct of the 
clinical study where they are likely to have a significant impact on: 
- 
the safety or physical or mental integrity of the patients; 
- 
the scientific value of the study; 
- 
the conduct or management of the study; or 
- 
the quality or safety of the study drug used in the study. 
Substantial amendments must be submitted to and approved by the IECs and relevant 
regulatory authorities, according to local regulations, prior to implementing changes. 
• 
Urgent amendments are those that require urgent safety measures to protect the study 
patients from immediate hazard and as such may be implemented immediately by the 
sponsor with subsequent IECs and regulatory authority notification, forthwith. 
The principal investigator and the sponsor will sign all protocol amendments. 
13.1.2 
Protocol Deviations and Exceptions 
All protocol deviations will be identified and recorded by the sponsor or sponsor’s 
representative. 
A major protocol deviation is any significant divergence from the protocol, i.e. nonadherence 
on the part of the patient, the investigator, or the sponsor to protocol-specific 
inclusion/exclusion criteria, primary objective evaluation criteria and/or GCP guidelines. 
Generally, a protocol deviation qualifies as major if: 
(1) 
the deviation has harmed or posed a significant or substantive risk of harm to the 
research patient; 
(2) 
the deviation compromises the scientific integrity of the data collected for the study; 
(3) 
the deviation is a wilful or knowing breach of human patient protection regulations, 
policies, or procedures on the part of the investigator(s); 
(4) 
the deviation involves a serious or continuing noncompliance with any applicable 
human patient protection regulations, policies, or procedures; 
(5) 
the deviation is inconsistent with the sponsor’s research, medical and/or ethical 
principles. 
See also Section 11.1.2 for details on the impact of major protocol deviations on the inclusion 
of patients in each analysis population. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 136/264 
 
 
A minor protocol deviation is any significant divergence from the protocol that does not 
impact the study results. 
As a matter of policy, the sponsor will not grant exceptions to protocol-specific entry criteria 
to allow patients to enter a study. If under extraordinary circumstances such action is 
considered ethically, medically and scientifically justified for a particular patient, prior 
approval from the sponsor and the responsible IRB/IEC, in accordance with the Standard 
Operating Procedure (SOP), is required before the patient will be allowed to enter the study. If 
investigative centre personnel learn that a patient who did not meet protocol eligibility criteria 
was entered in a study (a protocol violation), they must immediately inform the sponsor. Such 
patients will be discontinued from the study, except in an exceptional instance following 
review and written approval by the sponsor and the responsible IRB/IEC, according to the 
applicable SOP. Retention of these patients in the study will be discussed between the sponsor 
and investigator, taking into account patient safety and data reliability. The IRB/IEC will be 
informed if patient safety/protection is ignorantly impacted. 
13.2 
Information to Study Personnel 
To ensure accurate, complete and reliable data, the sponsor or its representatives will provide 
instructional material to the study sites, as appropriate. A study initiation visit will be 
conducted prior to screening start to instruct the investigators and study coordinators. This 
session will give instruction on the protocol, the completion of the eCRF and all study 
procedures. The investigator is responsible for giving information about the study to all staff 
members involved in the study or in any element of patient management, both before starting 
any study procedures and during the course of the study (for example when new staff become 
involved). The investigator must assure that all study staff members are qualified by 
education, experience and training to perform their specific responsibilities. These study staff 
members must be listed on the study centre authorisation form, which includes a clear 
description of each staff member’s responsibilities. This list must be updated throughout the 
study, as necessary. 
The study monitor is responsible for explaining the protocol to all study staff, including the 
investigator and for ensuring their compliance with the protocol. Additional information will 
be made available during the study when new staff become involved in the study and as 
otherwise agreed upon with either the investigator or the study monitor. 
13.3 
Study Monitoring 
The investigator is responsible for the validity of all data collected at the site. 
The sponsor or delegate is responsible for monitoring these data to verify that the rights and 
wellbeing of patients are protected, that study data are accurate (complete and verifiable to 
source data) and that the study is conducted in compliance with the protocol, GCP guidelines 
and regulatory requirements. 
The sponsor or delegate assigned monitors will conduct regular site visits. The investigator 
will allow direct access to all relevant files (for all patients) and clinical study supplies 
(dispensing and storage areas) for the purpose of verifying entries made in the eCRF and will 
assist with the monitor’s activities, if requested. Adequate time and space for monitoring 
visits should be made available by the investigator. 
The site must complete the eCRFs on an ongoing basis to allow regular review by the study 
monitor, both remotely by the internet and during site visits. The central study monitor at the 
sponsor will use functions of the EDC system to address any queries raised while reviewing 
the data entered by the study site personnel in a timely manner. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 137/264 
 
 
Whenever a patient name is revealed on a document required by the sponsor (for example 
laboratory print outs), the name must be blacked out permanently by the site personnel and 
annotated with the patient number as identification. 
An ISAC will be established to monitor the safety and progress of the study on a regular basis 
(see Section 11.3.4 for more details).  
13.4 
Investigator’s Regulatory Obligations 
All clinical work under this protocol will be conducted according to GCP guidelines. This 
includes that the study may be audited at any time by a quality assurance personnel designated 
by the sponsor, or inspected by regulatory bodies. The investigator must adhere to ICH GCP 
guidelines in addition to any applicable local regulations. 
If requested, the investigator will provide the sponsor, applicable regulatory agencies and 
applicable IECs with direct access to any original source documents. 
The investigator(s) should demonstrate due diligence in the recruitment and screening of 
potential study patients. The enrolment rate should be sufficient to complete the study as 
agreed with the sponsor. The sponsor should be notified of any projected delays, which may 
impact the completion of the study. 
This clinical study will be conducted in compliance with all international laws and regulations 
and national laws and regulations of the country(ies) in which the clinical study is performed, 
as well as any applicable guidelines. 
13.5 
Audit and Inspection 
Authorised personnel from external CAs and the sponsor’s authorised Quality Assurance 
personnel may carry out inspections and audits (see Section 12). 
13.6 
Data Quality Assurance 
Monitored eCRFs will be reviewed by the assigned data management group for completeness, 
consistency, legibility and protocol compliance. 
Reasons should be given on the relevant eCRF for any missing data and other protocol 
deviations. Any electronic queries and items not adequately explained will require additional 
electronic manual queries to be raised to the investigator by the monitor for 
clarification/correction. The investigator must ensure that queries are dealt with promptly. All 
data changes and clarifications can be viewed in the audit trail function of the eCRF. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 138/264 
 
 
14 
ETHICS 
14.1 
Compliance with Good Clinical Practice and Ethical Considerations 
This study will be conducted in compliance with IECs/IRBs, informed consent regulations, 
the Declaration of Helsinki, FDA 21 CFR Part 11, Electronic Records, Electronic Signatures 
and FDA, Guidance for Industry: Computerized Systems Used in Clinical Trials and ICH 
GCP guidelines (Section 1.7). 
In addition, this study will adhere to all local regulatory requirements.  
Before initiating the study, the investigator/institution should have written and dated 
approval/favourable opinion from the IEC/IRB for the study protocol/amendment(s), written 
ICF, any ICF updates, patient emergency study contact cards, patient recruitment procedures 
(for example advertisements), any written information to be provided to patients and a 
statement from the IEC/IRB that they comply with GCP requirements. The IEC/IRB approval 
must identify the protocol version as well as the documents reviewed. 
After IEC/IRB approval, changes will require a formal amendment. Once the study has 
started, amendments should be made only in exceptional circumstances. Changes that do not 
affect patient safety or data integrity are classified as administrative changes and generally do 
not require ethical approval. If ethically relevant aspects are concerned, the IEC/IRB must be 
informed and, if necessary, approval sought prior to implementation. Ethical approval on 
administrative changes will be obtained if required by local/site IEC/IRB. 
14.2 
Informed Consent for Participation in the Study 
Prior to study entry, the investigator, or a person designated by the investigator, will explain 
the nature, purpose, benefits and risks of participation in the study to each patient, patient’s 
legally acceptable representative or impartial witness. Written informed consent must be 
obtained prior to the patient entering the study (before initiation of any study-related 
procedure and administration of the IMP). Sufficient time will be allowed to discuss any 
questions raised by the patient. 
The sponsor will provide a sample ICF. The final version-controlled form must be agreed to 
by the sponsor and the IEC/IRB and must contain all elements included in the sample form, in 
language readily understood by the patient. Each patient’s original consent form, personally 
signed and dated by the patient or by the patient’s legally acceptable representative and by the 
person who conducted the informed consent discussion, will be retained by the investigator. 
The investigator will supply patients with a copy of their signed ICF. 
The ICF may need to be revised during the study should important new information become 
available that may be relevant to the safety of the patient or as a result of protocol 
amendments. In this instance, approval should always be given by the IEC/IRB. It is the 
investigator’s responsibility to ensure that all patients subsequently entered into the study and 
those currently in the study sign the amended form. This is documented in the same way as 
described above. Patients who have completed the study should be informed of any new 
information that may impact on their welfare/wellbeing. 
The investigator should, with the consent of the patient, inform the patient’s primary 
physician about their participation in the clinical study. 
14.2.1 
Optional Informed Consent for Biobanking 
This study has the option for patients to consent to the collection of samples for biobanking 
for future exploratory analysis and storage for up to 15 years (where local regulations allow). 
A specific informed consent is required for the collection of these samples and will be 
explained after the patient has given written informed consent for the main study. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 139/264 
 
 
Patients must receive an explanation that they are completely free to refuse to enter the 
exploratory part of the study and may withdraw from it at any time and for any reason up to 
15 years after the end of the study and will still be allowed to take part in the main study. 
14.3 
Health Authorities and Independent Ethics Committees/Institutional Review 
Boards 
As required by local regulations, the sponsor’s Regulatory Affairs and Clinical Operations 
groups (or their delegates) will ensure all legal regulatory aspects are covered and obtain 
approval of the appropriate regulatory bodies, prior to study initiation in regions where an 
approval is required. 
The following documents should be submitted to the relevant IEC/IRB for review and 
approval to conduct the study (this list may not be exhaustive): 
• 
protocol/amendment(s) approved by the sponsor; 
• 
currently applicable IB or package labelling; 
• 
relevant investigator’s curriculum vitae; 
• 
patient information and informed consent document(s) and form(s); 
• 
patient emergency study contact cards; 
• 
recruitment procedures/materials (advertisements), if any. 
The IEC(s)/IRB(s) will review all submission documents as required and a written favourable 
opinion for the conduct of the study should be made available to the investigator before 
initiating the study. This document must be dated and clearly identify the version number(s) 
and date(s) of the documents submitted/reviewed and should include a statement from the 
IEC/IRB that they comply with GCP requirements. 
The study may begin at the investigative site(s) only after receiving this dated and signed 
documentation of the IEC/IRB approval or favourable opinion. 
During the study, any update to the following documents will be sent to the IEC/IRB, either 
for information, or for review and approval, depending on how substantial the modifications 
are: (1) IB; (2) reports of SAEs; (3) all protocol amendments and revised informed consent(s), 
if any. 
At the end of the study, the IEC/IRB will be notified about the study completion. 
14.4 
Confidentiality Regarding Study Patients 
The investigator must assure that the privacy of the patients, including their personal identity 
and all personal medical information, will be maintained at all times. In eCRFs and other 
documents or image material submitted to the sponsor, patients will be identified not by their 
names, but by an identification code (for example initials and identification number). 
Personal medical information may be reviewed for the purpose of verifying data recorded on 
the eCRF. This review may be conducted by the study monitor, properly authorised persons 
on behalf of the sponsor, the quality assurance unit, or regulatory authorities. Personal 
medical information will always be treated as confidential. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 140/264 
 
 
15 
DATA HANDLING AND RECORD KEEPING 
15.1 
Recording of Study Data 
In compliance with GCP guidelines, the medical records/medical notes, etc., should be clearly 
marked and permit easy identification of a patient’s participation in the specified clinical 
study. 
The investigator must record all data relating to protocol procedures, IMP administration, 
laboratory data, safety data and efficacy ratings on the eCRFs provided for the study. The 
investigator, by completing the signature log, may formally designate authority to complete 
eCRFs to appropriately qualified staff having certified user access to the eCRF. 
The investigator (or authorised subinvestigator) must, as a minimum, provide an electronic 
signature (e-signature) to each eCRF to attest to the accuracy and completeness of all the data. 
If any changes are made to the eCRF after a form has been locked and electronically signed, 
the investigator (or authorised subinvestigator) will be required to perform an additional 
e-signature authorising agreement with any new information or changes to the eCRF. 
All corrections on the eCRF will be automatically tracked and a reason for the change is 
always required. In the eCRF, the audit trail function will allow the changes made to be 
viewed on each item entered. 
15.2 
Data Management 
Electronic data capture will be utilised for collecting patient data. Each site is required to have 
a computer and internet connection available for site entry of clinical data. All entries in the 
eCRF will be made under the e-signature of the person performing the action. This electronic 
signature consists of an individual and confidential username and password combination. It is 
declared to be the legally binding equivalent of the handwritten signature. Only sponsor 
authorised users will have access to the eCRF as appropriate to their study responsibilities. Users 
must have successfully undergone software application training prior to entering data into the 
eCRF. 
Data management will be conducted by a CRO, directed by the sponsor’s data management 
department. All data management procedures will be completed in accordance with the sponsor 
and the contracted CRO SOPs. Electronic CRF data will be monitored at the investigator site, 
(for further details see Section 13.3). The study data documentation removed from the 
investigator site(s) will be tracked by the CRO and the monitor. 
The sponsor or delegate will ensure that an appropriate eCRF is developed to capture the data 
accurately and suitable queries are raised to resolve any missing or inconsistent data. The 
investigator will receive their data, from the clinical study, in an electronic format (PDF files) 
which will be an exact copy of the eCRF and will include the full audit trail, for archiving 
purposes and future reference. 
Any queries generated during the data management process will also be tracked by the 
contracted data management CRO/will be raised within the EDC system. It is the central 
study monitor’s responsibility to ensure that all queries are resolved by the relevant parties. 
The sponsor will also ensure that SAE data collected in the eCRF are consistent with 
information provided to the sponsor’s pharmacovigilance department (and vice versa).  
The coding of an AE, medical history, surgical procedures and concomitant medication terms 
will be performed by the contracted CRO/a coding CRO, directed by the sponsor’s Biometry 
department and reviewed and approved by the sponsor. Concomitant medications will be 
coded using WHO-DD and AEs/medical history terms will be coded using MedDRA. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 141/264 
 
 
Only data from patients who give informed consent will be reported in the eCRFs and 
collected in the sponsor’s database. 
For screening failure patients, the Unique Patient Identifier, the date of informed consent 
signature, the reason why the patient failed screening and the potential AEs that occurred 
during the screening phase will be reported in the eCRFs at a minimum and collected in the 
sponsor’s database. 
15.3 
Record Archiving and Retention 
During the prestudy and initiation visits, the monitor must ensure the archiving facilities are 
adequate and archiving/retention responsibilities of the investigator have been discussed.  
Study documents should be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or planned marketing applications 
in an ICH region (that is at least 15 years) or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the product. However, these documents should be 
retained for a longer period if required by the applicable regulatory requirements or by an 
agreement with the sponsor. The investigator should take measures to prevent accidental or 
premature destruction of these documents. The final archiving arrangements will be confirmed 
by the monitor when closing out the site. The sponsor will inform the investigator, in writing, 
as to when these documents no longer need to be retained. 
If the principal investigator relocates or retires, or otherwise withdraws his/her responsibility 
for maintenance and retention of study documents, the sponsor must be notified (preferably in 
writing) so that adequate provision can be made for their future maintenance and retention. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 142/264 
 
 
16 
FINANCING AND INSURANCE 
16.1 
Contractual and Financial Details 
The investigator (and/or, as appropriate, the hospital administrative representative) and the 
sponsor will sign a clinical study agreement prior to the start of the study, outlining overall 
sponsor and investigator responsibilities in relation to the study. Financial remuneration will 
cover the cost per included patient, based on the calculated costs of performing the study 
assessments in accordance with the protocol and the specified terms of payment will be 
described in the contract. The contract should describe whether costs for pharmacy, laboratory 
and other protocol required services are being paid directly or indirectly. 
Financial disclosure statements will need to be completed, as requested by FDA 21 CFR 
Part 54. 
16.2 
Insurance, Indemnity and Compensation 
The sponsor will provide product liability insurance for all patients included in the clinical 
study. Where required, a hospital specific indemnity agreement will be used. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 143/264 
 
 
17 
REPORTING AND PUBLICATION OF RESULTS 
17.1 
Publication Policy 
The sponsor is committed to disclosing information about the clinical studies it sponsors. 
Results will be communicated at scientific meetings and all reasonable efforts must be made 
to seek publication in a peer-reviewed scientific journal. Specific publication concepts, 
including data to be covered, target congress/journal and proposed authors, should be 
discussed with the appropriate Global Publications Manager and incorporated in the relevant 
publication plan before initiation. A dedicated Publications Committee, involving interested 
members of the study Steering Committee as well as the Global Publications Manager, may 
be established to plan specific publications. As a minimum, summary results of this study 
should be posted on the relevant clinical study registry. When the study has been conducted 
by a large multicentre group, the principal investigator, the study steering committee (if 
applicable) and the sponsor’s responsible physician should discuss and agree the selection of 
authors for planned publications in advance. They may decide to use a group name and 
nominate authors on behalf of the study group. All contributing investigators will be listed in 
the acknowledgements together with any others who may have contributed but not 
sufficiently to qualify for authorship. 
Selection of authors for scientific publications will follow the International Committee of 
Medical Journal Editors guidelines  
[http://www.icmje.org/recommendations/browse/roles-and-responsibilities/defining-the-role-o
f-authors-and-contributors.html]. In particular, those named as authors, whether employed by 
a sponsor’s affiliate or the sponsor, or external investigators, ‘should have participated 
sufficiently in the work to take public responsibility for the content’. 
Authorship should be based on: 
• 
substantial contributions to the conception and design, or acquisition of data, or 
analysis and interpretation of data; AND 
• 
drafting the article or revising it critically for important intellectual content; AND 
• 
final approval of the version to be published; AND 
• 
agreement to be accountable for all aspects for the work, thereby ensuring that 
questions related to the accuracy or integrity of any part of the work were appropriately 
investigated and resolved. 
All authors of a publication should meet all four criteria. Each author must agree to their 
inclusion in the list of authors. Use of professional medical writing support may be employed.  
Resolution of scientific differences in the presentation or interpretation of study findings will 
be conducted along principles of honest scientific debate. The sponsor shall be promptly 
notified of any amendments subsequently requested by referees or journal editors. 
All publications arising from this study will be reviewed by relevant functions at the sponsor, 
coordinated by the Global Publications team. Requests and suggestions for changes will be 
discussed with all authors (and the medical writer, if applicable). Resolution of scientific 
differences in the presentation or interpretation of study findings will be conducted along 
principles of honest scientific debate. The sponsor’s review comments must be answered 
before a final version for submission can be approved by the author team. 
If patentability would be adversely affected by publication, this will be delayed until (i) a 
patent application is filed for the content of the publication in accordance with applicable 
provisions of the clinical study agreement concerned, (ii) the sponsor consents to the 
publication, or (iii) the time period as may be agreed in the contractual arrangements, 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 144/264 
 
 
including clinical study agreements, governing the relationship between the sponsor and 
authors (or authors’ institution) after receipt of the proposed publication by the sponsor, 
whichever of (i), (ii) or (iii) occurs first. 
17.2 
Clinical Study Report 
A final clinical study report (CSR) will be prepared according to the ICH E3 guideline on the 
structure and contents of CSRs. A final CSR will be prepared where any patient has signed 
informed consent, regardless of whether the study is completed or prematurely terminated. 
Where appropriate, an abbreviated report may be prepared. The CSR will comply with any 
applicable regulatory requirements and national laws in force, and will be in English. 
As indicated in Section 11, an analysis will be performed on the final response data after the 
last patient has completed the treatment period. This analysis will be included in the final 
CSR. An addendum to the CSR, including the analysis of data from the follow-up period, will 
be prepared after the last patient completes the follow-up period. 
Analysis of biobank samples will be performed outside the scope of the main study and 
reported separately. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 145/264 
 
 
18 
REFERENCES 
1 
De Michele A, Harding JJ, Telli ML, et al. Phase 1 study of CB-839, a small 
molecule inhibitor of glutaminase (GLS) in combination with paclitaxel (Pac) 
in patients (pts) with triple negative breast cancer (TNBC). Poster presented 
at ASCO 2016. 
2 
Tannir N, Fan AC, Lee RJ, et al. Phase 1 study of glutaminase (GLS) 
inhibitor CB-839 combined with either everolimus (E) or cabozantinib (Cabo) 
in patients (pts) with clear cell (cc) and papillary (pap) metastatic renal cell 
cancer (mRCC). Poster presented at Genitourinary Cancers symposium 2018. 
3 
Zakaria N, Satar NA, Abu Halim NH, et al. Targeting lung cancer stem cells: 
research and clinical impacts. Front Oncol 2017;7:80. 
4 
Molina JR, Yang P, Cassivi SD, et al. Non–small cell lung cancer: 
epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc 
2008;83(5):584-94. 
5 
Shaw AT, et al. Effect of crizotinib on overall survival in patients with 
advanced nonsmall-cell lung cancer harbouring ALK gene rearrangement: a 
retrospective analysis. Lancet Oncol 12, 1004-1012 (2011). 
6 
Lecia VS, et al. Response to Treatment and Survival of Patients with 
Non-Small Cell Lung Cancer Undergoing Somatic EGFR Mutation Testing. 
Oncologist 12, 90-98 (2007). 
7 
Sayin VI, LeBoeuf SE, Singh SX, et al. Activation of the NRF2 antioxidant 
program generates an imbalance in central carbon metabolism in cancer. 
eLife 2017 [Online]. Available at https://elifesciences.org/articles/28083 
[Accessed 09 August 2018]. 
8 
Skoulidis F, Goldberg ME, Greenawalt DM, et al. STK11/LKB1 Mutations 
and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma. Cancer 
Discov 2018 Jul;8(7):822-835. 
9 
Skoulidis F, Byers LA, Diao L, et al. Co-occurring genomic alterations define 
major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, 
immune 
profiles, 
and 
therapeutic 
vulnerabilities. 
Cancer 
Discov 
2015;5(8):860-77. 
10 
Hudson CD, Savadelis A, Nagaraj AB, et al. Altered glutamine metabolism in 
platinum resistant ovarian cancer. Oncotarget 2016;7(27):41637-49. 
11 
Meric-Bernstam F, DeMichele A, Telli ML, et al. Phase 1 study of CB-839, a 
first-in-class, orally administered small molecule inhibitor of glutaminase in 
patients with refractory solid tumors. Poster presented at AACR 2015. 
12 
Elgadi KM, Meguid RA, Qian M, et al. Cloning and analysis of unique 
human glutaminase isoforms generated by tissue-specific alternative splicing. 
Physiol Genomics 1999;1(2):51-62. 
13 
Campos-Sandoval JA, Mercedes Martín-Rufián M, Cardona C, et al. 
Glutaminases in brain: Multiple isoforms for many purposes. Neurochem Int 
2015; 88:1-5. 
14 
Food and Drug Administration. Guidance for Industry. Estimating the 
maximum safe starting dose in initial clinical trials for therapeutics in adult 
healthy 
volunteers. 
2005. 
[Online]. 
Available 
at 
https ://www .fda.gov/downloads/Drugs/Guidances/UCM078932.pdf%23searc


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 146/264 
 
 
h=%27guidekines+for+industry+sfe+starting%27 
[Accessed 
09 
August 
2018]. 
15 
International Council for Harmonisation (ICH) harmonised tripartite 
guideline nonclinical evaluation for anticancer pharmaceuticals S9. 2009 
[Online]. 
Available 
at: 
https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Sa
fety/S9/Step4/S9_Step4_Guideline.pdf [Accessed 06 September 2018]. 
16 
Liu S, and Yuan Y. Bayesian optimal interval designs for phase I clinical 
trials. 
2015 
[Online]. 
Available 
at: 
http://odin.mdacc.tmc.edu/~yyuan/Software/BOIN/paper.pdf [Accessed 28 
August 2018]. 
17 
Yuan Y, Hess KR, Hilsenbeck SG, et al. Bayesian optimal interval design: A 
simple and well-performing design for phase I oncology trials. Clin Cancer 
Res 2016;22(17):4291-301. 
18 
Lorenzi PL., Reinhold WC., Rudelius M et al. Asparagine synthetase as a 
causal, predictive biomarker for L-asparaginase activity in ovarian cancer 
cells. Mol Cancer Ther 2006;5:2613-23. 
19 
TAXOL® (Paclitaxel) Injection Label. Bristol Myers Squibb 2011 [Online]. 
Available 
at: 
https ://www .accessdata.fda.gov/drugsatfda_docs/label/2011/020262s049lbl.p
df (Accessed 03 September 2018). 
20 
Seymour L, Bogaerts J, Perrone A, et al. iRECIST: guidelines for response 
criteria for use in trials testing immunotherapeutics. Lancet Oncol 
2017;18(3):e143-e152.  
21 
Indiana University Cytochrome P450 Drug Interaction Table: Abbreviated 
“Clinically 
Relevant” 
Table. 
[Online]. 
Available 
at: 
https ://www .regionorebrolan.se/Files-sv/%C3%96rebro%20l%C3%A4ns%20
landsting/Arbete_utbildning/ST/ST-psykiatri/inbjudan/Clinical-Table-CYP45
0.pdf (Accessed 18 September 2018). 
22 
Lozano E, Herraez E, Briz O, et al. Role of the plasma membrane transporter 
of organic cations OCT1 and its genetic variants in modern liver 
pharmacology. Biomed Res Int 2013(1):692071. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 147/264 
 
 
19 
LIST OF APPENDICES 
Appendix 1 TREATMENT PLAN AND DOSE MODIFICATION 
GUIDELINES ......................................................................................................... 148 
Appendix 2 LIST OF STRONG INDUCERS AND INHIBITORS OF CYP3A4 . 156 
Appendix 3 LIST OF MODERATE INDUCERS AND INHIBITORS OF 
CYP3A4 .................................................................................................................. 158 
Appendix 4 LIST OF STRONG AND MODERATE INHIBITORS OF CYP2D6160 
Appendix 5 LIST OF STRONG INHIBITORS OF CYP2C8 ................................ 162 
Appendix 6 LIST OF MODERATE INHIBITORS AND INDUCERS OF 
CYP2C8 .................................................................................................................. 164 
Appendix 7 LIST OF IMMUNOSUPPRESSIVE AGENTS ................................. 166 
Appendix 8 LIST OF SUBSTRATES OF OATP1B3, OCT1 AND OCT2 ........... 170 
Appendix 9 DESCRIPTION OF THE iRECIST PROCESS FOR ASSESSMENT 
OF DISEASE PROGRESSION ............................................................................. 173 
Appendix 10 PROTOCOL AMENDMENT FORMS ............................................ 177 
 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 148/264 
 
 
Appendix 1 TREATMENT PLAN AND DOSE MODIFICATION GUIDELINES 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 149/264 
 
 
Treatment Plan and Dose Modification Guidelines  
Reduction for IPN60090 monotherapy  
Management of severe or intolerable adverse reactions requires dose reduction, temporary 
interruption, and/or discontinuation of IPN60090 therapy. Each patient is allowed a maximum 
of two dose reductions for IPN60090. After this, the patient will be discontinued from the 
study treatment.  
If a dose reduction is required, reduce the current dose by one dose level from the current 
dose.  
Dose Adjustment for IPN60090  
 
DL1 
DL2 
DL3 
DL4 
DL5 
DL6 
DL7 
Starting dose 
level 
20 mg BID 
40 mg BID 
80 mg BID 
180 mg BID 320 mg BID 480 mg BID 720 mg BID 
First dose 
reduction 
N/A 
20 mg BID 
40 mg BID 
80 mg BID 
180 mg BID 320 mg BID 480 mg BID 
Second dose 
reduction 
N/A 
N/A 
20 mg BID 
40 mg BID 
80 mg BID 
180 mg BID 320 mg BID 
BID=bis in die (twice daily); DL=dose level; N/A=not applicable 
Reduction of IPN60090 + Pembrolizumab  
Management of severe or intolerable adverse reactions requires dose reduction, temporary 
interruption, and/or discontinuation of IPN60090 therapy. Each patient is allowed a maximum 
of two dose reductions for IPN60090. Pembrolizumab will be a fixed dose and cannot be dose 
reduced, however treatment of pembrolizumab can be delayed >6 weeks (2 cycles) for any 
reason. In this case, the patient must be permanently discontinued from study therapy, except 
in cases where permission to resume treatment is granted by the Ipsen Medical Monitor or 
designee. If a patient discontinues IPN60090, they may remain on study on pembrolizumab 
monotherapy.  
If a dose reduction is required, reduce the current dose by one dose level from the current 
dose. This can be done up to two times before a patient must discontinue study treatment.  
Dose Adjustment for IPN60090 + Pembrolizumab 
 
DL1 
DL2 
DL3 
IPN60090 
Pembrolizumab 
IPN60090 
Pembrolizumab 
IPN60090 
Pembrolizumab 
Starting dose 
level 
180 mg BID In accordance with 
approved label 
320 mg BID In accordance with 
approved label 
480 mg BID In accordance with 
approved label 
First dose 
reduction 
80 mg BID 
180 mg BID 
320 mg BID 
Second dose 
reduction 
40 mg BID 
80 mg BID 
180 mg BID 
BID=bis in die (twice daily); DL=dose level 
Reduction of IPN60090 + Paclitaxel  
Management of severe or intolerable adverse reactions requires dose reduction, temporary 
interruption, and/or discontinuation of IPN60090 therapy. Each patient is allowed a maximum 
of two dose reductions for IPN60090, paclitaxel is a fixed dose and cannot be dose reduced. If 
treatment of paclitaxel is delayed >6 weeks (2 cycles) for any reason, the patient must be 
permanently discontinued from study therapy, except in cases where permission to resume 
treatment is granted by the Ipsen Medical Monitor or designee. If a patient discontinues 
IPN60090 they may remain on study on paclitaxel monotherapy. 
If a dose reduction is required, reduce the current dose by one dose level from the current 
dose. This can be done up to two times before a patient must discontinue study treatment.  


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 150/264 
 
 
Dose Adjustment for IPN60090 + Paclitaxel 
 
DL1 
DL2 
DL3 
IPN60090 
Paclitaxel 
IPN60090 
Paclitaxel 
IPN60090 
Paclitaxel 
Starting dose 
level 
180 mg BID 
In accordance 
with approved 
label 
320 mg BID 
In accordance 
with approved 
label 
480 mg BID 
In accordance 
with approved 
label 
First dose 
reduction 
80 mg BID 
180 mg BID 
320 mg BID 
Second dose 
reduction 
40 mg BID 
80 mg BID 
180 mg BID 
BID=bis in die (twice daily); DL=dose level 
Dose Adjustment/Modification Recommendation for Haematological Adverse Reactions 
Dose adjustments and modifications of pembrolizumab and paclitaxel therapy should be done 
according to the approved product information. For IPN60090 the instructions in the below 
tables are recommended for dose adjustment and management. 
The management of all study drugs, and any dose adjustments should be in line with the best 
clinical practice for individual patients and is ultimately left to the discretion of the 
investigator or treating physician.  


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 151/264 
 
 
Toxicity/grade 
Dose adjustment and management recommendations 
IPN60090 
Thrombocytopenia 
Grade 1 (≥75×109/L) 
No dose adjustment required. 
Grade 2 (≥50×109/L to <75×109/L) 
-Dose interruption until recovery to Grade ≤1. 
-Re-initiate at the same dose. 
Grade 3 (≥25×109/L to <50×109/L) 
-Dose interruption until recovery to Grade ≤1. 
-Re-initiate at the same dose level. 
-If toxicity recurs at Grade 3: temporary dose interruption until 
recovery to Grade ≤1 and reduce to the next lower dose level. 
Grade 4 (<25×109/L) 
-Dose interruption until recovery to Grade ≤1. 
-Re-initiate at the next lower dose level.  
-If toxicity recurs at Grade 4: discontinue IPN60090. 
Absolute neutrophil count (ANC) 
Grade 1 (≥1.5×109/L) 
No dose adjustment required. 
Grade 2 (≥1.0 to <1.5×109/L)  
No dose adjustment required. 
Grade 3 (≥0.5 to <1.0×109/L) 
-Dose interruption of IPN60090 until recovery to Grade 2 or 1 
≥1.0×109/L.  
-Re-initiate IPN60090 at the same dose level.  
-If toxicity recurs at Grade 3: temporary dose interruption until 
recovery to ≥1.0×109/L.  
-If resolved in ≤7 days, then maintain dose level.  
-If resolved in >7 days, then reduce IPN60090 dose to the next 
lower dose level. 
Grade 4 (<0.5×109/L) 
-Dose interruption of IPN60090 and pembrolizumab (if applicable) 
until recovery to Grade 2 or 1 ≥1.0×109/L.  
-Re-initiate IPN60090 at the next lower dose level. 
-If toxicity recurs at Grade 4: discontinue IPN60090. 
Febrile neutropenia 
Grade 3 
ANC <1.0×109/L with a single temperature 
of >38.3ºC (101 ºF) or a sustained 
temperature of ≥38ºC (100.4ºF) for more 
than one hour 
-Dose interruption of IPN60090 and pembrolizumab (if applicable) 
until improvement of ANC ≥1.0×109/L and no fever.  
-Restart at the next lower dose level. 
-If febrile neutropenia recurs, discontinue IPN60090. 
Grade 4 
Life threatening consequences; urgent 
intervention indicated 
-Discontinue IPN60090. 
Anaemia 
(Haemoglobin) 
Grade 1 (≥10.0 to LLN g/dL) 
No dose adjustment required. 
Grade 2 (≥8.0 to <10.0 g/dL) 
No dose adjustment required. 
Grade 3 (<8.0 g/dL) 
-Dose interruption until recovery to Grade ≤2. 
-Re-initiate IPN60090 at the same dose. 
Grade 4 
Life threatening consequences; urgent 
intervention indicated 
-Discontinue IPN60090. 
ANC=absolute neutrophil count 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 152/264 
 
 
Recommendations for Dose Modification in Case of Hepatotoxicity 
Hepatotoxicity (bilirubin, SGPT/ALT, SGOT/AST) 
Total bilirubin without ALT/AST increase above baseline value 
Grade 1 (>ULN to 1.5×ULN) (confirmed 
48 to 72 hrs later) 
Maintain dose level with LFTs monitored biweekly. 
Grade 2 (>1.5 to 3.0×ULN) 
-Dose interruption of IPN60090. 
-If resolved to ≤Grade 1 in ≤14 days, then maintain dose level. 
-If resolved to ≤Grade 1 in >14 days or toxicity recurs, then reduce 
IPN60090 by one dose level. 
-Repeat liver enzymes and bilirubin tests weekly for 2 weeks after 
dose resumption. 
-If toxicity recurs after two dose reductions, discontinue study 
treatment.  
Grade 3 (>3.0 to 10.0×ULN) 
-Dose interruption of IPN60090.  
-If resolved to ≤Grade 1 in ≤14 days, lower one dose level of 
IPN60090 
-Repeat liver enzymes and bilirubin tests weekly for 2 weeks after 
dose resumption. 
-If resolved to ≤Grade 1 in >14 days or toxicity recurs, discontinue 
IPN60090. 
Grade 4 (>10.0×ULN) 
Discontinue IPN60090. 
ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; SGOT=serum glutamic 
oxaloacetic transaminase; SGPT=serum glutamic pyruvic transaminase 
Confounding factors and/or alternative causes for increase of total bilirubin should be excluded before dose 
interruption/reduction. They include but are not limited to: evidence of obstruction, such as elevated ALP and GGT typical of 
gallbladder or bile duct disease, hyperbilirubinaemia due to the indirect component only (i.e. direct bilirubin component 
≤1×ULN) due to haemolysis or Gilbert’s syndrome, pharmacologic treatment, viral hepatitis, alcoholic or autoimmune 
hepatitis, other hepatotoxic drugs. For patients with Gilbert’s syndrome, these dose modifications apply to changes in direct 
bilirubin only. Bilirubin will be fractionated if elevated. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 153/264 
 
 
Recommendations for IPN60090 Dose Modification in Case of Cardiac Toxicities 
Adverse drug 
reaction 
Severity 
Dose adjustment and management recommendations 
QTcF 
prolongation 
For all grades 
-Check the quality of the ECG and the QT value and repeat if 
needed. 
-Perform analysis of serum electrolytes (K+, Ca++, 
Phos, Mg++). If outside of normal range, hold IPN60090, correct 
with supplements or appropriate therapy as soon as possible, and 
repeat electrolytes until documented as normal. 
-Review concomitant medication usage for the potential to 
prolong the QT interval. 
-Check compliance with correct dose and administration of 
IPN60090. 
-Consider collecting a time matched PK sample; record date and 
time of last study drug intake. 
Grade 1 
QTc 450 to 480 ms 
No dose adjustment required. 
Grade 2 
QTc 481 to 500 ms 
-Hold IPN60090.  
-Perform repeat triplicate ECGs one hour after the first QTcF of 
≥481 ms. 
-If QTcF <481 ms, restart IPN60090 at the same dose. No dose 
adjustment required for first occurrence. If QTcF remains 
≥481 ms, repeat ECG as clinically indicated until the QTcF 
returns to <481 ms. Restart IPN60090 and pembrolizumab (if 
applicable) at the same dose.  
-No dose adjustment required for first occurrence. 
-If QTcF ≥481 ms recurs, IPN60090 should be reduced by one 
dose level. 
-Repeat ECGs 7 days and 14 days after dose reduction (then as 
clinically indicated) for any patients who had therapy interrupted 
due to QTcF ≥481 ms. 
Grade 3 
QTc ≥501 ms on at least 
two 
separate ECGs 
-Hold IPN60090  
-Perform repeat triplicate ECGs within one hour of the first 
QTcF of ≥501 ms. 
-If QTcF remains ≥501ms, consult with a cardiologist (or 
qualified specialist) and repeat cardiac monitoring as indicated 
until the QTcF returns to <481 ms. 
-If QTcF returns to <481 ms, IPN60090 will be reduced by one 
dose level. 
-Repeat ECGs 7 days and 14 days after dose reduction (then as 
clinically indicated) for any patients who had therapy interrupted 
due to QTcF ≥501 ms. 
-If QTcF of ≥501 ms recurs, discontinue study treatment.  
-Hold IPN60090 and perform frequent ECGs until the QTcF is 
<500 ms. Address electrolyte, calcium and magnesium 
abnormalities. Restart IPN60090 at a lower dose. 
-If findings recur on the lower dose, hold study treatment until 
resolve to ≤Grade 1, and restart at the next lower dose level. 
-If findings recur, discontinue IPN60090. 
Grade 4 QT/QTc ≥501 or 
>60 ms change from 
baseline and Torsades de 
pointes or polymorphic 
ventricular tachycardia, or 
signs/symptoms of serious 
arrhythmia 
-Discontinue IPN60090 
-Obtain local cardiologist (or qualified specialist) consultation 
and repeat cardiac monitoring as indicated until the QTcF returns 
to <481 ms. 
-Stop study treatment, institute emergency care, address 
electrolyte, calcium and magnesium abnormalities and perform 
frequent ECGs until the QTcF is <500 ms. 
-Discontinue the patient from the study. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 154/264 
 
 
Adverse drug 
reaction 
Severity 
Dose adjustment and management recommendations 
Cardiac - Left 
Ventricular 
Systolic 
Dysfunction 
Asymptomatic, resting 
ejection fraction 40% to 
50%; or 10% to 20% drop 
from baseline 
-Maintain dose level, and continue study treatment with caution. 
-Repeat LVEF within 4 weeks or as clinically appropriate. 
Symptomatic, 
responsive to intervention, 
ejection fraction 20% to 
39% or >20% drop from 
baseline 
-Hold study treatment until resolved, then reduce one dose level. 
-LVEF measurement to be repeated, if not resolved, within 
28 days.  
Refractory or poorly 
controlled, ejection fraction 
<20% 
Discontinue IPN60090. 
ECG=electrocardiogram; LVEF=left ventricular ejection fraction; QTc=corrected QT interval; QTcF=Fridericia corrected 
QT interval 
Dose Adjustment and Management Recommendations for IPN60090 in Case of Other 
Toxicities 
Toxicity 
Action 
Hyperlipidaemia and/or hypertriglyceridaemia 
Any grade: 
Treat according to best clinical practice. No specific dose 
reductions are needed. 
Hyperglycaemia 
Any grade: 
Treat according to best clinical practice. No specific dose 
reductions are needed. 
All other toxicities 
Any grade: 
Treat according to best clinical practice. No specific dose 
reductions are needed. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 155/264 
 
 
Management of IPN60090 and Pembrolizumab for Noninfectious Pneumonitis 
Worst grade 
pneumonitis 
Required investigations Management of 
pneumonitis 
Dose adjustment 
Grade 1 
Asymptomatic, 
radiographic findings 
only 
CT scans with lung 
windows. 
Repeat at least every 
12 weeks until return to 
within normal limits. 
No specific therapy is 
required. 
-Administer 100% of study 
treatment. 
-Consider patient referral to 
pulmonary specialist. 
-For recurrent pneumonitis, treat as 
Grade 3 or 4 event. 
Grade 2 
Symptomatic, 
not interfering 
with ADL 
CT scan with lung 
windows. 
Consider pulmonary 
function testing includes: 
spirometry, DLCO, and 
room air O2 saturation at 
rest. 
Repeat at least every 
12 weeks until return to 
within normal limits. 
Consider a bronchoscopy 
with biopsy and / or BAL. 
Symptomatic only. 
Initial dose of 1 to 
2 mg/kg/day prednisone or 
equivalent followed by a 
taper. 
-Hold pembrolizumab (if 
applicable) until recovery to 
≤Grade 1. 
-Resume pembrolizumab if event 
resolves to Grade 1 or better within 
12 weeks. 
-Permanently discontinue 
pembrolizumab and contact the 
sponsor if event does not resolve to 
Grade 1 or better within 12 weeks. 
-Reduce IPN60090 dose by one 
dose level until recovery to ≤Grade 
1. 
-Study treatment may also be 
interrupted if symptoms are 
troublesome. 
-Patients will discontinue 
IPN60090 and pembrolizumab (if 
applicable) if they fail to recover to 
≤Grade 1 within 12 weeks. 
-If Grade 2 recurs discontinue 
study treatment. 
Grade 3 
Symptomatic, 
interfering with ADL; 
O2 indicated 
CT scan with lung 
windows and pulmonary 
function testing includes: 
spirometry, DLCO, and 
room air O2 saturation at 
rest. 
Repeat at least every 
6 weeks until return to 
within normal limits. 
Bronchoscopy with biopsy 
and / or BAL is 
recommended. 
Initial dose of 1 to 
2 mg/kg/day prednisone or 
equivalent followed by a 
taper. 
-Discontinue IPN60090 and 
pembrolizumab (if applicable). 
Grade 4 
Life threatening; 
ventilatory support 
indicated 
CT scan with lung 
windows and required 
pulmonary function 
testing, if possible, 
includes: spirometry, 
DLCO, and room air O2 
saturation at rest. 
Repeat at least every 
6 weeks until return to 
within normal limits. 
Bronchoscopy with biopsy 
and / or BAL is 
recommended if possible. 
Initial dose of 1 to 
2 mg/kg/day prednisone or 
equivalent followed by a 
taper. 
-Discontinue IPN60090 and 
pembrolizumab (if applicable). 
ADL=activities of daily living; BAL=bronchoalveolar lavage; CT=computed tomography; DLCO=diffusing capacity of the 
lungs for carbon monoxide 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 156/264 
 
 
Appendix 2 LIST OF STRONG INDUCERS AND INHIBITORS OF CYP3A4 
 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 157/264 
 
 
Based on the in-vitro results, CYP3A4 may be involved in the metabolism of IPN60090. 
A strong inhibitor for a specific CYP450 enzymes is defined as an inhibitor which increases 
the AUC of a sensitive substrate ‘victim drug’ for that CYP450 enzymes by 5-fold or greater. 
A strong inducer: decreases the AUC of a victim drug by ≥80%. 
Strong inhibitors of CYP3A4 
Strong inducers of CYP3A4 
Antivirals 
Boceprevir 
Cobicistat 
Conivaptan 
Danoprevir 
Dasabuvir 
Elvitegravir 
Indinavir  
Lopinavir  
Nelfinavir 
Ombitasvir  
Paritaprevir 
Ritonavir  
Saquinavir 
Telaprevir  
Tipranavir  
Antifungals 
Itraconazole 
Ketoconazole 
Posaconazole 
Voriconazole 
Antibiotics 
Clarithromycin 
Telithromycin 
Troleandomycin 
Other 
Mibefradil 
LCL161 
Grapefruit juice 
Idelalisib 
Nefazodone 
Carbamazepine 
Enzalutamide 
Mitotane 
Phenytoin 
Rifampin 
Rifabutin 
Phenobarbital 
Avasimib 
St. John’s Wort 
This above table is not all inclusive.  
The above lists were compiled from the Indiana University School of Medicine’s “P450 Drug 
Interaction Table – Clinically Relevant Table” [21], supplemented with the FDA Draft 
Guidance for Industry, Drug Interaction Studies – Study Design, Data Analysis, and 
Implications for Dosing and Labeling (October 2017) and the University of Washington’s 
Drug Interaction Database (January 2017). These lists are not comprehensive and are only 
meant to be used as a guide.  
The sponsor should be contacted in case of any doubt. If a medication appears on both the list 
of prohibited and the list of medications to be used with caution, the medication is prohibited. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 158/264 
 
 
Appendix 3 LIST OF MODERATE INDUCERS AND INHIBITORS OF CYP3A4 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 159/264 
 
 
A moderate inhibitor for a specific CYP450 enzymes is defined as an inhibitor which 
increases the AUC of a sensitive substrate for that CYP450 enzymes by 2-fold or greater, but 
less than 5-fold. 
A moderate inducer: decreases the AUC of a victim drug between 50% to 80%. 
Moderate inhibitors of CYP3A4 
Moderate inducers of CYP3A4 
Antivirals 
Amprenavir 
Atazanavir 
Darunavir 
Faldaprevir 
Antifungals 
Fluconazole 
Isavuconazole 
Antibiotics 
Ciprofloxacin  
Erythromicin 
Other 
ACT-178882 
Aprepitant  
Casopitant 
Cimetidine 
Crizotinib 
Cyclosporine 
Diltiazem 
Dronedarone 
FK1706 
GSK2647544 
Grapefruit juice 
Imatinib 
Nilotinib 
Netupitant 
Schisandra sphenanthera (herbal medications) 
Tofisopam  
Verapamil 
Bosentan  
Efavirenz 
Etravirine 
Genistein 
Lersivirine 
Lopinavir 
Modafinil 
Nafcillin 
Ritonavir and St. John’s Wort 
Semagacestat 
Talviraline 
Thioridazine 
Tipranavir 
This above table is not all inclusive.  
The above lists were compiled from the Indiana University School of Medicine’s “P450 Drug 
Interaction Table – Clinically Relevant Table” [21], supplemented with the FDA Draft 
Guidance for Industry, Drug Interaction Studies – Study Design, Data Analysis, and 
Implications for Dosing and Labeling (October 2017) and the University of Washington’s 
Drug Interaction Database (January 2017). These lists are not comprehensive and are only 
meant to be used as a guide. 
The sponsor should be contacted in case of any doubt. If a medication appears on both the list 
of prohibited and the list of medications to be used with caution, the medication is prohibited. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 160/264 
 
 
Appendix 4 LIST OF STRONG AND MODERATE INHIBITORS OF CYP2D6 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 161/264 
 
 
Based on the in-vitro results, CYP2D6 may be involved in the metabolism of IPN60090. 
Strong inhibitors of CYP2D6 
Moderate inhibitors of CYP2D6 
Bupropion 
Dacomitinib 
Fluoxetine 
3,4-Methyl-enedioxy-methamphetamine (Ecstasy) 
Paroxetine 
Quinidine 
Terbinafine 
AMD070 
Cinacalcet 
Dronedarone 
Duloxetine 
Eliglustat 
Mirabegron 
Moclobemide 
Rolapitant  
Terbinafine 
Tipranavir/Ritonavir 
Zuojin pill (herbal medications) 
This above table is not all inclusive.  
The above lists were compiled from the Indiana University School of Medicine’s “P450 Drug 
Interaction Table – Clinically Relevant Table” [21], supplemented with the FDA Draft 
Guidance for Industry, Drug Interaction Studies – Study Design, Data Analysis, and 
Implications for Dosing and Labeling (October 2017) and the University of Washington’s 
Drug Interaction Database (January 2017). These lists are not comprehensive and are only 
meant to be used as a guide.  
The sponsor should be contacted in case of any doubt. If a medication appears on both the list 
of prohibited and the list of medications to be used with caution, the medication is prohibited. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 162/264 
 
 
Appendix 5 LIST OF STRONG INHIBITORS OF CYP2C8 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 163/264 
 
 
Paclitaxel is mainly metabolised by CYP2C8. Therefore, inhibitors of CYP2C8 may have an 
impact on the AUC of paclitaxel. 
A strong inhibitor for a specific CYP450 enzyme is defined as an inhibitor which increases 
the AUC of a sensitive substrate for that CYP450 enzymes by 5-fold or greater. 
Strong inhibitors of CYP2C8 
Clopidogrel  
Gemfibrozil 
This above table is not all inclusive.  
The above lists were compiled from the Indiana University School of Medicine’s “P450 Drug 
Interaction Table – Clinically Relevant Table” [21], supplemented with the FDA Draft 
Guidance for Industry, Drug Interaction Studies – Study Design, Data Analysis, and 
Implications for Dosing and Labeling (October 2017) and the University of Washington’s 
Drug Interaction Database (January 2017). These lists are not comprehensive and are only 
meant to be used as a guide.  
The sponsor should be contacted in case of any doubt. If a medication appears on both the list 
of prohibited and the list of medications to be used with caution, the medication is prohibited. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 164/264 
 
 
Appendix 6 LIST OF MODERATE INHIBITORS AND INDUCERS OF CYP2C8 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 165/264 
 
 
Paclitaxel is mainly metabolised by CYP2C8. Therefore, inhibitors and inducers of CYP2C8 
may have an impact on the AUC of paclitaxel. 
A moderate inhibitor for a specific CYP450 enzymes is defined as an inhibitor which 
increases the AUC of a sensitive substrate for that CYP450 enzymes by 2-fold or greater, but 
less than 5-fold. 
A moderate inducer: decreases the AUC of a victim drug between 50% to 80%. 
Moderate Inhibitors of CYP2C8 
Letermovir 
Teriflunomide 
Deferasirox 
Moderate Inducers of CYP2C8 
Rifampin 
Carbamazepin 
Ivosidenib 
Hormonal contraceptives 
This above table is not all inclusive.  
The above lists were compiled from the Indiana University School of Medicine’s “P450 Drug 
Interaction Table – Clinically Relevant Table” [21], supplemented with the FDA Draft 
Guidance for Industry, Drug Interaction Studies – Study Design, Data Analysis, and 
Implications for Dosing and Labeling (October 2017) and the University of Washington’s 
Drug Interaction Database (January 2017). These lists are not comprehensive and are only 
meant to be used as a guide.  
The sponsor should be contacted in case of any doubt. If a medication appears on both the list 
of prohibited and the list of medications to be used with caution, the medication is prohibited. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 166/264 
 
 
Appendix 7 LIST OF IMMUNOSUPPRESSIVE AGENTS 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 167/264 
 
 
Immunosuppressants 
Azathioprine  
Betamethasone  
Dexamethasone  
Hydrocortisone  
Hydroxychloroquine  
Leflunamide  
Methotrexate  
Methylprednisolone  
Prednisolone  
Triamcinolone  
Tenflunomide 
Anti-rejection agents  
Ciclosporin  
Everolimus  
Mycophenolic acid  
Tacrolimus  
Sirolimus 
Biological agents 
Abatacept  
Adalimumab  
Alemtuzumab  
Anakinra  
Apremilast  
Basiliximab  
Bevacizumab  
Canakinumab  
Certolizumab  
Daclizumab  
Eculizumab  
Erlotinid  
Etanercept  
Golimumab  
Infliximab  
Imatinib  
Ixekizumab  
Natalizumab  
Nilotinib  
Perfenidone  
Pomalidomide  
Rituximab  
Secukinumab  
Siltuximab  
Sortatinib  
Thalidomide  
Tocilizumab  
Ustenkinumab  
Vedolizumab  
Fingolimod  
Lenalidomide 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 168/264 
 
 
Cytotoxic chemotherapy agents 
Paclitaxel  
Capecitabine  
Fludarabine  
Etoposide  
Bendamustine  
Busulfan  
Carmustine  
Chlorambucil  
Dacarbazine  
Ifosfamide  
Melphalan  
Temozolamide  
Thiotepa  
Treosulfan  
Daunorubicin  
Doxorubicin  
Epirubicin  
Idarubicin  
Mitoxanthrone  
Azacitidine  
Cladribine  
Clofarabine  
Cytarabine  
Decitabine  
Fluorouracil  
Gemcitabine  
Mercaptopurine  
Nelarabine  
Pemetrexed  
Tioguanine  
Crisantaspase  
Eribulin  
Hydroxycarbamide (previously hydroxyurea)  
Mitotane  
Raltitrexed  
Bleomycin  
Mitomycin  
Pentostatin  
Carboplatin  
Cisplatin  
Trabectedin  
Oxaliplatin  
Cabazitaxel  
Docetaxel  
Irinotecan  
Topotecan  
Vinblastine  
Vincristine  
Vinorelbine  
Vinflunine 
Others 
Carbimazole  
Clozapine  
Deferiprone  
Olanzapine  
Phenytoin  
Phenobarbital  
Propylthiouracil 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 169/264 
 
 
The above list can be found on: 
https ://www .hse.ie/eng/services/publications/clinical-strategy-and-programmes/list-of-
immunosuppressant-medication.pdf 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 170/264 
 
 
Appendix 8 LIST OF SUBSTRATES OF OATP1B3, OCT1 AND OCT2 
 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 171/264 
 
 
IPN60090 is an inhibitor of the human OATP1B3, OCT1 and OCT2 transporters. 
OATP1B3 substrates 
Ambrisentan 
Atorvastatin 
Caspofungin 
Cholecystokinin 
Cholic acid 
Cobimetinib 
Conjugated oestrogens 
Digoxin 
Docetaxel 
Gadoxetic acid 
Glecaprevir  
Grazoprevir 
Letermovir  
Levosalbutamol 
Levomenthol 
Liothyronine 
Liotrix 
Methotrexate 
Mycophelate mofetil 
Ouabain 
Olmesartan 
Paclitaxel  
Parachlorophenol  
Paritaprevir 
Pravastatin 
Pitavastatin 
Rifampicine 
Romidepsin 
Selexipag 
Simeprevir 
Technetium mebrofenin 
Valsartan 
Voxilaprevir 
 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 172/264 
 
 
OCT1 substrates 
Acyclovir 
Amantadine 
Bamet-UD2 
Bleomycin 
Cimetidine 
Ciprofloxacin 
Furamidine 
123I or 131I m-iodobenzylguanidine 
Imatinib 
Irinotecan 
Levodopa 
Lamivudine 
Lamotrigine 
Metformin 
Mitoxantrone 
O-desmethyltramadol 
Ondansetron 
Oxaliplatin 
Pancuronium 
Pentamidine 
Pramipexole 
Quinidine 
Rocuronium 
Sorafenib 
Sulpiride 
Tropisetron 
YM155 
 
OCT2 substrates 
Amantadine 
Amiloride  
Cimetidine 
Creatinine 
Dofetilide 
Dopamine 
Famotidine 
Memantine 
Metformin  
Oxaliplatin  
Pindolol  
Procainamide  
Ranitidine  
Trimethoprim  
Varenicline  
The above tables are not all inclusive.  
The above lists were compiled from the following sources: 
• 
OATP1B3: DrugBank https ://www .drugbank.ca/biodb/bio_entities/BE0003659 
• 
OCT1: Lozano E, Herraez E, Briz O, et al. Role of the plasma membrane transporter of 
organic cations OCT1 and its genetic variants in modern liver pharmacology. Biomed 
Res Int 2013(1):692071 [22]. 
• 
OCT2: https ://www .straighthealthcare.com/organic-cation-transporter-2.html 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 173/264 
 
 
Appendix 9 DESCRIPTION OF THE iRECIST PROCESS FOR ASSESSMENT OF 
DISEASE PROGRESSION 
 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 174/264 
 
 
Assessment at Screening and Prior to RECIST 1.1 Progression 
Until radiographic disease progression based on RECIST 1.1, there is no distinct iRECIST 
assessment. 
Assessment and Decision at RECIST 1.1 Progression 
For patients who show evidence of radiological progressive disease by RECIST v1.1 as 
determined by the investigator, the investigator will decide whether to continue a patient on 
study treatment until repeat imaging is obtained (using iRECIST for patient management). 
This decision by the investigator should be based on the patient’s overall clinical condition. 
Clinical stability is defined as the following:  
• 
absence of symptoms and signs indicating clinically significant progression of disease 
• 
no decline in ECOG performance status  
• 
no requirements for intensified management, including increased analgesia, radiation, 
or other palliative care 
Any patient deemed clinically unstable should be discontinued from study treatment at 
site-assessed first radiologic evidence of progressive disease, and is not required to have 
repeat tumour imaging for confirmation of progressive disease by iRECIST. 
If the investigator decides to continue treatment, the participant may continue to receive study 
treatment and the tumour assessment should be repeated 4 to 8 weeks later to confirm 
progressive disease by iRECIST, per investigator assessment. Images should continue to be 
sent in to the central imaging vendor for potential retrospective Blinded Independent Central 
Review. 
Tumour flare may manifest as any factor causing radiographic progression per RECIST v1.1, 
including: 
• 
Increase in the sum of diameters of target lesion(s) identified at baseline to ≥20% and 
≥5 mm from nadir 
- 
Note: the iRECIST publication uses the terminology “sum of measurements”, 
but “sum of diameters” will be used in this protocol, consistent with the original 
RECIST v1.1 terminology. 
• 
Unequivocal progression of non-target lesion(s) identified at baseline 
• 
Development of new lesion(s) 
iRECIST defines new response categories, including unconfirmed progressive disease (iUPD) 
and confirmed progressive disease (iCPD). For the purposes of iRECIST assessment, the first 
visit showing progression according to RECIST v1.1 will be assigned a visit (overall) 
response of iUPD, regardless of which factors caused the progression. 
At this visit, target and nontarget lesions identified at baseline by RECIST v1.1 will be 
assessed as usual. 
New lesions will be classified as measurable or nonmeasurable, using the same size 
thresholds and rules as for baseline lesion assessment in RECIST v1.1. From measurable new 
lesions, up to five lesions total (up to two per organ), may be selected as New Lesions – 
Target. The sum of diameters of these lesions will be calculated, and kept distinct from the 
sum of diameters for target lesions at baseline. All other new lesions will be followed 
qualitatively as New Lesions – Nontarget. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 175/264 
 
 
Assessment at the Confirmatory Imaging 
On the confirmatory imaging, the patient will be classified as progression confirmed (with an 
overall response of iCPD), or as showing persistent unconfirmed progression (with an overall 
response of iUPD), or as showing disease stability or response (iSD/iPR/iCR). 
Confirmation of Progression 
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the 
following occurs: 
• 
Any of the factors that were the basis for the initial iUPD show worsening 
- 
For target lesions, worsening is a further increase in the sum of diameters of 
≥5 mm, compared to any prior iUPD timepoint 
- 
For nontarget lesions, worsening is any significant growth in lesions overall, 
compared to a prior iUPD timepoint; this does not have to meet the 
“unequivocal” standard of RECIST v1.1 
- 
For new lesions, worsening is any of these: 
• 
An increase in the new lesion sum of diameters by ≥5 mm from a prior 
iUPD timepoint  
• 
Visible growth of new nontarget lesions  
• 
The appearance of additional new lesions 
• 
Any new factor appears that would have triggered PD by RECIST v1.1 
Persistent iUPD 
Progression is considered not confirmed, and the overall response remains iUPD, if: 
• 
None of the progression-confirming factors identified above occurs AND 
• 
The target lesion sum of diameters (initial target lesions) remains above the initial 
progressive disease threshold (by RECIST v1.1) 
Additional imaging for confirmation should be scheduled 4 to 8 weeks from the imaging on 
which iUPD is seen. This may correspond to the next visit in the original visit schedule. The 
assessment of the subsequent confirmation imaging proceeds in an identical manner, with 
possible outcomes of iCPD, iUPD, and iSD/iPR/iCR. 
Resolution of iUPD 
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if: 
• 
None of the progression-confirming factors identified above occurs, AND 
• 
The target lesion sum of diameters (initial target lesions) is not above the initial 
progressive disease threshold.  
The response is classified as iSD or iPR (depending on the sum of diameters of the target 
lesions), or iCR if all lesions resolve. 
In this case, the initial iUPD is considered to be pseudoprogression, and the level of suspicion 
for progression is “reset”. This means that the next visit that shows radiographic progression, 
whenever it occurs, is again classified as iUPD by iRECIST, and the confirmation process is 
repeated before a response of iCPD can be assigned. 
Management Following the Confirmatory Imaging 
If repeat imaging does not confirm progressive disease per iRECIST, as assessed by the 
investigator, and the patient continues to be clinically stable, study treatment may continue 
and follow the regular imaging schedule. If PD is confirmed, patients will be discontinued 
from study treatment. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 176/264 
 
 
NOTE: If a patient has confirmed radiographic progression (iCPD) as defined above, but the 
participant is achieving a clinically meaningful benefit, an exception to continue study 
treatment may be considered following consultation with the sponsor. In this case, if study 
treatment is continued, tumour imaging should continue to be performed following the 
intervals previously outlined and submitted to the central imaging vendor. 
Detection of Progression at Visits After Pseudoprogression Resolves 
After resolution of pseudoprogression (i.e. achievement of iSD/iPR/iCR), iUPD is indicated 
by any of the following events: 
• 
Target lesions 
- 
Sum of diameters reaches the progressive disease threshold (≥20% and ≥5 mm 
increase from nadir) either for the first time, or after resolution of previous 
pseudoprogression. The nadir is always the smallest sum of diameters seen 
during the entire study, either before or after an instance of pseudoprogression. 
• 
Nontarget lesions 
- 
If nontarget lesions have never shown unequivocal progression, their doing so 
for the first-time results in iUPD. 
- 
If nontarget lesions have shown previous unequivocal progression, and this 
progression has not resolved, iUPD results from any significant further growth of 
nontarget lesions, taken as a whole. 
• 
New lesions 
- 
New lesions appear for the first time 
- 
Additional new lesions appear 
- 
Previously identified new target lesions show an increase of ≥5 mm in the new 
lesion sum of diameters, from the nadir value of that sum 
- 
Previously identified nontarget lesions show any significant growth 
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD 
evaluation process (see Assessment at the Confirmatory Imaging above) is repeated. 
Progression must be confirmed before iCPD can occur. 
The decision process is identical to the iUPD confirmation process for the initial PD, with one 
exception: if new lesions occurred at a prior instance of iUPD, and at the confirmatory 
imaging the burden of new lesions has increased from its smallest value (for new target 
lesions, the sum of diameters is ≥5 mm increased from its nadir), then iUPD cannot resolve to 
iSD or iPR. It will remain iUPD until either a decrease in the new lesion burden allows 
resolution to iSD or iPR, or until a confirmatory factor causes iCPD. 
Additional details about iRECIST are provided in the iRECIST publication. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 177/264 
 
 
Appendix 10 PROTOCOL AMENDMENT FORMS 
 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 178/264 
 
 
STUDY NUMBER: 
D-US-60090-001 
PROTOCOL TITLE: 
PHASE I OPEN LABEL, DOSE ESCALATION 
AND DOSE EXPANSION STUDY TO 
INVESTIGATE THE SAFETY, 
PHARMACOKINETICS, PHARMACODYNAMICS 
AND ANTI TUMOUR ACTIVITY OF IPN60090 AS 
SINGLE AGENT AND IN COMBINATION IN 
PATIENTS WITH ADVANCED SOLID TUMOURS 
AMENDED PROTOCOL VERSION 
NUMBER & DATE 
Version 1.2, 21 December 2018 
REASON(S) FOR CHANGES 
Changes were made to address the FDA’s comments 
received during the review of the initial IND. 
THE FOLLOWING CHANGE(S) IS/ARE PROPOSED: Minor formatting, typos and rephrasing of text to 
enhance clarity have not been recorded. Any new or amended text added to the protocol is indicated in italic. 
Removed text is shown as stricken out. 
Version Date 
VERSION 1.0 29 OCT 2018 
VERSION 1.2 21 DEC 2018 
Section 
WAS 
IS 
Synopsis 
3.1 
3.1.3 
 
- 
Dose Expansion Cohort 6: KEAP1 
or NRF2 wild-type tumours 
- 
Dose Expansion Cohort 9: KEAP1 
or NRF2 wild-type tumours 
- 
Dose Expansion Cohort 6: 
KEAP1 or NRF2 wild-type 
tumours with any level of ASNS 
expression 
- 
Dose Expansion Cohort 9: 
KEAP1 or NRF2 wild-type 
tumours with any level of ASNS 
expression 
Synopsis 
3.1.2.1 
 
Part A monotherapy dose-escalation will 
enrol single-patient cohorts for the first 
three dose levels (if no Grade 2 adverse 
event (AE) clearly not due to underlying 
disease or DLT is observed) and then 
cohorts of three patients each at the 
predefined dose levels. If a Grade 2 AE 
clearly not due to underlying disease or a 
DLT is observed in a single patient cohort 
(first three dose levels), two additional 
patients will be added at this dose level 
with the same rules for escalation and de-
escalation as the cohorts of three patients. 
Part A monotherapy dose-escalation will 
enrol single-patient cohorts for the first 
three dose levels (if no Grade 2 adverse 
event (AE) that is at least possibly 
related to the study drug(s) or DLT is 
observed) and then cohorts of three 
patients each at the predefined dose 
levels. If a Grade 2 AE that is at least 
possibly related to the study drug(s) or a 
DLT is observed in a single patient 
cohort (first three dose levels), two 
additional patients will be added at this 
dose level with the same rules for 
escalation and de-escalation as the 
cohorts of three patients. 
Synopsis 
3.1.2.1 
3.1.2.2  
3.1.2.3 
 
DLT Criteria 
The DLTs for Part … are defined for the 
investigational medicinal product 
(IMP)-related related AEs according to 
National Cancer Institute-Common 
Terminology Criteria for Adverse Events 
(NCI-CTCAE) … 
DLT Criteria 
The DLTs for Part … are defined for the 
investigational medicinal product (IMP)-
related, probably related or possibly 
related AEs according to National Cancer 
Institute-Common Terminology Criteria 
for Adverse Events (NCI-CTCAE) … 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 179/264 
 
 
Version Date 
VERSION 1.0 29 OCT 2018 
VERSION 1.2 21 DEC 2018 
Section 
WAS 
IS 
3.1.2.1 
3.1.2.2  
3.1.2.3 
 
• 
Grade 3 or 4 Febrile neutropenia 
(absolute neutrophil count (ANC) 
<1000/mm3 with a single 
temperature episode of 38.3°C or a 
sustained temperature of 38°C for 
>1 hour). 
• 
Febrile neutropenia of any grade 
(absolute neutrophil count (ANC) 
<1000/mm3 with a single 
temperature episode of 38.3°C or 
a sustained temperature of 38°C 
for >1 hour). 
 
 
• 
ALT/AST ≥3×ULN with total 
bilirubin ≥2×ULN without 
elevation of alkaline phosphatase 
and no other reasonable 
explanation for the abnormality 
(Hy’s law criteria). 
 
• 
Grade 3 or higher 
nonhaematological toxicity lasting 
more than 72 hours despite 
adequate supportive care 
excluding: 
- 
Grade 3 nausea, vomiting or 
diarrhoea for more than 72 
hours with adequate 
supportive care. 
- 
Grade 3 fatigue lasting 
more than a week. 
- 
Grade 3 or higher 
electrolyte abnormality that 
lasts for more than 72 hours 
that is not clinically 
complicated and resolves 
spontaneously or with 
conventional medical 
interventions. 
- 
Grade 3 or higher amylase 
or lipase not associated with 
symptoms or clinical 
manifestations of 
pancreatitis. 
• 
Grade 3 or higher 
nonhaematological toxicity 
excluding: 
- 
Grade 3 nausea, vomiting 
or diarrhoea for less than 
72 hours with adequate 
supportive care. 
- 
Grade 3 fatigue lasting less 
than a week. 
- 
Grade 3 or higher 
electrolyte abnormality 
that lasts for less than 
72 hours that is not 
clinically complicated and 
resolves spontaneously or 
with conventional medical 
interventions. 
- 
Grade 3 or higher amylase 
or lipase lasting less than 
72 hours and not 
associated with clinical 
manifestations of 
pancreatitis. 
Synopsis 
3.1.2.1  
3.1.2.2 
3.1.2.3  
3.6 
 
Patients who experience a DLT (or other 
study treatment related toxicity) will be 
permitted to continue to receive study 
treatment at a lower dose level than the 
dose at which the DLT was observed, at 
the discretion of the investigator (see 
Section 6.4.4) and will be followed for 
safety. 
Patients who experience a DLT (or other 
toxicities considered related, probably 
related or possibly related to the study 
treatment) will be permitted to continue 
to receive study treatment at a lower dose 
level than the dose at which the DLT was 
observed, at the discretion of the 
investigator (see Section 6.4.4) and will 
be followed for safety. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 180/264 
 
 
Version Date 
VERSION 1.0 29 OCT 2018 
VERSION 1.2 21 DEC 2018 
Section 
WAS 
IS 
3.6 
 
All patients will then be followed post end 
of treatment at 30 days ±3 days for the 
end of treatment visit, at 180 days ±14 
days for the safety follow-up visit and 
then every 3 months +/-14 days for 
survival until the end of the study. 
All patients will then be followed post 
end of treatment at 30 days ±3 days (for 
Parts A and C) and 90±3 days (for Part 
B) for the end of treatment visit, at 180 
days ±14 days for the safety follow-up 
visit and then every 3 months +/-14 days 
for survival until the end of the study. 
Synopsis 
4.1.1  
 
(3) 
Histologically or cytologically 
confirmed advanced solid 
tumours including tumours known 
to harbour KEAP1 and NRF2 
mutations or have low ASNS 
expression levels 
(immunohistochemistry (IHC) 
Grade 0 or 1). 
(3) 
Histologically or cytologically 
confirmed advanced solid 
tumours including tumours 
known to harbour KEAP1 and 
NRF2 mutations or have low 
ASNS expression levels 
(immunohistochemistry (IHC) 
Grade 0 or 1). 
- 
In dose escalations of all Parts, 
patients may be KEAP1/NRF2 
wild-type or mutated and have 
tumours with any level of ASNS 
expression. For dose expansions, 
see specific inclusion criteria per 
Part below. 
 
(6) 
Fresh or archival tumour tissue is 
available for mutation and 
biomarker analysis. In addition 
archival tumour tissue from time 
of initial diagnosis will be 
collected if available. 
(6) 
Fresh or archival tumour tissue 
must be available for mutation 
and biomarker analysis. Patients 
should not be put at undue risk to 
obtain fresh tumour biopsy. 
Procedures more invasive than 
core biopsy should not be used. 
Procedures to obtain biopsy 
should only be performed if the 
risk is minimal (no greater than 
2% risk of serious or severe 
complications). If available, 
archival tumour tissue from time 
of initial diagnosis will be 
collected in addition to the most 
recent biopsy (archival or fresh). 
Synopsis 
4.1.3 
 
(B2) 
Patients with following tumour 
types will be recruited during 
dose expansion only: 
(c) 
KEAP1 or NRF2 wild-type 
tumours 
(B2) 
Patients with following tumour 
types will be recruited during 
dose expansion only: 
(c) 
KEAP1 or NRF2 wild-type 
tumours with any level of ASNS 
expression 
Note: Section 4.1.3. B1 should read B2 
Synopsis 
4.1.4 
 
(C2) 
Patients with following tumour 
types will be recruited during 
dose expansion only: 
(c) 
KEAP1 or NRF2 wild-type 
tumours 
(C2) 
Patients with following tumour 
types will be recruited during 
dose expansion only: 
(c) 
KEAP1 or NRF2 wild-type 
tumours with any level of ASNS 
expression 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 181/264 
 
 
Version Date 
VERSION 1.0 29 OCT 2018 
VERSION 1.2 21 DEC 2018 
Section 
WAS 
IS 
4.3.3 
Determining an AE to be a potential DLT 
is independent of the investigator’s 
causality assessment, but the event must 
be related to IMP administration (i.e. after 
IMP administration through the follow-up 
visit), clinically significant in the opinion 
of the investigator and of at least moderate 
severity. 
Determining an AE to be a potential DLT 
is independent of the investigator’s 
causality assessment, but the event must 
be at least possibly related to IMP 
administration (i.e. after IMP 
administration through the follow-up 
visit), clinically significant in the opinion 
of the investigator and of at least 
moderate severity. 
Table 12  
 
Header updated to reflect changes in 
Section 3.6. 
Footnote o: added text: 
Fresh tumour biopsy should only be 
performed if the risk of the procedure is 
minimal (no greater than 2% risk of 
serious or severe complications). 
8.1.2.2 
• 
Related: reports including good 
reasons and sufficient information 
(for example plausible time 
sequence, dose response 
relationship, pharmacology, 
positive dechallenge and/or 
rechallenge) to assume a causal 
relationship with IMP 
administration in the sense that it is 
plausible, conceivable or likely. 
• 
Related: reports including good 
reasons and sufficient information 
(for example plausible time 
sequence, dose response 
relationship, pharmacology, 
positive dechallenge and/or 
rechallenge) to assume a causal 
relationship with IMP 
administration in the sense that it 
is plausible, conceivable or likely. 
Since attribution of an observed 
toxicity to a new drug can be 
uncertain, related events should 
include any toxicities considered 
related, probably related or 
possibly related to the drug. 
10.2.8 
Fresh tumour biopsy is performed at the 
screening visit, Cycle 1 Day 15, and 
EOS/EW (separate consent is required). 
Archival tumour tissue post the most 
recent line of treatment is acceptable in 
lieu of fresh biopsy at screening. 
Fresh or archival tumour tissue must be 
available for mutation and biomarker 
analysis. Fresh tumour biopsy is 
performed at the screening visit, Cycle 1 
Day 15, and EOS/EW (separate consent 
is required). Archival tumour tissue post 
the most recent line of treatment is 
acceptable in lieu of fresh biopsy at 
screening. In case no archival tumour 
tissue is available in a patient, fresh 
biopsy should be performed only if the 
procedure to obtain biopsy has a 
serious/severe complication risk no 
greater than 2%. Procedures more 
invasive than core biopsy should not be 
used. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 182/264 
 
 
Version Date 
VERSION 1.0 29 OCT 2018 
VERSION 1.2 21 DEC 2018 
Section 
WAS 
IS 
Synopsis 
11.2.1.1 
The design will proceed with accelerated 
titration up to DL3, i.e. cohorts of one will 
be enrolled until either the third dose level 
is evaluated, a Grade 2 AE clearly not 
related to the underlying disease occurs, 
or a DLT is observed (whichever occurs 
first). If a Grade 2 AE clearly not due to 
underlying disease or a DLT is observed 
in a single patient cohort (i.e. in one of the 
first three dose levels), two additional 
patients will be added at this dose level 
with the same rules for escalation and de-
escalation as the cohorts of three patients 
detailed below. 
The design will proceed with accelerated 
titration up to DL3, i.e. cohorts of one 
will be enrolled until either the third dose 
level is evaluated, a Grade 2 AE that is at 
least possibly related to the study drug(s) 
occurs, or a DLT is observed (whichever 
occurs first). If a Grade 2 AE that is at 
least possibly related to the study drug(s) 
or a DLT is observed in a single patient 
cohort (i.e. in one of the first three dose 
levels), two additional patients will be 
added at this dose level with the same 
rules for escalation and de-escalation as 
the cohorts of three patients detailed 
below. 
 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 183/264 
 
 
STUDY NUMBER: 
D-US-60090-001 
PROTOCOL TITLE: 
A PHASE I OPEN LABEL, DOSE ESCALATION 
AND DOSE EXPANSION STUDY TO 
INVESTIGATE THE SAFETY, 
PHARMACOKINETICS, PHARMACODYNAMICS 
AND ANTI-TUMOUR ACTIVITY OF IPN60090 
AS SINGLE AGENT AND IN COMBINATION IN 
PATIENTS WITH ADVANCED SOLID TUMOURS 
AMENDED PROTOCOL VERSION 
NUMBER & DATE 
Amendment 1.0, Version 2.0, 24 May 2019 
The Following Amendment(S) Is/Are Proposed: 
Version Date 
VERSION 1.2 21 DEC 2018 
VERSION 2.0 24 MAY 2019 
Page 
Section 
WAS 
IS 
1 
Title Page PHASE I OPEN LABEL, DOSE 
ESCALATION AND DOSE 
EXPANSION STUDY TO 
INVESTIGATE THE SAFETY, 
PHARMACOKINETICS, 
PHARMACODYNAMICS AND 
ANTI-TUMOUR ACTIVITY OF 
IPN60090 AS SINGLE AGENT AND 
IN COMBINATION IN PATIENTS 
WITH ADVANCED SOLID 
TUMOURS 
A PHASE I OPEN LABEL, DOSE 
ESCALATION AND DOSE 
EXPANSION STUDY TO 
INVESTIGATE THE SAFETY, 
PHARMACOKINETICS, 
PHARMACODYNAMICS AND 
ANTI-TUMOUR ACTIVITY OF 
IPN60090 AS SINGLE AGENT AND 
IN COMBINATION IN PATIENTS 
WITH ADVANCED SOLID 
TUMOURS 
1 
Title Page ClinicalTrials.gov number: Not yet 
available 
ClinicalTrials.gov number: Not yet 
available NCT03894540 
5 
Synopsis 
This study will evaluate the safety, the 
pharmacokinetics (PK), 
pharmacodynamics (PD) and 
anti-tumour activity of IPN60090 as a 
single agent (Part A) and in 
combination with pembrolizumab 
(Part B) or paclitaxel (Part C) in 
patients with advanced solid tumours. 
Specific objectives and corresponding 
endpoints for the study are outlined 
below. 
This study will evaluate the safety, the 
pharmacokinetics (PK), 
pharmacodynamics (PD) and 
anti-tumour activity of IPN60090 as a 
single agent (Part A) and in 
combination with pembrolizumab 
(Part B) or paclitaxel (Part C) in 
patients with advanced solid tumours. 
Part D will evaluate the safety of 
IPN60090 as a single agent and 
explore the effect of food on 
IPN60090 PK profile. Specific 
objectives and corresponding endpoints 
for the study are outlined below. 
5 
Synopsis 
• 
To assess the safety and 
tolerability of oral IPN60090 as 
a single agent (Part A) and in 
combination therapy with 
pembrolizumab (Part B) or 
paclitaxel (Part C).  
• 
To assess the safety and 
tolerability of oral IPN60090 as 
a single agent (Part A and 
Part D) and in combination 
therapy with pembrolizumab 
(Part B) or paclitaxel (Part C). 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 184/264 
 
 
Version Date 
VERSION 1.2 21 DEC 2018 
VERSION 2.0 24 MAY 2019 
Page 
Section 
WAS 
IS 
5 
Synopsis 
• 
To assess the preliminary 
anti-tumour activity of 
IPN60090 as a single agent 
(Part A) and in combination 
with pembrolizumab (Part B) or 
paclitaxel (Part C) in patients 
with or without biomarker 
selected specific tumour types. 
• 
To assess the preliminary 
anti-tumour activity of 
IPN60090 as a single agent 
(Part A and Part D) and in 
combination with 
pembrolizumab (Part B) or 
paclitaxel (Part C) in patients 
with or without biomarker 
selected specific tumour types. 
5 
Synopsis 
• 
To characterise the PK and PD 
profile of IPN60090 as a single 
agent (Part A) and in 
combination with 
pembrolizumab (Part B) or 
paclitaxel (Part C).  
• 
To characterise the PK and PD 
profile of IPN60090 as a single 
agent (Part A and Part D) and 
in combination with 
pembrolizumab (Part B) or 
paclitaxel (Part C).  
5 
Synopsis 
New text 
• 
To assess the effect of food 
on the PK profile of a single 
administration of IPN60090 
(Part D). 
6 
Synopsis 
As summarised in Figure 1, the study 
will be divided into three parts. 
As summarised in Figure 1, the study 
will be divided into three four parts. 
6 
Synopsis 
Figure 1 
IPN60090: Summary of 
Early Clinical Development 
Figure 1 
IPN60090: Summary 
of Early Clinical Development 
Amended as follows to include Part D: 
PART D 
 
ASNS=asparagine synthetase; BID=bis in die (twice daily); BOIN= Bayesian optimal interval; HGSOC= high-grade serous 
ovarian cancer; KEAP1=Kelch-like ECH-associated protein 1; NRF2=nuclear factor erythroid 2–related factor 2; 
NSCLC=non-small cell lung carcinoma; Ph.=pharmacologically; RD=recommended dose 
Version Date 
VERSION 1.2 21 DEC 2018 
VERSION 2.0 24 MAY 2019 
Page 
Section 
WAS 
IS 
7 
Synopsis 
New text 
Part D: This cohort will evaluate the 
safety of IPN60090 administered as a 
single agent and explore the effect of 
a moderate fat meal on the PK 
profile of IPN60090 administered as 
a single dose under fasting and fed 
conditions at the RD as defined by 
the Safety Review Committee (SRC). 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 185/264 
 
 
Version Date 
VERSION 1.2 21 DEC 2018 
VERSION 2.0 24 MAY 2019 
Page 
Section 
WAS 
IS 
8 
Synopsis 
New text 
At the end of each part, up to two 
dose levels may be repeated in order 
to reach a total of 18 patients at each 
dose level to collect more PD/PK 
information to better define the RD. 
Decision to repeat a dose level will be 
made by the SRC. Safety data from 
these additional patients will not be 
included in the BOIN design to 
determine MTD but will be evaluated 
by the SRC and ultimately be taken 
into consideration for RD selection. 
9 
Synopsis 
At all dose levels, IPN60090 will be 
administered orally BID starting from 
Day 1 of each 21-day cycle and 
pembrolizumab will be administered as 
one intravenous (i.v.) infusion every 
21 days starting from Day 1 of each 
cycle. The predefined dose-escalation 
plan is described in Table 2.  
At all dose levels, IPN60090 will be 
administered orally BID starting from 
Day 1 of each 21-day cycle and 
pembrolizumab will be administered as 
one intravenous (i.v.) infusion every 
21 days (±1 day in Cycle 1 and ±3 
days in all other cycles) starting from 
Day 1 of each cycle. The predefined 
dose-escalation plan is described in 
Table 2 3.  
10 
Synopsis 
New text 
At the end of each part, up to two 
dose levels may be repeated in order 
to reach a total of 18 patients at each 
dose level to collect more PD/PK 
information to better define the RD. 
Decision to repeat a dose level will be 
made by the SRC. Safety data from 
these additional patients will not be 
included in the BOIN design to 
determine MTD but will be evaluated 
by the SRC and ultimately be taken 
into consideration for RD selection. 
11 
Synopsis 
At all dose levels, IPN60090 will be 
administered orally BID starting from 
Day 1 of each 21-day cycle and 
paclitaxel will be administered as one 
i.v. infusion every 21 days starting from 
Day 1 of each cycle. The predefined 
dose-escalation plan is described in 
Table 3. 
At all dose levels, IPN60090 will be 
administered orally BID starting from 
Day 1 of each 21-day cycle and 
paclitaxel will be administered as one 
i.v. infusion every 21 days (±1 day in 
Cycle 1 and ±3 days in all other 
cycles) starting from Day 1 of each 
cycle. The predefined dose-escalation 
plan is described in Table 3 4. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 186/264 
 
 
Version Date 
VERSION 1.2 21 DEC 2018 
VERSION 2.0 24 MAY 2019 
Page 
Section 
WAS 
IS 
11 
Synopsis 
New text 
At the end of each part, up to two 
dose levels may be repeated in order 
to reach a total of 18 patients at each 
dose level to collect more PD/PK 
information to better define the RD. 
Decision to repeat a dose level will be 
made by the SRC. Safety data from 
these additional patients will not be 
included in the BOIN design to 
determine MTD but will be evaluated 
by the SRC and ultimately be taken 
into consideration for RD selection. 
13 
Synopsis 
New text 
Part D – Food Effect Assessment  
Part D will start at the end of Part A 
dose escalation. Patients in Part D 
will not be part of the dose escalation 
and MTD assessment. 
Food effect evaluation will be 
conducted in patients with 
biomarker-positive and 
biomarker-negative advanced solid 
tumours. 
These patients will not be selected for 
KEAP1/NRF2 mutation status and 
may be wild-type or mutated. 
Patients may have tumours with any 
level of ASNS expression. Eligibility 
criteria for Part D will be the same as 
the criteria for Part A dose 
escalation. 
After screening, eight patients will 
enter a run-in period of 7 days. 
Full PK profiles will be obtained on 
Day -7 under fasting conditions and 
Day -3 after a moderate fat meal to 
assess the food effect on IPN60090 
PK profile. 
In Part D, the moderate fat meal is 
defined as the following: total 
calories of 500 to 750 kCal including 
30 to 35% fat. 
After the run-in period, patients will 
receive IPN60090 as a single agent 
administered orally BID (every 
12 hours), during or after a meal, 
starting from Day 1 at the single 
agent RD. Patients in Part D will 
follow the same schedule of 
assessments as described for Part A 
(with the exception of the urine 
sampling for PK). 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 187/264 
 
 
Version Date 
VERSION 1.2 21 DEC 2018 
VERSION 2.0 24 MAY 2019 
Page 
Section 
WAS 
IS 
14 
Synopsis 
Patients enrolled in monotherapy 
Part A may receive combination 
treatment with either pembrolizumab or 
with paclitaxel upon progression on 
IPN60090 monotherapy at the 
discretion of the investigator and with 
the approval of the sponsor. These 
patients will need to satisfy eligibility 
criteria for combination therapy prior to 
initiating treatment, and will be 
followed for safety and efficacy in a 
separate cohort. 
Patients enrolled in monotherapy 
Part A or Part D may receive 
combination treatment with either 
pembrolizumab or with paclitaxel upon 
progression on IPN60090 monotherapy 
at the discretion of the investigator and 
with the approval of the sponsor. These 
patients will need to satisfy eligibility 
criteria for combination therapy prior to 
initiating treatment, and will be 
followed for safety and efficacy in a 
separate cohort. 
14 
Synopsis 
New text 
Food Effect Assessment 
Part D (single agent): Eight patients 
for preliminary food effect 
assessment. 
15 
Synopsis 
(6)  
Fresh or archival tumour tissue 
must be available for mutation 
and biomarker analysis. Patients 
should not be put at undue risk to 
obtain fresh tumour biopsy. 
Procedures more invasive than 
core biopsy should not be used. 
Procedures to obtain biopsy 
should only be performed if the 
risk is minimal (no greater than 
2% risk of serious or severe 
complications). If available, 
archival tumour tissue from time 
of initial diagnosis will be 
collected in addition to the most 
recent biopsy (archival or fresh).  
(6a)  Fresh and/or archival tumour 
tissue from the biopsy obtained 
between the completion of the 
most recent line of treatment 
until study entry must be 
available for mutation and 
biomarker analysis unless 
KEAP1/NRF2 mutations were 
present in any previous biopsy, 
in which case, no further 
biopsy is required. For ovarian 
cancer patients, both archival 
biopsies obtained between the 
completion of the most recent 
line of treatment until study 
entry and fresh biopsies must 
be available to evaluate the 
evolution of ASNS levels over 
time. Patients should not be put 
at undue risk to obtain fresh 
tumour biopsy. Procedures more 
invasive than core biopsy should 
not be used. Procedures to obtain 
biopsy should only be performed 
if the risk is minimal (no greater 
than 2% risk of serious or severe 
complications). If available, 
archival tumour tissue from time 
of initial diagnosis will be 
collected in addition to the most 
recent biopsy (archival and/or 
fresh). 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 188/264 
 
 
Version Date 
VERSION 1.2 21 DEC 2018 
VERSION 2.0 24 MAY 2019 
Page 
Section 
WAS 
IS 
15 
Synopsis 
(8) 
Eastern Cooperative Oncology 
Group (ECOG) Performance 
Status (PS) ≤1. 
(8a) Eastern Cooperative Oncology 
Group (ECOG) Performance 
Status (PS) ≤1 and a Royal 
Marsden Hospital (RMH) 
score of 0 or 1. 
17 
Synopsis 
New text 
Part D Specific Inclusion Criteria 
(D1) Patients must be able to 
consume a moderate fat meal.  
18 
Synopsis 
New text 
(16) Patients unwilling to comply 
with protocol requirements 
related to the assigned part. 
18 
Synopsis 
Treatment with strong cytochrome 
P450 subtype 2C8 (CYP2C8) inhibitors 
and inducers within the 7 days of the 
paclitaxel infusion. 
(C1) Treatment with strong 
cytochrome P450 subtype 2C8 
(CYP2C8) inhibitors and 
inducers within the 7 days of the 
paclitaxel infusion. 
18 
Synopsis 
New text 
Part D Specific Exclusion Criteria 
(D1) Treatment with drugs that can 
alter the absorption of 
IPN60090 by affecting 
gastrointestinal motility or by 
changing the gastric pH during 
the run-in period (Day -7 to 
Day -3) of Part D.  
(D2) Patients suffering from 
conditions which are likely to 
adversely affect 
gastrointestinal motility and/or 
transit (for example, 
diarrhoea, vomiting or nausea, 
gastroparesis, irritable bowel 
syndrome and malabsorption) 
or patients with 
gastrointestinal resection 
(e.g. partial or total 
gastrectomy) likely to interfere 
with absorption of study 
treatment. Patients with Type 
1 diabetes and 
hypercholesterolaemia are 
excluded. 
(D3) Patients unable to fast for up to 
14 hours. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 189/264 
 
 
Version Date 
VERSION 1.2 21 DEC 2018 
VERSION 2.0 24 MAY 2019 
Page 
Section 
WAS 
IS 
18 
Synopsis 
Part B dose escalation: the starting 
dose of IPN60090 will be a dose 
showing pharmacological activity (at 
least 50% inhibition of Glu:Gln ratio in 
PBMC at Ctrough (12 hrs postdose) on 
Day 14 in 66% of patients at this dose 
level) and good tolerability as identified 
in Part A. IPN60090 intake should be 
performed at least 2 hours before the 
start of pembrolizumab infusion. The 
dose of pembrolizumab will be fixed at 
200 mg Q3W (or according to the local 
approved label for specific tumour 
types) as an i.v. infusion. 
Part B dose escalation: the starting 
dose of IPN60090 will be a dose 
showing pharmacological activity (at 
least 50% inhibition of Glu:Gln ratio in 
PBMC at Ctrough (12 hrs postdose) on 
Day 14 in 66% of patients at this dose 
level) and good tolerability as identified 
in Part A. IPN60090 intake should be 
performed at least 2 hours before the 
start of pembrolizumab infusion. The 
dose of pembrolizumab will be fixed at 
200 mg Q3W every 21 days (±1 day in 
Cycle 1 and ±3 days in all other 
cycles) (or according to the local 
approved label for specific tumour 
types) as an i.v. infusion. 
19 
Synopsis 
The dose of paclitaxel will be fixed at 
175 mg/m² or 135 mg/m2 Q3W (or 
according to the local approved label 
for specific tumour types) administered 
as an i.v. infusion. 
The dose of paclitaxel will be fixed at 
175 mg/m² or 135 mg/m2 Q3W every 
21 days (±1 day in Cycle 1 and ±3 
days in all other cycles) (or according 
to the local approved label for specific 
tumour types) administered as an i.v. 
infusion. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 190/264 
 
 
Version Date 
VERSION 1.2 21 DEC 2018 
VERSION 2.0 24 MAY 2019 
Page 
Section 
WAS 
IS 
19 
Synopsis 
New text 
Part D food effect assessment: single 
administration of IPN60090 at the 
RD (morning dose only), as defined 
by the SRC at the end of Part A dose 
escalation, will be performed during 
the run-in period at Day -7 and 
Day -3. On Day -7, IPN60090 will be 
administered following an overnight 
fast of at least 10 hours. On Day -3, 
IPN60090 will be administered 
30 minutes after the start of a 
moderate fat meal. The moderate fat 
meal should be eaten in 30 minutes 
or less. On both days, the patients 
should not consume any food for at 
least 4 hours after the dose. 
IPN60090 should be taken with 
240 mL (i.e. 8 fluid ounces) of water. 
Additional water is permitted ad 
libitum except for the period 1 hour 
before to 1 hour after administration 
of the drug product. Substitutions to 
the test meal can be made after 
discussion with the sponsor. It is 
understood that some patients may 
not be able to consume the entire 
meal. Study staff should record the 
percent of the test meal breakfast 
and the time it takes to be consumed. 
Then starting from Day 1, patients 
will receive IPN60090 BID (at the RD 
as defined by the SRC at the end of 
Part A) during or after a meal over 
21 days (one cycle) as described in 
Part A. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 191/264 
 
 
Version Date 
VERSION 1.2 21 DEC 2018 
VERSION 2.0 24 MAY 2019 
Page 
Section 
WAS 
IS 
20 
Synopsis 
• 
Define the safety and tolerability 
profile of oral IPN60090 as a 
single agent (Part A) and in 
combination therapy with 
pembrolizumab (Part B) or 
paclitaxel (Part C) as determined 
by the incidence and nature of 
AEs.  
• 
Define the The safety and 
tolerability profile of oral 
IPN60090 as a single agent 
(Part A and Part D) and in 
combination therapy with 
pembrolizumab (Part B) or 
paclitaxel (Part C) as determined 
by the incidence and nature will 
be assessed by continuous 
reporting of AEs and serious 
AEs (SAEs), clinical 
laboratory test results, the 
presence of 
anti-pembrolizumab antidrug 
antibodies (ADA; Part B only), 
vital signs measurements, 
ECG and physical 
examination results and 
concomitant medication usage. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 192/264 
 
 
Version Date 
VERSION 1.2 21 DEC 2018 
VERSION 2.0 24 MAY 2019 
Page 
Section 
WAS 
IS 
20 
Synopsis 
• 
Anti-tumour activity 
parameters assessed locally 
(for dose escalation) and 
centrally (for dose expansion) 
using RECIST version 1.1 for 
Part A and C and iRECIST 
for Part B only, including:  
- 
Clinical benefit rate 
(CBR) is defined as the 
proportion of patients 
in whom the Best 
Overall Response 
(BOR) is equal to 
complete response 
(CR), partial response 
(PR) or stable disease 
(SD) lasting at least 
12 weeks for Part A 
and C and equal to 
immune CR (iCR), 
immune PR (iPR) or 
immune SD (iSD) 
lasting at least 
12 weeks for Part B 
- 
Objective response rate 
(ORR) is defined as the 
proportion of patients in 
whom the BOR is equal 
to CR and PR for Part A 
and C or iCR and iPR for 
Part B 
- 
Disease control rate 
(DCR) is defined as the 
proportion of patients in 
whom the BOR is equal 
to CR, PR or SD for 
Part A and C and equal to 
iCR, iPR or iSD for 
Part B 
• 
Anti-tumour activity 
parameters assessed locally 
(for dose escalation) and 
centrally (for dose expansion) 
using RECIST version 1.1 for 
Part A, and C and D and 
iRECIST for Part B only, 
including: 
- 
Clinical benefit rate 
(CBR) is defined as the 
proportion of patients 
in whom the Best 
Overall Response 
(BOR) is equal to 
complete response 
(CR), partial response 
(PR) or stable disease 
(SD) lasting at least 
12 weeks for Part A, 
and C and D and equal 
to immune CR (iCR), 
immune PR (iPR) or 
immune SD (iSD) 
lasting at least 
12 weeks for Part B 
- 
Objective response rate 
(ORR) is defined as the 
proportion of patients in 
whom the BOR is equal 
to CR and PR for Part A, 
and C and D or iCR and 
iPR for Part B 
- 
Disease control rate 
(DCR) is defined as the 
proportion of patients in 
whom the BOR is equal 
to CR, PR or SD for 
Part A, and C and D and 
equal to iCR, iPR or iSD 
for Part B 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 193/264 
 
 
Version Date 
VERSION 1.2 21 DEC 2018 
VERSION 2.0 24 MAY 2019 
Page 
Section 
WAS 
IS 
20 
Synopsis 
• 
Pharmacokinetic parameters of 
IPN60090, including but not 
limited to maximum observed 
plasma concentration (Cmax), 
time to maximum observed 
plasma concentration (Tmax), 
Ctrough, area under the plasma 
concentration-time curve 
(AUC), elimination half-life 
(t1/2), apparent total clearance 
from plasma (CL/F), apparent 
volume of distribution (V/F) of 
IPN60090 (Parts A to C). 
• 
Pharmacokinetic parameters of 
IPN60090, including but not 
limited to maximum observed 
plasma concentration (Cmax), 
time to maximum observed 
plasma concentration (Tmax), 
Ctrough, area under the plasma 
concentration-time curve 
(AUC), elimination half-life 
(t1/2), apparent total clearance 
from plasma (CL/F), apparent 
volume of distribution (V/F) of 
IPN60090 (Parts A to C D). 
20 
Synopsis 
New text 
• 
Describe the PK of a single 
dose of IPN60090 
administered in fed state 
(Day -3) relative to fasted state 
(Day -7) using the following 
PK parameters: Cmax, AUC, 
Tmax, t1/2, CL/F, V/F (Part D). 
21 
Synopsis 
New text 
Food effect population: All patients 
in Part D who have received 
IPN60090 under fasting and fed 
conditions (Day -7 and Day -3), have 
consumed ≥80% of the moderate fat 
meal on Day -3, and who have no 
major protocol deviation affecting 
the PK variables and who have a 
sufficient number of IPN60090 
plasma concentrations to estimate 
the main PK parameters (Cmax, Tmax 
and AUC0-last) 
Pharmacodynamic population: All 
patients who have at least one PD 
endpoints measurement. PD 
endpoints refer to target engagement 
levels (Glu:Gln ratio in PBMC). 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 194/264 
 
 
Version Date 
VERSION 1.2 21 DEC 2018 
VERSION 2.0 24 MAY 2019 
Page 
Section 
WAS 
IS 
22 
Synopsis 
New text 
Food effect assessment – Part D 
The assessment of food effect will be 
based upon the ratio of the 
population geometric means (fed 
versus fasted, i.e. Day -3 versus 
Day -7) for the PK parameters (Cmax 
and AUC). The data will be 
transformed prior to analysis using a 
logarithmic transformation. Tmax 
between fed and fasted states will be 
compared using a non-parametric 
test such as the Wilcoxon test. 
Descriptive statistics of other PK 
parameters will be presented both in 
fasting and fed conditions. 
23 
Synopsis 
New text 
Food Effect Assessment - Part D 
The sample size (n=8) is not based on 
statistical calculation. A sample size 
of eight patients allows for a 
preliminary assessment of the 
potential effect of food on the PK of 
IPN60090. 
36 
List of 
abbreviations 
New text 
RMH Royal Marsden Hospital 
48/49 
1.5.5 
New text 
1.5.5 
Food Effect Assessment 
Rationale 
Part D will explore the effect of food 
on a single administration of 
IPN60090 (patients will receive the 
treatment under fed and fasted 
conditions). A moderate fat meal has 
been selected since patients with late 
stage cancer may have difficulties 
eating a high-fat meal as described in 
FDA Guidance for Industry 
Assessing the Effects of Food on 
Drugs in INDs and NDAs — Clinical 
Pharmacology Considerations. For 
ethical reasons, after the run-in 
period designed to evaluate the effect 
of food on IPN60090 PK profile, 
patients will be allowed to receive 
IPN60090 BID as described in 
Part A. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 195/264 
 
 
Version Date 
VERSION 1.2 21 DEC 2018 
VERSION 2.0 24 MAY 2019 
Page 
Section 
WAS 
IS 
49 
1.6 
• 
HGSOC with low expression 
levels of ASNS 
(approximatively 15% of 
HGSOC tumours). Tumours will 
be classified as ASNS low using 
a qualitative analysis of ASNS 
staining in tumour biopsies with 
a score of 0 or 1+ depending on 
the intensity (negative or weak) 
and pervasiveness of staining 
[18]. A quantitative method of 
ASNS staining using H SCORE 
will also be explored to evaluate 
the optimal range of H SCORE 
that would be associated with a 
clinical benefit. 
• 
HGSOC with low expression 
levels of ASNS 
(approximatively 15% of 
HGSOC tumours). Tumours will 
be classified as ASNS low using 
a qualitative analysis of ASNS 
staining in tumour biopsies with 
a score of 0 or 1+ depending on 
the intensity (negative or weak) 
and pervasiveness of staining 
[18]. A quantitative method of 
ASNS staining using H SCORE 
will may also be explored to 
evaluate the optimal range of H 
SCORE that would be 
associated with a clinical 
benefit. 
49 
1.6 
 
The dose escalation study will be 
performed in biomarker unselected 
patients with solid tumours to establish 
the RD of IPN60090. Patients will be 
actively screened for putative predictive 
biomarkers of response to IPN60090, 
for example KEAP1 and NRF2 
mutations, and low ASNS expression 
levels for this trial. A retrospective 
analysis of the correlation between 
KEAP1/NRF2 mutations versus 
wild-type or ASNSlow versus ASNShigh 
tumours and the sensitivity to 
IPN60090 will be performed. Patients 
will be enrolled in three separate parts 
either: 
• 
Part A: IPN60090 
monotherapy, or  
• 
Part B: IPN60090 + 
pembrolizumab, or 
• 
Part C: IPN60090 + paclitaxel 
The dose escalation study and the food 
assessment study will be performed in 
biomarker unselected patients with 
solid tumours to establish the RD of 
IPN60090. Patients will be actively 
screened for putative predictive 
biomarkers of response to IPN60090, 
for example KEAP1 and NRF2 
mutations, and low ASNS expression 
levels for this trial. A retrospective 
analysis of the correlation between 
KEAP1/NRF2 mutations versus 
wild-type or ASNSlow versus ASNShigh 
tumours and the sensitivity to 
IPN60090 will be performed. Patients 
will be enrolled in three four separate 
parts either: 
• 
Part A: IPN60090 monotherapy, 
or  
• 
Part B: IPN60090 + 
pembrolizumab, or 
• 
Part C: IPN60090 + paclitaxel, 
or 
• 
Part D: IPN60090 
monotherapy, food effect part 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 196/264 
 
 
Version Date 
VERSION 1.2 21 DEC 2018 
VERSION 2.0 24 MAY 2019 
Page 
Section 
WAS 
IS 
51 
2.1 
This is a phase I first in human dose 
escalation study with multiple 
expansion cohorts of IPN60090. The 
dose escalation part will investigate the 
safety and tolerability, and provide a 
better understanding of the mechanism 
of action of IPN60090 and of the 
potential of selected biomarkers to 
predict the clinical outcome in 
monotherapy as well as in combination 
with other cancer therapies. This study 
will also generate the first PK data in 
human and PK/PD correlation data that 
will support the choice of the RD. The 
dose expansion part will further define 
safety and tolerability of IPN60090 
alone and in combination and 
investigate the preliminary anti-tumour 
activity. 
This is a phase I first in human dose 
escalation study with multiple 
expansion cohorts of IPN60090. The 
dose escalation part will investigate the 
safety and tolerability, and provide a 
better understanding of the mechanism 
of action of IPN60090 and of the 
potential of selected biomarkers to 
predict the clinical outcome in 
monotherapy as well as in combination 
with other cancer therapies. This study 
will also generate the first PK data in 
human and PK/PD correlation data that 
will support the choice of the RD. An 
additional cohort will explore the 
effect of food on IPN60090 PK 
profile. The dose expansion part will 
further define safety and tolerability of 
IPN60090 alone and in combination 
and investigate the preliminary 
anti-tumour activity. 
51 
2.2 
This study will evaluate the safety, PK, 
PD and anti-tumour activity of 
IPN60090 as a single agent (Part A) 
and in combination with 
pembrolizumab (Part B) or paclitaxel 
(Part C) in patients with advanced solid 
tumours. Specific objectives and 
corresponding endpoints for the study 
are outlined below.  
This study will evaluate the safety, PK, 
PD and anti-tumour activity of 
IPN60090 as a single agent (Part A) 
and in combination with 
pembrolizumab (Part B) or paclitaxel 
(Part C) in patients with advanced solid 
tumours. Part D will evaluate the 
safety of IPN60090 as a single agent 
and explore the effect of food on 
IPN60090 PK profile. Specific 
objectives and corresponding endpoints 
for the study are outlined below.  
51 
2.2.1 
• 
To assess the safety and 
tolerability of oral IPN60090 as 
a single agent (Part A) and in 
combination therapy with 
pembrolizumab (Part B) or 
paclitaxel (Part C).  
• 
To assess the safety and 
tolerability of oral IPN60090 as 
a single agent (Part A and 
Part D) and in combination 
therapy with pembrolizumab 
(Part B) or paclitaxel (Part C).  
51 
2.2.2 
• 
To assess the preliminary 
anti-tumour activity of 
IPN60090 as a single agent 
(Part A) and in combination 
with pembrolizumab (Part B) or 
paclitaxel (Part C) in patients 
with or without biomarker 
selected specific tumour types. 
• 
To assess the preliminary 
anti-tumour activity of 
IPN60090 as a single agent 
(Part A and Part D) and in 
combination with 
pembrolizumab (Part B) or 
paclitaxel (Part C) in patients 
with or without biomarker 
selected specific tumour types. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 197/264 
 
 
Version Date 
VERSION 1.2 21 DEC 2018 
VERSION 2.0 24 MAY 2019 
Page 
Section 
WAS 
IS 
51 
2.2.2 
• 
To characterise the 
pharmacokinetic and 
pharmacodynamic profile of 
IPN60090 as a single agent 
(Part A) and in combination 
with pembrolizumab (Part B) or 
paclitaxel (Part C).  
• 
To characterise the 
pharmacokinetic PK and 
pharmacodynamic PD profile of 
IPN60090 as a single agent 
(Part A and Part D) and in 
combination with 
pembrolizumab (Part B) or 
paclitaxel (Part C).  
51 
2.2.2 
New text 
• 
To assess the effect of food on 
the PK profile of a single 
administration of IPN60090 
(Part D). 
53 
3.1 
As summarised in Figure 5, the study 
will be divided into three parts. 
As summarised in Figure 5, the study 
will be divided into three four parts. 
53 
3.1 
Figure 5 
IPN60090: Summary of 
Early Clinical Development 
Figure 5 
IPN60090: Summary 
of Early Clinical Development 
Amended as follows to include Part D: 
PART D 
 
ASNS=asparagine synthetase; BID=bis in die (twice daily); BOIN= Bayesian optimal interval; HGSOC= high-grade serous 
ovarian cancer; KEAP1=Kelch-like ECH-associated protein 1; NRF2=nuclear factor erythroid 2–related factor 2; 
NSCLC=non-small cell lung carcinoma; Ph.=pharmacologically; RD=recommended dose 
 
Version Date 
VERSION 1.2 21 DEC 2018 
VERSION 2.0 24 MAY 2019 
Page 
Section 
WAS 
IS 
55 
3.1 
New text 
Part D: This cohort will evaluate the 
safety of IPN60090 administered as 
a single agent and explore the effect 
of a moderate fat meal on the PK 
profile of IPN60090 administered as 
a single dose under fasting and fed 
conditions at the RD as defined by 
the SRC. 
55 
3.1.1 
New text 
Food Effect Assessment 
Part D: Eight patients for 
preliminary food effect assessment. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 198/264 
 
 
Version Date 
VERSION 1.2 21 DEC 2018 
VERSION 2.0 24 MAY 2019 
Page 
Section 
WAS 
IS 
55 
3.1.2.1 
New text 
Dose levels provided are examples 
and after the starting dose, the dose 
level will be determined by the SRC. 
After each SRC meeting, the tested 
dose level can be escalated, 
de-escalated or extended as 
indicated per BOIN. 
56 
3.1.2.1 
New text 
At the end of each part, up to two 
dose levels may be repeated in order 
to reach a total of 18 patients at each 
dose level to collect more PD/PK 
information to better define the RD. 
Decision to repeat a dose level will 
be made by the SRC. Safety data 
from these additional patients will 
not be included in the BOIN design 
to determine MTD but will be 
evaluated by the SRC and ultimately 
be taken into consideration for RD 
selection. 
58/59 
3.1.2.2 
At all dose levels, IPN60090 will be 
administered orally BID starting from 
Day 1 of each 21-day cycle and 
pembrolizumab will be administered as 
one intravenous (i.v.) infusion every 
21 days starting from Day 1 of each 
cycle. The predefined dose-escalation 
plan is described in Table 7.  
At all dose levels, IPN60090 will be 
administered orally BID starting from 
Day 1 of each 21-day cycle and 
pembrolizumab will be administered as 
one intravenous (i.v.) infusion every 
21 days (±1 day in Cycle 1 and ±3 
days in all other cycles) starting from 
Day 1 of each cycle. The predefined 
dose-escalation plan is described in 
Table 7 8. 
59 
3.1.2.2 
New text 
At the end of each part, up to two 
dose levels may be repeated in order 
to reach a total of 18 patients at each 
dose level to collect more PD/PK 
information to better define the RD. 
Decision to repeat a dose level will 
be made by the SRC. Safety data 
from these additional patients will 
not be included in the BOIN design 
to determine MTD but will be 
evaluated by the SRC and ultimately 
be taken into consideration for RD 
selection. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 199/264 
 
 
Version Date 
VERSION 1.2 21 DEC 2018 
VERSION 2.0 24 MAY 2019 
Page 
Section 
WAS 
IS 
61 
3.1.2.3 
At all dose levels, IPN60090 will be 
administered orally BID starting from 
Day 1 of each 21-day cycle and paclitaxel 
will be administered as one i.v. infusion 
every 21 days starting from Day 1 of each 
cycle. The predefined dose-escalation 
plan is described in Table 8. 
At all dose levels, IPN60090 will be 
administered orally BID starting from 
Day 1 of each 21-day cycle and 
paclitaxel will be administered as one 
i.v. infusion every 21 days (±1 day in 
Cycle 1 and ±3 days in all other 
cycles) starting from Day 1 of each 
cycle. The predefined dose-escalation 
plan is described in Table 8 9. 
61/62 
3.1.2.3 
New text 
At the end of each part, up to two 
dose levels may be repeated in order 
to reach a total of 18 patients at each 
dose level to collect more PD/PK 
information to better define the RD. 
Decision to repeat a dose level will 
be made by the SRC. Safety data 
from these additional patients will 
not be included in the BOIN design 
to determine MTD but will be 
evaluated by the SRC and ultimately 
be taken into consideration for RD 
selection. 
63/64 
3.1.3 
New text 
3.1.3 
Food Effect Assessment – 
Part D 
Part D will start at the end of Part A 
dose escalation. Patients in Part D 
will not be part of the dose 
escalation and MTD assessment. 
Food effect evaluation will be 
conducted in patients with 
biomarker-positive and 
biomarker-negative advanced solid 
tumours. 
These patients will not be selected 
for KEAP1/NRF2 mutation status 
and may be wild-type or mutated. 
Patients may have tumours with any 
level of ASNS expression. Eligibility 
criteria for Part D will be the same 
as the criteria for Part A dose 
escalation. 
After screening, eight patients will 
enter a run-in period of 7 days: 
• 
At Day -7, patients will 
receive a single 
administration of IPN60090 
at the RD (as defined by the 
SRC at the end of Part A dose 
escalation) following an 
overnight fast of at least 10 
hours. The patients should 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 200/264 
 
 
Version Date 
VERSION 1.2 21 DEC 2018 
VERSION 2.0 24 MAY 2019 
Page 
Section 
WAS 
IS 
not consume any food for at 
least 4 hours after the dose. 
IPN60090 should be taken 
with 240 mL (i.e. 8 fluid 
ounces) of water. Additional 
water is permitted ad libitum 
except for the period 1 hour 
before to 1 hour after 
administration of the drug 
product. 
• 
At Day -3, patients will 
receive a single 
administration of IPN60090 
at the RD (morning dose only, 
as defined by the SRC at the 
end of Part A dose escalation) 
30 minutes after the start of a 
moderate fat meal. The 
moderate fat meal should be 
eaten in 30 minutes or less. 
The patients should not 
consume any food for at least 
4 hours after the dose. 
IPN60090 should be taken 
with 240 mL (i.e. 8 fluid 
ounces) of water. Additional 
water is permitted ad libitum 
except for the period 1 hour 
before to 1 hour after 
administration of the drug 
product. Substitutions to the 
test meal can be made after 
discussion with the sponsor. It 
is understood that some 
patients may not be able to 
consume the entire meal. 
Study staff should record the 
percent of the test meal 
breakfast and the time it 
takes to be consumed. 
Full PK profiles will be obtained on 
Day -7 and Day -3 to assess the effect 
of a moderate fat meal on IPN60090 
PK profile. Blood samples will be 
collected on Day -7 and Day -3 for 
the evaluation of haematology and 
serum chemistry, and AEs will be 
reported 
In Part D, the moderate fat meal is 
defined as the following: total 
calories of 500-750 kCal including 30 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 201/264 
 
 
Version Date 
VERSION 1.2 21 DEC 2018 
VERSION 2.0 24 MAY 2019 
Page 
Section 
WAS 
IS 
to 35% fat (see Table 13). 
After the run-in period, patients will 
receive IPN60090 as a single agent 
administered orally BID (every 12 
hours), during or after a meal, 
starting from Day 1 at the single 
agent RD. Patients in Part D will 
follow the same schedule of 
assessments as described for Part A 
(with the exception of the urine 
sampling for PK). 
Patients enrolled in monotherapy 
Part D may receive combination 
treatment with either 
pembrolizumab or with paclitaxel 
upon progression on IPN60090 
monotherapy at the discretion of the 
investigator and with the approval 
of the sponsor, once the safe dose 
level for the combination is 
determined. These patients will need 
to satisfy eligibility criteria for 
combination therapy prior to 
initiating treatment (see Section 4.1), 
and will be followed for safety and 
efficacy in a separate cohort. 
65 
3.2.1 
• 
Define the safety and tolerability 
profile of oral IPN60090 as a 
single agent (Part A) and in 
combination therapy with 
pembrolizumab (Part B) or 
paclitaxel (Part C) as determined 
by the incidence and nature of 
AEs.  
• 
Define the The safety and 
tolerability profile of oral 
IPN60090 as a single agent 
(Part A and Part D) and in 
combination therapy with 
pembrolizumab (Part B) or 
paclitaxel (Part C) as 
determined by the incidence 
and nature will be assessed by 
continuous reporting of AEs 
and serious AEs (SAEs), 
clinical laboratory test 
results, the presence of 
anti-pembrolizumab antidrug 
antibodies (ADA; Part B 
only), vital signs 
measurements, ECG and 
physical examination results 
and concomitant medication 
usage. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 202/264 
 
 
Version Date 
VERSION 1.2 21 DEC 2018 
VERSION 2.0 24 MAY 2019 
Page 
Section 
WAS 
IS 
66 
3.2.2 
• 
Anti-tumour activity 
parameters assessed 
locally (for dose 
escalation) and 
centrally (for dose 
expansion) using 
RECIST version 1.1 
for Part A and C and 
iRECIST for Part B 
only, including:  
- 
Clinical benefit rate (CBR) 
is defined as the proportion 
of patients in whom the 
Best Overall Response 
(BOR) is equal to complete 
response (CR), PR or SD 
lasting at least 12 weeks for 
Part A and C and equal to 
immune complete response 
(iCR), immune partial 
response (iPR) or immune 
stable disease (iSD) lasting 
at least 12 weeks for Part B 
- 
ORR is defined as the 
proportion of patients in 
whom the BOR is equal to 
CR and PR for Part A and 
C or iCR and iPR for 
Part B 
- 
DCR is defined as the 
proportion of patients in 
whom the BOR is equal to 
CR, PR or SD for Part A 
and C and equal to iCR, 
iPR or iSD for Part B 
• 
Anti-tumour activity parameters 
assessed locally (for dose 
escalation) and centrally (for 
dose expansion) using RECIST 
version 1.1 for Part A, and C 
and D and iRECIST for Part B 
only, including:  
- 
Clinical benefit rate 
(CBR) is defined as the 
proportion of patients in 
whom the Best Overall 
Response (BOR) is 
equal to complete 
response (CR), PR or SD 
lasting at least 12 weeks 
for Part A, and C and D 
and equal to immune 
complete response 
(iCR), immune partial 
response (iPR) or 
immune stable disease 
(iSD) lasting at least 
12 weeks for Part B 
- 
ORR is defined as the 
proportion of patients in 
whom the BOR is equal 
to CR and PR for Part A, 
and C and D or iCR and 
iPR for Part B 
- 
DCR is defined as the 
proportion of patients in 
whom the BOR is equal 
to CR, PR or SD for 
Part A, and C and D and 
equal to iCR, iPR or iSD 
for Part B 
66 
3.2.2 
• 
Pharmacokinetic parameters of 
IPN60090, including but not 
limited to maximum observed 
plasma concentration (Cmax), time 
to maximum observed plasma 
concentration (Tmax), Ctrough, area 
under the plasma 
concentration-time curve (AUC), 
elimination half-life (t1/2), apparent 
total clearance from plasma 
(CL/F), apparent volume of 
distribution (V/F) of IPN60090 
(Parts A to C). 
• 
Pharmacokinetic parameters of 
IPN60090, including but not 
limited to maximum observed 
plasma concentration (Cmax), 
time to maximum observed 
plasma concentration (Tmax), 
Ctrough, area under the plasma 
concentration-time curve 
(AUC), elimination half-life 
(t1/2), apparent total clearance 
from plasma (CL/F), apparent 
volume of distribution (V/F) of 
IPN60090 (Parts A to C D). 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 203/264 
 
 
Version Date 
VERSION 1.2 21 DEC 2018 
VERSION 2.0 24 MAY 2019 
Page 
Section 
WAS 
IS 
66 
3.2.2 
New text 
• 
Describe the PK of a single 
dose of IPN60090 
administered in fed state 
(Day -3) relative to fasted 
state (Day -7) using the 
following PK parameters: 
Cmax, AUC, Tmax, t1/2, CL/F, 
V/F (Part D). 
67 
3.2.5 
For subjects participating in the optional 
research biobanking program, the 
samples listed below will be biobanked 
for potential future exploratory 
biomarkers evaluation: 
For subjects participating in the 
optional research biobanking program, 
whom consent to optional ICF 
procedures, the samples listed below 
will be biobanked for potential future 
exploratory biomarkers evaluation: 
68 
3.5 
In Part B, the dose of pembrolizumab 
will be fixed at 200 mg administered as 
an i.v. infusion over 30 minutes every 21 
days (Day 1 of every cycle), consistent 
with pembrolizumab prescribing 
information. Premedication with 
antipyretic and antihistamine should be 
considered. The table below outlines the 
defined dose levels and the number of 
capsules in the dose escalation portion of 
the study. The RD for dose expansion, 
and number of capsules, will be 
determined at the completion of the dose 
escalation. 
In Part B, the dose of pembrolizumab 
will be fixed at 200 mg administered 
as an i.v. infusion over 30 minutes 
every 21 days (±1 day in Cycle 1 and 
±3 days in all other cycles) (Day 1 of 
every cycle), consistent with 
pembrolizumab prescribing 
information. Premedication with 
antipyretic and antihistamine should be 
considered. The table below outlines 
the defined dose levels and the number 
of capsules in the dose escalation 
portion of the study. The RD for dose 
expansion, and number of capsules, 
will be determined at the completion of 
the dose escalation. 
68 
3.5 
In Part C, the dose of paclitaxel will be 
fixed at 175 or 135 mg/m² (or according 
to the local approved label for particular 
tumour types) administered as an i.v. 
infusion as per standard practice or at the 
approved recommended dose per 
indication every 21 days (Day 1 of each 
cycle), consistent with paclitaxel 
prescribing information. Premedication 
(e.g. dexamethasone, diphenhydramine, 
histamine H2 blockers) to prevent 
hypersensitivity reactions should be 
considered. 
In Part C, the dose of paclitaxel will 
be fixed at 175 or 135 mg/m² (or 
according to the local approved label 
for particular tumour types) 
administered as an i.v. infusion as per 
standard practice or at the approved 
recommended dose per indication 
every 21 days (±1 day in Cycle 1 and 
±3 days in all other cycles) (Day 1 of 
each cycle), consistent with paclitaxel 
prescribing information. Premedication 
(e.g. dexamethasone, 
diphenhydramine, histamine 
H2 blockers) to prevent 
hypersensitivity reactions should be 
considered. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 204/264 
 
 
Version Date 
VERSION 1.2 21 DEC 2018 
VERSION 2.0 24 MAY 2019 
Page 
Section 
WAS 
IS 
69 
3.5 
New text 
In Part D, single administration of 
IPN60090 at the RD (morning dose 
only) as defined by the SRC at the 
end of Part A dose escalation will be 
performed during the run-in period 
at Day -7 and Day -3. On Day -7, 
IPN60090 will be administered 
following an overnight fast of at least 
10 hours. On Day -3, IPN60090 will 
be administered 30 minutes after the 
start of a moderate fat meal (see 
Table 13). The moderate fat meal 
should be eaten in 30 minutes or 
less. On both days, the patients 
should not consume any food for at 
least 4 hours after the dose. 
IPN60090 should be taken with 240 
mL (i.e. 8 fluid ounces) of water. 
Additional water is permitted ad 
libitum except for the period 1 hour 
before to 1 hour after administration 
of the drug product. Substitutions to 
the test meal can be made after 
discussion with the sponsor. It is 
understood that some patients may 
not be able to consume the entire 
meal. Study staff should record the 
percent of the test meal breakfast 
eaten and the time it takes to be 
consumed.  
69 
3.5 
New text 
Table 13 
Composition of the 
Moderate Fat Meal 
Shown below: 
 
Type of meal 
Total calories 
(Kcal) 
Calories from fat (%) Calories from 
carbohydrates (%) 
Calories from 
proteins (%) 
Moderate fat 
500-750 
30-35 
≥55% 
≥12-14 
 
Version Date 
VERSION 1.2 21 DEC 2018 
VERSION 2.0 24 MAY 2019 
Page 
Section 
WAS 
IS 
69 
3.5 
New text 
Then starting from Day 1, patients 
will receive IPN60090 BID (at the RD 
as defined by the SRC at the end of 
Part A) during or after a meal over 
21 days (one cycle) as described in 
Part A. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 205/264 
 
 
Version Date 
VERSION 1.2 21 DEC 2018 
VERSION 2.0 24 MAY 2019 
Page 
Section 
WAS 
IS 
70 
3.6 
During dose escalation, for each patient 
the study duration will consist of an up 
to 28-day screening period), followed 
by the DLT assessment period, which 
will consist of first 21 days of treatment 
(one cycle). 
During dose escalation, for each patient 
the study duration will consist of an up 
to 28-day screening period (up to 
21 days in Part D), followed by the 
DLT assessment period, which will 
consist of first 21 days of treatment 
(one cycle). 
70 
3.6 
All patients will then be followed post 
end of treatment at 30 days ±3 days (for 
Parts A and C) and 90±3 days (for 
Part B) for the end of treatment visit, at 
180 days ±14 days for the safety 
follow-up visit and then every 3 months 
+/-14 days for survival until the end of 
the study. 
All patients will then be followed post 
end of treatment at 30 days ±3 days (for 
Parts A, and C and D) and 90±3 days 
(for Part B) for the end of treatment 
visit, at 180 days ±14 days for the 
safety follow-up visit and then every 3 
months +/-±14 days for survival until 
the end of the study. 
72 
4.1 
(6)  
Fresh or archival tumour tissue 
must be available for mutation 
and biomarker analysis. Patients 
should not be put at undue risk to 
obtain fresh tumour biopsy. 
Procedures more invasive than 
core biopsy should not be used. 
Procedures to obtain biopsy 
should only be performed if the 
risk is minimal (no greater than 
2% risk of serious or severe 
complications). If available, 
archival tumour tissue from time 
of initial diagnosis will be 
collected in addition to the most 
recent biopsy (archival or fresh).  
(6a)  Fresh and/or archival tumour 
tissue from the biopsy obtained 
between the completion of the 
most recent line of treatment 
until study entry must be 
available for mutation and 
biomarker analysis unless 
KEAP1/NRF2 mutations were 
present in any previous biopsy, 
in which case, no further 
biopsy is required. For ovarian 
cancer patients, both archival 
biopsies obtained between the 
completion of the most recent 
line of treatment until study 
entry and fresh biopsies must 
be available to evaluate the 
evolution of ASNS levels over 
time. Patients should not be put 
at undue risk to obtain fresh 
tumour biopsy. Procedures more 
invasive than core biopsy should 
not be used. Procedures to obtain 
biopsy should only be performed 
if the risk is minimal (no greater 
than 2% risk of serious or severe 
complications). If available, 
archival tumour tissue from time 
of initial diagnosis will be 
collected in addition to the most 
recent biopsy (archival and/or 
fresh). 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 206/264 
 
 
Version Date 
VERSION 1.2 21 DEC 2018 
VERSION 2.0 24 MAY 2019 
Page 
Section 
WAS 
IS 
72 
4.1 
(8) 
Eastern Cooperative Oncology 
Group (ECOG) Performance 
Status (PS) ≤1. 
(8a) Eastern Cooperative Oncology 
Group (ECOG) Performance 
Status (PS) ≤1 and a Royal 
Marsden Hospital (RMH) 
score of 0 or 1 (Appendix 2). 
74 
4.1.5 
New text 
4.1.5 Part D Specific Inclusion 
Criteria 
(D1) Patients must be able to 
consume a moderate fat meal.  
75 
4.2.1 
New text 
(16) Patients unwilling to comply 
with protocol requirements 
related to the assigned part. 
75 
4.2.5 
New text 
4.2.5 Part D Specific Exclusion 
Criteria 
(D1) Treatment with drugs that can 
alter the absorption of 
IPN60090 by affecting 
gastrointestinal motility or by 
changing the gastric pH during 
the run-in period (Day -7 to 
Day -3) of Part D.  
(D2) Patients suffering from 
conditions which are likely to 
adversely affect 
gastrointestinal motility and/or 
transit (for example, diarrhoea, 
vomiting or nausea, 
gastroparesis, irritable bowel 
syndrome and malabsorption) 
or patients with 
gastrointestinal resection 
(e.g. partial or total 
gastrectomy) likely to interfere 
with absorption of study 
treatment. Patients with Type 1 
diabetes and 
hypercholesterolaemia are 
excluded. 
(D3) Patients unable to fast for up to 
14 hours. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 207/264 
 
 
Version Date 
VERSION 1.2 21 DEC 2018 
VERSION 2.0 24 MAY 2019 
Page 
Section 
WAS 
IS 
76 
4.3.1 
Both safety and anti-tumour activity of 
IPN60090 in patients in dose expansion 
cohorts as well as of patients from dose 
escalation receiving additional cycles 
of IPN60090 treatment will continue to 
be monitored by the SRC, and by the 
ISAC on an ongoing basis. The 
decision to halt enrolment or to 
discontinue a patient or a cohort may be 
made by SRC and ISAC at any point if 
a safety signal or unacceptable toxicity 
are observed. Anti-tumour activity of 
IPN60090 will be accessed by SRC and 
ISAC after Stage I of the sequential two 
stage design, and if the study treatment 
does not demonstrate sufficient 
anti-tumour activity in any given 
cohort(s) as defined in Section 11.3.1 
(CBR at 12 weeks in at least one 
patient out of 10), then the cohort(s) 
will be discontinued. 
Both safety and anti-tumour activity of 
IPN60090 in patients in dose expansion 
cohorts as well as of patients from dose 
escalation receiving additional cycles of 
IPN60090 treatment will continue to be 
monitored by the SRC, and by the 
ISAC on an ongoing basis. The ISAC 
will meet after 1 year of the start of 
the study or at the end of the dose 
escalation, whichever occurs first. 
The decision to halt enrolment or to 
discontinue a patient or a cohort may be 
made by SRC and ISAC at any point if 
a safety signal or unacceptable toxicity 
are observed. Anti-tumour activity of 
IPN60090 will be accessed by SRC and 
ISAC after Stage I of the sequential two 
stage design, and if the study treatment 
does not demonstrate sufficient 
anti-tumour activity in any given 
cohort(s) as defined in Section 11.3.1 
(CBR at 12 weeks in at least one patient 
out of 10), then the cohort(s) will be 
discontinued. 
77 
4.3.3 
Patients who experience a DLT will be 
allowed to continue to receive study 
treatment at a lower dose level at the 
discretion of the investigator and will 
be closely monitored for safety. Criteria 
for DLTs are described in Section 
3.1.2.1 for Part A, Section 3.1.2.2 for 
Part B, and Section 3.1.2.3 for Part C. 
Patients who experience a DLT will be 
allowed to continue to receive study 
treatment at a lower dose level at the 
discretion of the investigator and will 
be closely monitored for safety. The 
SRC may consider additional sparse 
PK samples for DLT assessment. 
Criteria for DLTs are described in 
Section 3.1.2.1 for Part A, 
Section 3.1.2.2 for Part B, and 
Section 3.1.2.3 for Part C. 
78 
5.1 
The schedule of procedures and 
assessments during the study is 
summarised in Table 12. 
The schedule of procedures and 
assessments during the study is 
summarised in Table 12 14 (Parts A to 
C) and Table 15 (Part D). 
79 
5.1 
Table 12 
Study Procedures and 
Assessments 
Table 12 14 
Study Procedures and 
Assessments (Parts A to C) 
Amended as follows: 
83 
5.1 
New table 
Table 15 
Study Procedures and 
Assessments (Part D) 
 


IPSEN GROUP 
D-US-60090-001 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 208/264 
 
Table 14 Study Procedures and Assessments (Parts A to C) 
Procedures and assessments 
Protocol section 
Screening 
Treatment 
Follow-up 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
All Cycles after 
Cycle 4 
EOS/EW 
Safety FU Survival FU 
D -28 to -1 
D1 
D2 D8 D14 
D15 
D1 
D8 D15 D1 
D8 D15 D1 
D8 D15 D1 
D8 D15 
30 days 
(Parts A 
and C) or 
90 days 
(Part B) 
after last 
dose 
Up to 
180 days 
after last 
dose 
Every 
3 months 
after safety 
FU 
D1 
D2 D8 D14 
D15 
D22 D29 D36 D43 D50 D57 D64 D71 D78 Dx 
Dx 
Dx 
Visit window (days) 
 
N/A 
N/A 
±1 
±3 
±3 
±3 
±3 
±3 
±14 
±14 
Baseline documentation and physical examination 
Informed consent  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and disease history 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and height  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
 
X 
X[a] 
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Body weight  
 
X 
X[a] 
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Vital signs 
 
X 
X[a] 
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
ECOG performance status 
 
X 
X[a] 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
RMH status 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enrolment 
Inclusion/Exclusion criteria  
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
End of phase disposition 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Safety/Laboratory assessments 
Haematology 
 
X 
X[a] 
X 
X 
X 
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Chemistry (including liver 
function tests) 
 
X 
X[a] 
X 
X 
X 
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
INR 
 
X 
X[a] 
 
 
 
 
 
 
 
Day 1 of every 3rd cycle starting with Day 1 
(i.e. Day 1, Cycle 6 Day 1, etc.) 
X 
 
 
TSH (Part B only) 
 
X 
X[a] 
 
 
 
 
 
 
 
Day 1 of every 3rd cycle starting with Day 1 
(i.e. Day 1, Cycle 6 Day 1, etc.) 
X 
 
 
Urinalysis 
 
X 
X[a] 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Serum pregnancy test  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
ECHO/MUGA 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Triplicate ECG (12-lead)  
 
X 
X[b] 
 
 
 
 
X [b] 
[c] 
 
 
X[c] 
 
 
X[c] 
 
 
As clinically 
indicated 
X 
 
 


IPSEN GROUP 
D-US-60090-001 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 209/264 
 
Procedures and assessments 
Protocol section 
Screening 
Treatment 
Follow-up 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
All Cycles after 
Cycle 4 
EOS/EW 
Safety FU Survival FU 
D -28 to -1 
D1 
D2 D8 D14 
D15 
D1 
D8 D15 D1 
D8 D15 D1 
D8 D15 D1 
D8 D15 
30 days 
(Parts A 
and C) or 
90 days 
(Part B) 
after last 
dose 
Up to 
180 days 
after last 
dose 
Every 
3 months 
after safety 
FU 
D1 
D2 D8 D14 
D15 
D22 D29 D36 D43 D50 D57 D64 D71 D78 Dx 
Dx 
Dx 
Visit window (days) 
 
N/A 
N/A 
±1 
±3 
±3 
±3 
±3 
±3 
±14 
±14 
PK/Biomarkers 
Blood sampling for PK of 
IPN60090 
 
 
X[d] 
X 
[c] 
 
X[d] 
X[e] 
X[f] 
 
 
X[f] 
 
 
X[f] 
 
 
X[f] 
 
 
X 
 
 
Blood sampling for PK of 
combined drug: 
Pembrolizumab (Part B only) 
 
 
X[c] 
 
 
 
 
X[c] 
 
 
X[c] 
 
 
X[c] 
 
 
X[c] 
 
 
 
 
 
Blood sampling for PK of 
combined drug: paclitaxel 
(Part C only) 
 
 
X[g]  
 
 
 
 
X[g] 
 
 
X[g] 
 
 
 
 
 
 
 
 
 
 
 
Urine sampling for PK (Part 
A dose escalation only) 
 
 
X[h]  
 
 
X[h] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood/PBMC samples for PD 
biomarker[i]  
 
 
X[j]  
 
 
X[j] 
X[f][e] 
 
 
 
 
 
 
 
 
 
 
 
 
X[f] 
 
 
Serum Ca-125 
 
 
X[k]  
 
 
 
 
 
 
 
X[k] 
 
 
 
 
 
X[k] 
 
 
 
 
 
CcfDNA 
 
X[c] 
 
 
 
 
X[c] 
 
 
 
X[c] 
 
 
 
 
 
X[c] 
[l]  
 
 
X[c] 
 
 
Fresh tumour biopsy[m] 
 
X[n][o] 
 
 
 
 
X[n][p]  
 
 
 
 
 
 
 
 
 
 
 
 
X[n][q] 
 
 
Archival tumour biopsies[r]  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ADA samples for 
pembrolizumab (binding and 
neutralising) (Part B only) 
 
X 
 
 
 
 
 
 
 
 
X[c] 
 
 
 
 
 
X[c] 
 
 
X 
 
 
Biobanking (optional) 
Biobanking serum[s]  
 
 
X[t]  
 
 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Biobanking PBMC[s] 
 
 
Remaining and not used PBMC for PD biomarker should be biobanked 
 
 
Biobanking plasma[s]  
 
 
X[t] 
 
 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Biobanking paxgene RNA[s]   
 
X[t] 
 
 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Biobanking paxgene DNA[s] 
 
 
X[c] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biobanking stools[s]  
 
 
X[c] 
 
 
 
X[c] 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 


IPSEN GROUP 
D-US-60090-001 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 210/264 
 
Procedures and assessments 
Protocol section 
Screening 
Treatment 
Follow-up 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
All Cycles after 
Cycle 4 
EOS/EW 
Safety FU Survival FU 
D -28 to -1 
D1 
D2 D8 D14 
D15 
D1 
D8 D15 D1 
D8 D15 D1 
D8 D15 D1 
D8 D15 
30 days 
(Parts A 
and C) or 
90 days 
(Part B) 
after last 
dose 
Up to 
180 days 
after last 
dose 
Every 
3 months 
after safety 
FU 
D1 
D2 D8 D14 
D15 
D22 D29 D36 D43 D50 D57 D64 D71 D78 Dx 
Dx 
Dx 
Visit window (days) 
 
N/A 
N/A 
±1 
±3 
±3 
±3 
±3 
±3 
±14 
±14 
Biobanking cfDNA[s]  
 
 
X[c] 
 
 
 
X[c] 
Blood collection for cfDNA should occur at the same time as efficacy 
assessments. 
Every 6 weeks from Cycle 1 Day 1[c]. 
X[c] 
 
 
Biobanking remaining 
leftover tissue material and 
additional biopsies obtained 
from fresh frozen biopsies[s] 
 
Remaining and not used tumour materials from biopsies from biomarkers collection should be biobanked along with any 
additional tumour material collected at these visits (archival and/or fresh). 
 
 
Tumour assessments 
CT/MRI chest, abdomen, 
pelvis, or other (if clinically 
indicated) 
 
X 
Images required every 6 weeks (±1 week) from Cycle 1 Day 1 for the first 24 weeks of treatment, and every 
12 weeks (±2 weeks) thereafter. 
To ensure image consistency, the same imaging modalities and acquisition protocols used at screening are 
to be used for subsequent tumour assessments. 
X 
X 
 
CT/MRI brain 
 
 
Required in patients with documented, treated brain metastasis. As clinically indicated for patients with 
suspected brain metastasis.  
Images required every 6 weeks (±1 week) from Cycle 1 Day 1 for the first 24 weeks of treatment, and every 
12 weeks (±2 weeks) thereafter. 
To ensure image consistency, the same imaging modalities and acquisition protocols used at screening are 
to be used for subsequent tumour assessments. 
X (if 
applicable) 
X 
 
Other clinical assessments 
Adverse events 
 
 
Document new or worsening AEs from informed consent through 30 days after the date of the decision to permanently 
discontinue study treatment. AE information will be collected at study visits and may also be collected at any time over 
the phone or by spontaneous patient report. Certain AEs and all SAEs that are ongoing 30 days after of the date of the 
decision to permanently discontinue study treatment are to be followed until resolution or determination by the 
investigator that the event is stable or irreversible. 
 
Prior and concomitant 
medication/procedures/non-
drug therapies  
 
 
Document prior, and concomitant medication taken from 28 days before first dose of study treatment 
through 30 days after the date of the decision to discontinue study treatment. 
 
 
 
Further anti-tumour treatment  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
IPN60090 
 
 
Daily BID starting on Cycle 1 Day 1. Dose will be determined by phase and cohort. 
 
 
 


IPSEN GROUP 
D-US-60090-001 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 211/264 
 
Procedures and assessments 
Protocol section 
Screening 
Treatment 
Follow-up 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
All Cycles after 
Cycle 4 
EOS/EW 
Safety FU Survival FU 
D -28 to -1 
D1 
D2 D8 D14 
D15 
D1 
D8 D15 D1 
D8 D15 D1 
D8 D15 D1 
D8 D15 
30 days 
(Parts A 
and C) or 
90 days 
(Part B) 
after last 
dose 
Up to 
180 days 
after last 
dose 
Every 
3 months 
after safety 
FU 
D1 
D2 D8 D14 
D15 
D22 D29 D36 D43 D50 D57 D64 D71 D78 Dx 
Dx 
Dx 
Visit window (days) 
 
N/A 
N/A 
±1 
±3 
±3 
±3 
±3 
±3 
±14 
±14 
Pembrolizumab 
 
 
200 mg (or per approved label) every 21 days (Day 1 of every cycle) as i.v. infusion. 
 
 
 
Paclitaxel 
 
 
175 mg/m2 or 135 mg/m2 (or per approved label) every 21 days (Day 1 of every cycle) i.v. infusion. 
 
 
 
ADA=antidrug antibodies; AE=adverse events; BID=bis in die (twice daily); cfDNA=circulating free DNA; CT=computed tomography; D=day; DNA=deoxyribonucleic acid; 
ECG=electrocardiogram; ECHO=echocardiogram; ECOG=Eastern Cooperative Oncology Group; EOS=end of study; EW=early withdrawal; FU=follow-up; HGSOC= high-grade serous ovarian 
cancer; INR=international normalised ratio; i.v.=intravenous; MRI=magnetic resonance imaging; MUGA=multigated acquisition; N/A=not applicable; PBMC=peripheral blood mononuclear 
cells; PD=pharmacodynamics; PK=pharmacokinetics; RMH=Royal Marsden Hospital; RNA=ribonucleic acid; SAE=serious adverse event; TSH=thyroid stimulating hormone 
a 
assessment does not need to be repeated if done within 3 days of first dose. 
b thirty 30 minutes (±15 minutes), 1 hour (±15 minutes), 2 hours (±15 minutes), 4 hours (±15 minutes), 8 hours (±15 minutes) and 12 hours (±15 minutes) postdose. 
c 
predose. 
d predose, 30 minutes (±5 minutes), 1 hour (±5 minutes), 2 hours (±5 minutes), 4 hours (±10 minutes), 8 hours (±30 minutes) and 12 hours (±1 hour) postdose. 
e 
predose, and between 2 to 4 hours postdose. 
f 
predose, 2 hours (±5 minutes) postdose. 
g two time points: immediately before paclitaxel infusion and at the end of the paclitaxel infusion i.e. 3 hours after the start of the infusion. 
h twenty four hour interval urine 0-12 h urine time collection interval (only performed for Part A Dose Escalation). 
i 
see Table 28 32 for more details on collection timepoints and volumes. 
j 
predose, 2 and 12 hours postdose. 
k serum Ca-125 assessments will be performed at baseline, on Day 1 of Cycle 3 and then on Day 1 of every other cycle. This assessment will be performed in patients with HGSOC only. 
l 
cfDNA sample on Day 1 of every other cycle after Cycle 3. 
m remaining tumour materials should be biobanked. 
n cfDNA should be collected at the same day of biopsy, if feasible. 
o fresh tumour must be available for mutation and biomarker analysis unless KEAP1/NRF2 mutations were present in any previous biopsy, in which case, no further biopsy is required. For 
ovarian cancer patients, fresh biopsies must be collected in addition to the archival biopsies. Procedures to obtain biopsy should only be performed if the risk is minimal (no greater than 2% 
risk of serious or severe complications). 
p performed 2 to 4 hours postdose. 
q the EOS fresh biopsy is optional. 
r 
archival biopsies collected after the completion of the last line of treatment until study entry and archival biopsies from initial diagnosis if available. 
s 
biobanking samples will only be collected for subjects who have signed the optional biobanking informed consent form. 
t 
predose and 12 hours postdose. 


IPSEN GROUP 
D-US-60090-001 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 212/264 
 
Table 15 Study Procedures and Assessments (Part D) 
Procedures and assessments 
Protocol section 
Screening 
Run-in 
Treatment 
Follow-up 
 
 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
All cycles after 
Cycle 4 
 
 
 
D -28 to 
D -8 
D -7 D -3 D1 
D2 
D8 D14 D15 D1 
D8 D15 D1 
D8 D15 D1 
D8 D15 D1 
D8 D15 EOS/E
W 
Safety 
FU 
Survival 
FU 
 
D1 
D2 
D8 D14 D15 D22 D29 D36 D43 D50 D57 D64 D71 D78 Dx 
Dx 
Dx 30 days 
after last 
dose 
Up to 
180 days 
after last 
dose 
Every 
3 months 
after 
safety FU 
Visit windows (days) 
 
N/A 
N/A N/A 
N/A 
±1 
±3 
±3 
±3 
±3 
±3 
±14 
±14 
Baseline documentation and physical examination 
Informed consent  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and disease history 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and height  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
 
X 
 
 
X[a] 
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Body weight  
 
X 
 
 
X[a] 
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Vital signs 
 
X 
 
 
X[a] 
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
ECOG performance status 
 
X 
 
 
X[a] 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
RMH status 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enrolment 
Inclusion/Exclusion criteria  
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
End of phase disposition 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Safety/Laboratory assessments 
Haematology 
 
X 
X 
X 
X[a] 
X 
X 
X 
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Chemistry (including liver 
function tests) 
 
X 
X 
X 
X[a] 
X 
X 
X 
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
INR 
 
X 
 
 
X[a] 
 
 
 
 
 
 
 
Day 1 of every 3rd cycle starting with Day 1 
(i.e. Day 1, Cycle 6 Day 1, etc.) 
X 
 
 
Urinalysis 
 
X 
 
 
X[a] 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Serum pregnancy test  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
ECHO/MUGA 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Triplicate ECG (12-lead)  
 
X 
X[b] X[b] X[c] 
 
 
 
 
 
X[c] 
[d] 
 
 
X[d] 
 
 
X[d] 
 
 
As clinically 
indicated 
X 
 
 
PK/Biomarkers 
Blood sampling for PK of 
IPN60090 
 
 
X[e] X[e] X[f] X[d] 
 
X[f] X[g] X[h] 
 
 
X[h] 
 
 
X[h]  
 
 
X[h] 
 
 
X 
 
 
Blood/PBMC samples for PD 
biomarker[i]  
 
 
 
 
X[j] 
 
 
X[j]  X[g] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


IPSEN GROUP 
D-US-60090-001 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 213/264 
 
Procedures and assessments 
Protocol section 
Screening 
Run-in 
Treatment 
Follow-up 
 
 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
All cycles after 
Cycle 4 
 
 
 
D -28 to 
D -8 
D -7 D -3 D1 
D2 
D8 D14 D15 D1 
D8 D15 D1 
D8 D15 D1 
D8 D15 D1 
D8 D15 EOS/E
W 
Safety 
FU 
Survival 
FU 
 
D1 
D2 
D8 D14 D15 D22 D29 D36 D43 D50 D57 D64 D71 D78 Dx 
Dx 
Dx 30 days 
after last 
dose 
Up to 
180 days 
after last 
dose 
Every 
3 months 
after 
safety FU 
Visit windows (days) 
 
N/A 
N/A N/A 
N/A 
±1 
±3 
±3 
±3 
±3 
±3 
±14 
±14 
Serum Ca-125 
 
 
 
 
X[k] 
 
 
 
 
 
 
 
X[k] 
 
 
 
 
 
X[k] 
 
 
 
 
 
cfDNA 
 
X[d] 
 
 
 
 
 
 
X[d] 
 
 
 
X[d] 
 
 
 
 
 
X[d] 
[l] 
 
 
X 
 
 
Fresh tumour biopsy[m] 
 
X[n][o]  
 
 
 
 
 
 
X[n] 
[p] 
 
 
 
 
 
 
 
 
 
 
 
 
X[n][q]  
 
 
Archival tumour biopsies[r] 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biobanking (optional) 
Biobanking serum[s]  
 
 
 
 
X[t] 
 
 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Biobanking PBMC[s] 
 
 
 
 
Remaining and not used PBMC for PD biomarker should be biobanked 
 
 
Biobanking plasma[s] 
 
 
 
 
X[t] 
 
 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Biobanking paxgene RNA[s] 
 
 
 
 
X[t]  
 
 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Biobanking paxgene DNA[s] 
 
 
 
 
X[d] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biobanking stools[s] 
 
 
 
 
X[d] 
 
 
 
X[d] 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Biobanking cfDNA[s] 
 
 
 
 
X[d] 
 
 
 
X[d]  Blood collection for cfDNA should occur at the same time as efficacy 
assessments.  
Every 6 weeks from Cycle 1 Day 1[d]. 
X[d] 
 
 
Biobanking leftover material 
and additional biopsies 
obtained from fresh frozen 
biopsies[s] 
 Remaining biopsies from biomarkers collection should be biobanked along with any additional tumour material collected at these 
visits (archival and/or fresh) 
 
 
Tumour assessments 
CT/MRI chest, abdomen, 
pelvis, or other (if clinically 
indicated) 
 
X 
 
 
Images required every 6 weeks (±1 week) from Cycle 1 Day 1 for the first 24 weeks of treatment, 
and every 12 weeks (±2 weeks) thereafter. 
To ensure image consistency, the same imaging modalities and acquisition protocols used at 
screening are to be used for subsequent tumour assessments. 
X 
X 
 
CT/MRI brain 
 
 
 
 
Required in patients with documented, treated brain metastasis. As clinically indicated for 
patients with suspected brain metastasis.  
Images required every 6 weeks (±1 week) from Cycle 1 Day 1 for the first 24 weeks of treatment, 
and every 12 weeks (±2 weeks) thereafter. 
To ensure image consistency, the same imaging modalities and acquisition protocols used at 
screening are to be used for subsequent tumour assessments. 
X (if 
applicab
le) 
X 
 


IPSEN GROUP 
D-US-60090-001 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 214/264 
 
Procedures and assessments 
Protocol section 
Screening 
Run-in 
Treatment 
Follow-up 
 
 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
All cycles after 
Cycle 4 
 
 
 
D -28 to 
D -8 
D -7 D -3 D1 
D2 
D8 D14 D15 D1 
D8 D15 D1 
D8 D15 D1 
D8 D15 D1 
D8 D15 EOS/E
W 
Safety 
FU 
Survival 
FU 
 
D1 
D2 
D8 D14 D15 D22 D29 D36 D43 D50 D57 D64 D71 D78 Dx 
Dx 
Dx 30 days 
after last 
dose 
Up to 
180 days 
after last 
dose 
Every 
3 months 
after 
safety FU 
Visit windows (days) 
 
N/A 
N/A N/A 
N/A 
±1 
±3 
±3 
±3 
±3 
±3 
±14 
±14 
Other clinical assessments 
Adverse events 
 
 
Document new or worsening AEs from informed consent through 30 days after the date of the decision to permanently 
discontinue study treatment. AE information will be collected at study visits and may also be collected at any time over 
the phone or by spontaneous patient report. Certain AEs and all SAEs that are ongoing 30 days after of the date of the 
decision to permanently discontinue study treatment are to be followed until resolution or determination by the 
investigator that the event is stable or irreversible. 
 
 
Prior and concomitant 
medication/procedures/non-
drug therapies  
 
 
 
 
Document prior and concomitant medication taken from 28 days before first dose of study 
treatment through 30 days after the date of the decision to discontinue study treatment. 
 
 
 
Further anti-tumour 
treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
IPN60090 
 
 
X[u] X[u] Daily BID starting on Cycle 1 Day 1. Dose will be at the RD (as defined by the SRC at the end of 
Part A dose escalation) 
 
 
 


IPSEN GROUP 
D-US-60090-001 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 215/264 
 
Procedures and assessments 
Protocol section 
Screening 
Run-in 
Treatment 
Follow-up 
 
 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
All cycles after 
Cycle 4 
 
 
 
D -28 to 
D -8 
D -7 D -3 D1 
D2 
D8 D14 D15 D1 
D8 D15 D1 
D8 D15 D1 
D8 D15 D1 
D8 D15 EOS/E
W 
Safety 
FU 
Survival 
FU 
 
D1 
D2 
D8 D14 D15 D22 D29 D36 D43 D50 D57 D64 D71 D78 Dx 
Dx 
Dx 30 days 
after last 
dose 
Up to 
180 days 
after last 
dose 
Every 
3 months 
after 
safety FU 
Visit windows (days) 
 
N/A 
N/A N/A 
N/A 
±1 
±3 
±3 
±3 
±3 
±3 
±14 
±14 
Pembrolizumab 
 
 
 
 
200 mg (or per approved label) every 21 days (Day 1 of every cycle) as i.v. infusion. 
 
 
 
Paclitaxel 
 
 
 
 
175 mg/m2 or 135 mg/m2 (or per approved label) every 21 days (Day 1 of every cycle) i.v. infusion. 
 
 
 
AE=adverse events; BID=bis in die (twice daily); cfDNA=circulating free DNA; CT=computed tomography; D=day; DNA=deoxyribonucleic acid; ECG=electrocardiogram; 
ECHO=echocardiogram; ECOG=Eastern Cooperative Oncology Group; EOS=end of study; EW=early withdrawal; FU=follow-up; HGSOC=high-grade serous ovarian cancer; 
INR=international normalised ratio; i.v.=intravenous; MRI=magnetic resonance imaging; MUGA=multigated acquisition; N/A=not applicable; PBMC=peripheral blood 
mononuclear cells; PD=pharmacodynamics; PK=pharmacokinetics; RMH=Royal Marsden Hospital; RNA=ribonucleic acid; SAE=serious adverse event 
a 
assessment does not need to be repeated if done within 3 days of first dose. 
b 1 hour (±15 minutes), 2 hours (±15 minutes) and 4 hours (±15 minutes) postdose. 
c 
30 minutes (±15 minutes), 1 hour (±15 minutes), 2 hours (±15 minutes), 4 hours (±15 minutes), 8 hours (±15 minutes) and 12 hours (±15 minutes) postdose. 
d predose. 
e 
predose, 30 minutes (±5 minutes), 1 hour (±5 minutes), 2 hours (±5 minutes), 4 hours (±10 minutes), 8 hours (±30 minutes), 12 hours (±1 hour), 24 hours (±2 hours), 48 hours 
(±2 hours) and 72 hours (±2 hours) postdose. 
f 
predose, 30 minutes (±5 minutes), 1 hour (±5 minutes), 2 hours (±5 minutes), 4 hours (±10 minutes), 8 hours (±30 minutes) and 12 hours (±1 hour) postdose. 
g 
predose, and between 2 to 4 hours postdose. 
h predose, 2 hours (±5 minutes)  postdose. 
i 
see Table 32 for more details on collection timepoints and volumes. 
j  predose, 2 and 12 hours postdose. 
 
k serum Ca-125 assessments will be performed at baseline, on Day 1 of Cycle 3 and then on Day 1 of every other cycle. This assessment will be performed in patients with HGSOC 
only. 
l 
cfDNA sample on Day 1 of every other cycle after Cycle 3. 
m remaining tumour materials should be biobanked. 
n cfDNA should be collected at the same day of biopsy, if feasible. 
o 
fresh tumour must be available for mutation and biomarker analysis unless KEAP1/NRF2 mutations were present in any previous biopsy, in which case, no further biopsy is 
required. For ovarian cancer patients, fresh biopsies must be collected in addition to the archival biopsies. Procedures to obtain biopsy should only be performed if the risk is 
minimal (no greater than 2% risk of serious or severe complications). 
p performed 2 to 4 hours postdose. 
q the EOS fresh biopsy is optional. 
r 
archival biopsies collected after the completion of the last line of treatment until study entry and archival biopsies from initial diagnosis if available. 
s 
biobanking samples will only be collected for subjects who have signed the optional biobanking informed consent form. 
t 
predose and 12 hours postdose. 
u morning dose only. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 216/264 
 
Version Date 
VERSION 1.2 21 DEC 2018 
VERSION 2.0 24 MAY 2019 
Page 
Section 
WAS 
IS 
87 
5.2 
The schedule of visits and main 
procedures at each visit are summarised 
in Table 12. 
The schedule of visits and main 
procedures at each visit are summarised 
in Table 12 14 (Parts A to C) and 
Table 15 (Part D). 
87 
5.3 
The total volume of blood collected for 
all evaluations throughout this study 
varies depending on the study Part, and 
will reach a maximum of 
approximately 215.0 mL per month for 
any one patient (in Part B) (Table 13). 
An additional 50.5 mL of blood will be 
collected from patients who have 
signed the optional biobanking 
informed consent. 
Therefore, the maximum total blood 
volume collected per month from any 
one patient will not reach more than 
265.5 mL per patient over the study 
duration. 
The total volume of blood collected for 
all evaluations throughout this study 
varies depending on the study Part, and 
will reach a maximum of 
approximately 215.0 278.0 mL per 
month for any one patient (in Part B D) 
(Table 13 16 and Table 17). An 
additional 50.5 60.5 mL of blood will 
be collected from patients who have 
signed the optional biobanking 
informed consent. 
Therefore, the maximum total blood 
volume collected per month from any 
one patient will not reach more than 
265.5 338.5 mL per patient over the 
study duration. 
88 
5.3 
Table 13 
Total Blood Volume 
for All Evaluations  
Table 13 16 
Total Blood Volume 
for All Evaluations (Parts A to C) 
Amended as follows: 
 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 217/264 
 
Table 16 Total Blood Volume for All Evaluations (Parts A to C) 
Assessments 
Volume per sample  
(mL) 
Max number of 
samples/month 
Total max 
volume/month (mL) 
Laboratory assessments 
Haematology 
2 
6 
14 12 
Chemistry (including liver function tests) 
5 
6 
35 30 
INR 
2 
2 
4 
TSH (Part B only) 
2 
2 
4 
Serum pregnancy test 
2 
1 
2 
PK and Biomarkers 
Blood sampling for PK of IPN60090 
2 
17 
34 
Blood sampling for PK of paclitaxel 
(Part C only) 
2.5 
2 
5 
Blood sampling for PK of pembrolizumab 
(Part B only) 
2 
1 
2 
Blood sampling for ADA against 
pembrolizumab (Part B only) 
6 
1 
6 
Blood sampling for Ca-125 (HGSOC only) 
2 
2 
4 
Blood/PBMC samples 
5 6 
18 
90 108 
CcfDNA 
10 
2 3 
20 30 
Total volume Part A 
 
 
203 224 
Total volume Part B 
 
 
215 236 
Total volume Part C 
 
 
208 229 
Biobanking (optional) 
Biobanking serum 
2.5 
4 
10 
Biobanking plasma 
2 
4 
8 
Biobanking paxgene RNA 
2.5 
4 
10 
Biobanking paxgene DNA 
2.5 
1 
2.5 
Biobanking cfDNA 
10 
2 3 
20 30 
Total biobanking 
 
 
50.5 60.5 
Maximum Total 
 
 
265.5 296.5 
ADA=antidrug antibody; BAbs=binding antibodies; cfDNA=circulating free deoxyribonucleic acid; DNA=deoxyribonucleic 
acid; HGSOC=high-grade serious serous ovarian cancer; INR=international normalised ratio; max=maximum; 
NAbs=neutralising antibodies; PBMC=peripheral blood mononuclear cells; PK=pharmacokinetic; RNA=ribonucleic acid; 
TSH=thyroid stimulating hormone. 
 
Version Date 
VERSION 1.2 21 DEC 2018 
VERSION 2.0 24 MAY 2019 
Page 
Section 
WAS 
IS 
89 
5.3 
New table 
Table 17 
Total Blood Volume 
for All Evaluations (Part D Only) 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 218/264 
 
Table 17 Total Blood Volume for All Evaluations (Part D) 
Assessments 
Volume per sample  
(mL) 
Max number of 
samples/month 
Total max 
volume/month (mL) 
Laboratory assessments 
Haematology 
2 
8 
16 
Chemistry (including liver function tests) 
5 
8 
40 
INR 
2 
2 
4 
Serum pregnancy test 
2 
1 
2 
PK and Biomarkers 
Blood sampling for PK of IPN60090 
2 
37 
74 
Blood sampling for Ca-125 (HGSOC 
only) 
2 
2 
4 
Blood/PBMC samples 
6 
18 
108 
cfDNA 
10 
3 
30 
Total volume Part D 
 
 
278 
Biobanking (optional) 
Biobanking serum 
2.5 
4 
10 
Biobanking plasma 
2 
4 
8 
Biobanking paxgene RNA 
2.5 
4 
10 
Biobanking paxgene DNA 
2.5 
1 
2.5 
Biobanking cfDNA 
10 
3 
30 
Total biobanking 
 
 
60.5 
Maximum Total 
 
 
338.5 
cfDNA=circulating free deoxyribonucleic acid; DNA=deoxyribonucleic acid; HGSOC=high-grade serous ovarian 
cancer; INR=international normalised ratio; max=maximum; PBMC =peripheral blood mononuclear cells; 
PK=pharmacokinetic; RNA=ribonucleic acid. 
 
Version Date 
VERSION 1.2 21 DEC 2018 
VERSION 2.0 24 MAY 2019 
Page 
Section 
WAS 
IS 
89 
5.3 
 
Technical instructions will be provided 
in a separate laboratory manual. During 
dose escalation, all samples will be 
analysed locally except urine PK 
samples for IPN60090, PK samples for 
pembrolizumab and paclitaxel analyses 
and anti-pembrolizumab ADA samples. 
During dose expansion, all samples will 
be sent for central analysis (with the 
exception of laboratory safety tests for 
clinical decision making, which will be 
analysed locally). 
Technical instructions will be provided 
in a separate laboratory manual. During 
dose escalation (Parts A to C) and 
during Part D, all samples will be 
analysed locally except urine PK 
samples for IPN60090, PK samples for 
pembrolizumab and paclitaxel analyses 
and anti-pembrolizumab ADA samples. 
During dose expansion, all samples will 
be sent for central analysis (with the 
exception of laboratory safety tests for 
clinical decision making, which will be 
analysed locally). 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 219/264 
 
Version Date 
VERSION 1.2 21 DEC 2018 
VERSION 2.0 24 MAY 2019 
Page 
Section 
WAS 
IS 
91 
6.2.1 
Patients in all Parts (A, B and C) should 
take IPN60090 BID (every 12 hours), 
during or after a meal. IPN60090 will 
be administered in the clinic on the first 
treatment day so that each patient can 
be observed for initial tolerability. 
Subsequent doses will be 
self-administered at home by taking 
IPN60090 BID at the same time each 
day until next visit. Patients will be 
given a medication diary to record day 
and time of administration, missed 
administration if any with related 
reasons if available or retake 
medication in case of rejection if 
applicable. Any unused study treatment 
must be returned to the study site for 
drug accountability and disposal. 
Patients in Part D will receive 
IPN60090 as a single dose in the 
morning on Day -7 and Day -3 as 
described in Section 3.1.3. Patients in 
all Parts (A, B, and C and D [from 
Day 1]) should take IPN60090 BID 
(every 12 hours), during or after a meal. 
IPN60090 will be administered in the 
clinic on the first treatment day so that 
each patient can be observed for initial 
tolerability. Subsequent doses will be 
self-administered at home by taking 
IPN60090 BID at the same time each 
day until next visit. Patients will be 
given a medication diary to record day 
and time of administration, missed 
administration if any with related 
reasons if available or retake 
medication in case of rejection if 
applicable. Any unused study treatment 
must be returned to the study site for 
drug accountability and disposal. 
92 
6.2.1 
New text 
During Part D, the administered dose 
during the run-in period (Day -7 and 
Day -3) will be the RD (morning dose 
only) as defined by the SRC at the 
end of Part A dose escalation. Then, 
starting from Day 1, IPN60090 will 
be administered at the RD BID 
during or after a meal. 
92 
6.2.2.1 
Pembrolizumab will be supplied as 100 
mg/4 mL (25 mg/mL) solution in 
single-use vial to be diluted for 
infusion. It is a sterile, 
preservative-free, clear to slightly 
opalescent, colourless to slightly yellow 
solution that requires dilution for i.v. 
infusion. It is supplied in a vial as a 
white-to off-white lyophilised powder. 
Each 1 mL of solution contains 25 mg 
of pembrolizumab and is formulated in 
L-histidine (1.55 mg), polysorbate 80 
(0.2 mg), sucrose (70 mg) and water for 
injection. 
Pembrolizumab will be supplied as 100 
mg/4 mL (25 mg/mL) solution in 
single-use vial to be diluted for 
infusion. It is a sterile, 
preservative-free, clear to slightly 
opalescent, colourless to slightly yellow 
solution that requires dilution for i.v. 
infusion. It is supplied in a vial as a 
white-to off-white lyophilised powder. 
Each vial contains 100 mg of 
pembrolizumab in 4 mL of solution. 
Each 1 mL of solution contains 25 mg 
of pembrolizumab and is formulated in 
L-histidine (1.55 mg), polysorbate 80 
(0.2 mg), sucrose (70 mg) and water for 
injection, USP. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 220/264 
 
Version Date 
VERSION 1.2 21 DEC 2018 
VERSION 2.0 24 MAY 2019 
Page 
Section 
WAS 
IS 
92 
6.2.2.1 
Pembrolizumab dose will be fixed at 
200 mg (or according to the approved 
local label for particular tumour types) 
administered as an i.v. infusion over 
30 minutes every 21 days (Day 1 of 
every cycle) through an i.v. line 
containing a sterile, non-pyrogenic, 
low-protein binding 0.2 μm to 5 μm 
in-line or add-on filter. Premedication 
with antipyretic and antihistamine may 
be considered. Reconstitution and 
preparation of pembrolizumab solution 
for infusion should be done as per 
locally-approved product information. 
Pembrolizumab dose will be fixed at 
200 mg (or according to the approved 
local label for particular tumour types) 
administered as an i.v. infusion over 
30 minutes every 21 days (±1 day in 
Cycle 1 and ±3 days in all other 
cycles) (Day 1 of every cycle) through 
an i.v. line containing a sterile, 
non-pyrogenic, low-protein binding 
0.2 μm to 5 μm in-line or add-on filter. 
Premedication with antipyretic and 
antihistamine may be considered. 
Reconstitution and preparation of 
pembrolizumab solution for infusion 
should be done as per locally-approved 
product information. 
92 
6.2.2.1 
New text 
Unopened vials must be stored under 
refrigeration between 2°C to 8°C.  
93 
6.2.2.2 
The dose of paclitaxel will be fixed at 
175 mg/m² or 135 mg/m² (or according 
to the local approved label for 
particular tumour types) administered 
as an i.v. infusion every 21 days. 
The dose of paclitaxel will be fixed at 
175 mg/m² or 135 mg/m² (or according 
to the local approved label for 
particular tumour types) administered 
as an i.v. infusion every 21 days (±1 
day in Cycle 1 and ±3 days in all 
other cycles). 
94 
6.3.1 
New text 
H2 blockers, proton pump inhibitors 
and antacids are prohibited during 
the run-in period (Day -7 to Day -3) 
of Part D. 
94 
6.3.2 
Caution should be exercised when 
administering IPN60090 concomitantly 
with medicines known to be moderate 
inhibitors of CYP3A4 or CYP2D6. 
Administering IPN60090 
concomitantly with medicines known to 
be moderate inducers of CYP3A4 is not 
recommended. 
The lists of moderate inhibitors of 
CYP3A4 and of CYP2D6 are provided 
in Appendix 3 and Appendix 4.The list 
of moderate inducers of CYP3A4 is 
provided in Appendix 3. 
Caution should be exercised when 
administering IPN60090 concomitantly 
with medicines known to be moderate 
inhibitors of CYP3A4 or CYP2D6. 
Administering IPN60090 
concomitantly with medicines known 
to be moderate inducers of CYP3A4 is 
not recommended. Moreover, 
moderate inhibitors/inducers of 
CYP2C8 should also be used with 
caution for Part C as well as 
immunosuppressive agents for 
Part B. 
The lists of moderate inhibitors of 
CYP3A4 and of CYP2D6 are provided 
in Appendix 3 4 and Appendix 4 5. The 
list of moderate inducers of CYP3A4 is 
provided in Appendix 3 4. The lists of 
moderate inhibitors/inducers of 
CYP2C8 are provided in Appendix 7. 
The list of immunosuppressive agents 
is provided in Appendix 8.  


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 221/264 
 
Version Date 
VERSION 1.2 21 DEC 2018 
VERSION 2.0 24 MAY 2019 
Page 
Section 
WAS 
IS 
95 
6.3.3 
• 
Drugs used to control bone loss 
(e.g. bisphosphonates and 
denosumab) are allowed if 
started prior to screening 
activities but may not be 
initiated or exchanged during the 
course of the study and require 
sponsor approval. 
• 
Drugs used to control bone loss 
(e.g. bisphosphonates and 
denosumab) are allowed if 
started prior to screening. 
activities but may not If 
indicated to be initiated or 
exchanged during the course of 
the study, and require sponsor’s 
approval is required. 
101 
6.4.5 
Patients enrolled in monotherapy 
Part A may receive combination 
treatment with either pembrolizumab or 
with paclitaxel upon progression on 
IPN60090 monotherapy at the 
discretion of the investigator and with 
the approval of the sponsor, once the 
safe dose level for the combination is 
determined. These patients will need to 
satisfy eligibility criteria for 
combination therapy prior to initiating 
treatment, and will be followed for 
safety and efficacy in a separate cohort. 
Patients enrolled in monotherapy 
Part A and Part D may receive 
combination treatment with either 
pembrolizumab or with paclitaxel upon 
progression on IPN60090 monotherapy 
at the discretion of the investigator and 
with the approval of the sponsor, once 
the safe dose level for the combination 
is determined. These patients will need 
to satisfy eligibility criteria for 
combination therapy prior to initiating 
treatment, and will be followed for 
safety and efficacy in a separate cohort. 
102 
7.1.1 
7.1.1 
Dose Escalation 
(Part A - Monotherapy and Parts B and 
C - Combinations) 
7.1.1 
Dose Escalation 
(Part A - Monotherapy and Parts B and 
C - Combinations) and Food Effect 
Cohort (Part D) 
102 
7.1.1 
Secondary tumour activity endpoints 
and evaluations planned during the 
dose escalation phase are summarised 
in Table 22. All tumour endpoints will 
be assessed locally. 
Secondary tumour activity endpoints 
and evaluations planned during the 
dose escalation phase and food effect 
cohort are summarised in Table 22 26. 
All tumour endpoints will be assessed 
locally. 
102 
7.1.1 
Table 22 
Efficacy Endpoints and 
Evaluations During Dose Escalation 
Table 22 26 
Efficacy Endpoints and 
Evaluations During Dose Escalation 
and Food Effect Cohort 
Amended as follows: 
 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 222/264 
 
Table 26 Efficacy Endpoints and Evaluations During Dose Escalation and Food Effect Cohort 
Measure 
Timepoint 
Variable  
Endpoint 
Tumour size (longest 
diameter) 
Parts A, B and C and D: 
Baseline and every 6 weeks 
Tumour response according to 
RECIST v1.1 
CBR 
ORR 
PFS 
DCR 
OS 
Part B: Baseline and every 
6 weeks  
Tumour response according to 
iRECIST  
CBR 
ORR 
DCR 
iPFS 
OS 
CBR=clinical benefit rate; DCR=disease control rate; iPFS=immune progression-free survival; ORR=objective response rate; 
OS=overall survival; PFS=progression free survival  
 
Version Date 
VERSION 1.2 21 DEC 2018 
VERSION 2.0 24 MAY 2019 
Page 
Section 
WAS 
IS 
102 
7.1.1 
Table 23 
Efficacy Endpoints and 
Evaluations During Dose Escalation 
Table 23 27 
Efficacy Endpoints and 
Evaluations During Dose Escalation 
Amended as follows: 
 
Table 27 Efficacy Endpoints and Evaluations During Dose Expansion 
Measure 
Timepoint 
Variable  
Endpoint 
Tumour size (longest diameter) 
Parts A, B and C: 
Baseline and every 6 
weeks 
Tumour response according to 
RECIST v1.1 
CBR 
ORR 
PFS 
DCR 
OS 
Part B: Baseline and 
every 6 weeks  
Tumour response according to 
iRECIST  
CBR 
ORR 
DCR 
iPFS 
OS 
CBR=clinical benefit rate; DCR=disease control rate; iPFS=immune progression-free survival; ORR=objective response rate; 
OS=overall survival; PFS=progression free survival  
 
Version Date 
VERSION 1.2 21 DEC 2018 
VERSION 2.0 24 MAY 2019 
Page 
Section 
WAS 
IS 
106 
8.1.4 
All SAEs (as defined below), 
regardless of treatment group or 
suspected relationship to IMP, must be 
reported immediately (within 24 hours 
of the investigator’s knowledge of the 
event) using the email specified at the 
beginning of this protocol. If the 
immediate report is submitted by 
telephone, this must be followed by 
detailed written reports using the SAE 
report form. 
 
All SAEs (as defined below), regardless 
of treatment group or suspected 
relationship to IMP, must be reported 
immediately (within 24 hours of the 
investigator’s knowledge of the event) 
via the electronic data capture (EDC) 
system or using the email specified at 
the beginning of this protocol in case 
the EDC is not available. If the 
immediate report is submitted by 
telephone, or if the EDC was not 
available at initial reporting, this 
must be followed by detailed written 
reports using the SAE report form in 
the eCRF. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 223/264 
 
Version Date 
VERSION 1.2 21 DEC 2018 
VERSION 2.0 24 MAY 2019 
Page 
Section 
WAS 
IS 
107 
8.1.4 
Any SAE must be reported 
immediately (within 24 hours), using 
the email specified at the beginning of 
this protocol, independent of the 
circumstances or suspected cause, if it 
occurs or comes to the attention of the 
investigator at any time during the 
study period. 
Any SAE must be reported 
immediately (within 24 hours) in the 
eCRF or using the email specified at 
the beginning of this protocol in case 
the EDC system is not available, 
independent of the circumstances or 
suspected cause, if it occurs or comes to 
the attention of the investigator at any 
time during the study period. 
107 
8.1.4 
The additional information included in 
the SAE form must be provided to the 
sponsor or representative as soon as it 
is available. The investigator should 
always provide an assessment of 
causality for each event reported to the 
sponsor. Upon receipt of the initial 
report, the sponsor will ask for the 
investigator's causality assessment if it 
was not provided with the initial report. 
The additional information included in 
the SAE form must be provided to the 
sponsor or representative collected in 
the eCRF as soon as it is available. The 
investigator should always provide an 
assessment of causality for each event 
reported to the sponsor. Upon receipt of 
the initial report, the sponsor will ask 
for the investigator's causality 
assessment if it was not provided with 
the initial report initially. 
108 
8.1.5 
Information regarding pregnancies 
must be collected on the AE page of the 
eCRF and reported to the sponsor as an 
SAE. The sponsor will request further 
information from the investigator as to 
the course and outcome of the 
pregnancy using the Standard 
Pregnancy Outcome Report Form. 
Information regarding pregnancies 
must be collected on the AE/SAE page 
of the eCRF and reported to the sponsor 
as an SAE via the EDC system. The 
sponsor will request further information 
from the investigator as to the course 
and outcome of the pregnancy using the 
Standard Pregnancy Outcome Report 
Form.  
109 
8.2 
During dose escalation part, all clinical 
safety laboratory tests listed below will 
be performed at local laboratories. A 
list of laboratory normal ranges should 
be provided to the sponsor. Any change 
in laboratory normal ranges during the 
trial will be forwarded to the sponsor. 
During dose expansion part, safety 
blood samples will also be analysed 
centrally. 
 
During dose escalation part, all clinical 
safety laboratory tests listed below will 
be performed at local laboratories 
(except anti-pembrolizumab 
antibodies). A list of laboratory normal 
ranges should be provided to the 
sponsor. Any change in laboratory 
normal ranges during the trial will be 
forwarded to the sponsor. During dose 
expansion part, safety blood samples 
will also be analysed centrally. 
110 
8.2.5 
Antipembrolizumab Antibody Testing  Antipembrolizumab Antibody Testing 
(Part B Only) 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 224/264 
 
Version Date 
VERSION 1.2 21 DEC 2018 
VERSION 2.0 24 MAY 2019 
Page 
Section 
WAS 
IS 
110 
8.2.5 
The determination of putative 
antibodies against pembrolizumab will 
be evaluated using a validated method 
by at Kymos Pharma Services S.L., 
Parc Tecnòlogic del Vallès, Ronda de 
Can Fatjó 7-B, 08290 Cerdanyola del 
Vallès, Barcelona, Spain. 
The determination of putative 
antibodies against pembrolizumab will 
be evaluated using a validated methods 
by at Kymos Pharma Services S.L., 
Parc Tecnòlogic del Vallès, Ronda de 
Can Fatjó 7-B, 08290 Cerdanyola del 
Vallès, Barcelona, Spain 
ElectroChemiLuminiscence Assay 
(ECLA) electrochemiluminescent 
bridging assay for binding antibodies 
and cell-based assay for neutralising 
antibodies. 
111 
8.6 
Table 24 
Electrocardiograms 
Timepoints 
Table 24 28 
Electrocardiograms 
Timepoints 
Amended as follows: 
Table 28 Electrocardiograms Timepoints 
Visit 
Timepoint 
Method  
Screening 
Day (D) -28 to D -1 (Parts A to 
C) and D -28 to D -8 (Part D) 
Triplicate 
Run-in, Day -7 and Day -3  
(Part D only) 
1 hours postdose 
Triplicate 
2 hours postdose 
Triplicate 
4 hours postdose 
Triplicate 
Cycle 1, Day 1 
30 minutes postdose 
Triplicate 
1 hours postdose 
Triplicate 
2 hours postdose 
Triplicate 
4 hours postdose 
Triplicate 
8 hours postdose 
Triplicate 
12 hours postdose 
Triplicate 
Cycle 2, Day 1 
Predose 
Triplicate 
30 minutes postdose 
Triplicate 
1 hours postdose 
Triplicate 
2 hours postdose 
Triplicate 
4 hours postdose 
Triplicate 
8 hours postdose 
Triplicate 
12 hours postdose 
Triplicate 
Cycle 3, Day 1 
Predose 
Triplicate 
Cycle 4, Day 1 
Predose 
Triplicate 
End of treatment 
30 days after last dose 
Triplicate 
 
Version Date 
VERSION 1.2 21 DEC 2018 
VERSION 2.0 24 MAY 2019 
Page 
Section 
WAS 
IS 
112 
9.1.1 
Table 25 
Timepoints for 
IPN60090 PK Blood Sample 
Determination 
Table 25 29 
Timepoints for 
IPN60090 PK Blood Sample 
Determination 
Amended as follows: 
 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 225/264 
 
Table 29 Timepoints for IPN60090 PK Blood Sample Determination 
Visit 
Timepoint 
Volume  
Run-in phase Day -7 
(Part D only) 
Predose 
2.0 mL 
30 minutes postdose 
2.0 mL 
1 hour postdose 
2.0 mL 
2 hours postdose 
2.0 mL 
4 hours postdose 
2.0 mL 
8 hours postdose 
2.0 mL 
12 hours postdose 
2.0 mL 
24 hours postdose 
2.0 mL 
48 hours postdose 
2.0 mL 
72 hours postdose 
2.0 mL 
Run-in phase Day -3 
(Part D only) 
Predose 
2.0 mL 
30 minutes postdose 
2.0 mL 
1 hour postdose 
2.0 mL 
2 hours postdose 
2.0 mL 
4 hours postdose 
2.0 mL 
8 hours postdose 
2.0 mL 
12 hours postdose 
2.0 mL 
24 hours postdose 
2.0 mL 
48 hours postdose 
2.0 mL 
72 hours postdose 
2.0 mL 
Cycle 1, Day 1 
Predose 
2.0 mL 
30 minutes postdose 
2.0 mL 
1 hour postdose 
2.0 mL 
2 hours postdose 
2.0 mL 
4 hours postdose 
2.0 mL 
8 hours postdose 
2.0 mL 
12 hours postdose 
2.0 mL 
Cycle 1, Day 2 
Predose 
2.0 mL 
Cycle 1, Day 14 
Predose 
2.0 mL 
30 minutes postdose 
2.0 mL 
1 hour postdose 
2.0 mL 
2 hours postdose 
2.0 mL 
4 hours postdose 
2.0 mL 
8 hours postdose 
2.0 mL 
12 hours postdose 
2.0 mL 
Cycle 1, Day 15 
Predose 
2.0 mL 
2 to 4 hours postdose 
2.0 mL 
Cycle 2, Day 1 
Predose 
2.0 mL 
2 hours postdose 
2.0 mL 
Cycle 3, Day 1 
Predose 
2.0 mL 
2 hours postdose 
2.0 mL 
Cycle 4, Day 1 
Predose 
2.0 mL 
2 hours postdose 
2.0 mL 
All cycles after Cycle 4 
Predose 
2.0 mL 
2 hours postdose 
2.0 mL 
End of study 
 
2.0 mL 
 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 226/264 
 
Version Date 
VERSION 1.2 21 DEC 2018 
VERSION 2.0 24 MAY 2019 
Page 
Section 
WAS 
IS 
113 
9.1.1.3 
The time points for sampling are 
indicated in Table 12 and Table 26. 
Blood should be collected (2.0 mL) 
collected at each time point with serum 
clot activator for the determination of 
serum pembrolizumab levels. Blood 
samples should be collected from the 
contralateral arm used for the study 
drug infusion, or from another 
anatomical site. After blood collection, 
the tubes should be inverted 8 times 
and left for 30 minutes (for a maximum 
of 60 minutes) at ambient temperature 
and then centrifuged for 10 minutes at 
1300g at 4°C. The resulting serum 
should be transferred into two aliquots 
in 2.0 mL cryovials (0.5 mL for the 
determination of the PK of 
pembrolizumab and <0.5 mL for 
backup samples). Samples should be 
stored at ≤-20°C. 
The time points for blood sampling for 
pembrolizumab determination are 
indicated in Table 12 14 and Table 26 
30. Blood should be collected (2.0 mL) 
collected at each time point with serum 
clot activator for the determination of 
serum pembrolizumab levels. Blood 
samples should be collected from the 
contralateral arm used for the study 
drug infusion, or from another 
anatomical site. After blood collection, 
the tubes should be inverted 8 times 
and left for 30 minutes (for a maximum 
of 60 minutes) at ambient temperature 
and then centrifuged for 10 minutes at 
1300g at 4°C. The resulting serum 
should be transferred into two aliquots 
in 2.0 mL cryovials (0.5 mL for the 
determination of the PK of 
pembrolizumab and <0.5 mL for 
backup samples). Samples should be 
stored at ≤̻20°C prior to shipment to 
the analysis laboratory: Kymos 
Pharma Services, Spain for 
pembrolizumab level determination. 
113 
9.1.1.3 
Pembrolizumab blood levels will be 
determined using a validated analytical 
method by at Kymos Pharma Services 
S.L., Parc Tecnòlogic del Vallès, 
Ronda de Can Fatjó 7-B, 08290 
Cerdanyola del Vallès, Barcelona, 
Spain. 
Pembrolizumab blood levels will be 
determined using a validated, analytical 
method by at Kymos Pharma Services 
S.L., Parc Tecnòlogic del Vallès, 
Ronda de Can Fatjó 7-B, 08290 
Cerdanyola del Vallès, Barcelona, 
Spain specific and sensitive solid 
phase enzyme-linked immunosorbent 
assay (ELISA) based on the sandwich 
principle. 
113 
9.1.1.4 
Blood samples for the determination of 
IPN60090 are described in Table 27.  
Blood samples for the determination of 
IPN60090 paclitaxel are described in 
Table 27 31.  
114 
9.1.1.4 
Blood should be collected (2.5 mL) 
from the uninfused arm, in an EDTA 
tube at each time point and gently 
inverted eight times. The samples 
should be centrifuged at 4°C for 
10 minutes. The resulting plasma will 
be stored at -80°C +/- 10°C in 
polypropylene tubes as two 500 μL 
aliquots (primary and back-up) prior to 
shipment to the analysis laboratory: 
Kymos Pharma Services, Spain for 
paclitaxel level determination. 
Blood should be collected (2.5 mL) 
from the uninfused arm, in an a 
K2-EDTA tube at each time point and 
gently inverted eight times. The 
samples should be centrifuged at 2000g 
4°C for 10 minutes. The resulting 
plasma will be stored at -80°C 
+/- ±10°C in polypropylene tubes as 
two 500 μL aliquots (primary and 
back-up) prior to shipment to the 
analysis laboratory: Kymos Pharma 
Services, Spain for paclitaxel level 
determination. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 227/264 
 
Version Date 
VERSION 1.2 21 DEC 2018 
VERSION 2.0 24 MAY 2019 
Page 
Section 
WAS 
IS 
114 
9.1.2 
Plasma samples will be analysed to 
determine concentrations of IPN60090 
during dose expansion and paclitaxel 
(dose escalation and dose expansion) 
using a validated, specific and sensitive 
LC-MS/MS method at Kymos Pharma 
Services. 
Plasma samples will be analysed to 
determine concentrations of IPN60090 
during dose expansion and paclitaxel 
(dose escalation and dose expansion) 
using a validated, specific and sensitive 
LC-MS/MS method at Kymos Pharma 
Services. 
114 
9.1.2 
Serum samples will be analysed to 
determine concentrations of 
pembrolizumab using a validated, 
specific and sensitive solid phase 
enzyme-linked immunosorbent assay 
(ELISA) based on the sandwich 
principle. 
Serum samples will be analysed to 
determine concentrations of 
pembrolizumab using a validated, 
specific and sensitive solid phase 
enzyme-linked immunosorbent assay 
(ELISA) based on the sandwich 
principle.  
114 
9.1.2 
An analytical method for the 
determination of the presence of 
binding antibodies to pembrolizumab in 
human serum by 
ElectroChemiLuminiscence Assay 
(ECLA) in a bridging format will be 
developed and validated. 
An analytical method for the 
determination of the presence of 
binding antibodies to pembrolizumab in 
human serum by 
ElectroChemiLuminiscence Assay 
(ECLA) in a bridging format will be 
developed and validated. 
115 
9.2 
9.2 
Biomarkers Evaluation 
Pharmacodynamic biomarkers with the 
evaluation of Glu:Gln ratio will be 
assessed in PBMC at the timepoints 
shown in Table 28. 
9.2 
Pharmacodynamic 
Biomarkers Evaluation 
Pharmacodynamic biomarkers 
endpoints with the evaluation of 
Glu:Gln ratio will be assessed in 
PBMC at the timepoints shown in 
Table 28 32. 
115 
9.2 
Table 28 
Collection Time Points 
for PD evaluation in PBMC 
Table 28 32 
Collection Time Points 
for PD evaluation in PBMC 
Amended as follows: 
Table 32 Collection Time Points for PD evaluation in PBMC 
Visit 
Timepoint 
Volume 
Cycle 1, Day 1 
Predose  
4 tubes x 5 6 mL for PBMC isolation 
2 hours postdose 
2 tubes x 5 6 mL for PBMC isolation 
12 hours postdose 
2 tubes x 5 6 mL for PBMC isolation 
Cycle 1, Day 14 
Predose 
2 tubes x 5 6 mL for PBMC isolation 
2 hours postdose 
2 tubes x 5 6 mL for PBMC isolation 
12 hours postdose 
2 tubes x 5 6 mL for PBMC isolation 
Cycle 1, Day 15 and EOS/EW Predose 
2 tubes x 5 6 mL for PBMC isolation 
2 to 4 hours postdose 
2 tubes x 5 6 mL for PBMC isolation 
EOS=end of study; EW=early withdrawal 
 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 228/264 
 
Version Date 
VERSION 1.2 21 DEC 2018 
VERSION 2.0 24 MAY 2019 
Page 
Section 
WAS 
IS 
115 
9.2 
Two tubes of 5 ml collections per 
timepoint are needed to ensure the 
possibility of running the assay by 
purifying a sufficient number of 
PBMCs for analysis and procuring a 
back-up pellet for biobanking. At Cycle 
1 Day 1 predose only, two additional 
tubes of 5 mL blood are needed to be 
used as QC samples. In this case, a total 
of four tubes of 5 mL of blood are 
required at Cycle 1 Day 1 predose and 
at end of study (EOS)/early withdrawal 
(EW). 
Biomarkers of patient stratification 
such as tumour mutation status (e.g. 
KEAP1/NRF2) and tumour ASNS 
expression will be evaluated in archival 
and/or fresh biopsies available at 
screening and could be also re-assessed 
on biopsies collected on Cycle 1 Day 
15 if data are not conclusive at 
screening and/or if needed. A panel of 
mutations including NRF2 could be 
also explored in collected cfDNA at 
screening, at Cycle 1 Day 15 and at 
EOS/EW. 
In HGSOC patients, blood samples 
(2 mL) will also be collected for serum 
Ca-125 assessment at Baseline, on Day 
1 of Cycle 3 and then on Day 1 of 
every other cycle. 
 
Two tubes of 5 ml 6 mL collections per 
timepoint are needed to ensure the 
possibility of running the assay by 
purifying a sufficient number of 
PBMCs for analysis and procuring a 
back-up pellet for biobanking. At Cycle 
1 Day 1 predose only, two additional 
tubes of 5 6 mL blood are needed to be 
used as QC samples. In this case, a total 
of four tubes of 5 6 mL of blood are 
required at Cycle 1 Day 1 predose and 
at end of study (EOS)/early withdrawal 
(EW). At Cycle 1 Day 14 and Cycle 1 
Day 15, two tubes of 6 mL will be 
collected at each time point. 
Biomarkers of patient stratification 
such as tumour mutation status (e.g. 
KEAP1/NRF2) and tumour ASNS 
expression will be evaluated in archival 
and/or fresh biopsies available at 
screening and could be also re-assessed 
on biopsies collected on Cycle 1 Day 
15 if data are not conclusive at 
screening and/or if needed. A panel of 
mutations including NRF2 could be 
also explored in collected cfDNA at 
screening, at Cycle 1 Day 15 and at 
EOS/EW. 
In HGSOC patients, blood samples 
(2 mL) will also be collected for serum 
Ca-125 assessment at Baseline, on Day 
1 of Cycle 3 and then on Day 1 of every 
other cycle. 
116 
10 
10 
EXPLORATORY 
BIOMARKERS AND BIOBANKING 
10.1 
Exploratory Biomarkers 
Biomarkers of tumour biology 
evolution under treatment (e.g. immune 
profiling, PD-L1 expression, Ki67, 
phosphorylation of histone variant 
H2AX (γH2AX), LKB1, etc) may be 
evaluated and correlated with clinical 
outcome. 
10 
EXPLORATORY 
BIOMARKERS EVALUATION AND 
BIOBANKING 
10.1 
Exploratory Biomarkers 
Evaluation 
Biomarkers of tumour biology 
evolution under treatment (e.g. immune 
profiling, PD-L1 expression, Ki67, 
phosphorylation of histone variant 
H2AX (γH2AX), LKB1, etc) may be 
evaluated and correlated with clinical 
outcome. 
10.1.1 Collection of Biopsies for 
Biomarker Analysis 
Fresh and/or archival tumour tissue 
from the biopsy obtained between the 
completion of the most recent line of 
treatment until study entry must be 
available for mutation and 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 229/264 
 
Version Date 
VERSION 1.2 21 DEC 2018 
VERSION 2.0 24 MAY 2019 
Page 
Section 
WAS 
IS 
biomarker analysis unless 
KEAP1/NRF2 mutations were 
present in any previous biopsy, in 
which case, no further biopsy is 
required. For ovarian cancer 
patients, both archival biopsies 
obtained between the completion of 
the most recent line of treatment 
until study entry and fresh biopsies 
must be available to evaluate the 
evolution of ASNS levels over time. 
Fresh tumour biopsy is performed at 
the screening visit, Cycle 1 Day 15, 
and end of study/early 
withdrawal (EOS/EW [separate 
consent is required]). The EOS fresh 
biopsy is optional and requires an 
additional informed consent for 
collection. If available, biopsy at 
initial diagnosis will be also collected 
for biomarker analysis. 
10.1.2 Collection of cfDNA for 
Biomarker Analysis 
Blood (10 mL) will be collected in 
cfDNA (Streck tubes) for plasma 
isolation and will be used for 
biomarker analysis. Sampling is done 
at screening, on Cycle 1 Day 15 
(predose), Cycle 3 Day 1 (predose), 
then on Day 1 of every other cycle 
after Cycle 3 (predose) and at 
EOS/EW. 
10.1.3 Biomarkers of Patient 
Stratification 
KEAP1/NRF2 mutations and ASNS 
levels will be evaluated in fresh 
and/or archival biopsies and will be 
correlated with clinical outcome. 
10.1.4 Biomarkers of Disease 
Evolution Under Treatment 
In HGSOC patients, blood samples (2 
mL) will also be collected for serum 
Ca-125 assessment at Baseline, on 
Day 1 of Cycle 3 and then on Day 1 of 
every other cycle. 
117 
10.3.4 
10.2.4 Blood for DNA for Biobank 
Blood (2.5 mL) will be collected in 
PAXgene RNA tubes and frozen for 
storage 
Sampling is done on Cycle 1 Day 1 
predose only 
10.2.4 10.3.4 
Blood for DNA for 
Biobank 
Blood (2.5 mL) will be collected in 
PAXgene RNA DNA tubes and frozen 
for storage. 
Sampling is done on Cycle 1 Day 1 
predose only. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 230/264 
 
Version Date 
VERSION 1.2 21 DEC 2018 
VERSION 2.0 24 MAY 2019 
Page 
Section 
WAS 
IS 
117 
10.3.5 
10.2.5 Blood for CfDNA for Biobank 
Blood (10 mL) will be collected in 
CfDNA (Streck tubes) for plasma 
isolation and frozen for storage. 
Sampling is done on Cycle 1 Day 1, 
Cycle 1 Day 15, Cycle 3 Day 1, then on 
Day 1 of every other cycle after Cycle 
3 EOS/EW. 
10.2.5 10.3.5 Blood for CfDNA for 
Biobank 
Blood (10 mL) will be collected in 
CfDNA (Streck tubes) for plasma 
isolation and frozen for storage. 
Sampling is done on Cycle 1 Day 1, 
Cycle 1 Day 15, Cycle 3 Day 1, then on 
Day 1 of every other cycle after Cycle 3 
and at EOS/EW. 
117 
10.3.6 
10.2.6 Blood for PBMC 
Remaining and not used PBMC for PD 
biomarker evaluation (see Section 9.2) 
should be biobanked.  
Sampling is done on Cycle 1 Day 1 
(predose, and 2 and 12 hours postdose), 
Cycle 1 Day 14 (predose, and 2 and 12 
hours postdose), Cycle 1 Day 15 
(predose, and 2 hours postdose), and 
EOS/EW (predose and 2 hours 
postdose). 
10.2.6 10.3.6 Blood for PBMC 
Remaining and not used PBMC for PD 
biomarker evaluation (see Section 9.2) 
should be biobanked.  
Sampling is done on Cycle 1 Day 1 
(predose, and 2 and 12 hours postdose), 
Cycle 1 Day 14 (predose, and 2 and 12 
hours postdose), and Cycle 1 Day 15 
(predose, and 2  to 4 hours postdose), 
and EOS/EW (predose and 2 hours 
postdose). 
117 
10.3.7 
10.2.7 Stools 
Sampling procedure will be outlined in 
a laboratory manual. 
Sampling is done on Cycle 1 Day 1 
(predose and postdose), Cycle 1 Day 
15, Day 1 of each following Cycle and 
EOS/EW 
10.2.7 10.3.7 Stools 
Sampling procedure will be outlined in 
a laboratory manual. 
Sampling is done on Cycle 1 Day 1 
(predose and postdose), Cycle 1 Day 15 
(predose), Day 1 of each following 
Cycle and EOS/EW. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 231/264 
 
Version Date 
VERSION 1.2 21 DEC 2018 
VERSION 2.0 24 MAY 2019 
Page 
Section 
WAS 
IS 
 
10.3.8 
10.2.8 Biopsies 
Fresh or archival tumour tissue must be 
available for mutation and biomarker 
analysis. Fresh tumour biopsy is 
performed at the screening visit, Cycle 
1 Day 15, and EOS/EW (separate 
consent is required). Archival tumour 
tissue post the most recent line of 
treatment is acceptable in lieu of fresh 
biopsy at screening. In case no archival 
tumour tissue is available in a patient, 
fresh biopsy should be performed only 
if the procedure to obtain biopsy has a 
serious/severe complication risk no 
greater than 2%. Procedures more 
invasive than core biopsy should not be 
used. The EOS fresh biopsy is optional 
and requires an additional informed 
consent for collection. Any limitations 
in tissue availability and sampling in 
patients with known KEAP1/NRF2 or 
ASNS status should be discussed with 
the sponsor. 
Remaining tumour material from 
biopsies should be biobanked (separate 
check box on the Biobanking ICF 
compared to blood sampling for 
biobanking). 
10.2.8 10.3.8 Leftover Tissue 
Material and Additional Biopsies for 
Biobanking 
Fresh or archival tumur tissue must be 
available for mutation and biomarker 
analysis. Fresh tumour biopsy is 
performed at the screening visit, Cycle 
1 Day 15, and EOS/EW (separate 
consent is required). Archival tumour 
tissue post the most recent line of 
treatment is acceptable in lieu of fresh 
biopsy at screening. In case no archival 
tumour tissue is available in a patient, 
fresh biopsy should be performed only 
if the procedure to obtain biopsy has a 
serious/severe complication risk no 
greater than 2%. Procedures more 
invasive than core biopsy should not be 
used. The EOS fresh biopsy is optional 
and requires an additional informed 
consent for collection. Any limitations 
in tissue availability and sampling in 
patients with known KEAP1/NRF2 or 
ASNS status should be discussed with 
the sponsor. 
Remaining tumour Leftover tissue 
material from mandatory biopsies 
used for biomarker analysis 
(e.g. remaining formalin-fixed 
paraffin-embedded blocks) and 
additional fresh biopsies (fine-needle 
aspiration and/or core biopsies) 
collected will should be used for 
biobanked biobanking (separate if 
patient consent is on the check box on 
for the Biobanking in the ICF 
compared to blood sampling for 
biobanking). 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 232/264 
 
Version Date 
VERSION 1.2 21 DEC 2018 
VERSION 2.0 24 MAY 2019 
Page 
Section 
WAS 
IS 
119 
11.1 
New text 
• 
Food effect population: All 
patients in Part D who have 
received IPN60090 under 
fasting and fed conditions 
(Day -7 and Day -3), have 
consumed ≥80% of the 
moderate fat meal in 
approximately 30 minutes on 
Day -3, and who have no 
major protocol deviation 
affecting the PK variables and 
who have a sufficient number 
of IPN60090 plasma 
concentrations to estimate the 
main PK parameters (Cmax, 
Tmax and AUC0-last) 
• 
Pharmacodynamic 
population: All patients who 
have at least one PD endpoints 
measurement. PD endpoints 
refer to target engagement 
levels (Glu:Gln ratio in 
PBMC). 
120 
11.1.1 
New text 
The analyses of PD parameters will 
be performed on the PD population. 
The analyses of food effect PK 
parameters will be performed on the 
food effect population. 
120 
11.2 
11.2 
Statistical Methods for Dose 
Escalation Phase 
11.2 
Statistical Methods for Dose 
Escalation Phase and Food Effect 
123 
11.2.1.3 
New text 
11.2.1.3 
Sample Size for Part D 
The sample size (n=8) is not based on 
statistical calculation. A sample size 
of eight patients allows for a 
preliminary assessment of the 
potential effect of food on the PK of 
IPN60090. 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 233/264 
 
Version Date 
VERSION 1.2 21 DEC 2018 
VERSION 2.0 24 MAY 2019 
Page 
Section 
WAS 
IS 
125 
11.2.3.6 
New text 
11.2.3.6 
Food Effect 
Assessment 
The assessment of food effect will be 
based upon the ratio of the 
population geometric means (fed 
versus fasted, i.e. Day -3 versus 
Day -7) for the PK parameters (Cmax 
and AUC). The data will be 
transformed prior to analysis using a 
logarithmic transformation. Tmax 
between fed and fasted states will be 
compared using a non-parametric 
test such as the Wilcoxon test. 
Descriptive statistics of other PK 
parameters will be presented both in 
fasting and fed conditions. 
128 
11.3.4 
New text 
The ISAC will meet after 1 year of 
the start of the study or at the end of 
the dose escalation, whichever occurs 
first. 
141 
18 
New text 
23 
Arkenau HT, Barriuso J, 
Olmos D, et al. Prospective 
Validation of a Prognostic Score to 
Improve Patient Selection for 
Oncology Phase I Trials. J Clin 
Oncol 2009;27(16):2692-6. 
150/151 Appendix 2 New text 
Appendix 2 ROYAL MARSDEN 
HOSPITAL SCORE 
 
Royal Marsden Hospital Prognostic Score 
Variable 
Score 
Hazard Ratio[a] 
LDH 
 
1.85 
≤ULN 
0 
 
>ULN 
1 
 
Albumin, g/L 
 
1.83 
≥35 
0 
 
<35 
1 
 
Sites of metastasis 
 
1.54 
0-2 
0 
 
>2 
1 
 
LDH=lactate dehydrogenase; ULN=upper limit of normal 
The prognostic score ranges from 0 to 3. The good-prognosis group comprises patients with a score of 0 to 1, and the 
poor-prognosis group comprises patients with a score of 2 to 3. 
a 
hazard ratios are based on the retrospective analysis 
Source: Arkenau et al [23] 
 
Version Date 
VERSION 1.2 21 DEC 2018 
VERSION 2.0 24 MAY 2019 
Page 
Section 
WAS 
IS 
160/161 Appendix 7 New text 
Appendix 7 LIST OF MODERATE 
INHIBITORS AND INDUCERS OF 
CYP2C8 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 234/264 
 
Paclitaxel is mainly metabolised by CYP2C8. Therefore, inhibitors and inducers of 
CYP2C8 may have an impact on the AUC of paclitaxel. 
A moderate inhibitor for a specific CYP450 enzymes is defined as an inhibitor which 
increases the AUC of a sensitive substrate for that CYP450 enzymes by 2-fold or greater, 
but less than 5-fold. 
A moderate inducer: decreases the AUC of a victim drug between 50% to 80%. 
Moderate Inhibitors of CYP2C8 
Letermovir 
Teriflunomide 
Deferasirox 
Moderate Inducers of CYP2C8 
Rifampin 
Carbamazepin 
Ivosidenib 
Hormonal contraceptives 
This above table is not all inclusive.  
The above lists were compiled from the Indiana University School of Medicine’s “P450 
Drug Interaction Table – Clinically Relevant Table” [21], supplemented with the FDA 
Draft Guidance for Industry, Drug Interaction Studies – Study Design, Data Analysis, 
and Implications for Dosing and Labeling (October 2017) and the University of 
Washington’s Drug Interaction Database (January 2017). These lists are not 
comprehensive and are only meant to be used as a guide.  
The sponsor should be contacted in case of any doubt. If a medication appears on both 
the list of prohibited and the list of medications to be used with caution, the medication 
is prohibited. 
 
Version Date 
VERSION 1.2 21 DEC 2018 
VERSION 2.0 24 MAY 2019 
Page 
Section 
WAS 
IS 
162 
Appendix 8 New text 
APPENDIX 8 LIST OF 
IMMUNOSUPPRESSIVE AGENTS 
 
Immunosuppressants 
Azathioprine  
Betamethasone  
Dexamethasone  
Hydrocortisone  
Hydroxychloroquine  
Leflunamide  
Methotrexate  
Methylprednisolone  
Prednisolone  
Triamcinolone  
Tenflunomide 
Anti-rejection agents  
Ciclosporin  
Everolimus  
Mycophenolic acid  
Tacrolimus  
Sirolimus 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 235/264 
 
Biological agents 
Abatacept  
Adalimumab  
Alemtuzumab  
Anakinra  
Apremilast  
Basiliximab  
Bevacizumab  
Canakinumab  
Certolizumab  
Daclizumab  
Eculizumab  
Erlotinid  
Etanercept  
Golimumab  
Infliximab  
Imatinib  
Ixekizumab  
Natalizumab  
Nilotinib  
Perfenidone  
Pomalidomide  
Rituximab  
Secukinumab  
Siltuximab  
Sortatinib  
Thalidomide  
Tocilizumab  
Ustenkinumab  
Vedolizumab  
Fingolimod  
Lenalidomide 
Cytotoxic chemotherapy agents 
Paclitaxel  
Capecitabine  
Fludarabine  
Etoposide  
Bendamustine  
Busulfan  
Carmustine  
Chlorambucil  
Dacarbazine  
Ifosfamide  
Melphalan  
Temozolamide  
Thiotepa  
Treosulfan  
Daunorubicin  
Doxorubicin  
Epirubicin  
Idarubicin  
Mitoxanthrone  
Azacitidine  
Cladribine  
Clofarabine  
Cytarabine  
Decitabine  
Fluorouracil  
Gemcitabine  
Mercaptopurine  
Nelarabine  
Pemetrexed  
Tioguanine  
Crisantaspase  
Eribulin  
Hydroxycarbamide (previously hydroxyurea)  
Mitotane  
Raltitrexed  


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 236/264 
 
Bleomycin  
Mitomycin  
Pentostatin  
Carboplatin  
Cisplatin  
Trabectedin  
Oxaliplatin  
Cabazitaxel  
Docetaxel  
Irinotecan  
Topotecan  
Vinblastine  
Vincristine  
Vinorelbine  
Vinflunine 
Others 
Carbimazole  
Clozapine  
Deferiprone  
Olanzapine  
Phenytoin  
Phenobarbital  
Propylthiouracil 
The above list can be found on: https  ://www .hse.ie/eng/services/publications/clinical-
strategy-and-programmes/list-of-immunosuppressant-medication.pdf 


IPSEN GROUP 
D-US-60090-001 
 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 237/264 
 
SUMMARY & OUTCOME OF CHANGES: 
 
STUDY NUMBER 
D-US-60090-001 
AMENDED PROTOCOL 
VERSION NUMBER & 
DATE 
Amendment 1.0, Version 2.0, 24 May 2019 
 
 
SUBSTANTIAL  
 
NON-SUBSTANTIAL  
 
REASONS FOR CHANGES 
 
To implement comments from the FDA including food effect Part D. 
Minor changes were made to resolve inconsistencies within the 
protocol. 
OTHER ACTION REQUIRED? 
CRF UPDATE  
 
Yes 
 
No 
 
(tick one) 
 
LOCAL CONSENT FORM UPDATE  Yes 
  
No 
 
(tick one) 
 
DATABASE UPDATE  
Yes 
  
No 
 
(tick one) 
 
REPORTING & ANALYSIS PLAN 
(RAP) UPDATE 
Yes 
 
No 
 
(tick one) 
 


,36(1*5283
'86
&21),'(17,$/
35272&2/),1$/9(56,21'(&(0%(5
3$*(

678'<180%(5
'86
35272&2/7,7/(
$3+$6(,23(1/$%(/'26((6&$/$7,21$1''26((;3$16,21
678'<72,19(67,*$7(7+(6$)(7<3+$50$&2.,1(7,&6
3+$50$&2'<1$0,&6$1'$17,780285$&7,9,7<2),31$6
6,1*/($*(17$1',1&20%,1$7,21,13$7,(176:,7+$'9$1&('
62/,'7802856
$0(1'('35272&2/9(56,21180%(5	'$7(
$PHQGPHQW9HUVLRQ'HFHPEHU
7+()2//2:,1*$0(1'0(176,6$5(352326('0LQRUIRUPDWWLQJW\SRJUDSKLFDOHUURUVDQGUHSKUDVLQJRIWH[WWRHQKDQFHFODULW\KDYHQRWEHHQUHFRUGHG$Q\QHZ
RUDPHQGHGWH[WDGGHGWRWKHSURWRFROLVLQGLFDWHGLQEROG5HPRYHGWH[WLVVKRZQDVVWULNHWKURXJK
6HFWLRQ
9(56,210$<
9(56,21'(&(0%(5
5$7,21$/()25
&+$1*(
:$6
,6
7LWOH3DJH
6SRQVRU6LJQDWRU\DQG0HGLFDO0RQLWRU

6SRQVRU
6LJQDWRU\
0HGLFDO
0RQLWRU
DQG
(PHUJHQF\&RQWDFW

$GPLQLVWUDWLYHXSGDWH
7LWOH3DJH
(PHUJHQF\&RQWDFW

3KDUPDFRYLJLODQFH&RQWDFW

$GPLQLVWUDWLYHXSGDWH
7LWOH3DJH
)D[
IRUVHULRXV
DGYHUVHHYHQW6$(UHSRUWLQJDQG
SUHJQDQF\QRWLILFDWLRQ
)D[
IRUVHULRXVDGYHUVH
HYHQW6$(UHSRUWLQJDQGSUHJQDQF\
QRWLILFDWLRQ
7RSURYLGHFODULILFDWLRQVDQG
VSHFLILFDWLRQVUHJDUGLQJ6$(
UHSRUWLQJUHTXLUHPHQWV
7LWOH3DJH
)RU6$(UHSRUWLQJDQGSUHJQDQF\QRWLILFDWLRQ
(PDLO

)RU6$(UHSRUWLQJDQGSUHJQDQF\QRWLILFDWLRQ
(PDLO
$OOVHULRXV
DGYHUVHHYHQWV6$(VDQGSUHJQDQFLHVPXVWEH
UHSRUWHGLPPHGLDWHO\XVLQJWKHHOHFWURQLFGDWD
FDSWXUH('&V\VWHP,IWKH('&V\VWHPLVQRW
DYDLODEOHWKH6$(IRUPPXVWEHHPDLOHGWR
RUID[HGWR
LIQRWSRVVLEOHWRHPDLO
7RSURYLGHFODULILFDWLRQVDQG
VSHFLILFDWLRQVUHJDUGLQJ6$(
UHSRUWLQJUHTXLUHPHQWV
33'
33'
33'
33'
33'
33'
33'
33'
33'
33'


,36(1*5283
'86
&21),'(17,$/
35272&2/),1$/9(56,21'(&(0%(5
3$*(

6HFWLRQ
9(56,210$<
9(56,21'(&(0%(5
5$7,21$/()25
&+$1*(
:$6
,6
7LWOH3DJH
6SRQVRU&OLQLFDO3KDUPDFRORJLVW

,SVHQ,QQRYDWLRQ
*OREDO'UXJ'HYHORSPHQW
=,GH&RXUWDERHXI$YHQXHGX&DQDGD
/HV8OLV)UDQFH


6SRQVRU&OLQLFDO3KDUPDFRORJLVW

,SVHQ,QQRYDWLRQ
*OREDO'UXJ'HYHORSPHQW
=,GH&RXUWDERHXI$YHQXHGX&DQDGD
/HV8OLV)UDQFH


$GPLQLVWUDWLYHXSGDWH
6\QRSVLV
H[SORUDWRU\
REMHFWLYHV

7RDQDO\VHH[SORUDWRU\ELRPDUNHUVLQFOXGLQJ
ELRPDUNHUVRIUHVSRQVHRUUHVLVWDQFHWRWKH
WUHDWPHQWDQGDVVRFLDWHWKHPZLWKFOLQLFDO
RXWFRPH
7RDQDO\VHH[SORUDWRU\ELRPDUNHUVLQDUFKLYDODQG
IUHVKELRSV\VDPSOHVLQFOXGLQJELRPDUNHUVRI
UHVSRQVHRUUHVLVWDQFHWRWKHWUHDWPHQWDQGDVVRFLDWH
WKHPZLWKFOLQLFDORXWFRPH
&ODULILFDWLRQ
6\QRSVLV

$Q\RWKHUFOLQLFDOO\VLJQLILFDQWRUSHUVLVWHQW
WR[LFLW\LQFOXGLQJWKRVHRXWVLGHWKH'/7
DVVHVVPHQWSHULRGPD\EHFRQVLGHUHGD'/7
IROORZLQJUHYLHZE\WKH65&
$Q\R2WKHUFOLQLFDOO\VLJQLILFDQWRUSHUVLVWHQW
WR[LFLWLHV\LQFOXGLQJWKRVHRXWVLGHWKH'/7
DVVHVVPHQWSHULRGPD\EHFRQVLGHUHGD'/7
IROORZLQJUHYLHZE\WKH65&
5HZRUGHGWRFODULI\WKH'/7
GHWHUPLQDWLRQIRUWKH
FOLQLFDOO\VLJQLILFDQWRU
SHUVLVWHQWWR[LFLWLHV
6\QRSVLV

$Q\SDWLHQWZKRGRHVQRWFRPSOHWHWKH'/7
DVVHVVPHQWSHULRGIRUDQ\UHDVRQRWKHUWKDQD
'/7ZLOOEHFRQVLGHUHGQRQHYDOXDEOHIRUGRVH
HVFDODWLRQGHFLVLRQVDQG07'DVVHVVPHQWDQG
ZLOOEHUHSODFHGDWWKDWVDPHGRVHOHYHO
3DWLHQWVZLOOEHFRQVLGHUHGHOLJLEOHIRUWKH'/7
DVVHVVPHQWRQO\LIWKH\ZHUHDEOHWRUHFHLYH
RIWKHWRWDOSODQQHG,31GRVHRYHU
WKH'/7DVVHVVPHQWSHULRG1RQFRPSOLDQW
SDWLHQWVZLOODOVREHUHSODFHG
$Q\SDWLHQWZKRGRHVQRWFRPSOHWHWKH'/7
DVVHVVPHQWSHULRGIRUDQ\UHDVRQRWKHUWKDQD'/7
ZLOOEHFRQVLGHUHGQRQHYDOXDEOHIRUGRVHHVFDODWLRQ
GHFLVLRQVDQG07'DVVHVVPHQWDQGZLOOEHUHSODFHG
E\DQDGGLWLRQDOSDWLHQWDWWKDWVDPHGRVHOHYHO
3DWLHQWVZLOOEHFRQVLGHUHGHOLJLEOHIRUWKH'/7
DVVHVVPHQWRQO\LIWKH\ZHUHDEOHWRUHFHLYHRI
WKHWRWDOSODQQHG,31GRVHRYHUWKH'/7
DVVHVVPHQWSHULRG1RQFRPSOLDQWSDWLHQWVZLOODOVREH
UHSODFHG7KH65&PD\GHFLGHWRHQURODGGLWLRQDO
SDWLHQWVEDVHGRQWKHVDIHW\3.RU3'GDWD
&ODULILFDWLRQ
33'
33'
33'
33'


IPSEN GROUP 
D-US-60090-001 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 240/264 
 
Section 
VERSION 2.0 24 MAY 2019 
VERSION 3.0 10 DECEMBER 2019 
RATIONALE FOR 
CHANGE 
WAS 
IS 
Synopsis, 
3.1.2.2 
Any patient who does not complete the DLT 
assessment period for any reason other than a 
DLT will be considered nonevaluable for 
dose-escalation decisions and MTD assessment 
and will be replaced by an additional patient at 
that same dose level. Moreover, patients will be 
considered eligible for the DLT assessment 
only if they received ≥75% of the total planned 
IPN60090 dose and one infusion of 
pembrolizumab over the DLT assessment 
period. Noncompliant patients will also be 
replaced. 
Any patient who does not complete the DLT 
assessment period for any reason other than a DLT 
will be considered nonevaluable for dose escalation 
decisions and MTD assessment and will be replaced 
by an additional patient at that same dose level. 
Moreover, patients will be considered eligible for the 
DLT assessment only if they received ≥75% of the 
total planned IPN60090 dose and one infusion of 
pembrolizumab over the DLT assessment period. 
Noncompliant patients will also be replaced. The 
SRC may decide to enrol additional patients based 
on the safety, PK or PD data. 
Clarification 
Synopsis, 
3.1.2.3 
Any patient who does not complete the DLT 
assessment period for any reason other than a 
DLT will be considered nonevaluable for dose 
escalation decisions and MTD assessment and 
will be replaced by an additional patient at that 
same dose level. Moreover, patients will be 
considered eligible for the DLT assessment 
only if they were able to receive ≥75% of the 
total planned IPN60090 dose and one infusion 
of paclitaxel over the DLT assessment period. 
Any patient who does not complete the DLT 
assessment period for any reason other than a DLT 
will be considered nonevaluable for dose escalation 
decisions and MTD assessment and will be replaced 
by an additional patient at that same dose level. 
Moreover, patients will be considered eligible for the 
DLT assessment only if they were able to receive 
≥75% of the total planned IPN60090 dose and one 
infusion of paclitaxel over the DLT assessment 
period. The SRC may decide to enrol additional 
patients based on the safety, PK or PD data. 
Clarification 
Synopsis, 3.1.4 
Enrolment into dose expansion cohorts will 
occur simultaneously and independently of each 
other. 
Enrolment into dose expansion cohorts will occur 
simultaneously and independently of each other. 
Clarification 


IPSEN GROUP 
D-US-60090-001 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 241/264 
 
Section 
VERSION 2.0 24 MAY 2019 
VERSION 3.0 10 DECEMBER 2019 
RATIONALE FOR 
CHANGE 
WAS 
IS 
Synopsis 
(inclusion 
criteria), 4.1.1 
(3) Histologically or cytologically confirmed 
advanced solid tumours including tumours 
known to harbour KEAP1 and NRF2 
mutations or have low ASNS expression 
levels (IHC Grade 0 or 1). 
-  In dose escalations of all Parts, patients 
may be KEAP1/NRF2 wild-type or 
mutated and have tumours with any 
level of ASNS expression. For dose 
expansions, see specific inclusion 
criteria per Part below. 
(3) Histologically or cytologically confirmed 
advanced solid tumours including tumours 
known to harbour KEAP1 and/or NRF2 
mutations or have low ASNS expression levels 
(IHC Grade 0 or 1). 
-  In dose escalations of all parts, patients may 
be KEAP1 and /NRF2 wild-type or mutated 
and have tumours with any level of ASNS 
expression. For dose expansions, see specific 
inclusion criteria per part below. 
Amended for consistency 
with the 
immunohistochemistry 
cut-off investigation. 
Synopsis 
(inclusion 
criteria), 4.1.1 
(8) Eastern Cooperative Oncology Group 
Performance Status ≤1 and a Royal 
Marsden Hospital score of 0 or 1≤1. 
(8) 
Eastern Cooperative Oncology Group 
Performance Status ≤1 and a Royal Marsden 
Hospital score of 0 or 1≤1. 
Requested by the principal 
investigator. 
Synopsis 
(inclusion 
criteria), 4.1.1 
(9) Adequate organ function as indicated by 
the following laboratory values 
independent of transfusion within 2 weeks 
before first study treatment: 
(9) Adequate organ function as indicated by the 
following laboratory values independent of 
transfusion within 2 weeks before first study 
treatment: 
No counter-indication for 
transfusions prior to study 
entry 
Synopsis (Part 
A specific 
inclusion 
criteria), 4.1.2 
(A2) Patients with following tumour types 
will be recruited: 
(a) NSCLC KEAP1/NRF2 mutant  
(b) KEAP1/NRF2 other tumours 
(c) HGSOC ASNSlow 
(A1) Patients with the following tumour types will 
be recruited: 
(a) NSCLC KEAP1 and/or NRF2 mutant  
(b) KEAP1 and/or NRF2 mutant other 
tumours 
 
   (c)    HGSOC ASNSlow 
Clarification 


IPSEN GROUP 
D-US-60090-001 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 242/264 
 
Section 
VERSION 2.0 24 MAY 2019 
VERSION 3.0 10 DECEMBER 2019 
RATIONALE FOR 
CHANGE 
WAS 
IS 
Synopsis (Part 
B specific 
inclusion 
criteria), 4.1.3 
New text. 
(B2) Patients may have received previous treatment 
with any anti-programmed cell death protein 1 
(PD-1)/programmed death-ligand 1 PD-L1) 
monoclonal antibody (mAb) administered either 
as monotherapy, or in combination with other 
checkpoint inhibitors or other therapies. PD-1 
treatment progression is defined by meeting all 
of the following criteria: 
(a) Has received at least 2 doses of an 
approved anti-PD-1/L1 mAb. 
(b) Has demonstrated disease progression 
after PD-1/L1 as defined by iRECIST 
v1.1. The initial evidence of disease 
progression is to be confirmed by a 
second assessment no less than four 
weeks from the date of the first 
documented disease progression, in the 
absence of rapid clinical progression. 
Added per Merck 
requirement. 
Synopsis 
(Part B specific 
inclusion 
criteria), 4.1.3 
(B2) Patients with following tumour types 
will be recruited during the dose 
expansion only: 
(a) NSCLC KEAP1 or NRF2 mutant  
(b) Other KEAP1 or NRF2 mutant 
tumours 
(c) KEAP1 or NRF2 wild type tumours 
with any level of ASNS expression 
(B3) Patients with the following tumour types will 
be recruited during the dose expansion only: 
(a) NSCLC KEAP1 and/or NRF2 mutant  
(b) Other KEAP1 and/or NRF2 mutant 
tumours 
(c) KEAP1 and or NRF2 wild type tumours 
with any level of ASNS expression 
Clarification 


IPSEN GROUP 
D-US-60090-001 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 243/264 
 
Section 
VERSION 2.0 24 MAY 2019 
VERSION 3.0 10 DECEMBER 2019 
RATIONALE FOR 
CHANGE 
WAS 
IS 
Synopsis 
(Part B specific 
exclusion 
criteria), 4.2.3 
New text  
(B4) 
Patient has received a live vaccine within 
30 days prior to the first dose of study drug. 
Examples of live vaccines include, but are 
not limited to, the following: measles, 
mumps, rubella, varicella/zoster (chicken 
pox), yellow fever, rabies, Bacillus 
Calmette–Guérin and typhoid vaccine. 
Seasonal influenza vaccines for injection are 
generally killed virus vaccines and are 
allowed; however, intranasal influenza 
vaccines (e.g. FluMist®) are live attenuated 
vaccines and are not allowed. 
Pembrolizumab 
administration requirement 
Synopsis (test 
product, dose, 
mode of 
administration) 
IPN60090 intake should be performed at least 
2 hours before the start of pembrolizumab 
infusion. 
IPN60090 intake should be performed at least 
1 2 hours before the start of pembrolizumab infusion. 
Clarification due to the PK 
blood sampling schedule 
Synopsis 
(primary 
endpoint), 3.2.1 
The safety and tolerability of IPN60090 as a 
single agent (Part A and Part D) and in 
combination with pembrolizumab (Part B) or 
paclitaxel (Part C) will be assessed by 
continuous reporting of AEs and serious AEs 
(SAEs), clinical laboratory test results, the 
presence of anti-pembrolizumab antidrug 
antibodies (ADA; Part B only), vital signs 
measurements, ECG and physical examination 
results and concomitant medication usage. 
The safety and tolerability of IPN60090 as a single 
agent (Part A and Part D) and in combination with 
pembrolizumab (Part B) or paclitaxel (Part C) will be 
assessed by continuous reporting the rate of DLTs at 
each dose level in the dose escalation, and the rate 
of AEs and the rate of Grade 3 and higher AEs in 
the dose escalation and dose expansion. 
Continuous monitoring of AEs and serious AEs 
(SAEs), clinical laboratory test results, the presence of 
anti -pembrolizumab antidrug antibodies (ADA; 
Part B only), vital signs measurements, 
electrocardiogram (ECG) and physical examination 
results and concomitant medication usage will be 
performed. 
Clarification. 


IPSEN GROUP 
D-US-60090-001 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 244/264 
 
Section 
VERSION 2.0 24 MAY 2019 
VERSION 3.0 10 DECEMBER 2019 
RATIONALE FOR 
CHANGE 
WAS 
IS 
Synopsis 
(secondary 
endpoints), 
3.2.2 
Tumour mutation status (for example 
KEAP1/NRF2, serine/threonine kinase 11, 
Kirsten Rat Sarcoma Viral Oncogene Homolog 
and Myc overexpression and/or amplification, 
etc) 
Tumour mutation status (for example KEAP1/NRF2, 
serine/threonine kinase 11, Kirsten Rat Sarcoma Viral 
Oncogene Homolog and Myc overexpression and/or 
amplification, etc other mutations) and correlation 
with clinical outcome 
Amended as this is not 
collected in the EDC. 
Synopsis (safety 
endpoint), 3.2.4  
The safety and tolerability of IPN60090 will be 
assessed by continuous monitoring of the rate 
of AEs and SAEs, clinical laboratory test 
results, the presence of anti-pembrolizumab 
ADA (Part B only), vital signs measurements, 
ECG and physical examination results, and 
concomitant medication usage. 
The safety and tolerability of IPN60090 will be 
assessed by continuous monitoring of the rate of 
DLTs at each dose level in the dose escalation, and 
the rate of AEs and the rate of Grade 3 and higher 
AEs in the dose escalation and dose expansion. 
Continuous monitoring of AEs and SAEs, clinical 
laboratory test results, the presence of anti-
pembrolizumab ADA (Part B only), vital signs 
measurements, ECG and physical examination results, 
and concomitant medication usage will be 
performed. 
Clarification 
Synopsis 
(statistical 
methods) 
Food effect population: All patients in Part D 
who have received IPN60090 under fasting and 
fed conditions (Day  7 and Day  3), have 
consumed ≥80% of the moderate fat meal on 
Day  3, and who have no major protocol 
deviation affecting the PK variables and who 
have a sufficient number of IPN60090 plasma 
concentrations to estimate the main PK 
parameters (Cmax, Tmax and AUC0-last). 
Food effect population: All patients in Part D who 
have received IPN60090 under fasting and fed 
conditions (Day  7 and Day  3), have consumed ≥80% 
of the moderate fat meal in approximately 30 
minutes on Day  3, and who have no major protocol 
deviation affecting the PK variables and who have a 
sufficient number of IPN60090 plasma concentrations 
to estimate the main PK parameters (Cmax, Tmax and 
AUC0-last). 
Amended for consistency 
with Section 11.1 
Synopsis 
(statistical 
methods) 
Duration of PFS is defined as time from first 
study drug to the earlier of either PD per 
RECIST 1.1, iPD per iRECIST or death from 
any cause.  
Duration of PFS is defined as time from first study 
drug to the earlier of either PD per RECIST 1.1, iPD 
per iRECIST or death from any cause.  
Will be defined in the 
Statistical Analysis Plan. 


IPSEN GROUP 
D-US-60090-001 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 245/264 
 
Section 
VERSION 2.0 24 MAY 2019 
VERSION 3.0 10 DECEMBER 2019 
RATIONALE FOR 
CHANGE 
WAS 
IS 
Synopsis 
Based on the dose escalation data, the protocol 
may be amended to further define the dose 
expansion cohorts. 
Based on the dose escalation data, the protocol may be 
amended to further define the dose expansion cohorts. 
Deleted to remove 
duplication with later 
sentence 
1.1 
IPN60090 is currently in preclinical 
development with expected first treatment in 
humans by Q1 2019. 
IPN60090 is currently in preclinical development with 
expected and the first treatment in humans by Q1 
took place on 04 April 2019. 
Updated to reflect current 
status 
2.2.2 
To document the steady state concentrations of 
pembrolizumab and paclitaxel (Parts B and C). 
 
To document the steady state concentrations of 
pembrolizumab and paclitaxel (Parts B and C). 
 
Amended for consistency 
with the synopsis 
3.1.2.2 
At all dose levels, IPN60090 will be 
administered orally BID starting from Day 1 of 
each 21-day cycle and pembrolizumab will be 
administered as one intravenous (i.v.) infusion 
every 21 days (±1 day in Cycle 1 and ±3 days 
in all other cycles) starting from Day 1 of each 
cycle. 
At all dose levels, IPN60090 will be administered 
orally BID starting from Day 1 of each 21-day cycle 
and pembrolizumab will be administered as one 
intravenous (i.v.) infusion every 21 days (±1 day in 
Cycle 1 and ±3 days in all other cycles) starting from 
Day 1 of each cycle. The planned dose of 
pembrolizumab for this study is 200 mg every 
3 weeks (Q3W). Based on the totality of data 
generated in the Keytruda development program, 
200 mg Q3W is the appropriate dose of 
pembrolizumab for adults across all indications 
and regardless of tumour type. 
Clarification of 
pembrolizumab 
administration  


IPSEN GROUP 
D-US-60090-001 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 246/264 
 
Section 
VERSION 2.0 24 MAY 2019 
VERSION 3.0 10 DECEMBER 2019 
RATIONALE FOR 
CHANGE 
WAS 
IS 
3.1.2.2 
The DLT assessment period will consist of the 
first 21 days of treatment (one cycle). The SRC 
will evaluate safety, available PK and PD data 
in order to make a decision on dose escalation, 
and to determine the MTD and the RD. The 
safety data reviewed by the SRC will include 
the safety findings and DLTs observed during 
the DLT assessment period from the previous 
cohort. The SRC may decide to evaluate an 
intermediate, not predefined, previously 
evaluated or not previously-evaluated dose or a 
less frequent dosing schedule that will not 
exceed the MTD level if evaluation of toxicity 
at such a dose or schedule is desired. 
The DLT assessment period for IPN60090 in 
combination with pembrolizumab (Part B) will 
consist of the first 21 days of treatment (one cycle). 
An additional safety assessment for delayed onset 
AEs will be performed at 6 weeks (42 days), and at 
12 weeks (84 days). The SRC will evaluate safety 
and available PK and PD data in order to make a 
decision on dose escalation, and to determine the 
MTD and the RD. The safety data reviewed by the 
SRC will include the safety findings and DLTs 
observed during the DLT assessment period from the 
previous cohort. The SRC may decide to evaluate an 
intermediate, not predefined, previously evaluated or 
not previously-evaluated dose of IPN60090 or a less 
frequent dosing schedule that will not exceed the 
MTD level if evaluation of toxicity at such a dose or 
schedule is desired. 
Clarification of 
pembrolizumab AE 
assessment 
3.1.2.2, 3.1.2.3 
Any other clinically significant or persistent 
toxicity may be considered a DLT following 
review by the SRC. 
Any o Other clinically significant or persistent 
toxicitiesy may be considered a DLT following 
review by the SRC. 
Reworded to clarify the DLT 
determination for the 
clinically significant or 
persistent toxicities 
4.1.4 
(C2) Patients with the following tumour types 
will be recruited during the dose 
expansion only: 
(a) KEAP1 or NRF2 mutant tumours 
(b) ASNSlow tumours  
(c) KEAP1 or NRF2 wild type tumours 
with any level of ASNS expression 
(C2) Patients with the following tumour types will 
be recruited during the dose expansion only: 
(a) 
KEAP1 or NRF2 mutant tumours 
(b) 
HGSOC ASNSlow tumours  
(c) 
KEAP1 or NRF2 wild type tumours with 
any level of ASNS expression 
Amended for consistency 
with the rest of the protocol 


IPSEN GROUP 
D-US-60090-001 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 247/264 
 
Section 
VERSION 2.0 24 MAY 2019 
VERSION 3.0 10 DECEMBER 2019 
RATIONALE FOR 
CHANGE 
WAS 
IS 
5.1 
Table 14 Study Procedures and Assessments 
(Parts A to C) 
New assessment added 
Ophthalmological examination at screening added. 
Additional baseline safety 
evaluation 
5.1 
Table 14 Study Procedures and Assessments 
(Parts A to C) 
Assessment deleted 
RMH status at screening deleted 
Requested by the principal 
investigator. 
5.1 
Table 15 Study Procedures and Assessments 
(Part D) 
New assessment added 
Ophthalmological examination at screening added. 
Additional baseline safety 
evaluation 
5.1 
Table 15 Study Procedures and Assessments 
(Part D) 
Assessment deleted 
RMH status at screening deleted 
Requested by the principal 
investigator. 
5.3 
Table 16 Total Blood Volume for All 
Evaluations (Parts A to C) 
Blood sampling for PK of paclitaxel (Part C 
only): 
Volume per sample (mL): 2.5 
Total max volume/month (mL): 5 
Total volume (Part C): 229 
Table 16 Total Blood Volume for All Evaluations 
(Parts A to C) 
Blood sampling for PK of paclitaxel (Part C only): 
Volume per sample (mL): 2 2.5 
Total max volume/month (mL): 4 5 
Total volume (Part C): 228 229 
Clarification of blood 
volume required for PK 
analysis. 


IPSEN GROUP 
D-US-60090-001 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 248/264 
 
Section 
VERSION 2.0 24 MAY 2019 
VERSION 3.0 10 DECEMBER 2019 
RATIONALE FOR 
CHANGE 
WAS 
IS 
6.2.2.1 
IPN60090 capsules should be taken before the 
pembrolizumab infusion.  
Pembrolizumab dose will be fixed at 200 mg 
(or according to the approved local label for 
particular tumour types) administered as an i.v. 
infusion over 30 minutes every 21 days (±1 day 
in Cycle 1 and ±3 days in all other cycles) (Day 
1 of every cycle) through an i.v. line containing 
a sterile, non-pyrogenic, low protein binding 
0.2 μm to 5 μm in line or add on filter. 
Premedication with antipyretic and 
antihistamine may be considered. 
Reconstitution and preparation of 
pembrolizumab solution for infusion should be 
done as per locally approved product 
information.  
IPN60090 capsules should be taken at least 1 hour 
before the pembrolizumab infusion. The predose, 
30-minute (±5 minutes) and 1-hour (±5 minutes) 
blood samples for PK analysis should be drawn 
before initiating the pembrolizumab infusion. 
The pembrolizumab dose will be fixed at 200 mg (or 
according to the approved local label for particular 
tumour types) administered as an i.v. infusion over 30 
minutes every 21 days (±1 day in Cycle 1 and ±3 days 
in all other cycles) (Day 1 of every cycle) through an 
i.v. line containing a sterile, non-pyrogenic, low 
protein binding 0.2 μm to 5 μm in line or add on filter. 
Premedication with antipyretic and antihistamine may 
be considered. Reconstitution and preparation of 
pembrolizumab solution for infusion should be done 
as per the locally approved product information. Sites 
should make every effort to target infusion timing 
to be as close to 30 minutes as possible. However, 
given the variability of infusion pumps from site to 
site, a window between -5 minutes and +10 minutes 
is permitted (i.e. infusion time is 30 minutes 
(-5 minutes/+10 minutes). 
Clarification of 
pembrolizumab 
administration 
6.4.4.1 
New heading added 
6.4.4.1 Dose Adjustments and Modifications for 
Nonimmune Related Adverse Events 
Heading amended to allow 
for new Section 6.4.4.2. 


IPSEN GROUP 
D-US-60090-001 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 249/264 
 
Section 
VERSION 2.0 24 MAY 2019 
VERSION 3.0 10 DECEMBER 2019 
RATIONALE FOR 
CHANGE 
WAS 
IS 
6.4.4.2 
New section added 
6.4.4.2 Dose Adjustments and Modifications for 
Immune-Related Adverse Events Associated with 
Pembrolizumab 
Adverse events associated with pembrolizumab 
exposure 
may 
represent 
an 
immune-related 
response. These immune-related AEs (irAEs) may 
occur shortly after the first dose or several months 
after the last dose of pembrolizumab treatment 
and may affect more than one body system 
simultaneously. Therefore, early recognition and 
initiation of treatment is critical to reduce 
complications. Based on existing clinical study 
data, most irAEs were reversible and could be 
managed with interruptions of pembrolizumab, 
administration of corticosteroids and/or other 
supportive care. For suspected irAEs, ensure 
adequate evaluation to confirm aetiology or 
exclude other causes. Additional procedures or 
tests such as bronchoscopy, endoscopy, skin biopsy 
may be included as part of the evaluation. Dose 
modification and toxicity management guidelines 
for irAEs associated with pembrolizumab are 
provided in Table 24. 
Clarification of 
pembrolizumab AE 
assessment 


IPSEN GROUP 
D-US-60090-001 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 250/264 
 
Table 24 Dose Modification and Toxicity Management Guidelines for Immune-Related AEs Associated with Pembrolizumab 
irAEs 
Toxicity grade 
(CTCAE v5.0) 
Action with 
pembrolizumab 
Corticosteroid and/or other therapies 
Monitoring and follow-up  
Pneumonitis  
Grade 2 
Withhold  
x Administer corticosteroids (initial dose 
of 1 to 2 mg/kg prednisone or 
equivalent) followed by taper 
x Add prophylactic antibiotics for 
opportunistic infections 
x Monitor participants for signs and symptoms of 
pneumonitis 
x Evaluate participants with suspected pneumonitis with 
radiographic imaging and initiate corticosteroid 
treatment 
Recurrent 
Grade 2, Grade 3 
or 4  
Permanently 
discontinue 
Diarrhoea/colitis  
Grade 2 or 3 
Withhold 
x Administer corticosteroids (initial dose 
of 1 to 2 mg/kg prednisone or 
equivalent) followed by taper 
x Monitor participants for signs and symptoms of 
enterocolitis (i.e. diarrhoea, abdominal pain, blood or 
mucus in stool with or without fever) and of bowel 
perforation (i.e. peritoneal signs and ileus) 
x Participants with ≥Grade 2 diarrhoea suspecting colitis 
should consider GI consultation and performing 
endoscopy to rule out colitis 
x Participants with diarrhoea/colitis should be advised to 
drink liberal quantities of clear fluids. If sufficient oral 
fluid intake is not feasible, fluid and electrolytes should 
be substituted via i.v. infusion 
Recurrent Grade 3 
or Grade 4 
Permanently 
discontinue 
AST or ALT 
elevation or 
increased 
bilirubin 
Grade 2a 
Withhold 
x Administer corticosteroids (initial dose 
of 0.5 to 1 mg/kg prednisone or 
equivalent) followed by taper 
x Monitor with liver function tests (consider weekly or 
more frequently until liver enzyme value returned to 
baseline or is stable) 
Grade 3b or 4 c 
Permanently 
discontinue 
x Administer corticosteroids (initial dose 
of 1 to 2 mg/kg prednisone or 
equivalent) followed by taper 
T1DM or 
hyperglycaemia 
New onset T1DM 
or Grade 3 or 4 
hyperglycaemia 
associated with 
evidence of E-cell 
failure 
Withholdd 
x Initiate insulin replacement therapy for 
participants with T1DM 
x Administer antihyperglycaemic in 
participants with hyperglycaemia 
x Monitor participants for hyperglycaemia or other signs 
and symptoms of diabetes 


IPSEN GROUP 
D-US-60090-001 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 251/264 
 
irAEs 
Toxicity grade 
(CTCAE v5.0) 
Action with 
pembrolizumab 
Corticosteroid and/or other therapies 
Monitoring and follow-up  
Hypophysitis 
Grade 2 
Withhold 
x Administer corticosteroids and initiate 
hormonal replacements as clinically 
indicated 
x Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal insufficiency) 
Grade 3 or 4 
Withhold or 
permanently 
discontinue d 
Hyperthyroidism  
Grade 2 
Continue 
x Treat with nonselective beta-blockers 
(e.g. propranolol) or thionamides as 
appropriate 
x Monitor for signs and symptoms of thyroid disorders 
Grade 3 or 4 
Withhold or 
permanently 
discontinue d 
Hypothyroidism 
Grade 2, 3, 4 
Continue 
x Initiate thyroid replacement hormones 
(e.g. levothyroxine or liothyronine) per 
standard of care 
x Monitor for signs and symptoms of thyroid disorders 
Nephritis: grading 
according to 
increased 
creatinine or acute 
kidney injury 
Grade 2 
Withhold 
x Administer corticosteroids (prednisone 
1 to 2 mg/kg or equivalent) followed by 
taper 
x Monitor changes of renal function 
Grade 3 or 4 
Permanently 
discontinue 
Myocarditis 
Grade 1 or 2 
Withhold 
x Based on severity of AE administer 
corticosteroids 
x Ensure adequate evaluation to confirm aetiology and/or 
exclude other causes 
Grade 3 or 4 
Permanently 
discontinue 


IPSEN GROUP 
D-US-60090-001 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 252/264 
 
irAEs 
Toxicity grade 
(CTCAE v5.0) 
Action with 
pembrolizumab 
Corticosteroid and/or other therapies 
Monitoring and follow-up  
All other irAEs 
Persistent Grade 2 
Withhold 
x Based on severity of AE administer 
corticosteroids 
x Ensure adequate evaluation to confirm aetiology or 
exclude other causes 
Grade 3 
Withhold or 
discontinue based on 
the evente  
Recurrent Grade 3 
or 4  
Permanently 
discontinue 
AE=adverse event; ALT=alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; GI=gastrointestinal; irAE=immune-related 
adverse event; i.v.=intravenous; T1DM=Type 1 diabetes mellitus; ULN=upper limit of normal 
a AST/ALT: >3.0 to 5.0 × ULN if baseline normal; >3.0 to 5.0 × baseline, if baseline abnormal; bilirubin:>1.5 to 3.0 × ULN if baseline normal; >1.5 to 3.0 × baseline, if baseline abnormal 
b AST/ALT: >5.0 to 20.0 × ULN if baseline normal; >5.0 to 20.0 × baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 × ULN if baseline normal; >3.0 to 10.0 × baseline, if baseline 
abnormal 
c AST/ALT: >20.0 × ULN if baseline normal; >20.0 × baseline, if baseline abnormal; bilirubin: >10.0 × ULN if baseline normal; >10.0 × baseline, if baseline abnormal 
d The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician. If control achieved or ≤ Grade 2, pembrolizumab may be 
resumed. 
e Events that require discontinuation include but are not limited to: Guillain-Barre Syndrome, encephalitis, Stevens-Johnson Syndrome and toxic epidermal necrolysis. 
 


IPSEN GROUP 
D-US-60090-001 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 253/264 
 
Section 
VERSION 2.0 24 MAY 2019 
VERSION 3.0 10 DECEMBER 2019 
RATIONALE FOR 
CHANGE 
WAS 
IS 
6.4.4.2 
New text 
General instructions: 
(1) Severe and life-threatening irAEs should be treated with i.v. 
corticosteroids followed by oral steroids. Other 
immunosuppressive treatment should begin if the irAEs are not 
controlled by corticosteroids.  
(2) Pembrolizumab must be permanently discontinued if the irAE 
does not resolve or the corticosteroid dose is not ≤10 mg/day 
within 12 weeks of the last pembrolizumab treatment. 
(3) The corticosteroid taper should begin when the irAE is ≤ Grade 1 
and continue for at least 4 weeks. 
(4) If pembrolizumab has been withheld, pembrolizumab may resume 
after the irAE decreased to ≤ Grade 1 after the corticosteroid 
taper. 
Clarification of 
pembrolizumab AE 
management 


IPSEN GROUP 
D-US-60090-001 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 254/264 
 
Section 
VERSION 2.0 24 MAY 2019 
VERSION 3.0 10 DECEMBER 2019 
RATIONALE FOR 
CHANGE 
WAS 
IS 
7.2.2 
New text 
iRECIST is adapted to account for the unique tumour response seen 
with immunotherapeutic drugs. When clinically stable, patients should 
not be discontinued until progression is confirmed by the investigator. 
Some patients can have initial radiographic progressive disease due to a 
transient tumour flare in the first few months after the start of 
immunotherapy, and then experience subsequent disease response.  
Clinical stability is defined as the following:  
• absence of symptoms and signs indicating clinically significant 
progression of disease 
• no decline in ECOG performance status  
• no requirements for intensified management, including increased 
analgesia, radiation or other palliative care 
Any patient deemed clinically unstable should be discontinued from 
study treatment at first radiologic evidence of progressive disease and 
will not be required to have repeat tumour imaging for confirmation of 
progressive disease by iRECIST. 
Patients who are clinically stable and exhibit initial radiographic 
progressive disease may continue to receive study treatment and the 
tumour assessment should be repeated 4 to 6 weeks later to confirm 
progressive disease by iRECIST, per investigator assessment. If 
repeated imaging does not confirm progressive disease per iRECIST, as 
assessed by the investigator, and the patient continues to be clinically 
stable, study treatment may continue and follow the regular imaging 
schedule. If progressive disease is confirmed, patients will be 
discontinued from study treatment. 
If a patient has confirmed radiographic progression as defined in 
Appendix 10, study treatment should be discontinued; however, if the 
patient is achieving a clinically meaningful benefit, an exception to 
continue study treatment may be considered following consultation 
with the sponsor. In this case, if study treatment is continued, tumour 
imaging should follow the 6-week tumour assessment schedule.  
A summary of imaging and treatment requirements after first 
radiologic evidence of progression is provided in Table 29. 
Clarification of 
pembrolizumab 
response assessment 


IPSEN GROUP 
D-US-60090-001 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 255/264 
 
Table 29 Imaging and Treatment after First Radiologic Evidence of Progressive Disease 
 
Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
First radiologic evidence of 
PD by RECIST v1.1  
Repeat imaging at 4 to 
8 weeks to confirm PD 
May continue study treatment at 
the investigator’s discretion while 
awaiting confirmatory tumour 
imaging by site by iRECIST 
Repeat imaging at 4 to 
8 weeks to confirm PD per 
investigator’s discretion only 
Discontinue treatment 
Repeat tumour imaging 
confirms PD (iCPD) by 
iRECIST per investigator 
assessment 
No additional imaging 
required 
Discontinue treatment (exception is 
possible upon consultation with 
sponsor) 
No additional imaging 
required 
Not applicable 
Repeat tumour imaging shows 
iUPD by iRECIST per 
investigator assessment 
Repeat imaging at 4 to 
8 weeks to confirm PD.  
May occur at next regularly 
scheduled imaging visit. 
Continue study treatment at the 
investigator’s discretion 
Repeat imaging at 4 to 
8 weeks to confirm PD per 
investigator’s discretion only 
Discontinue treatment 
Repeat tumour imaging shows 
iSD, iPR or iCR by iRECIST 
per investigator assessment. 
Continue regularly scheduled 
imaging assessments 
Continue study treatment at the 
investigator’s discretion 
Continue regularly scheduled 
imaging assessments 
May restart study treatment if 
condition has improved and/or 
clinically stable per investigator’s 
discretion. Next tumour imaging 
should occur according to the regular 
imaging schedule. 
BICR=Blinded Independent Central Review; iCPD=iRECIST confirmed progressive disease; iCR=iRECIST complete response; iRECIST=modified Response Evaluation Criteria in Solid 
Tumors for immune-based therapeutics; iSD=iRECIST stable disease; iUPD=iRECIST unconfirmed progressive disease; PD=progressive disease; RECIST=Response Evaluation Criteria in 
Solid Tumors; VOP=verification of progression 
 


IPSEN GROUP 
D-US-60090-001 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 256/264 
 
Section 
VERSION 2.0 24 MAY 2019 
VERSION 3.0 10 DECEMBER 2019 
RATIONALE FOR 
CHANGE 
WAS 
IS 
8.1.1 
The following is considered an 
event of special interest and must 
be reported to Ipsen within 24 
hours of site awareness, irrespective 
of causality: serum 
aminotransferases ALT/AST 
>3×ULN, with increase in total 
serum bilirubin >2×ULN. 
The following events is considered an event of special interest and must be 
reported to the sponsor Ipsen within 24 hours of the site’s awareness, 
irrespective of causality: serum aminotransferases ALT/AST >3×ULN, with 
increase in total serum bilirubin >2×ULN. 
To provide 
clarifications and 
specifications 
regarding additional 
AEs that require 
immediate reporting to 
the sponsor from the 
site. 
8.1.4 
All SAEs (as defined below), 
regardless of treatment group or 
suspected relationship to IMP, must 
be reported immediately (within 24 
hours of the investigator’s 
knowledge of the event) via the 
electronic data capture (EDC) 
system or using the email specified 
at the beginning of this protocol in 
case the EDC is not available. If the 
immediate report is submitted by 
telephone, or if the EDC was not 
available at initial reporting, this 
must be followed by detailed 
written reports using the SAE form 
in the eCRF. 
All SAEs (as defined below), regardless of treatment group or suspected 
relationship to IMP, must be reported immediately (within 24 hours of the 
investigator’s knowledge of the event) via using the electronic data capture 
(EDC) system. In instances where the EDC system is not available, the 
SAE form must be completed and sent to the email address or fax 
number (if not possible to email) or using the email specified at the 
beginning of this protocol in case the EDC is not available. If the immediate 
report is submitted by telephone, or if the EDC was not available at initial 
reporting, this must be followed by the reporting of this SAE using the 
EDC system as soon as it becomes available detailed written reports using 
the SAE form in the eCRF. 
To provide 
clarifications and 
specifications 
regarding SAE 
reporting requirements 
and timelines. 


IPSEN GROUP 
D-US-60090-001 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 257/264 
 
Section 
VERSION 2.0 24 MAY 2019 
VERSION 3.0 10 DECEMBER 2019 
RATIONALE FOR 
CHANGE 
WAS 
IS 
8.1.4 
In addition to the above criteria, 
any additional AE that the sponsor 
or an investigator considers serious 
should be immediately reported to 
the sponsor and included in the 
corporate SAEs database system. 
In addition to the above criteria, the following events must be reported to 
the sponsor within 24 hours of the site’s awareness, irrespective of 
causality: serum aminotransferases ALT/AST >3×ULN, with increase 
in total serum bilirubin >2×ULN any additional AE that the sponsor or an 
investigator considers serious should be immediately reported to the 
sponsor and included in the corporate SAEs database system. 
To provide 
clarifications and 
specifications 
regarding additional 
AEs that require 
immediate reporting to 
the sponsor from the 
site. 
8.1.4 
Any SAE must be reported 
immediately (within 24 hours) in 
the eCRF or using the email 
specified at the beginning of this 
protocol in case the EDC system is 
not available, independent of the 
circumstances or suspected cause, if 
it occurs or comes to the attention 
of the investigator at any time 
during the study period. 
Any SAE must be reported immediately (within 24 hours) using the EDC 
system in the eCRF or using the email address or fax number (if not 
possible to email) specified at the beginning of this protocol in case the 
EDC system is not available, independent of the circumstances or suspected 
cause, if it occurs or comes to the attention of the investigator at any time 
during the study period. 
To provide 
clarifications and 
specifications 
regarding SAE 
reporting 
requirements. 
8.1.4 
New text  
All AEs meeting serious criteria, from the time of treatment/allocation 
through 90 days following cessation of study treatment, or 30 days 
following cessation of study treatment if the participant initiates new 
anticancer therapy, whichever occurs first, must be reported by the 
investigator. 
Additionally, any SAE brought to the attention of an investigator at 
any time outside of the time period specified above must be reported 
immediately to the sponsor if the event is considered to be drug-related. 
To provide 
clarifications and 
specifications 
regarding SAE 
reporting requirements 
and timelines. 


IPSEN GROUP 
D-US-60090-001 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 258/264 
 
Section 
VERSION 2.0 24 MAY 2019 
VERSION 3.0 10 DECEMBER 2019 
RATIONALE FOR 
CHANGE 
WAS 
IS 
8.1.5 
Pregnancies with a conception date 
within 4 months after patient’s last 
dose of IMP must also be reported 
to the investigator for onward 
reporting to the sponsor. 
Pregnancies with a conception date within 4 months after patient’s last dose 
of IMP must also be reported to the investigator for onward reporting to the 
sponsor. 
All pregnancies, from the time of treatment/allocation through 120 
days following cessation of study treatment, or 30 days following 
cessation of study treatment if the participant initiates new anticancer 
therapy, must be reported by the investigator. 
To provide 
clarifications and 
specifications 
pregnancy reporting 
requirements and 
timelines. 
9.1.1.3 
Samples should be stored at ≤‑20°C 
prior to shipment to the analysis 
laboratory: Kymos Pharma 
Services, Spain for pembrolizumab 
level determination. 
Samples should be stored at ≤‑20°C prior to shipment to the analysis 
laboratory: Kymos Pharma Services, Spain for pembrolizumab level 
determination. 
Details of CRO 
performing analysis 
not needed in the 
protocol. 
9.1.1.4 
Blood volumes in table updated. 
Was: 2.5 mL 
Blood volumes in table: 
2.5 mL 2.0 mL 
Clarification of blood 
volume required for 
PK analysis. 
9.1.1.4 
Blood should be collected (2.5 mL) 
from the uninfused arm, in a K2 
EDTA tube at each time point and 
gently inverted eight times. The 
samples should be centrifuged at 
2000g at 4°C for 10 minutes. The 
resulting plasma will be stored 
at -80°C ±10°C in polypropylene 
tubes as two 500 μL aliquots 
(primary and back-up) prior to 
shipment to the analysis laboratory: 
Kymos Pharma Services, Spain for 
paclitaxel level determination. 
Blood samples (2.0 mL) should be collected (2.5 mL) from the uninfused 
arm, in a K2 EDTA tube at each time point and gently inverted eight times. 
The samples should be centrifuged at 2000g at 4°C for 10 minutes. The 
resulting plasma will be stored at -80°C ±10°C in polypropylene tubes as 
two 500 μL aliquots (primary and back-up) prior to shipment to the analysis 
laboratory: Kymos Pharma Services, Spain for paclitaxel level 
determination. 
Clarification of blood 
volume required for 
PK analysis. 


IPSEN GROUP 
D-US-60090-001 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 259/264 
 
Section 
VERSION 2.0 24 MAY 2019 
VERSION 3.0 10 DECEMBER 2019 
RATIONALE FOR 
CHANGE 
WAS 
IS 
11.2.3.5 
A TEAE is defined as any AE that 
occurs during the active phase of 
the study if:  
• It was not present prior to 
receiving the first administration 
of study drugs; or  
• It was present prior to receiving 
the first administration of study 
drugs but the intensity increased 
during the active phase of the 
study; or  
• It was present prior to receiving 
the first administration of one of 
the study drugs, the intensity is 
the same but the drug relationship 
became related during the active 
phase of the study. 
A TEAE is defined as any AE that occurs during the active phase of the 
study if:  
• It was not present prior to receiving the first administration of study 
drugs; or  
• It was present prior to receiving the first administration of study drugs but 
the intensity increased during the active phase of the study; or  
• It was present prior to receiving the first administration of one of the 
study drugs, the intensity is the same but the drug relationship became 
related during the active phase of the study. 
Removed reference to 
‘active phase’ as term 
not used elsewhere in 
protocol. 
14.3 
As required by local regulations, 
the sponsor’s Regulatory Affairs 
group (or its delegates) will ensure 
all legal regulatory aspects are 
covered and obtain approval of the 
appropriate regulatory bodies, prior 
to study initiation in regions where 
an approval is required. 
As required by local regulations, the sponsor’s Regulatory Affairs and 
Clinical Operations groups (or its their delegates) will ensure all legal 
regulatory aspects are covered and obtain approval of the appropriate 
regulatory bodies, prior to study initiation in regions where an approval is 
required. 
Administrative update. 
Appendix 2 
Royal Marsden Hospital Score 
Appendix deleted 
Requested by the 
principal investigator. 
Appendix 9 
New appendix added 
See below. 
Clarification of 
pembrolizumab 
response assessment 


IPSEN GROUP 
D-US-60090-001 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 260/264 
 
 
Appendix 9 DESCRIPTION OF THE iRECIST PROCESS FOR ASSESSMENT OF DISEASE PROGRESSION 
Assessment at Screening and Prior to RECIST 1.1 Progression 
Until radiographic disease progression based on RECIST 1.1, there is no distinct iRECIST assessment. 
Assessment and Decision at RECIST 1.1 Progression 
For patients who show evidence of radiological progressive disease by RECIST v1.1 as determined by the investigator, the investigator will 
decide whether to continue a patient on study treatment until repeat imaging is obtained (using iRECIST for patient management). This decision 
by the investigator should be based on the patient’s overall clinical condition. 
Clinical stability is defined as the following:  
• 
absence of symptoms and signs indicating clinically significant progression of disease 
• 
no decline in ECOG performance status  
• 
no requirements for intensified management, including increased analgesia, radiation, or other palliative care 
Any patient deemed clinically unstable should be discontinued from study treatment at site-assessed first radiologic evidence of progressive 
disease, and is not required to have repeat tumour imaging for confirmation of progressive disease by iRECIST. 
If the investigator decides to continue treatment, the participant may continue to receive study treatment and the tumour assessment should be 
repeated 4 to 8 weeks later to confirm progressive disease by iRECIST, per investigator assessment. Images should continue to be sent in to the 
central imaging vendor for potential retrospective Blinded Independent Central Review. 
Tumour flare may manifest as any factor causing radiographic progression per RECIST v1.1, including: 
• 
Increase in the sum of diameters of target lesion(s) identified at baseline to ≥20% and ≥5 mm from nadir 
- 
Note: the iRECIST publication uses the terminology “sum of measurements”, but “sum of diameters” will be used in this protocol, 
consistent with the original RECIST v1.1 terminology. 
• 
Unequivocal progression of non-target lesion(s) identified at baseline 
• 
Development of new lesion(s) 
iRECIST defines new response categories, including unconfirmed progressive disease (iUPD) and confirmed progressive disease (iCPD). For the 
purposes of iRECIST assessment, the first visit showing progression according to RECIST v1.1 will be assigned a visit (overall) response of 
iUPD, regardless of which factors caused the progression. 
At this visit, target and nontarget lesions identified at baseline by RECIST v1.1 will be assessed as usual. 


IPSEN GROUP 
D-US-60090-001 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 261/264 
 
New lesions will be classified as measurable or nonmeasurable, using the same size thresholds and rules as for baseline lesion assessment in 
RECIST v1.1. From measurable new lesions, up to five lesions total (up to two per organ), may be selected as New Lesions – Target. The sum of 
diameters of these lesions will be calculated, and kept distinct from the sum of diameters for target lesions at baseline. All other new lesions will 
be followed qualitatively as New Lesions – Nontarget. 
Assessment at the Confirmatory Imaging 
On the confirmatory imaging, the patient will be classified as progression confirmed (with an overall response of iCPD), or as showing persistent 
unconfirmed progression (with an overall response of iUPD), or as showing disease stability or response (iSD/iPR/iCR). 
Confirmation of Progression 
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the following occurs: 
• 
Any of the factors that were the basis for the initial iUPD show worsening 
- 
For target lesions, worsening is a further increase in the sum of diameters of ≥5 mm, compared to any prior iUPD timepoint 
- 
For nontarget lesions, worsening is any significant growth in lesions overall, compared to a prior iUPD timepoint; this does not have 
to meet the “unequivocal” standard of RECIST v1.1 
- 
For new lesions, worsening is any of these: 
• 
An increase in the new lesion sum of diameters by ≥5 mm from a prior iUPD timepoint  
• 
Visible growth of new nontarget lesions  
• 
The appearance of additional new lesions 
• 
Any new factor appears that would have triggered PD by RECIST v1.1 
Persistent iUPD 
Progression is considered not confirmed, and the overall response remains iUPD, if: 
• 
None of the progression-confirming factors identified above occurs AND 
• 
The target lesion sum of diameters (initial target lesions) remains above the initial progressive disease threshold (by RECIST v1.1) 
Additional imaging for confirmation should be scheduled 4 to 8 weeks from the imaging on which iUPD is seen. This may correspond to the next 
visit in the original visit schedule. The assessment of the subsequent confirmation imaging proceeds in an identical manner, with possible 
outcomes of iCPD, iUPD, and iSD/iPR/iCR. 
Resolution of iUPD 
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if: 


IPSEN GROUP 
D-US-60090-001 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 262/264 
 
• 
None of the progression-confirming factors identified above occurs, AND 
• 
The target lesion sum of diameters (initial target lesions) is not above the initial progressive disease threshold.  
The response is classified as iSD or iPR (depending on the sum of diameters of the target lesions), or iCR if all lesions resolve. 
In this case, the initial iUPD is considered to be pseudoprogression, and the level of suspicion for progression is “reset”. This means that the next 
visit that shows radiographic progression, whenever it occurs, is again classified as iUPD by iRECIST, and the confirmation process is repeated 
before a response of iCPD can be assigned. 
Management Following the Confirmatory Imaging 
If repeat imaging does not confirm progressive disease per iRECIST, as assessed by the investigator, and the patient continues to be clinically 
stable, study treatment may continue and follow the regular imaging schedule. If PD is confirmed, patients will be discontinued from study 
treatment. 
NOTE: If a patient has confirmed radiographic progression (iCPD) as defined above, but the participant is achieving a clinically meaningful 
benefit, an exception to continue study treatment may be considered following consultation with the sponsor. In this case, if study treatment is 
continued, tumour imaging should continue to be performed following the intervals previously outlined and submitted to the central imaging 
vendor. 
Detection of Progression at Visits After Pseudoprogression Resolves 
After resolution of pseudoprogression (i.e. achievement of iSD/iPR/iCR), iUPD is indicated by any of the following events: 
• 
Target lesions 
- 
Sum of diameters reaches the progressive disease threshold (≥20% and ≥5 mm increase from nadir) either for the first time, or after 
resolution of previous pseudoprogression. The nadir is always the smallest sum of diameters seen during the entire study, either 
before or after an instance of pseudoprogression. 
• 
Nontarget lesions 
- 
If nontarget lesions have never shown unequivocal progression, their doing so for the first-time results in iUPD. 
- 
If nontarget lesions have shown previous unequivocal progression, and this progression has not resolved, iUPD results from any 
significant further growth of nontarget lesions, taken as a whole. 
• 
New lesions 
- 
New lesions appear for the first time 
- 
Additional new lesions appear 


IPSEN GROUP 
D-US-60090-001 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 263/264 
 
- 
Previously identified new target lesions show an increase of ≥5 mm in the new lesion sum of diameters, from the nadir value of that 
sum 
- 
Previously identified nontarget lesions show any significant growth 
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD evaluation process (see Assessment at the 
Confirmatory Imaging above) is repeated. Progression must be confirmed before iCPD can occur. 
The decision process is identical to the iUPD confirmation process for the initial PD, with one exception: if new lesions occurred at a prior 
instance of iUPD, and at the confirmatory imaging the burden of new lesions has increased from its smallest value (for new target lesions, the 
sum of diameters is ≥5 mm increased from its nadir), then iUPD cannot resolve to iSD or iPR. It will remain iUPD until either a decrease in the 
new lesion burden allows resolution to iSD or iPR, or until a confirmatory factor causes iCPD. 
Additional details about iRECIST are provided in the iRECIST publication. 
 


IPSEN GROUP 
D-US-60090-001 
CONFIDENTIAL 
PROTOCOL: FINAL VERSION: 10 DECEMBER 2019 
PAGE 264/264 
 
SUMMARY & OUTCOME OF CHANGES: 
STUDY NUMBER 
D-US-60090-001 
AMENDED PROTOCOL VERSION NUMBER & DATE 
Amendment 2.0, Version 3.0, 10 December 2019 
 
SUBSTANTIAL  
 
NON-SUBSTANTIAL  
 
 
REASON(S) FOR CHANGES 
 
Additional baseline safety evaluation added. Pembrolizumab standard text for 
administration, AE assessment and response assessment added per Merck 
requirements. Clarifications and specifications regarding SAE and pregnancy 
reporting requirements and timelines added. 
OTHER ACTION REQUIRED? 
CRF UPDATE  
 
Yes 
 
  
No 
 
 
 
(tick one) 
 
LOCAL CONSENT FORM UPDATE  
Yes 
 
  
No 
 
 
 
(tick one) 
 
DATABASE UPDATE  
Yes 
 
  
No 
 
 
 
(tick one) 
 
STATISTICAL ANALYSIS PLAN (SAP) 
UPDATE 
Yes 
 
  
No 
 
 
 
(tick one) 
 

SAP_001.pdf: 
'RFXPHQW1DPHGXVVWDWLVWLFDODQDO\VLVSODQ'HF
$SSURYHG
&OLQLFDO
*07
&OLQLFDO
*07
PPD
PPD


 
 
 
 
STATISTICAL ANALYSIS PLAN 
Protocol Title: 
PHASE I OPEN LABEL, DOSE ESCALATION AND DOSE 
EXPANSION STUDY TO INVESTIGATE THE SAFETY, 
PHARMACOKINETICS, PHARMACODYNAMICS AND 
ANTI-TUMOUR ACTIVITY OF IPN60090 AS SINGLE 
AGENT AND IN COMBINATION IN PATIENTS WITH 
ADVANCED SOLID TUMOURS 
Protocol Number: 
D-US-60090-001 
Protocol Version/Date: 
Version 1.0/18 October 2018 
Version 1.1/20 December 2018 
Version 1.2/21 December 2018 
Version 2.0/24 May 2019 
Version 3.0/10 December 2019 
Investigational Product: 
IPN60090 
 
 
Sponsor: 
IPSEN Bioscience, Ipsen Group 
650 East Kendall Street, 
Cambridge MA 02142, USA 
Tel: 
 
 
 
SAP Version/Date: 
Version 2.0/17 December 2020 
 
CONFIDENTIAL 
Persons supplied with this information must understand that it is strictly confidential. Information contained 
herein cannot be disclosed, submitted for publication or used for any purpose other than that contemplated 
herein without the sponsor’s prior written authorisation. 
 
 
PPD


PPD
PPD
PPD
PPD
PPD
PPD


IPSEN GROUP 
CONFIDENTIAL 
Statistical Analysis Plan 
D-US-60090-001 
 
Version 2.0, 17 December 2020 
Page 3 of 48 
 
VERSION HISTORY 
Version 
Version Date 
Description 
1.0 
26 July 2019 
Original signed version 
2.0 
17 December 2020 
• 
Updates to be consistent with protocol 
version 3.0 from protocol version 2.0. 
• 
Section 3.3.7 add actual cumulative 
dose in mg for IPN60090 descriptive 
summary 
• 
Section 2.3.2.1 PFS includes clinical 
disease progression collected at end of 
treatment 
• 
Section 3.3.2 add COVID-19 analysis 
impact language. 
 
 


IPSEN GROUP 
CONFIDENTIAL 
Statistical Analysis Plan 
D-US-60090-001
Version 2.0, 17 December 2020 
Page 4 of 48 
TABLE OF CONTENTS 
1 
Introduction ........................................................................................................................................... 8 
2 
Study Overview .................................................................................................................................... 8 
2.1 
Study Objectives ........................................................................................................................... 8 
2.1.1 
Primary Objective ................................................................................................................. 8 
2.1.2 
Secondary Objectives ............................................................................................................ 8 
2.1.3 
Exploratory Objectives ......................................................................................................... 8 
2.2 
Study Design ................................................................................................................................. 9 
2.2.1 
Overview ............................................................................................................................... 9 
2.2.2 
Number of Patients.............................................................................................................. 11 
2.2.3 
Dose Escalations ................................................................................................................. 11 
2.2.4 
3.1.3 Food Effect Assessment – Part D ............................................................................... 20 
2.2.5 
Dose Expansion Cohorts ..................................................................................................... 21 
2.2.6 
Study Drug .......................................................................................................................... 22 
2.2.7 
Sample Size Determination ................................................................................................. 22 
2.3 
Study Endpoints .......................................................................................................................... 26 
2.3.1 
Primary Endpoints............................................................................................................... 26 
2.3.2 
Secondary Endpoints........................................................................................................... 26 
2.3.3 
Exploratory Endpoints ........................................................................................................ 29 
2.3.4 
Biobanking .......................................................................................................................... 29 
3 
Statistical Methodology ...................................................................................................................... 29 
3.1 
General Considerations ............................................................................................................... 29 
3.1.1 
Analysis Day Conventions .................................................................................................. 29 
3.1.2 
Analysis Visits .................................................................................................................... 29 
3.1.3 
Definition of Baseline ......................................................................................................... 29 
3.1.4 
Summary Statistics .............................................................................................................. 30 
3.1.5 
Hypothesis Testing .............................................................................................................. 30 
3.1.6 
Evaluation of Site Effect ..................................................................................................... 30 
3.1.7 
Handling of Missing Data ................................................................................................... 30 
3.2 
Analysis Populations ................................................................................................................... 31 
3.2.1 
Screened Population ............................................................................................................ 31 
3.2.2 
Safety Population ................................................................................................................ 31 
3.2.3 
DLT Evaluable Population for Dose-escalation Phase Only .............................................. 31 
3.2.4 
Efficacy Population ............................................................................................................. 31 
3.2.5 
Pharmacokinetic Population for Noncompartmental Analysis ........................................... 31 
3.2.6 
Pharmacokinetic population for population PK modelling ................................................. 31 
3.2.7 
Food Effect Population ....................................................................................................... 31 
3.2.8 
Pharmacodynamic Population ............................................................................................. 31 
3.3 
Patient Data and Study Conduct ................................................................................................. 31 
3.3.1 
Patient Disposition .............................................................................................................. 31 
3.3.2 
Protocol Deviations ............................................................................................................. 32 


IPSEN GROUP 
CONFIDENTIAL 
Statistical Analysis Plan 
D-US-60090-001 
 
Version 2.0, 17 December 2020 
Page 5 of 48 
 
3.3.3 
Analysis Populations ........................................................................................................... 32 
3.3.4 
Demographic and Baseline Characteristics ......................................................................... 32 
3.3.5 
Medical or Surgical History ................................................................................................ 33 
3.3.6 
Concomitant Medications ................................................................................................... 33 
3.3.7 
Study Drug Exposure and Compliance ............................................................................... 34 
3.4 
Efficacy Assessment ................................................................................................................... 34 
3.4.1 
Anti-tumour Activity Evaluation ........................................................................................ 34 
3.5 
Pharmacodynamic parameters .................................................................................................... 34 
3.5.1 
Target Engagement ............................................................................................................. 34 
3.5.2 
Biomarkers of Patient Stratification .................................................................................... 35 
3.6 
Pharmacokinetic Assessment and PK/PD Assessment ............................................................... 35 
3.6.1 
PK Assessment Using NCA ................................................................................................ 35 
3.6.2 
PK Modeling ....................................................................................................................... 35 
3.6.3 
PK/PD Modeling ................................................................................................................. 35 
3.6.4 
Dose Response Analysis ..................................................................................................... 35 
3.7 
Safety Assessment ...................................................................................................................... 35 
3.7.1 
Adverse Events (AEs) ......................................................................................................... 36 
3.7.2 
Dose Limiting Toxicity ....................................................................................................... 37 
3.7.3 
Clinical Laboratory Tests .................................................................................................... 37 
3.7.4 
Vital Signs ........................................................................................................................... 38 
3.7.5 
Electrocardiograms ............................................................................................................. 38 
3.7.6 
Physical Examinations ........................................................................................................ 39 
3.7.7 
Local Tolerance at Infusion site .......................................................................................... 39 
3.7.8 
ECOG Performance Status .................................................................................................. 39 
3.7.9 
Echocardiogram .................................................................................................................. 39 
3.7.10 
Antidrug Antibodies for Pembrolizumab (Part B only) ...................................................... 39 
3.8 
Exploratory Assessments ............................................................................................................ 40 
3.9 
Biobanking .................................................................................................................................. 40 
3.10 
Subgroups ................................................................................................................................... 40 
4 
Data Safety Monitoring Board ............................................................................................................ 40 
4.1 
Safety Review Committee .......................................................................................................... 40 
4.2 
Independent Safety Assessment Committee ............................................................................... 40 
5 
Interim Analysis .................................................................................................................................. 41 
6 
Changes from Protocol-Specified Statistical Analyses ....................................................................... 41 
7 
Programming Specifications ............................................................................................................... 42 
Appendix A:  References ............................................................................................................................ 43 
Appendix B: Assessment of Disease Response using RECIST, Version 1.1 ............................................. 44 
Appendix C: Assessment of Disease Response using iRECIST ................................................................. 46 


IPSEN GROUP 
CONFIDENTIAL 
Statistical Analysis Plan 
D-US-60090-001 
 
Version 2.0, 17 December 2020 
Page 6 of 48 
 
 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ADA 
Antidrug antibodies 
AE 
Adverse event 
ALK 
Anaplastic Lymphoma Kinase 
ANC 
Absolute Neutrophil Count 
ASNS 
Asparagine synthetase 
ASNSlow 
Low protein expression level of asparagine synthetase 
AST 
Aspartate aminotransferase 
ATC 
Anatomical therapeutic class 
AUC 
Area under the plasma concentration time curve 
AUC0-last 
Area under the plasma concentration time curve from time 0 to the 
last time point with quantifiable concentrations 
BID 
Bis in die (twice daily) 
BOIN 
Bayesian Optimal Interval 
BOR 
Best overall response 
CBR 
Clinical benefit rate 
CD8 
Cluster of differentiation 8 
cfDNA 
Circulating free deoxyribonucleic acid 
CI 
Confidence interval 
CL/F 
Apparent total clearance from plasma 
Cmax 
Maximum observed plasma drug concentration 
Cmin 
Minimum observed plasma concentration 
CPI 
Checkpoint inhibitor 
CR 
Complete response 
CSR 
Clinical Study Report 
Ctrough 
Trough plasma concentration 
DAP 
Data Analysis Plan  
DCR 
Disease control rate 
DL 
Dose level 
DLT 
Dose limiting toxicity 
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EGFR 
Epidermal growth factor receptor 
Glu:Gln 
glutamate:glutamine ratio 
GLS1 
Glutaminase-1 
HCC 
Hepatocellular carcinoma 
HGSOC 
High-grade serous ovarian cancer 
HGSCC 
Head and neck squamous cell carcinoma 
iCR 
immune complete response 
iCPD 
immune confirmed progressive disease 
iPFS 
immune progression-free survival 
iPR 
immune partial response 


IPSEN GROUP 
CONFIDENTIAL 
Statistical Analysis Plan 
D-US-60090-001 
 
Version 2.0, 17 December 2020 
Page 7 of 48 
 
Abbreviation 
Definition 
iRECIST 
immune-related Response Evaluation Criteria in Solid Tumours 
ISAC 
Independent safety assessment committee 
iSD 
immune stable disease 
iUPD 
Immune unconfirmed progressive disease 
i.v. 
intravenous 
KEAP1 
Kelch-like ECH-associated protein 1 
KRAS 
Kirsten Rat Sarcoma Viral Oncogene Homolog 
LEVF 
Left Ventricle Ejection Fraction 
LKB1 
Liver kinase B1 
MedDRA 
Medical Dictionary for Regulatory Activities 
MTD 
Maximum tolerated dose 
MUGA 
Multigated acquisition 
NCI-CTCAE 
National Cancer Institute – Common Terminology Criteria for 
Adverse Events 
NSCLC 
Non-small cell lung cancer 
ORR 
Objective response rata 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cells 
PD 
Pharmacodynamics 
PD-1 
Programmed cell death protein 1 
PFS 
Progression free survival 
PK 
Pharmacokinetics 
Q3W 
Every 3 weeks 
PR 
Partial response 
RD 
Recommended dose 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Stable disease 
SRC 
Safety review committee 
STK11 
Serine/threonine kinase 11 
T1/2 
Elimination half life 
TEAE 
Treatment-emergent adverse event 
Tmax 
time to maximum observed drug concentration 
Treg 
regulatory T-cells 
V/F 
Apparent volume of distribution 
WHO 
World Health Organization 
 
 
 


IPSEN GROUP 
CONFIDENTIAL 
Statistical Analysis Plan 
D-US-60090-001 
 
Version 2.0, 17 December 2020 
Page 8 of 48 
 
1 INTRODUCTION 
The purpose of this Statistical Analysis Plan (SAP) is to provide a description of the statistical methods to 
be implemented for the analysis of data from the study with protocol number D-US-60090-001.  The 
initial version of SAP was finalized prior to  the end of Part A.  Any deviations from the SAP will be 
documented in SAP amendments before database lock and in the final Clinical Study Report (CSR) after 
database lock. 
2 STUDY OVERVIEW 
2.1 Study Objectives 
This study will evaluate the safety, the pharmacokinetics (PK), pharmacodynamics (PD) and anti-tumour 
activity of IPN60090 as a single agent (Part A) and in combination with pembrolizumab (Part B) or 
paclitaxel (Part C) in patients with advanced solid tumours. Part D will evaluate the safety of IPN60090 
as a single agent and explore the effect of food on IPN60090 PK profile. 
Specific objectives and corresponding endpoints for the study are outlined below. 
2.1.1 Primary Objective 
• 
To assess the safety and tolerability of oral IPN60090 as a single agent (Part A and Part D) and in 
combination therapy with pembrolizumab (Part B) or paclitaxel (Part C). 
For Dose Escalation Only: 
• 
To determine the maximum tolerated dose (MTD) if reached, the recommended dose (RD) of 
IPN60090 as a single agent (Part A) and in combination therapy with pembrolizumab (Part B) or 
paclitaxel (Part C). 
2.1.2 Secondary Objectives 
• 
To assess the preliminary anti-tumour activity of IPN60090 as a single agent (Part A and Part D) 
and in combination with pembrolizumab (Part B) or paclitaxel (Part C) in patients with or without 
biomarker selected specific tumour types. 
• 
To characterise the PK and PD profile of IPN60090 as a single agent (Part A and Part D) and in 
combination with pembrolizumab (Part B) or paclitaxel (Part C). 
• 
To assess the effect of food on the PK profile of a single administration of IPN60090 (Part D). 
• 
To document the concentrations of pembrolizumab and paclitaxel (Parts B and C). 
• 
To document the potential development of antibodies against pembrolizumab (Part B). 
• 
To evaluate biomarkers of patient stratification and correlate them with clinical outcome.  
2.1.3 Exploratory Objectives 
• 
To analyse exploratory biomarkers in archival and fresh biopsy samples, including biomarkers of 
response or resistance to the treatment and associate them with clinical outcome. 
• 
To collect biobank samples for potential future analysis of biomarkers (optional informed consent 
required). 


IPSEN GROUP 
CONFIDENTIAL 
Statistical Analysis Plan 
D-US-60090-001 
 
Version 2.0, 17 December 2020 
Page 9 of 48 
 
2.2 Study Design 
2.2.1 Overview 
This is a phase I first in human, open-label, dose-escalation and expansion study of IPN60090 as a single 
agent and in combination in patients with advanced solid tumours.  
As summarized in Figure 1, the study will be divided into three parts. 
Figure 1 IPN60090: Summary of Early Clinical Development 
 
PART D 
ASNS=asparagine synthetase; BOIN=Bayesian Optimal Interval; CPI=checkpoint inhibitor; HGSOC=high-grade serous ovarian 
cancer; KEAP1=Kelch-like ECH-associated protein 1; NRF2=nuclear factor erythroid 2–related factor 2; NSCLC=non-small-cell 
lung cancer; Ph.=pharmacologically; RD=recommended dose. 
Part A: The dose escalation will explore the safety profile and establish the MTD (if reached), the target 
engagement or PD levels (glutamate:glutamine (Glu:Gln) ratio in PBMC (peripheral blood mononuclear 
cells)) and the RD of single agent IPN60090 in biomarker unselected patient populations. During the dose 
expansion portion, safety and tolerability at the RD will be assessed further, and the preliminary anti-
tumour activity of IPN60090 will be explored in three different cohorts (NSCLC KEAP1 or NRF2 
mutant, other KEAP1 or NRF2 mutant tumours and HGSOC ASNSlow). The scientific rationale for 
conducting these cohorts is described below: 


IPSEN GROUP 
CONFIDENTIAL 
Statistical Analysis Plan 
D-US-60090-001 
 
Version 2.0, 17 December 2020 
Page 10 of 48 
 
Dose Expansion Cohort 1: NSCLC KEAP1 or NRF2 Mutant: Due to the inherent heterogeneity of 
NSCLC and despite recent advances in targeted and combination treatment approaches, management of 
advanced NSCLC in the absence of targetable mutation, such as epidermal growth factor receptor 
(EGFR), anaplastic lymphoma kinase (ALK), or BRAF, represents an unmet medical need as these 
patients inevitably relapse post each subsequent line of chemotherapy and have limited response to CPI 
blockade. KEAP1 and NRF2 mutations may represent novel markers of GLS1 inhibition. These 
mutations are present in about 20% of NSCLC, and often co-occur with KRAS mutations, for which no 
available targeted treatment option exists. 
Dose Expansion Cohort 2: Other KEAP1 or NRF2 Mutant Tumours: KEAP1 and NRF2 mutations 
are present in about 6% of HNSCC, 5% HCC, and 3% to 5% of urothelial carcinomas respectively, and 
convey tumour dependence on glutaminase and sensitivity to GLS1 inhibition, which warrants further 
exploration as there may be a potential to induce sensitivity to conventional therapy by including a 
tumour metabolism altering agent in the treatment paradigm. 
Dose Expansion Cohort 3: HGSOC ASNSlow: Treatment of advanced recurrent HGSOC represents a 
highly unmet medical need, especially in platinum resistant/refractory setting. By the time patients are 
determined to be platinum resistant or refractory, treatment options available to them become extremely 
limited. Targeting a specific subset of patients with low ASNS expression and sensitive to GLS1 
inhibition will explore therapeutic potential of IPN60090 in this highly unmet medical need population. 
Part B: The dose escalation will explore the safety profile and establish the MTD (if reached) and the RD 
of IPN60090 in combination with pembrolizumab. During the dose expansion portion, safety and 
tolerability at the RD will be assessed further, and preliminary anti-tumour activity of this combination 
will be explored. 
In general, response to CPI blockade monotherapy is limited, however those responses are durable. There 
is a need to explore treatment strategies that will increase response or overcome resistance to PD-1 
inhibition. 
Dose Expansion Cohort 4: KEAP1 or NRF2 Mutant NSCLC: Preclinical data indicates that adding a 
GLS1 inhibitor to anti-PD-1 therapy has potential to boost response via increase of CD8/Treg ratio. Dose 
expansion Cohort 4 will focus on KEAP1/NRF2 mutant NSCLC. Within that patient population, patients 
with co-occurring KRAS/KEAP1/LKB1 mutations are of particular interest, as presence of this cluster 
mutation may convey resistance to CPI therapy. 
Dose Expansion Cohort 5: Other KEAP1 or NRF2 Mutant Tumours: A similar approach is applied 
in Cohort 5 in additional biomarker positive KEAP1/NRF2 mutant tumour types for which 
pembrolizumab is approved as SoC, to explore if addition of IPN60090 would prevent or reverse 
resistance to CPI. 
Dose Expansion Cohort 6: KEAP1 or NRF2 Wild-type Tumours with Any Level of ASNS 
Expression: In addition, the combination of IPN60090 and pembrolizumab will be explored in 
KEAP1/NRF2 wild-type tumours, as there's early clinical data from CB-839 that indicate preliminary 
anti-tumour activity of the combination in biomarker-unselected patient population. 
Part C: The dose escalation will explore the safety profile and establish the MTD (if reached) and the RD 
of IPN60090 in combination with paclitaxel. During the dose expansion portion, safety and tolerability at 
the RD will be assessed further, and preliminary anti-tumour activity of this combination will be 
explored. 


IPSEN GROUP 
CONFIDENTIAL 
Statistical Analysis Plan 
D-US-60090-001 
 
Version 2.0, 17 December 2020 
Page 11 of 48 
 
Dose Expansion Cohort 7: KEAP1 or NRF2 Mutant Tumours and Dose Expansion Cohort 8: 
ASNSlow HGSOC: Preclinical data for the combination of IPN60090 and paclitaxel provides rationale for 
synergistic activity of the combination in HGSOC and NSCLC models. Given the high unmet medical 
need in treatment of these tumour types, dose expansion Cohorts 7 and 8 will look into this combination 
in KEAP1/NRF2 mutant tumours and ASNSlow HGSOC, respectively, to explore if adding a glutaminase 
inhibitor may enhance response to treatment. 
Dose Expansion Cohort 9: KEAP1 or NRF2 Wild-type Tumours with Any Level of ASNS 
Expression: In addition, Cohort 9 will explore the combination of IPN60090 and paclitaxel in biomarker-
unselected patient population across approved tumour types, based on early clinical data from CB-839 
which indicate potential synergy of IPN60090 and paclitaxel. 
Parts B and C: These dose escalations in combination with pembrolizumab or paclitaxel will be initiated 
at the first dose with pharmacological activity (at least 50% inhibition of Glu:Gln ratio in PBMCs at 
Ctrough (12 hours postdose) on Day 14 in 66% of patients treated at this dose level) and with good 
tolerability as identified in Part A. The threshold of 50% inhibition of the PD marker has been selected 
since in a mouse model of NSCLC (H2122), maximum tumour growth inhibition (at 50 and 100 mg/kg 
BID) was observed when at least 50% up to 96% inhibition of PD marker in PBMC was maintained over 
a dosing interval (i.e. 12 hours). 
Part D: This cohort will evaluate the safety of IPN60090 administered as a single agent and explore the 
effect of a moderate fat meal on the PK profile of IPN60090 administered as a single dose under fasting 
and fed conditions at the RD as defined by the SRC. 
2.2.2 Number of Patients 
Number of Patients Planned 
Dose Escalation  
Part A (single agent): Approximately 30 patients for the dose escalation. 
Part B (combination with pembrolizumab): Approximately 18 patients for the dose escalation. 
Part C (combination with paclitaxel): Approximately 18 patients for the dose escalation. 
Food Effect Assessment 
Part D: Eight patients for preliminary food effect assessment. 
Dose Expansion 
Parts A, B and C: Approximately 162 patients (90 patients in stage one of dose expansion and 72 patients 
in stage two). Section 2.2.7.3 explains the details of 2-stage design for expansion phase. 
2.2.3 Dose Escalations 
2.2.3.1 
Part A – Dose Escalation with IPN60090 as a Single Agent 
The dose escalation portion of Part A is to evaluate the safety, tolerability, PK and PD of IPN60090 given 
as a BID oral dose (every 12 hours), during or after a meal, over a 21-day cycle. 
Dose escalation of IPN60090 will be conducted in patients with biomarker-positive and biomarker-
negative advanced solid tumours. 
These patients will not be selected for KEAP1/NRF2 mutation status (wild-type or mutated). Patients may 
have tumours with any level of ASNS expression. 


IPSEN GROUP 
CONFIDENTIAL 
Statistical Analysis Plan 
D-US-60090-001 
 
Version 2.0, 17 December 2020 
Page 12 of 48 
 
Seven dose levels are planned to be tested (as presented in Figure 2). The study will follow a BOIN 
design for dose escalation and de-escalation (Liu S and Yuan Y, 2015). Dose levels provided are 
examples and after the starting dose, the dose level to be tested will be determined by the SRC. After each 
SRC meeting, the tested dose level can be escalated, de-escalated or extended as indicated per BOIN. 
Figure 2 Part A-IPN60090 Monotherapy - Predefined Escalation and De-escalation Scheme 
 
BOIN=Bayesian Optimal Interval; DL=dose level; MTD=maximum tolerated dose; SRC=safety review committee. 
Dose levels are examples; after the starting dose, dose level will be determined by each SRC meeting. After each SRC meeting, 
dose level can be escalated,de-escalated, expanded or eliminated as permitted by the BOIN design.  
At all dose levels, IPN60090 will be administered orally BID starting from Day 1 of each 21-day cycle. 
The predefined dose-escalation plan is described in Table 1. 
Table 1 Dose Escalation Phase I-Part A in Monotherapy 
DL1 
DL2 
DL3 
DL4 
DL5 
DL6 
DL7 
20 mg BID 
40 mg BID 
80 mg BID 
180 mg BID[a] 
320 mg BID 
480 mg BID 
720 mg BID 
BID=bis in die (twice daily); DL=dose level. 
a 180 mg BID was selected instead of 160 mg BID to reduce the number of capsules and therefore reduce the burden for patients. 
The dose of 160 mg BID would correspond to six capsules BID (2×60 mg+4×10 mg) whereas the dose of 180 mg corresponds to 
three capsules BID (3×60 mg). 
Part A monotherapy dose-escalation will enroll single-patient cohorts for the first three dose levels (if no 
Grade 2 adverse event (AE) that is at least possibly related to the study drug(s) or DLT is observed) and 
then cohorts of three patients each at the predefined dose levels. If any Grade 2 AE that is at least possibly 
related to the study drug(s) or a DLT is observed in a single patient cohort (first three dose levels), two 
additional patients will be added at this dose level with the same rules for escalation and de-escalation as 
the cohorts of three patients. Following each cohort DLT assessment period, the observed DLT data will 
be used to determine the dose level for the next cohort in accordance with the escalation and de-escalation 
rules for a local BOIN design using target toxicity rate of 30% with escalation and de-escalation 
thresholds of 23.6% and 35.9%, respectively. Following the completion of enrolment, the MTD will be 
estimated at the dose level at which the isotonic estimate of the DLT rate is closest to 30%. The decision 


IPSEN GROUP 
CONFIDENTIAL 
Statistical Analysis Plan 
D-US-60090-001 
 
Version 2.0, 17 December 2020 
Page 13 of 48 
 
rules for dose-escalation and de-escalation from a local BOIN design are defined in Table 4 in section 
2.2.7.1. At any point, additional patients may be enrolled for required safety and/or biomarker analysis.  
MTD Definition 
The MTD is defined as the maximum dose of IPN60090 that may be administered BID for 21 days, so 
that no more than 30% of patients experience a DLT. The MTD will be determined by the dose for which 
the isotonic estimate of DLT rate is closest to 30% of patients experiencing a DLT. 
DLT Assessment Period 
The DLT assessment period will consist of the first 21 days of treatment (one cycle). The Safety Review 
Committee (SRC) will evaluate safety, and available PK and PD data after patients have completed at 
least one cycle of treatment in order to make a decision on dose-escalation, and to determine the MTD 
and the RD. The SRC may decide to evaluate an intermediate, not predefined, previously evaluated or not 
previously-evaluated dose or a less frequent dosing schedule that will not exceed the MTD level, if 
evaluation of toxicity at such a dose or schedule is desired. 
DLT Criteria 
The DLTs for Part A are defined for any of the following investigational medicinal product (IMP)- 
related, probably related or possibly related AEs according to National Cancer Institute – Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 that occur during the defined DLT 
assessment period (over the 21 days following the first dose of IPN60090): 
• 
Grade 4 neutropenia lasting >7 days 
• 
Febrile neutropenia of any grade (absolute neutrophil count (ANC) <1000/mm3 with a single 
temperature episode of 38.3°C or a sustained temperature of 38°C for >1 hour).  
• 
Grade 3 or 4 neutropenia with infection.  
• 
Grade 3 thrombocytopenia with bleeding and Grade 4 thrombocytopenia.  
• 
Grade 4 life threatening anaemia.  
• 
ALT/AST ≥3×ULN with total bilirubin ≥2×ULN without elevation of alkaline phosphatase 
(ALP) and no other reasonable explanation for the abnormality (Hy’s law criteria). 
• 
Grade 3 lasting more than 7 days or Grade 4 laboratory abnormalities of aspartate amino 
transferase/alanine amino transferase (ALT/AST) and/or bilirubin, with the following exceptions: 
− 
for patients with Grade 1 ALT/AST at baseline (>upper limit of normal (ULN) to 
3×ULN), an ALT/AST value of >7.5×ULN will be considered a DLT.  
− 
for patients with Grade 2 ALT/AST at baseline (>3×ULN to 5×ULN), an ALT/AST 
value >10×ULN will be considered a DLT. 
• 
Grade 3 or higher nonhaematological toxicity excluding: 
− 
Grade 3 nausea, vomiting or diarrhoea for less than 72 hours with adequate supportive 
care. 
− 
Grade 3 fatigue lasting less than a week. 


IPSEN GROUP 
CONFIDENTIAL 
Statistical Analysis Plan 
D-US-60090-001 
 
Version 2.0, 17 December 2020 
Page 14 of 48 
 
− 
Grade 3 or higher electrolyte abnormality that lasts for less than 72 hours that is not 
clinically complicated and resolves spontaneously or with conventional medical 
interventions. 
− 
Grade 3 or higher amylase or lipase lasting less than 72 hours and not associated with 
clinical manifestations of pancreatitis. 
• 
Grade 5 (death). 
Other clinically significant or persistent toxicities may be considered a DLT following review by the 
SRC. 
Patient Eligibility for Dose Escalation Decision 
Any patient who does not complete the DLT assessment period for any reason other than a DLT will be 
considered non-evaluable for dose-escalation decisions and MTD assessment and will be replaced by an 
additional patient at that same dose level. Patients will be considered eligible for the DLT assessment 
only if they are able to receive ≥75% of the total planned IPN60090 dose over the DLT assessment 
period. Patients who received less than 75% of total planned dose due to DLT will be included for dose-
escalation decisions. Noncompliant (<75% without DLT) patients will also be replaced. 
The SRC may decide to enrol additional patients based on the safety, PK or PD data. 
Treatment Duration - Additional Cycles 
Patients will be offered IPN60090 treatment beyond Cycle 1 as long as they continue to experience 
clinical benefit in the opinion of the investigator until the earlier of disease progression, symptomatic 
deterioration, poor tolerability despite appropriate medical management or any of the other reasons for 
treatment discontinuation. Patients who experience a DLT (or other toxicities considered related, probably 
related or possibly related to the study treatment) will be permitted to continue to receive study treatment 
at a lower dose level than the dose at which the DLT was observed, at the discretion of the investigator 
and will be followed for safety. Biomarker-positive patients who are enrolled and receive study treatment 
at initial dose levels below the pharmacologically active range for at least two cycles with good 
tolerability and achieve and maintain at least stable disease (SD), may be escalated to a higher dose level 
that has been tested and proven to be well tolerated at the recommendation of the SRC. These patients 
will be treated outside of the BOIN design. Patients who discontinue study treatment for reasons other 
than disease progression (for example toxicity) should continue to undergo scheduled tumour assessments 
approximately every 12 weeks until disease progression, initiation of further systemic cancer therapy, 
death, or until the study closes, whichever occurs first. 
2.2.3.2 
Part B – Pembrolizumab Combination Dose Escalation 
The dose escalation portion of Part B is to evaluate the safety, tolerability, PK and PD of IPN60090 given 
as a BID oral dose (every 12 hours) during or after a meal in combination with pembrolizumab, over a 
21-day cycle. The intake of IPN60090 will be made before the start of the pembrolizumab infusion. 
Dose escalation of IPN60090 in combination with pembrolizumab will be conducted in patients with 
biomarker-positive and biomarker-negative advanced solid tumours. 
These patients will be unselected for KEAP1/NRF2 mutation status and may be KEAP1/NRF2 wild-type 
or mutated. The same applies for ASNS expression levels; patients may have tumours with any level of 
ASNS expression. Previous treatment with CPI therapy is allowed. 


IPSEN GROUP 
CONFIDENTIAL 
Statistical Analysis Plan 
D-US-60090-001 
 
Version 2.0, 17 December 2020 
Page 15 of 48 
 
This dose escalation in combination with pembrolizumab will be initiated at a dose level showing 
pharmacological activity (at least 50% inhibition of Glu:Gln ratio in PBMCs at Ctrough (12 hours postdose 
and predose for the following dose) on Day 14 of Cycle 1 in 66% of patients treated at this dose level) 
and with good tolerability as identified in Part A. The IPN60090 dose being tested in the dose escalation 
of Part B will always remain lower than that being tested in the dose escalation of Part A (at least one 
dose level lower than the highest dose tested in Part A). 
Three dose levels of IPN60090 are planned to be tested with an additional lower dose level (DL-1) if DL1 
is not tolerated. The study will follow a BOIN design for dose escalation.  
At all dose levels, IPN60090 will be administered orally BID starting from Day 1 of each 21-day cycle 
and pembrolizumab will be administered as one intravenous (i.v.) infusion every 21 days starting from 
Day 1 of each cycle. The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W). 
Based on the totality of data generated in the Keytruda development program, 200 mg Q3W is the 
appropriate dose of pembrolizumab for adults across all indications and regardless of tumour type. The 
predefined dose-escalation plan is described in Table 2. 
Table 2 Dose Escalation Phase I-Part B in Combination with Pembrolizumab 
Dose level 
Dose level -1 
Dose level 1 
Dose level 2 
Dose level 3 
Planned dose of 
IPN60090 [a] 
80 mg BID 
180 mg BID 
320 mg BID 
480 mg BID 
Planned dose of 
pembrolizumab 
200 mg Q3W [b] 
200 mg Q3W [b] 
200 mg Q3W [b] 
200 mg Q3W [b] 
BID=bis in die (twice daily); Q3W=every 3 weeks (21 days). 
[a] dose levels are examples; the actual starting dose will be determined by PD from the Part A dose escalation  
[b] or according to the local approved label for particular tumour types 
Dose finding will begin at DL1. The study will enroll in cohorts of three patients at the predefined dose 
levels until up to six cohorts have been enrolled. Following each cohort, the observed DLT data will be 
used to determine the dose level for the next cohort in accordance with the escalation and de-escalation 
rules for a local BOIN design using target toxicity rate of 30% with escalation and de-escalation 
thresholds of 23.6% and 35.9%, respectively. The decision rules for dose-escalation and de-escalation 
from a local BOIN design is defined in Table 4 in section 2.2.7.1. 
Following the completion of enrolment, the MTD will be estimated as the dose level at which the isotonic 
estimate of the DLT rate is closest to 30%. 
If the first dose level of IPN60090 in combination with 200 mg pembrolizumab is not well tolerated, upon 
the decision of the SRC, the dose of IPN60090 may be de-escalated and thus a new cohort may start with 
DL-1. 
MTD Definition 
The MTD is defined as the maximum dose of IPN60090 that may be administered BID for 21 days in 
combination with an i.v. infusion of 200 mg pembrolizumab (or according to the local approved label for 
particular tumour types), so that no more than 30% of patients experience a DLT. The MTD will be 
determined by the dose for which the isotonic estimate of DLT rate is closest to 30% of patients 
experiencing a DLT. 
DLT Assessment Period 
The DLT assessment period for IPN60090 in combination with pembrolizumab (Part B) will consist of 
the first 21 days of treatment (one cycle). An additional safety assessment for 


IPSEN GROUP 
CONFIDENTIAL 
Statistical Analysis Plan 
D-US-60090-001 
 
Version 2.0, 17 December 2020 
Page 16 of 48 
 
delayed onset AEs will be performed at 6 weeks (42 days), and at 12 weeks (84 days). The SRC will 
evaluate safety, and available PK and PD data in order to make a decision on dose-escalation, and to 
determine the MTD and the RD. The safety data reviewed by the SRC will include the safety findings and 
DLTs observed during the DLT assessment period from the previous cohort. The SRC may decide to 
evaluate an intermediate, not predefined, previously evaluated or not previously-evaluated dose of 
IPN60090 or a less frequent dosing schedule that will not exceed the MTD level if evaluation of toxicity 
at such a dose or schedule is desired. 
DLT Criteria 
The DLTs for Part B are defined for any of the following IMP- related, probably related or possibly 
related AEs according to NCI-CTCAE version 5.0 that occur during the defined DLT assessment period 
(over the 21 days following the first dose of IPN60090 combined with pembrolizumab): 
• 
Grade 4 neutropenia lasting >7 days 
• 
Febrile neutropenia of any grade (ANC <1000/mm3 with a single temperature episode of 38.3°C 
or a sustained temperature of 38°C for >1 hour 
• 
Grade 3 or 4 neutropenia with infection. 
• 
Grade 3 thrombocytopenia with bleeding and Grade 4 thrombocytopenia. 
• 
Grade 4 life threatening anaemia. 
• 
ALT/AST ≥3×ULN with total bilirubin ≥2×ULN without elevation of ALP and no other 
reasonable explanation for the abnormality (Hy’s law criteria). 
• 
Grade 3 lasting more than 7 days or Grade 4 laboratory abnormalities of ALT/AST and/or 
bilirubin, with the following exceptions: 
− 
for patients with Grade 1 ALT/AST at baseline (>ULN to 3×ULN, an ALT/AST value of 
>7.5×ULN will be considered a DLT. 
− 
for patients with Grade 2 ALT/AST at baseline (>3×ULN to 5×ULN), an ALT/AST 
value >10×ULN will be considered a DLT. 
• 
Grade 3 or Grade 4 pneumonitis, hepatitis, colitis, nephritis, encephalitis, etc 
• 
Grade 3 or Grade 4 rash lasting more than 72 hours with adequate supportive care. 
• 
Grade 3 or higher non-haematological toxicity excluding: 
− 
Grade 3 nausea, vomiting or diarrhoea lasting less than 72 hours with adequate 
supportive care. 
− 
Grade 3 fatigue lasting less than a week. 
− 
Grade 3 or higher electrolyte abnormality that lasts for less than 72 hours, that is not 
clinically complicated and resolves spontaneously or with conventional medical 
interventions. 
− 
Grade 3 or higher amylase or lipase lasting less than 72 hours and not associated with 
clinical manifestations of pancreatitis. 
• 
Grade 5 (death) 


IPSEN GROUP 
CONFIDENTIAL 
Statistical Analysis Plan 
D-US-60090-001 
 
Version 2.0, 17 December 2020 
Page 17 of 48 
 
Other clinically significant or persistent toxicities may be considered a DLT following review by the 
SRC. 
Transient infusion-related AEs that can be controlled with medical management (i.e. flu-like 
symptoms, fever) are not considered DLTs. 
Patient Eligibility for Dose Escalation Decision 
Any patient who does not complete the DLT assessment period for any reason other than a DLT will be 
considered non-evaluable for dose-escalation decisions and MTD assessment and will be replaced by an 
additional patient at that same dose level. Moreover, patients will be considered eligible for the DLT 
assessment only if they received ≥75% of the total planned IPN60090 dose and one infusion of 
pembrolizumab over the DLT assessment period. Patients who received less than 75% of total planned 
dose due to DLT will be included for dose-escalation decisions. Noncompliant (<75% without DLT) 
patients will also be replaced. 
The SRC may decide to enrol additional patients based on the safety, PK or PD data. 
Treatment Duration - Additional Cycles 
Patients will be offered IPN60090 + pembrolizumab treatment beyond Cycle 1 as long as they continue to 
experience clinical benefit in the opinion of the investigator until the earlier of confirmed disease 
progression, symptomatic deterioration, poor tolerability despite appropriate medical management or any 
of the other reasons for treatment discontinuation. 
Patients who experience a DLT (or other toxicities considered related, probably related or possibly related 
to the study treatment) will be permitted to continue to receive study treatment at a lower dose level than 
the dose at which the DLT was observed, at the discretion of the investigator and will be followed for 
safety. Patients who discontinue study treatment for reasons other than disease progression (for example 
toxicity) should continue to undergo scheduled tumour assessments approximately every 12 weeks until 
confirmed disease progression, or initiation of further systemic cancer therapy, death, or until the study 
closes, whichever occurs first. 
2.2.3.3 
Part C – Paclitaxel Combination Dose Escalation 
The dose escalation portion of Part C is to evaluate the safety, tolerability, PK and PD of IPN60090 given 
as a BID oral dose (every 12 hours) in combination with paclitaxel, during or after a meal, over a 21-day 
cycle. The intake of IPN60090 will be made before the paclitaxel infusion. 
Dose escalation of IPN60090 in combination with paclitaxel will be conducted in patients with 
biomarker-positive and biomarker-negative advanced solid tumours. 
These patients will be unselected for KEAP1/NRF2 mutation and may be KEAP1/NRF2 wild-type or 
mutated. The same applies for ASNS expression levels, patients may have tumours with any level of 
ASNS expression. Dose escalation in combination with paclitaxel will be initiated at a dose level showing 
pharmacological activity (at least 50% inhibition of Glu:Gln ratio in PBMC at Ctrough (12 hours postdose 
and predose for the following dose) on Day 14 of Cycle 1 in 66% of patients treated at this dose level) 
and good tolerability as identified in Part A. The IPN60090 dose being tested in Part C will always 
remain lower than that being tested in Part A (at least one dose level lower than the highest dose tested in 
Part A). 
Three dose levels of IPN60090 are planned to be tested with an additional lower dose level (DL-1) if DL1 
is not tolerated. The study will follow a BOIN design for dose escalation. 


IPSEN GROUP 
CONFIDENTIAL 
Statistical Analysis Plan 
D-US-60090-001 
 
Version 2.0, 17 December 2020 
Page 18 of 48 
 
At all dose levels, IPN60090 will be administered orally BID starting from Day 1 of each 21-day cycle 
and paclitaxel will be administered as one i.v. infusion every 21 days starting from Day 1 of each cycle. 
The predefined dose-escalation plan is described in Table 3. 
Table 3 Dose Escalation Phase I-Part C in Combination with Paclitaxel 
Dose level 
DL-1 
DL1 
DL2 
DL3 
Planned dose of 
IPN60090 [a] 
80 mg BID 
180 mg BID 
320 mg BID 
480 mg BID 
Planned dose of 
paclitaxel 
175 or 135 mg/m2 
Q3W [b] 
175 or 135 mg/m² 
Q3W [b] 
175 or 135 mg/m² 
Q3W [b] 
175 or 135 mg/m² 
Q3W [b] 
BID=bis in die (twice daily); DL=dose level; Q3W=every 3 weeks (21 days). 
[a] dose levels are examples; the actual starting dose will be determined by PD from the Part A dose escalation 
[b] or according to the local approved label for particular tumour types. 
Dose finding will begin at DL1. The study will enroll in cohorts of three patients at the predefined dose 
levels until up to six cohorts have been enrolled. Following each cohort, the observed DLT data will be 
used to determine the dose level for the next cohort in accordance with the escalation and de-escalation 
rules for a local BOIN design using a target toxicity rate of 30% with escalation and de-escalation 
thresholds of 23.6% and 35.9%, respectively. The decision rules for dose-escalation and de-escalation 
from a local BOIN design is defined in Table 4in section 2.2.7.1. 
Following the completion of enrolment, the MTD will be estimated as the dose level at which the isotonic 
estimate of the DLT rate is closest to 30%. 
If the first dose level of IPN60090 in combination with paclitaxel 175 or 135 mg/m² (or according to the 
local approved label for particular tumour types) given intravenously is not well tolerated, the dose of 
IPN60090 may be de-escalated and thus a new cohort may start with DL-1. 
MTD Definition 
The MTD is defined as the maximum dose of IPN60090 that may be administered BID for 21 days in 
combination with an i.v. infusion of 175 or 135 mg/m² paclitaxel (or according to the local approved label 
for particular tumour types), so that no more than 30% of patients experience a DLT. The MTD will be 
determined by the dose for which the isotonic estimate of DLT rate is closest to 30% of patients 
experiencing a DLT. 
DLT Assessment Period 
The DLT assessment period will consist of the first 21 days of treatment (one cycle). The SRC will 
evaluate safety, and available PK and PD data in order to make a decision on dose escalation, and to 
determine the MTD and the RD. The safety data reviewed by the SRC will include the safety findings and 
DLTs observed during the DLT assessment period from the previous cohort. The SRC may decide to 
evaluate an intermediate, not predefined, previously evaluated or not previously evaluated dose or a less 
frequent dosing schedule that will not exceed the MTD level, if evaluation of toxicity at such a dose or 
schedule is desired. 
DLT Criteria 
The DLTs for Part C are defined for any of the following IMP- related, probably related or possibly 
related AEs according to NCI-CTCAE version 5.0 that occur during the defined DLT assessment period 
(over the 21 days following the first dose of IPN60090 combined with paclitaxel): 
• 
Grade 4 neutropenia lasting >7 days 


IPSEN GROUP 
CONFIDENTIAL 
Statistical Analysis Plan 
D-US-60090-001 
 
Version 2.0, 17 December 2020 
Page 19 of 48 
 
• 
Febrile neutropenia of any grade (ANC <1000/mm3 with a single temperature episode of 38.3°C 
or a sustained temperature of 38°C for >1 hour. 
• 
Grade 3 or 4 neutropenia with infection. 
• 
Grade 3 thrombocytopenia with bleeding and Grade 4 thrombocytopenia. 
• 
Grade 4 life threatening anaemia. 
• 
ALT/AST ≥3×ULN with total bilirubin ≥2×ULN without elevation of ALP and no other 
reasonable explanation for the abnormality (Hy’s law criteria).  
• 
Grade 3 lasting more than 7 days or Grade 4 laboratory abnormalities of ALT/AST and/or 
bilirubin, with the following exceptions: 
− 
for patients with Grade 1 ALT/AST at baseline >ULN to 3×ULN, an ALT/AST value of 
>7.5×ULN will be considered a DLT. 
− 
for patients with Grade 2 ALT/AST at baseline (>3×ULN to 5×ULN), an ALT/AST value 
>10×ULN will be considered a DLT. 
• 
Grade 3 or Grade 4 rash lasting more than 72 hours with adequate supportive care. 
• 
Grade 3 or higher non-haematological toxicity excluding: 
− 
Grade 3 nausea, vomiting, or diarrhoea for less than 72 hours with adequate supportive care. 
− 
Grade 3 fatigue lasting less than 1 week. 
− 
Grade 3 or higher electrolyte abnormality that lasts for less than 72 hours, that is not 
clinically complicated and resolves spontaneously or with conventional medical 
interventions. 
− 
Grade 3 or higher amylase or lipase lasting less than 72 hours and not associated with clinical 
manifestations of pancreatitis. 
• 
Grade 5 (death). 
Other clinically significant or persistent toxicities may be considered a DLT following review by the 
SRC. 
Transient infusion-related AEs which can be controlled with medical management (i.e. flu-like 
symptoms, fever) are not considered DLTs. 
Patient Eligibility for Dose Escalation Decision 
Any patient who does not complete the DLT assessment period for any reason other than a DLT will be 
considered non-evaluable for dose-escalation decisions and MTD assessment and will be replaced by an 
additional patient at that same dose level. Moreover, patients will be considered eligible for the DLT 
assessment only if they are able to receive ≥75% of the total planned IPN60090 dose and one infusion of 
paclitaxel over the DLT assessment period. Patients who received less than 75% of total planned dose due 
to DLT will be included for dose-escalation decisions. Noncompliant (<75% without DLT) patients will 
also be replaced. 
The SRC may decide to enrol additional patients based on the safety, PK or PD data. 
Treatment Duration - Additional Cycles 


IPSEN GROUP 
CONFIDENTIAL 
Statistical Analysis Plan 
D-US-60090-001 
 
Version 2.0, 17 December 2020 
Page 20 of 48 
 
Patients will be offered IPN60090 + paclitaxel treatment beyond Cycle 1 as long as they continue to 
experience clinical benefit in the opinion of the investigator until the earlier of disease progression, 
symptomatic deterioration, poor tolerability despite appropriate medical management or any of the other 
reasons for treatment discontinuation. Patients who experience a DLT (or other toxicities considered 
related, probably related or possibly related to the study treatment) will be permitted to continue to 
receive study treatment at a lower dose level than the dose at which the DLT was observed, at the 
discretion of the investigator and will be followed for safety. Patients who discontinue study treatment for 
reasons other than disease progression (for example toxicity) should continue to undergo scheduled 
tumour assessments approximately every 12 weeks until, disease progression, or initiation of further 
systemic cancer therapy, death, or until the study closes, whichever occurs first. 
2.2.3.4 
Transition to Recommended Dose or Different Regimen 
In Parts A, B and C, when the RD is determined, if a patient is still in the study at a different dose, this 
patient can be moved to the RD at the discretion of the investigator. 
In Part A, biomarker-positive patients who are enrolled and receive study treatment at initial dose levels 
below the pharmacologically active range for at least two cycles with good tolerability and achieve and 
maintain at least SD, may be escalated to a higher dose level that has been tested and proven to be well 
tolerated at the recommendation of the SRC. These patients will be treated outside of the BOIN design. 
Patients enrolled in monotherapy Part A may receive combination treatment with either pembrolizumab 
or with paclitaxel upon progression on IPN60090 monotherapy at the discretion of the investigator and 
with the approval of the sponsor, once the safe dose level for the combination is determined. These 
patients will need to satisfy the eligibility criteria for combination therapy prior to initiating treatment, 
and will be followed for safety and efficacy in a separate cohort. 
2.2.4 3.1.3 Food Effect Assessment – Part D  
Part D will start at the end of the Part A dose escalation. Patients in Part D will not be part of the dose 
escalation and MTD assessment.  
Food effect evaluation will be conducted in patients with biomarker-positive and biomarker-negative 
advanced solid tumours.  
These patients will not be selected for KEAP1/NRF2 mutation status and may be wild-type or mutated. 
Patients may have tumours with any level of ASNS expression. Eligibility criteria for Part D will be the 
same as the criteria for the Part A dose escalation.  
After screening, eight patients will enter a run-in period of 7 days: 
• 
At Day -7, patients will receive a single administration of IPN60090 at the RD (as defined by the 
SRC at the end of the Part A dose escalation) following an overnight fast of at least 10 hours.  
• 
• At Day -3, patients will receive a single administration of IPN60090 at the RD (morning dose 
only, as defined by the SRC at the end of the Part A dose escalation) 30 minutes after the start of 
a moderate fat meal.  
After the run-in period, patients will receive IPN60090 as a single agent administered orally BID (every 
12 hours), during or after a meal, starting from Day 1 at the single agent RD. Patients in Part D will 
follow the same schedule of assessments as described for Part A (with the exception of the urine sampling 
for PK).  


IPSEN GROUP 
CONFIDENTIAL 
Statistical Analysis Plan 
D-US-60090-001 
 
Version 2.0, 17 December 2020 
Page 21 of 48 
 
Patients enrolled in monotherapy Part D may receive combination treatment with either pembrolizumab 
or with paclitaxel upon disease progression on the IPN60090 monotherapy at the discretion of the 
investigator and with the approval of the sponsor, once the safe dose level for the combination is 
determined. These patients will need to satisfy the eligibility criteria for combination therapy prior to 
initiating treatment, and will be followed for safety and efficacy in a separate cohort. 
2.2.5 Dose Expansion Cohorts 
The multicohort dose expansion part of the study will further explore the safety and tolerability of 
IPN60090 in monotherapy and in combination; assess the preliminary anti-tumour activity of IPN60090 
as single agent and in combination with pembrolizumab or paclitaxel at the RD in biomarker positive 
and/or unselected patient population and will explore the potential of selected biomarkers as predictors of 
efficacy (candidate biomarkers will include, but will not be limited to, KEAP1/NRF2 mutation status, 
ASNS expression level, and known or new emerging predictive or prognostic markers of efficacy in 
selected tumour types). 
Enrolment into dose expansion cohorts will occur independently of each other. Each cohort will follow a 
sequential 2-stage design and enroll 10 patients in Stage 1 and up to a total of 18 patients (Stage 1 + Stage 
2). 
The dose expansion cohorts that will be explored in each part of the study are defined as the following 
(which may be further expanded if an efficacy signal is observed): 
• 
Part A-IPN60090 monotherapy 
− 
Dose Expansion Cohort 1: KEAP1 or NRF2 mutant NSCLC 
− 
Dose Expansion Cohort 2: Other KEAP1 or NRF2 mutant tumours 
− 
Dose Expansion Cohort 3: ASNSlow HGSOC 
• 
Part B- IPN60090 + pembrolizumab: 
− 
Dose Expansion Cohort 4: KEAP1 or NRF2 mutant NSCLC 
− 
Dose Expansion Cohort 5: Other KEAP1 or NRF2 mutant tumours 
− 
Dose Expansion Cohort 6: KEAP1 or NRF2 wild-type tumours with any level of ASNS 
expression 
• 
Part C- IPN60090 + paclitaxel: 
− 
Dose Expansion Cohort 7: KEAP1 or NRF2 mutant tumours 
− 
Dose Expansion Cohort 8: ASNSlow HGSOC 
− 
Dose Expansion Cohort 9: KEAP1 or NRF2 wild-type tumours with any level of ASNS 
expression 
Dose expansion cohorts (study populations and sample size) may be revised in light of the dose escalation 
data and would then be described in a protocol amendment. 
Patients enrolled in monotherapy Part A may receive combination treatment with either pembrolizumab 
or with paclitaxel upon progression on IPN60090 monotherapy at the discretion of the investigator and 
with the approval of the sponsor. These patients will need to satisfy the eligibility criteria for combination 
therapy prior to initiating treatment, and will be followed for safety and efficacy in a separate cohort. 


IPSEN GROUP 
CONFIDENTIAL 
Statistical Analysis Plan 
D-US-60090-001 
 
Version 2.0, 17 December 2020 
Page 22 of 48 
 
2.2.6 Study Drug 
2.2.6.1 
IPN60090 
Patients in all Parts (A, B and C) should take IPN60090 BID (every 12 hours), during or after a meal. 
IPN60090 will be administered in the clinic on the first treatment day so that each patient can be observed 
for initial tolerability. Subsequent doses will be self-administered at home by taking IPN60090 BID at the 
same time each day until next visit. Patients will be given a medication diary to record day and time of 
administration, missed administration if any with related reasons if available or retake medication in case 
of rejection if applicable. 
The assigned dose of IPN60090 will vary from cohort-to-cohort and will be defined by each SRC 
meeting, except for Part A starting dose for each part that is defined in the protocol. Patients should 
maintain their assigned dose in absence of treatment-emergent toxicity. 
During Part A dose escalation, doses of IPN60090 will range from 20 mg BID (40 mg total daily dose) 
(starting dose) to 720 mg BID (1440 mg daily dose) (maximum dose). 
During Part B dose escalation, the starting dose of IPN60090 will be a dose showing pharmacological 
activity (at least 50% inhibition of Glu:Gln ratio in PBMC at Ctrough (12 hours postdose) on Day 14 in 
66% of patients at this dose level) and good tolerability as identified in Part A.  
During Part C dose escalation, the starting dose of IPN60090 will be a dose showing pharmacological 
activity (at least 50% inhibition of Glu:Gln ratio in PBMC at Ctrough (12 hours postdose) on Day 14 in 
66% of patients at this dose level) and good tolerability as identified in Part A. When H2 blockers are 
administered for paclitaxel premedication, they must be administered at least 30 minutes prior to 
paclitaxel infusion. IPN60090 intake should be performed at least 2.5 hours before the start of paclitaxel 
infusion and at least 2 hours prior to H2 blocker administration. 
In the expansion phases, the dose tested will be the RD determined in the dose escalation part. 
During Part D, the administered dose during the run-in period (Day -7 and Day -3) will be the RD 
(morning dose only) as defined by the SRC at the end of the Part A dose escalation. Then, starting from 
Day 1, IPN60090 will be administered at the RD BID during or after a meal. 
2.2.6.2 
Part B: Pembrolizumab 
IPN60090 capsules should be taken before the pembrolizumab infusion. 
Pembrolizumab dose will be fixed at 200 mg (or according to the approved local label for particular 
tumour types) administered as an i.v. infusion over 30 minutes every 21 days (Day 1 of every cycle). 
2.2.6.3 
Part C: Paclitaxel 
IPN60090 intake should be performed at least 2.5 hours before the start of paclitaxel infusion and at least 
2 hours prior to H2 blocker administration. The dose of paclitaxel will be fixed at 175 mg/m² or 135 
mg/m² (or according to the local approved label for particular tumour types) administered as an i.v. 
infusion every 21 days. 
2.2.7 Sample Size Determination 
2.2.7.1 
Monotherapy Dose Escalation – Part A 
A BOIN design with target toxicity rate of 30% (with escalation and de-escalation thresholds of 23.6% 
and 35.9%, respectively) with maximum number of approximately 30 patients will be used to estimate the 
IPN60090 monotherapy MTD. 


IPSEN GROUP 
CONFIDENTIAL 
Statistical Analysis Plan 
D-US-60090-001 
 
Version 2.0, 17 December 2020 
Page 23 of 48 
 
The design will proceed with accelerated titration up to DL3, i.e. cohorts of one will be enrolled until 
either the third dose level is evaluated, a Grade 2 AE that is at least possibly related to the study drug(s) 
occurs, or a DLT is observed (whichever occurs first). If a Grade 2 AE that is at least possibly related to 
the study drug(s) or a DLT is observed in a single patient cohort (i.e. in one of the first three dose levels), 
two additional patients will be added at this dose level with the same rules for escalation and de-
escalation as the cohorts of three patients detailed below. 
If the DLT rate within a cohort at a given dose level is less than the escalation boundary of 23.6% the rule 
is then to escalate, if the DLT rate is higher than the de-escalation boundary of 35.9% then the rule is 
either to de-escalate, or to retain the dose or to stop if the maximum sample size is reached. Following the 
requisite follow-up in a cohort, the dose level for the next cohort will be determined using the decision 
rules in Table 4, where ↑indicates the next cohort at one dose level higher, ↓ indicates the next dose level 
at one dose level lower and “Elim” indicates that the dose level (and all higher dose levels) is removed 
from further consideration. 
Table 4 Dose Escalation Decision Rules 
 
Number of patients at current dose level 
Action 
3 
4 
5 
6 
7 
8 
9 
10 
↑ if number of DLT ≤ 
0 
0 
1 
1 
1 
1 
2 
2 
Stay current dose if DLT 
1 
1 
- 
2 
2 
2 
3 
3 
↓ if number of DLT ≥ 
2 
2 
2 
3 
3 
3 
4 
4 
Elim if number of DLT ≥ 
3 
3 
4 
4 
5 
5 
5 
6 
DLT=dose limiting toxicity; Elim=eliminate. 
In the event that operational/practical circumstances result in an over-enrolment (i.e. n>3) for a BOIN 
cohort, the next dose level decision would be based on the actual number of patients exposed in the cohort 
and the BOIN criteria. 
If none of the actions is indicated, then the next cohort is enrolled at the same dose level as current. If the 
current dose level is the lowest dose level and the action indicated is de-escalation, then the next cohort is 
enrolled at the same dose level (i.e. the lowest dose level). Similarly, if the current dose level is the 
highest dose level and the action indicated is escalation then the next cohort is treated at the same dose 
level. When a dose is eliminated, the next cohort is enrolled at the next lower dose level. If the lowest 
dose is eliminated, then the study is stopped and none of the dose levels is selected as the MTD. 
The study will continue until one of the following occurs: 
(a) the maximum number of patients has been reached (approximately 30) 
(b) the decision indicated by the table would result in adding patients to a dose level where at least 
nine patients have already been treated 
(c) the number of patients treated at the lowest dose level is ≥3 and the probability that the DLT rate 
at the lowest dose level exceeds the target is >0.90. 
When (a) or (b) occurs, the MTD of IPN60090 will be estimated as the dose level at which the isotonic 
estimate of the DLT rate is closest to 30%. If there are ties, the MTD is selected as the higher dose level 
when the isotonic estimate is lower than the target toxicity rate and selected as the lower dose level when 
the isotonic estimate is greater than or equal to the target toxicity rate. 
The operating characteristics for the MTD dose selected for the planned design for seven true DLT rate 
scenarios were estimated by simulation of 2000 studies per scenario (Table 5). From each scenario, 
%MTD identified at dose level with true DLT at 30% is the highest and the average number of patients 
treated at MTD dose level is between 4.1 and 7.0 patients. 


 
 
 
 
Table 5 Operating Characteristics for Monotherapy BOIN Dose Finding from Simulation 
Scenario 
True DLT rate 
for DL1 
%MTD is DL1 
(avg n ) 
True DLT rate 
for DL2 
%MTD is DL2 
(avg n) 
True DLT rate 
for DL3 
%MTD is DL3 
(avg n) 
True DLT rate 
for DL4 
%MTD is DL4 
(avg n) 
True DLT rate 
for DL5 
%MTD is DL5 
(avg n) 
True DLT rate 
for DL6 
%MTD is DL6 
(avg n) 
True DLT rate 
for DL7 
%MTD is DL7 
(avg n) 
Average 
number of 
patients to be 
enrolled 
% early stop 
1 
0.025 
<1 
(1.1) 
0.05 
<1 
(1.4) 
0.075 
1 
(1.7) 
0.10 
4 
(4.4) 
0.15 
13  
(5.0) 
0.20 
20  
(5.2) 
0.25 
61 
(5.9) 
24.7 
<1 
2 
0.025 
<1 
(1.1) 
0.05 
<1  
(1.4) 
0.075 
2  
(1.9) 
0.125 
10 
(4.9) 
0.20 
23 
(5.6) 
0.25 
26 
(5.0) 
0.30 
39  
(4.1) 
24.0 
<1 
3 
0.025 
<1 
(1.1) 
0.05 
<1 
(1.5) 
0.10 
4  
(2.2) 
0.15 
17  
(5.5) 
0.25 
33  
(6.1) 
0.30 
32  
(4.6) 
0.45 
14  
(2.3) 
23.3 
<1 
4 
0.025 
<1  
(1.1) 
0.05 
<1  
(1.5) 
0.10 
6  
(2.7) 
0.20 
30  
(6.3) 
0.30 
45  
(6.3) 
0.45 
16  
(3.4) 
0.55 
2  
(0.7) 
22.0 
<1 
5 
0.05 
<1  
(1.4) 
0.10 
5 
(2.6) 
0.20 
27 
(4.9) 
0.30 
47  
(6.8) 
0.45 
17  
(3.9) 
0.55 
3  
(0.9) 
0.65 
<1  
(0.1) 
20.5 
<1 
6 
0.075 
2  
(1.8) 
0.15 
22  
(4.8) 
0.30 
55 
(7.4) 
0.50 
20  
(4.9) 
0.70 
<1 
(0.9) 
0.80 
0 
(<0.1) 
0.85 
0  
(<0.1) 
19.8 
1 
7 
0.15 
20 
(4.7) 
0.30 
58  
(7.7) 
0.50 
17 
(5.0) 
0.70 
1  
(1.6) 
0.80 
0 
(0.1) 
0.85 
0 
(<0.1) 
0.90 
0  
( 0) 
19.1 
5 
8 
0.30 
50 
(7.0) 
0.45 
23  
(5.5) 
0.60 
3 
(2.3) 
0.75 
0  
(0.6) 
0.85 
0  
(<0.1) 
0.90 
0  
( 0) 
0.95 
0  
( 0) 
10.4 
24 
avg n=the average number of patients treated at each dose level; BOIN=Bayesian Optimal Interval; DL=dose level; DLT=dose limiting toxicity; MTD=maximum tolerated dose 
% early stop is the percentage of times the study would stop early due to case (c). 
% MTD is DLx means selection percentage at dose level x 


 
 
 
 
2.2.7.2 
Combination Dose Escalation – Parts B and C 
A BOIN design with target toxicity rate of 30% (with escalation and de-escalation thresholds of 23.6% 
and 35.9%, respectively) with maximum number of approximately 18 patients (for each combination dose 
finding) will be used to estimate the IPN60090 combination MTD. The design will enroll up to six 
cohorts of three patients. Patients in the first cohort will be treated at combination DL1. Because the 
escalation and de-escalation thresholds are the same as those used for the monotherapy, the escalation and 
de-escalation rules as a function of number of patients treated are the same as those presented for the 
monotherapy. 
The trial will continue until one of the following occurs: 
(a) the maximum number of patients has been reached (approximately18) 
(b) the decision indicated by the table would result in the number of patients at a dose level 
exceeding nine patients 
(c) the number of patients treated at the lowest dose level is ≥3 and the probability that the DLT rate 
at the lowest dose level exceeds the target is greater than 0.90. 
In the event that operational/practical circumstances result in an over-enrolment (i.e. n>3) for a BOIN 
cohort, the next dose level decision would be based on the actual number of patients exposed in the cohort 
and the BOIN criteria. 
When (a) or (b) occurs, the MTD of IPN60090 will be estimated as the dose level at which the isotonic 
estimate of the DLT rate is closest to 30%. If there are ties, the MTD is selected as the higher dose level 
when the isotonic estimate is lower than the target toxicity rate and selected as the lower dose level when 
the isotonic estimate is greater than or equal to the target toxicity rate. 
2.2.7.3 
Sample Size for Part D 
The sample size (n=8) is not based on statistical calculation. A sample size of eight patients allows for a 
preliminary assessment of the potential effect of food on the PK of IPN60090. 
2.2.7.4 
Sample Size Determination for the Expansion Phase 
Preliminary anti-tumour activity will be evaluated in each dose expansion cohort (each regimen and 
indication combination) according to a sequential two-stage design based on a fixed sample size with look 
at 10 and at 18. The first stage will enroll 10 patients and stop for futility if no patients or only one patient 
achieves the efficacy criterion defined by a BOR of CR, PR or SD lasting at least 12 weeks for Part A and 
C cohorts (respectively iCR, iPR or iSD for 12 weeks for Part B cohorts). If an expansion cohort passes 
the first stage, then a total of 18 patients (eight additional patients) would be enrolled. Six or more 
patients achieving the efficacy criterion already defined would suggest promising anti-tumour activity in 
the corresponding expansion cohort. Table 6 shows the operating characteristics for a range of true CBRs. 
                                           Table 6 Operating Characteristics for True CBRs 
True CBR  
Pr(find encouraging) 
Pr(stop at stage 1) 
0.10 
0.01 
0.74 
0.20 
0.13 
0.38 
0.30 
0.46 
0.15 
0.35 
0.64 
0.09 
0.40 
0.78 
0.05 
0.45 
0.89 
0.02 
0.50 
0.95 
0.01 
CBR=clinical benefit rate; Pr=probability 


IPSEN GROUP 
CONFIDENTIAL 
Statistical Analysis Plan 
D-US-60090-001 
 
Version 2.0, 17 December 2020 
Page 26 of 48 
 
For expansion phase, the planned 2-stage procedure has an unadjusted type 1 error rate of less than 0.15 
within each dose expansion cohort for a null hypothesis that the true CBR is 20%. 
The CBR will be analyzed at the end of Stage 1 for each cohort separately after the inclusion of 10 
patients by cohort. If no patients or only one patient is responding at the second scheduled tumour 
assessment i.e. with a BOR of CR, PR or SD lasting at least 12-weeks (iCR, iPR or iSD for 12 weeks for 
part B) the respective study cohort will be stopped for futility. Otherwise, eight additional patients will be 
treated to complete the planned enrolment. 
At the end of Stage 2, the null hypothesis will be rejected suggesting promising anti-tumour activity in the 
corresponding cohort if six patients or more are responding. The CBR will be calculated along with its CI 
for each cohort. 
2.3 Study Endpoints 
2.3.1 Primary Endpoints 
The safety and tolerability of IPN60090 as a single agent (Part A and Part D) and in combination with 
pembrolizumab (Part B) or paclitaxel (Part C) will be assessed by the rate of DLTs at each dose level in 
the dose escalation, and the rate of AEs and the rate of Grade 3 and higher AEs in the dose escalation and 
dose expansion. Continuous monitoring of AEs and serious AEs (SAEs), clinical laboratory test results, 
the presence of anti-pembrolizumab antidrug antibodies (ADA; Part B only), vital signs measurements, 
ECG and physical examination results and concomitant medication usage will be performed.  
For dose escalation only: 
• 
The incidence of DLTs (Parts A, Part B and Part C) during the DLT assessment period in order to 
determine the MTD. 
MTD is further defined in section 2.2.3 using a BOIN design. DLT is further defined in section 
2.2.3. The DLT assessment period will be the first 21 days of treatment (one cycle). The BOIN 
design described in section 2.2.7.1 
• 
Safety, PK and PD parameters (Parts A, Part B, Part C) in order to determine the RD.  
2.3.2 Secondary Endpoints 
2.3.2.1 Efficacy Endpoints 
• 
Anti-tumour activity parameters assessed locally for dose escalation and centrally for dose 
expansion and collected on eCRF using Response Evaluation Criteria in Solid Tumours 
(RECIST) v1.1 (Appendix B, Eisenhauer EA, 2009) for Parts A, C, and D and immune-related 
RECIST (iRECIST) (Appendix C, Seymour L, 2017) for Part B only, including: 
o Clinical benefit rate (CBR) is defined as the proportion of patients in whom the Best Overall 
Response (BOR) is equal to complete response (CR), PR or SD lasting at least 12 weeks for 
Parts A, C, and D and equal to immune CR (iCR), immune PR (iPR) or immune SD (iSD) 
lasting at least 12 weeks for Part B 
− 
The BOR for Parts A, C, and D is defined as the best response designation (in the 
order of CR, PR, SD, PD) for each subject that is recorded between the date of the 
first dose of the study drug and the date of documented disease progression per 
RECIST 1.1 or the date of subsequent anticancer therapy whichever occurs first. 


IPSEN GROUP 
CONFIDENTIAL 
Statistical Analysis Plan 
D-US-60090-001 
 
Version 2.0, 17 December 2020 
Page 27 of 48 
 
− 
The BOR for Part B is defined as the best response designation (in the order of iCR, 
iPR, iSD, iUPD, iCPD) for each subject that is recorded between the date of the first 
dose of the study drug and the date of documented disease progression per iRECIST 
or the date of subsequent anticancer therapy whichever occurs first. 
o Objective Response Rate (ORR) is defined as the proportion of patients in whom the BOR is 
equal to CR and PR for Parts A, C, and D or iCR and iPR for Part B. 
o Disease control rate (DCR) is defined as the proportion of patients in whom the BOR is equal 
to CR, PR or SD for Parts A, C and D, and equal to iCR, iPR or iSD for Part B. 
o Progression free survival (PFS) for Parts A, C, and D is defined as the time from first dose of 
study medication to the first documented objective disease progression (for RECIST), clinical 
disease progression collected at end of treatment, or death due to any cause, whichever occurs 
first.  
Progression free survival (PFS) for Part B is defined as the time from first dose of study 
medication to the first confirmed objective disease progression (for iRECIST), clinical 
disease progression collected at end of treatment or death due to any cause, whichever occurs 
first.  
PFS (months) = (event or censoring date – first dose date + 1)/30.4375 
PFS will be right-censored for patients who met one or more of the following conditions:  
− 
no baseline disease assessment or no evaluable post baseline disease assessments 
unless death occurred prior to the first planned assessment at post baseline (in which 
case death will be considered a PFS event).  
− 
amputation or surgical resection of tumour in the absence of documented disease 
progression.  
− 
subsequent anticancer therapy in the absence of documented disease progression. 
− 
died or documented disease progression after missing two or more consecutively 
scheduled disease assessment visits 
− 
alive and without documented disease progression on or before the data cutoff date 
If a patient meets more than one of these conditions, then the scenario that occurs first will be 
used for analysis. The progression or censoring date will be determined based on the 
conventions listed in Table 7: 


IPSEN GROUP 
CONFIDENTIAL 
Statistical Analysis Plan 
D-US-60090-001 
 
Version 2.0, 17 December 2020 
Page 28 of 48 
 
Table 7: Date of Progression or Censoring for PFS 
Situation 
Date of event or censoring 
Outcome 
Death before first planned disease assessment 
Date of death 
Event 
Death or disease progression (per RECIST 1.1 for 
Parts A, Part C, and Part D or iRECIST for Part B) 
or clinical disease progression collected at end of 
treatment between planned disease assessments 
Date of death or first disease assessment 
showing disease progression, whichever 
occurs first 
Event 
No baseline disease assessment or no evaluable 
post-baseline disease assessments 
Date of first dose of IPN60090 
Censored 
Surgical 
resection 
or 
subsequent 
anticancer 
treatment started before disease progression (per 
RECIST 1.1 for Parts A, Part C, and Part D or 
iRECIST for Part B) or clinical disease progression 
collected at end of treatment or death (without 
disease progression beforehand) 
Date of last adequate disease assessment 
prior to surgery or start of subsequent 
anticancer treatment 
Censored 
Death or disease progression (per RECIST 1.1 for 
Parts A, Part C, and Part D or iRECIST for Part B) 
or clinical disease progression collected at end of 
treatment immediately after missing two scan 
intervals* 
consecutively 
scheduled 
disease 
assessments 
Date of last adequate disease assessment 
visit without documentation of disease 
progression before the first missed visit 
Censored 
Alive and without disease progression 
Date of last adequate disease assessment 
Censored 
*two scan interval is defined as 12 weeks + 2 weeks or 98 days. 
 
The PFS time will always be derived based on scan dates and not visit dates.  Scans 
contributing towards a particular visit may be performed on different dates.  The following 
rules will be applied: 
− 
Date of progression will be determined based on the earliest scan dates that triggered 
the progression per RECIST 1.1 or iRECIST criteria or clinical disease progression 
collected at end of treatment.   
− 
When censoring a subject for PFS, the subject will be censored at the latest of the 
scan date for overall assessment. 
For Part B, the event date to be used for calculation of PFS should be the first date that 
progression criteria are met (i.e. the date of immune unconfirmed progressive disease 
(iUPD)) providing that iCPD is confirmed at the next assessment. If iUPD occurs, but is 
disregarded because of later iSD, iPR or iCR, that iUPD date should not be used as the 
progression event date. If progression is not confirmed and there is no subsequent iSD, iPR or 
iCR then the iUPD date should still be used in the following scenarios: if the patient stops 
study treatment because they were not considered to be clinically stable, or no further 
response assessments are done (patient refusal or protocol non-compliance or patient death); 
the next time point responses are all iUPD, and immune confirmed progressive disease 
(iCPD) never occurs; or the patient dies of cancer. 
o Overall survival (OS) is defined as the time from first dose of study medication to death due 
to any cause. Patients who were lost to follow-up or who were still alive at the time of 
analysis will be censored at the last day the patient was known to be alive or data cut-off date, 
whichever occurs first. OS will be calculated as follows: 
OS (months) = (Death or Censoring Date – First Dose Date + 1)/30.4375  


IPSEN GROUP 
CONFIDENTIAL 
Statistical Analysis Plan 
D-US-60090-001 
 
Version 2.0, 17 December 2020 
Page 29 of 48 
 
2.3.2.2 Pharmacodynamic Endpoints 
• 
Pharmacodynamic parameters and biomarkers, including: 
− 
Target engagement: Glu:Gln ratio in PBMC 
− 
Tumour mutation status (for example KEAP1/NRF2, STK11, KRAS and other mutations) 
and correlation with clinical outcome  
− 
Tumour ASNS expression (ASNS level and ASNSlow and ASNShigh) 
2.3.2.3 Pharmacokinetic Endpoints 
Pharmacokinetic parameters of IPN60090, including but not limited to maximum observed 
plasma concentration (Cmax), time to Cmax (Tmax), Ctrough, area under the plasma concentration-time 
curve (AUC), elimination half-life (t1/2), apparent total clearance from plasma (CL/F) apparent 
volume of distribution (V/F) of IPN60090 (Parts A to D), the PK of a single dose of IPN60090 
administered in fed state (Day -3) relative to fasted state (Day -7) using the following PK 
parameters: Cmax, AUC, Tmax, t1/2, CL/F and V/F (Part D), assessment of concentrations of the 
combined product (Parts B and C) will be detailed in a separate Data Analysis Plan (DAP) and 
the PK report will be a standalone report. 
2.3.3 Exploratory Endpoints 
• 
Biomarkers of tumour biology parameters, including immune profiling, PD-L1 expression, 
nuclear antigen Ki67 (Ki67), phosphorylation of histone variant H2AX (γH2AX), LKB1 will be 
detailed in a separate DAP and reported as a standalone report. 
• 
Exploratory IPN60090 concentrations in urine in Part A of dose escalation, including PK 
parameters, the amount of IPN60090 excreted in urine and renal clearance will also be detailed in 
the  separate DAP and reported as a standalone report. 
2.3.4 Biobanking 
Biobanked for potential future exploratory biomarkers parameters, including PBMC, plasma, serum, 
circulating free DNA (cfDNA), paxgene DNA, paxgene ribonucleic acid (RNA), stools, and 
remaining material from tumour biopsies  will be performed outside the scope of the main study and 
reported separately. 
3 STATISTICAL METHODOLOGY 
3.1 General Considerations 
3.1.1 Analysis Day Conventions 
Analysis day will be calculated from the date of first dose of study drug.  The day of the first dose of 
study drug will be Day 1, and the day immediately before Day 1 will be Day -1.  There will be no Day 0. 
3.1.2 Analysis Visits 
No study visit windows will be used for analyses.  
3.1.3 Definition of Baseline  
Baseline is defined as the last measurement prior to the first dose of study treatment. 


IPSEN GROUP 
CONFIDENTIAL 
Statistical Analysis Plan 
D-US-60090-001 
 
Version 2.0, 17 December 2020 
Page 30 of 48 
 
3.1.4 Summary Statistics 
Unless otherwise noted, data will be listed by dose level and part in the dose escalation phase and by 
cohort and part in the dose expansion phase. Data will be summarized by dose level, part and overall in 
the dose escalation phase and by cohort, part and overall in the dose expansion phase. Data will be also 
summarized for all the patients included in the study at the RD (dose escalation and dose expansion 
phases). 
Categorical variables will be summarized by frequency distributions (number and percentages of 
patients). The 95% exact binomial confidence interval (CI) using the Clopper-Pearson method will be 
calculated when specified.  
Continuous variables will be summarized by descriptive statistics (mean, standard deviation, median, 
minimum, and maximum). 
Time-to-event variables will be summarized using the Kaplan-Meier estimates of the median and the 
corresponding 2-sided 95% confidence intervals using Greenwood’s formula when specified. 
3.1.5 Hypothesis Testing 
No formal statistical testing will be carried out. 
3.1.6 Evaluation of Site Effect 
It is not planned to perform a subgroup analysis on individual or groups of centres. 
3.1.7 Handling of Missing Data 
Missing data will not be imputed. Only observed data will be used in the summaries and analyses. 
In all listings, missing or incomplete dates should be left as they have been recorded. However, for 
calculation / sorting / assignation based on dates, the following methods will be used: 
1) The most conservative approach will be systematically considered (i.e. if the onset date of an 
AE/concomitant medication is missing / incomplete, it is assumed to have occurred during the 
study (i.e. a TEAE for AEs) except if the partial onset date or other data [stop date, …] indicates 
differently). 
2) A missing/incomplete date of medical history or disease diagnosis will be assumed to have 
occurred before any study treatment. 
3) If a partial date and the associated information do not allow to state about the assignation to a 
group / category, all the possible groups / categories will be considered (i.e.: an AE could be 
assigned to several possible doses at event onset according to its partial onset date and stop date. 
Particularly an AE with missing start date will be assigned to each dose received before its end 
date. Similarly a medication with partial start and stop dates could be considered as prior and 
concomitant treatment). 
4) Where this is possible, the derivations based on a partial date will be presented as superior 
inequalities (i.e.: for an AE started in FEB2004 after the  administration performed on 
31JAN2004, the days since last dose will be “≥2”, similarly the duration of ongoing AEs or 
medication will be“≥xx” according to the start and last visit dates). 


IPSEN GROUP 
CONFIDENTIAL 
Statistical Analysis Plan 
D-US-60090-001 
 
Version 2.0, 17 December 2020 
Page 31 of 48 
 
3.2 Analysis Populations 
3.2.1 Screened Population 
All patients screened (i.e. who signed the informed consent). 
3.2.2 Safety Population 
All patients who are exposed to (or started receiving) IPN60090 and/or the combination agents. 
3.2.3 DLT Evaluable Population for Dose-escalation Phase Only 
All patients from the safety population who are evaluable for DLT (patients who have completed at least 
one cycle of treatment and have received ≥75% of the total planned dose of IPN60090 over the DLT 
assessment period). Patients who received less than 75% of total planned dose due to DLT will be 
included in this population. Patients in Part B and Part C need to have at least 1 dose of pembrolizumab or 
paclitaxel in order to be included in this population. 
3.2.4 Efficacy Population 
All patients who receive at least one dose of IPN60090. 
3.2.5 Pharmacokinetic Population for Noncompartmental Analysis 
All patients who have no major protocol deviation affecting the PK variables and who have a sufficient 
number of IPN60090 plasma concentrations to estimate the main PK parameters (Cmax, Tmax, AUC0-last). 
3.2.6 Pharmacokinetic population for population PK modelling 
All patients who receive at least one IPN60090 dose and who have at least one plasma IPN60090 
concentration and who have no major protocol deviation affecting the PK variables. 
The NCA, the Pop PK and PK/PD modeling will be described in separate data analysis plans. 
Pharmacokinetic population for noncompartmental analysis and pharmacokinetic population for 
population PK modelling will be presented in standalone PK reports. 
3.2.7 Food Effect Population 
All patients in Part D who have received IPN60090 under fasting and fed conditions (Day -7 and Day -3), 
have consumed ≥80% of the moderate fat meal on Day -3, and who have no major protocol deviation 
affecting the PK variables and who have a sufficient number of IPN60090 plasma concentrations to 
estimate the main PK parameters (Cmax, Tmax and AUC0-last). 
3.2.8 Pharmacodynamic Population  
All patients who have at least one PD endpoint measurement. PD endpoints refer to target engagement 
levels (Glu:Gln ratio in PBMC). 
3.3 Patient Data and Study Conduct 
3.3.1 Patient Disposition 
The numbers and percentages of patients enrolled and included in each analysis population will be 
tabulated. The reasons for patient exclusions from each of the analysis populations will also be tabulated.  
The numbers and percentages of patients screened, received study treatment, entered Cycle 2, Cycle 3, 
Cycle 4, and additional cycles will be summarized.  


IPSEN GROUP 
CONFIDENTIAL 
Statistical Analysis Plan 
D-US-60090-001 
 
Version 2.0, 17 December 2020 
Page 32 of 48 
 
Primary reasons for discontinuation of study treatments (Part A: IPN60090, Part B: IPN60090 and 
pembrolizumab, Part C: IPN60090 and paclitaxel or Part D: IPN60090) and primary reasons for ending 
long-term follow-up will be tabulated. 
The number and percentages of patients in Stage 1 and Stage 2 of the expansion phase will be 
summarized. 
For Part A and Part D, the number and percentages of patients switched to Part B or Part C will be 
summarized. 
3.3.2 Protocol Deviations 
Any major protocol deviation will be documented as described in the protocol deviation plan, and its 
impact on population for any patient will be specified. The final list of protocol deviations impacting the 
analysis populations will be reviewed prior to database lock.  Counts and percentages of patients with 
major protocol deviations by deviation category will be summarized. 
Major protocol deviations related to COVID-19 will be flagged.  
In addition, study visits not performed, performed remotely, performed at an alternative location, and 
visits delayed or partially completed will be listed. Patients or treatment discontinued related to COVID-
19 will also be listed. 
3.3.3 Analysis Populations 
The analyses of safety data will be performed on the safety population and DLT evaluable population 
when applicable. 
The analyses of anti-tumour activity and exploratory efficacy assessments will be performed on efficacy 
population. 
The analyses of pharmacodynamic parameters will be performed on pharmacodynamic population. 
3.3.4 Demographic and Baseline Characteristics 
All demographic and baseline characteristics will be listed for all screened patients. 
Summary statistics will be provided for demographic and baseline characteristics for the safety population 
and repeated for each analysis population if they are different from the safety population.  
Demographic characteristics will include 
• 
age (years),  
• 
sex (male, female), 
• 
ethnicity (Hispanic or Latino, Not Hispanic or Latino, not reported), 
• 
race (Asian, American Indian or Alaska Native, Black or African American, Native Hawaiian or 
Other Pacific Islander, White, not reported, Other), 
• 
weight (kg), 
• 
height (cm) 
• 
body mass index (BMI) in kg/m2, 
• 
ECOG performance status (0, 1, 2, 3, 4) 
• 
Baseline disease characteristics will include  
• 
primary disease cancer type (breast cancer, ovarian cancer, renal cell carcinoma, non-
small cell lung cancer, head and neck cancer, urothelial carcinoma, hepatocellular 
carcinoma, other) 


IPSEN GROUP 
CONFIDENTIAL 
Statistical Analysis Plan 
D-US-60090-001 
 
Version 2.0, 17 December 2020 
Page 33 of 48 
 
• 
time from initial diagnosis of primary disease until the informed consent date (months) 
• 
time from first relapse after last treatment until the informed consent date (months) 
• 
Classification of Malignant Tumours (TNM) Staging for tumour, node, metastasis at 
diagnosis and at screening 
• 
mutations prior screening assessment (wild type, mutated, not tested) 
• 
ASNS grade (0, 1, 2, 3) 
• 
ASNS H-score (0-300) 
• 
prior chemotherapy for cancer (yes, no) 
• 
prior hormonal therapy for cancer (yes, no) 
• 
prior immunotherapy for cancer (yes, no) 
• 
prior radiotherapy for cancer (yes, no) 
• 
prior surgical procedures for cancer (yes, no) 
• 
Best response to prior chemotherapy, hormonal, immunotherapy (CR, PR, SD, 
progressive disease (PD), inevaluable (NE), not available (NA)) 
• 
pembrolizumab antibody (positive, negative) for Part B only 
3.3.5 Medical or Surgical History 
Medical and surgical history will be coded initially using the latest version of MedDRA in use in Ipsen 
system. 
Listings will present the preferred term and verbatim text.  
A frequency table of the number and percentage of patients will be provided for medical and surgical 
history by primary system organ class and preferred term. 
3.3.6 Concomitant Medications 
Prior or concomitant therapy or medications. Prior, concomitant, and post-treatment medications are 
defined as following: 
• 
Prior medications will include medications which started prior to the first IPN60090 
administration date.  
• 
Concomitant medications will include medications taken any time from the first IPN60090 
administration date through 30 days following the last IPN60090 administration date or until the 
start of a subsequent anticancer therapy, whichever is earlier. Medications that started prior to the 
first dose of study drug but continued into treatment are considered concomitant. 
• 
Post-treatment medications will include medications taken any time after from the first IPN60090 
administration date through 30 days following the last IPN60090 administration date or until the 
start of a subsequent anticancer therapy, whichever is earlier. 
Prior and concomitant therapies will be coded using the latest version of WHO-Drug Dictionary in use in 
Ipsen system. The therapeutic class will correspond to the second level of ATC code, which is, 
corresponding to the first 3 figures of ATC code. 
Listings will be presented for the therapeutic class, preferred term and verbatim text.  
A frequency table of the number and percentage of patients will be provided for concomitant therapies by 
therapeutic class and preferred name for each cohort and cancer type. Prior, concomitant, and post-
treatment medications will be summarized separately.  


IPSEN GROUP 
CONFIDENTIAL 
Statistical Analysis Plan 
D-US-60090-001 
 
Version 2.0, 17 December 2020 
Page 34 of 48 
 
Anticancer treatment collected in eCRF during the follow-up period will be summarized separately.  
3.3.7 Study Drug Exposure and Compliance 
Number of treatment cycles completed by each patients will be summarized for each study drug 
(IPN60090, pembrolizumab, and paclitaxel). 
The number and percentage of patients with dose interruptions, missed doses, intra-subject dose 
escalations, intra-subject dose de-escalations, actual cumulative dose in mg for IPN60090 will be 
summarized. The number and percentage of patients with interruptions in i.v. infusion for pembrolizumab 
or paclitaxel will be summarized. 
All information collected on the eCRF related to IPN60090 administration, pembrolizumab infusion, and 
paclitaxel infusion including any dose interruptions or modifications, pembrolizumab infusion and 
paclitaxel infusion will be listed. 
3.4 Efficacy Assessment 
3.4.1 Anti-tumour Activity Evaluation 
Overall response at each time point captured on the tumour response eCRF will be used for the analysis 
and will not be programmatically derived using target and non-target lesions data. BOR will be derived at 
each time point. 
Overall response  and BOR at each time point will be presented in data listings. 
 
The efficacy proportions CBR, ORR and DCR will be summarized using descriptive statistics and will be 
graphically displayed if appropriate. The corresponding exact binomial 95% CI using the 
Clopper-Pearson method will be provided. 
In addition to the analyses described above, the best overall response (CR, PR, SD, PD, and NE for Part 
A, Part C, and Part D, and iCR, iPR, iSD, iUPD, iCPD and NE for Part B) will be summarized 
descriptively to show the number and percentage of subjects in each response category. 
The baseline and the best change (%) or largest reduction (%) from baseline in tumour size (sum of the 
diameters) of the target lesion will be summarized using descriptive statistics (n, mean, standard 
deviation, median, minimum, and maximum). Waterfall plots will be used to depict graphically for 
individual patients of their best change (%) or largest reduction (%) from baseline in the sum of the 
diameters in target lesions. Spider and swimmer plots will be used to display the change in tumour burden 
over time for individual patients and the occurrence of clinical outcomes of interest (e.g., tumour 
response, disease progression, treatment discontinuation, death). 
Time-to-event variables (PFS and OS), will be analysed using survival methods (Kaplan-Meier). The 
results will be presented both in summary tables and graphically in Kaplan-Meier plots. In addition, 95% 
CI for median duration using Greenwood’s formula will be provided. 
3.5 Pharmacodynamic parameters 
3.5.1 Target Engagement  
The target engagement or PD levels (Glu:Gln ratio in peripheral blood mononuclear cells (PBMC)) at 
each time point will be summarized descriptively. The number and percentage of patients with at least 
50%, 60%, 70%, 80%, and 90% inhibition of Glu:Gln ratio will be summarized. The maximum target 


IPSEN GROUP 
CONFIDENTIAL 
Statistical Analysis Plan 
D-US-60090-001 
 
Version 2.0, 17 December 2020 
Page 35 of 48 
 
engagement will be summarized using descriptive statistics (n, mean, standard deviation, median, 
minimum, and maximum). 
 
The correlation between the level of maximum target engagement Glu:Gln ratio and clinical outcome 
(efficacy and safety) will be explored. 
3.5.2 Biomarkers of Patient Stratification  
The number and percentage of patients in KEAP1/NRF2 mutant versus wild type will be summarized. 
The numbers and percentages of patients with all mutations for each indication collected from the eCRF 
will be summarized. 
The number and percentage of patients for the expression levels of ASNS, which could be presented as a 
grade from 0 to 3; and/or as a H-Score from 0 to 300, and/or as % of positive cells, will be summarized. 
Clinical outcomes (efficacy and safety) will be summarized by biomarker positive patients, biomarker 
negative patients and by tumor type. 
These will be summarized (1) by study part for dose escalation phase and by study part for expansion 
phase, (2) by pooling Parts A, Part B and Part C in escalation phase and pooling Parts A, Part B and Part 
C expansion phase, and (3) by pooling escalation phase, expansion phase and food effect cohort. 
Pharmacodynamic parameter tables will be presented in section 14.2. 
3.6 Pharmacokinetic Assessment and PK/PD Assessment 
3.6.1 PK Assessment Using NCA 
The PK data analysis will be detailed in a separate DAP and reported as a standalone report. 
3.6.2 PK Modeling 
The PK modeling data analysis will be detailed in a separate DAP and reported as a standalone report. 
3.6.3 PK/PD Modeling 
PK/PD modeling will be performed as feasible, to describe the relationships between relevant selected 
biomarkers, efficacy parameters, safety parameters, safety parameters and/or PK descriptors. The PK/PD 
plan will be detailed in the PK modeling plan and reported in the same standalone report than the PK 
modeling report. 
There will be two separate PK data analysis plans and reported as standalone reports, the NCA PK data 
analysis plan and Pop PK modeling and PK/PD modeling (including PK/QT modeling if needed). 
3.6.4 Dose Response Analysis 
A dose response will be performed to describe any relationship between the dose received and markers of 
the activity or of the response. This analysis will be performed for the dose escalation in Parts A, B and C. 
Part D data may be included in the dose response analysis. The dose response analysis will be detailed in 
a separate DAP and reported as a standalone report. 
3.7 Safety Assessment 
Unless otherwise specified, the safety analyses will be carried out on patients in the safety population. 


IPSEN GROUP 
CONFIDENTIAL 
Statistical Analysis Plan 
D-US-60090-001 
 
Version 2.0, 17 December 2020 
Page 36 of 48 
 
3.7.1 Adverse Events (AEs) 
Adverse events will be monitored from the time that the patient gives informed consent and throughout the 
study. Adverse events will be coded using the latest version of MedDRA in use in Ipsen system and graded 
according to NCI-CTCAE version 5.0. 
TEAE is defined as any AE that occurs during active phase of the study if: 
− 
It was not present prior to receiving the first administration of study drugs; or  
− 
It was present prior to receiving the first administration of study drugs but the 
intensity increased during the study; or 
− 
It was present prior to receiving the first administration of one of the study drugs, the 
intensity is the same but the drug relationship became related during the study. 
An overall summary table of all adverse events will be presented, which will summarize the number and 
percentages of patients and number of events of the following categories: 
• 
Any AEs, 
• 
Any TEAEs,  
• 
Any study treatment – related TEAEs,  
• 
NCI CTCAE grade 3/4/5 TEAEs,  
• 
Study treatment –related NCI CTCAE grade 3/4/5 TEAEs, 
• 
DLT TEAEs,  
• 
Deaths due to TEAEs,  
• 
Study treatment-related TEAEs leading to death,  
• 
Treatment-emergent SAEs,  
• 
Study treatment-related treatment-emergent SAEs,  
• 
Discontinuation of study treatment due to TEAEs,    
• 
Discontinuation of study treatment due to study treatment-related TEAEs,  
• 
Dose reduction due to TEAEs,  
• 
Dose reduction due to study treatment-related TEAEs,  
• 
Dose interruption due to TEAEs,  
• 
Dose interruption due to study treatment-related TEAEs, 
• 
Dose increased due to TEAEs,  
• 
Dose increased due to study treatment-related TEAEs, 
Summary tables of adverse events in each above category will be provided with the number and 
percentage of patients with adverse events and the number of events classified by primary system organ 
class, and preferred term and associated NCI/CTC worst grade. System organ classes are sorted by 
decreasing frequency. Preferred terms are sorted by decreasing frequency within each system organ class. 
In the event of multiple occurrences of the same adverse events being reported by the same patient, the 


IPSEN GROUP 
CONFIDENTIAL 
Statistical Analysis Plan 
D-US-60090-001 
 
Version 2.0, 17 December 2020 
Page 37 of 48 
 
maximum intensity (Grade 5 > Grade 4 > Grade 3 > Grade 2 > Grade 1 > missing > not applicable) and 
the most serious causality (related) will be chosen.  
Listings will be presented specifically for all adverse events, SAEs and TEAEs leading to discontinuation 
of study drug. 
3.7.2 Dose Limiting Toxicity 
DLTs during Cycle 1 will be summarized by cohort/dose level with the number and percentage of patients 
with DLTs classified by primary system organ class and preferred term. The number of occurrences of a 
DLT will also be presented. 
Listings of all DLTs will also be presented. 
DLTs will be captured in AEs eCRF page and used in the analysis. Programming check will be performed 
and reconciled prior to each SRC, database lock and analysis generation. 
3.7.3 Clinical Laboratory Tests 
During dose escalation part, all clinical safety laboratory tests will be performed at local laboratories. 
During dose expansion part, safety blood samples will be analysed centrally. 
Clinical laboratory parameters, including  
• 
Haematology: red blood cell count, haemoglobin, haematocrit, mean corpuscular volume, mean 
corpuscular, haemoglobin, mean corpuscular haemoglobin concentration, white blood cell (WBC) 
count, with differential (neutrophils, lymphocytes, monocytes, eosinophils, basophils and others) 
and platelet count. 
• 
Biochemistry: urea, creatinine, total bilirubin, conjugated bilirubin, chloride, bicarbonate, sodium, 
potassium, calcium, phosphate, ALP, AST, ALT, GGT, albumin total protein, total cholesterol, 
triglycerides, fasting glucose. Creatine clearance will be calculated using the Cockcroft-Gault 
equation and eGFR will be calculated based on serum creatinine levels using modification of diet 
in renal disease (MDRD) formula. 
• 
Urinalysis: pH, protein, ketones, bilirubin, blood, urobilinogen, nitrites, leukocytes, glucose and 
specific gravity by dipstick. 
A separate listing of normal ranges for SI units will be provided by gender and age where relevant. 
Hematological and biochemistry toxicities when available will be recorded and graded according to the 
NCI-CTC criteria, version 5.0. Laboratory data must be listed in Standard International (SI) units and also 
be listed in local units.  Abnormal values will be flagged (High, [H], Low [L], clinically significant [C], 
NCI-CTC grade (G)) where applicable. Any unscheduled laboratory assessments will be flagged [U] in 
the listings. 
Descriptive statistics will be provided for selected clinical laboratory test results (hematology, 
coagulation, and chemistry) and changes from baseline for the minimum post-baseline value, maximum 
post-baseline value, and last post-baseline value. Both scheduled and unscheduled post-baseline values 
will be considered for the summaries.  
Directional shifts in laboratory toxicity grades (comparing baseline grade with worst post-baseline grade) 
will be analyzed using standard shift tables, presenting number and proportion of patients and their 
maximum grade shift for selected laboratory parameters (ALT, AST, total bilirubin, ALP, creatinine, 


IPSEN GROUP 
CONFIDENTIAL 
Statistical Analysis Plan 
D-US-60090-001 
 
Version 2.0, 17 December 2020 
Page 38 of 48 
 
hemoglobin, absolute neutrophils, platelet counts, white blood cell counts, aPTT, and INR). Plots over 
time will also be presented for these selected laboratory parameters.  
The number and percentage of patients with the following potentially clinically significant abnormal liver 
function tests will be summarized: 
• 
ALT ≥3xULN, ≥5xULN, ≥10xULN, and ≥20xULN 
• 
AST ≥3xULN, ≥5xULN, ≥10xULN, and ≥20xULN 
• 
Total bilirubin ≥2xULN 
• 
ALT/AST ≥3×ULN with total bilirubin ≥2×ULN without elevation of ALP (< 2xULN) 
• 
ALT or AST ≥3xULN, total bilirubin ≥2xULN, and ALP ≥2xULN  
3.7.4 Vital Signs 
Baseline values will be defined as the last vital signs measurement collected prior to the first dose of 
study treatment.  
Vital signs include blood pressures, heart rate, respiratory rate and temperature.  
Summary statistics will be presented for baseline and changes from baseline for the minimum post-
baseline value, maximum post-baseline value. 
Vital signs will be listed at each assessment. Any unscheduled vital signs will be flagged [U] in the 
listing.   
3.7.5 Electrocardiograms 
Baseline will be defined as the last ECG measurement collected prior to the first dose of study treatment. 
Standard 12-lead ECG parameters include sinus rhythm (yes/no), RR interval, PR interval, QRS duration, 
QT interval, QTcF interval, QTcB interval, and interpretation of clinical significance. 
QTcB is the duration of the QT interval corrected for heart rate by Bazett’s formula: QTcB = QT/(RR)½; 
and QTcF is the duration of the QT interval corrected for heart rate by Fridericia’s formula: QTcF = 
QT/(RR)1/3. 
Number and percentage of patients with QTcF and QTcB intervals in the categories  below will be 
provided. 
• 
Absolute QTc interval >450 msec, 
• 
Absolute QTc interval >480 msec,  
• 
Absolute QTc interval >500 msec. 
• 
Change from baseline QTc interval increase >30 msec,  
• 
Change from baseline QTc interval increase >60 msec. 
For continuous ECG parameters, summary statistics will be presented for baseline and changes from 
baseline for the minimum post-baseline value and maximum post-baseline value. 
For interpretation of clinical significance (normal / abnormal, not clinically significant / abnormal, 
clinically significant / not evaluable), a frequency table will be presented at each post-dose assessment 
and for the worst value between post-dose assessments (abnormal, clinically significant > abnormal, not 
clinically significant > not evaluable). 


IPSEN GROUP 
CONFIDENTIAL 
Statistical Analysis Plan 
D-US-60090-001 
 
Version 2.0, 17 December 2020 
Page 39 of 48 
 
ECG results will be listed at each assessment. Any unscheduled ECG will be flagged [U] in the listings. 
For RR interval, PR interval, QRS duration, QT interval, QTcF interval, QTcB interval and the average of 
the three triplicate measurements will be used for summary. ECG results will be listed at each assessment.  
3.7.6 Physical Examinations 
Physical examinations include overall assessment and neurological status assessments (abnormal, not 
clinically significant / abnormal, clinically significant /normal). 
 A frequency table will be presented at each post-dose assessment and for the worst value between post-
dose assessments (abnormal, clinically significant > abnormal, not clinically significant > normal > not 
evaluable). 
3.7.7 Local Tolerance at Infusion site 
Local tolerance of pembrolizumab or paclitaxel infusions for Parts B and C include assessments for 
characteristics such as tenderness, erythema, swelling, rash, pain, itching, induration, haematoma, 
ulceration or necrosis, and the extent of erythema, haematoma, rash, ulceration or necrosis using the 
measurement of maximum length and maximum width. 
For Parts B and C, number and percentage of patients with any infusion site reactions and each type of 
infusion site reaction (tenderness, erythema, swelling, rash, pain, itching, induration, haematoma, 
ulceration or necrosis) will be tabulated.   
3.7.8 ECOG Performance Status 
The frequency and percentage of patients with each performance status score will be displayed by visit. A 
shift table presenting the shift from baseline to worst post-baseline score will also be presented.  
A listing of ECOG will be provided. 
3.7.9 Echocardiogram 
Echocardiogram (ECHO) or multigated acquisition (MUGA) parameters include left ventricle ejection 
fraction (LVEF) (%) and interpretation of clinical significance. 
For echocardiogram assessments (abnormal, not clinically significant / abnormal, clinically significant 
/normal), a frequency table will be presented at each post-dose assessment and for the worst value 
between post-dose assessments (abnormal, clinically significant > abnormal, not clinically significant > 
normal > not evaluable).  
For LVEF (%), summary statistics will be presented at each scheduled assessment for actual values and 
changes from baseline. The number and percentage of patients with LVEF less than 50% will be 
summarized at Screening and the end of study. 
3.7.10 Antidrug Antibodies for Pembrolizumab (Part B only) 
Antidrug antibodies (ADA) for pembrolizumab (Part B), anti-pembrolizumab antibodies, include both 
binding and neutralizing. 
The number and percentage of patients with the presence of anti-pembrolizumab antibodies (both binding 
and neutralizing) at baseline will be summarized. The number of seroconverters (patients having a 
negative result at Screening and at least one positive result at any post-treatment timepoint) for binding 
and neutralizing antibodies will be summarized.  


IPSEN GROUP 
CONFIDENTIAL 
Statistical Analysis Plan 
D-US-60090-001 
 
Version 2.0, 17 December 2020 
Page 40 of 48 
 
3.8 Exploratory Assessments 
The exploratory biomarker data analysis will be detailed in a separate DAP and reported as a standalone 
report. 
Exploratory IPN60090 concentrations in urine in Part A of dose escalation data analysis will be detailed 
in a separate DAP and reported as a standalone report also. 
3.9 Biobanking 
Analysis of biobank samples will be performed outside the scope of the main study and reported 
separately. 
3.10 Subgroups 
Clinical outcomes (efficacy and safety) will be summarized by the following subgroups: 
• 
biomarker positive and negative 
• 
tumor type.  
Additional subgroups could be considered if needed. All patients treated at PD active doses (i.e. at least 
50% inhibition of Glu:Gln ratio in PBMCs at Ctrough on Day 14 of Cycle 1 in 66% of patients treated at 
this dose level) will be pooled by Part in the escalation and the expansion phases.  
Subgroups analyses will also be performed for patients treated at PD active doses (1) by pooling Part A, 
Part B and Part C in escalation phase, (2) by pooling Parts A, Part B and Part C in expansion phase, and 
(3) by pooling escalation phase, expansion phase and food effect cohort. 
4 DATA SAFETY MONITORING BOARD 
4.1 Safety Review Committee 
Safety, in particular DLT occurrence, as well as PK and PD data will be reviewed on an ongoing basis 
during the dose escalation phases. An SRC will be set up at the end of each dose escalation cohort to 
review DLTs and overall safety data and judge the relevance of events to the dose escalation scheme. At 
the time of the SRC meeting, all cumulative available information will be reviewed. In case of emerging 
safety issues, the SRC will immediately be informed and an ad hoc SRC meeting may be organized. The 
composition of the SRC and its specific working procedures are described in a separate SRC charter 
established prior to the screening of the first patient. 
BOIN modelling of DLT rates will be performed before the planned review meetings in order to generate 
additional relevant information for the adaptive dose selection decisions. The SRC will review all 
available data and make the final decision as to dose escalation, de-escalation, or cohort expansion during 
the dose escalation. This group will also determine when to implement predefined stopping rules. 
4.2 Independent Safety Assessment Committee 
An independent safety assessment committee (ISAC) will be established to monitor the safety and 
progress of the study on a regular basis. The committee will operate independently from the Sponsor and 
the clinical investigators. To minimize the potential introduction of bias, these individuals will not have 
any direct contact with the study site personnel or patients. ISAC members will be selected for their 
expertise in oncology. 


IPSEN GROUP 
CONFIDENTIAL 
Statistical Analysis Plan 
D-US-60090-001 
 
Version 2.0, 17 December 2020 
Page 41 of 48 
 
The ISAC will meet and evaluate all available data once all patients in Stage 1 (n=10) of each respective 
cohort have either been on treatment for 12 weeks or have discontinued study treatment for any reason. 
Evaluation may be done sooner if enough CBR events at 12 weeks have occurred to inform a decision on 
moving to Stage 2, prior to all patients being enrolled. Upon evaluation, the ISAC will make the 
recommendation to the Sponsor based on the results of the analyses over continuation to Stage 2, or 
stoppage of the cohort. This decision will be made based on, but not limited to: safety events, any 
available results of PK, PD and tumour assessments (local and/or central). 
The ISAC will meet and evaluate all available data again once all patients in Stage 2 (n=18) of each 
respective cohort have either been on treatment for 12 weeks or have discontinued study treatment for any 
reason. Upon evaluation the ISAC will give a recommendation to further peruse the given drug 
combination and patient population in the clinical development plan, or to stop any further investigation. 
This decision will be made based on, but not limited to: safety events, any available results of PK, PD and 
tumour assessments (local and/or central). 
The ISAC will also be responsible for any adhoc assessments of safety and futility for each cohort, and 
can meet as needed to recommend protocol modifications, or any other actions including but not limited 
to: 
• 
Changing the eligibility criteria if the risks of the intervention seem to be higher in a subgroup; 
• 
Altering the drug product dosage and/or schedule if the AEs observed appear likely to be reduced 
by such changes; 
• 
Identifying information needed to inform current and future study patients of newly identified 
risks via changes in the ICF and, in some cases, obtaining reconsent of current patients for 
continued study participation. 
Further details regarding the ISAC and their requirements will be outlined in the ISAC charter. 
Both safety and anti-tumour activity of IPN60090 in patients in dose expansion cohorts as well as of 
patients from dose escalation receiving additional cycles of IPN60090 treatment will continue to be 
monitored by the SRC, and by the ISAC on an ongoing basis. 
5 INTERIM ANALYSIS 
An interim analysis will be performed at the end of the dose escalation to characterize the safety and 
define the RD but also to investigate preliminary anti-tumour activity in biomarker selected and 
unselected patients. 
As the expansion phase study will follow a 2-stage design, an interim analysis will be performed after the 
first 10 patients enrolled and have either been on treatment for 12 weeks or have discontinued study 
treatment for any reason. Evaluation may be done sooner if enough CBR events at 12 weeks have 
occurred to inform a decision on moving to Stage 2, prior to all patients being enrolled. Details of the 2-
stage design is described in section 2.2.7.3 and section 4.2.  
6 CHANGES FROM PROTOCOL-SPECIFIED STATISTICAL 
ANALYSES 
No changes affecting the statistical analysis defined in the protocol are made. 


IPSEN GROUP 
CONFIDENTIAL 
Statistical Analysis Plan 
D-US-60090-001 
 
Version 2.0, 17 December 2020 
Page 42 of 48 
 
7 PROGRAMMING SPECIFICATIONS 
Analyses will be performed using SAS® version 9.3 or higher.  All available data will be presented in 
patient data listings which will be sorted by patient and visit date as applicable.  Detailed Programming 
Specifications will be provided in a separate document. 
 
 


IPSEN GROUP 
CONFIDENTIAL 
Statistical Analysis Plan 
D-US-60090-001 
 
Version 2.0, 17 December 2020 
Page 43 of 48 
 
APPENDIX A:  REFERENCES 
1. 
Brookmeyer R, Crowley J. A Confidence Interval for the Median Survival Time. 
1982: 38: 29-41. 
2. 
Eisenhauera EA, Therasseb P, et al. New response evaluation criteria in solid 
tumours: Revised RECIST guideline (version 1.1). European Journal of Cancer 
2009; 45: 228 –247. 
3. 
Seymour L, Bogaerts J, Perrone A, et al. iRECIST: guidelines for response criteria 
for use in trials testing immunotherapeutics. Lancet Oncol 2017;18(3):e143-e152. 
4. 
Liu S and Yuan Y. Bayesian Optimal Interval Designs for Phase I Clinical Trials, 
Journal of the Royal Statistical Society. 2015. Series C. 64. 507-523. 
 
 


IPSEN GROUP 
CONFIDENTIAL 
Statistical Analysis Plan 
D-US-60090-001 
 
Version 2.0, 17 December 2020 
Page 44 of 48 
 
APPENDIX B: ASSESSMENT OF DISEASE RESPONSE USING RECIST, 
VERSION 1.1 
A summary of the overall tumor response calculation made by the investigator at each time point is 
summarized in Table B-1 for patients with target (± nontarget) disease, and Table B-2 for patients with 
nontarget disease only.  When no imaging/measurement is done at all at a particular time point, the 
patients will be considered inevaluable (NE) at that point.  If only a subset of target or nontarget lesion 
measurements are made at an assessment, the patient will be considered NE at that time point unless the 
contribution of the individual missing lesion(s) would not change the assigned time point response (eg, if 
a patient has a baseline sum of 50 mm with 3 measured lesions and at a follow-up time point only 2 
lesions are assessed, but these give a sum of 80 mm, the patient will have achieved progressive disease 
status, regardless of the contribution of the missing lesion).   
Table B-1: 
Time Point Response (Overall Response) for Patients with Target ± Nontarget 
Disease (Lesions) 
Target lesions 
Nontarget lesions 
New 
lesions 
Overall 
response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD/not all evaluated 
No 
PR 
Stable 
Non-PD/not all evaluated 
No 
Stable 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response; NE = inevaluable; PD = progressive disease; PR = partial response 
Source:  Eisenhauer 2009 
Table B-2: 
Time Point Response (Overall Response) for Patients with Nontarget Disease Only 
(Non Target Lesions) 
Nontarget lesions 
New lesions 
Overall response 
CR 
No 
CR 
Non-CR/Non-PD 
No 
Non-CR/Non-PD1 
Not all evaluated 
No 
NE 
PD 
Yes or No 
PD 
Any 
Yes 
PD 
CR = complete response; NE = inevaluable; PD = progressive disease 
Non-CR/Non-PD refers to stable disease 
Source:  Eisenhauer 2009 
A summary of the best overall tumor response calculation is provided in Table B-3 
Unless specified otherwise, tumor assessments will be excluded from the BOR calculation if they occur 
after the start of other anticancer therapy or surgical intervention.   


IPSEN GROUP 
CONFIDENTIAL 
Statistical Analysis Plan 
D-US-60090-001 
 
Version 2.0, 17 December 2020 
Page 45 of 48 
 
BOR will be classified as NE for patients with early progression or early death.  Early progression will 
include patients who discontinue study drug due to worsening disease but without objective evidence of 
disease progression, and their BOR cannot be determined because tumor assessments were either 
incomplete or were never performed or not repeated.  Similarly, early death will include patients who die 
without objective evidence of disease progression beforehand, and their BOR cannot be determined 
because tumor assessments were either incomplete or were never performed or were not repeated. 
Table B-3: 
Best Overall Response 
Overall response 
First time point 
Overall response 
Subsequent time 
point 
Best overall response 
CR 
CR 
CR 
CR 
PR 
Stable, PD, or PR1 
CR 
Stable 
Stable provided that minimum criteria for Stable 
duration met.  Otherwise PD. 
CR 
PD 
Stable provided that minimum criteria for Stable 
duration met.  Otherwise PD. 
CR 
NE 
Stable provided that minimum criteria for Stable 
duration met.  Otherwise PD. 
PR 
CR2 
PR 
PR 
PR 
PR 
PR 
Stable 
Stable 
PR 
PD 
Stable provided that minimum criteria for Stable 
duration met.  Otherwise PD. 
PR 
NE 
Stable provided that minimum criteria for Stable 
duration met.  Otherwise PD. 
NE 
NE 
NE 
CR = complete response; NE = inevaluable; PD = progressive disease; PR = partial response 
1 If a CR is truly met at a first time point, then any disease seen at a subsequent time point, 
even disease meeting PR criteria relative to baseline, makes the disease PD at that point 
(since disease must have reappeared after CR).  Best response will depend on whether 
minimum duration of Stable is met.  However, sometimes ‘CR’ may be claimed when 
subsequent scans suggest small lesions were likely still present and in fact the patient has 
PR, not CR at the first time point.  Under these circumstances, the original CR will be 
changed to PR and the best response is PR. 
2 Every effort will be made to confirm the CR.  For such cases where CR is not subsequently 
confirmed, then best overall response is PR.   
Source:  Eisenhauer 2009 
 


IPSEN GROUP 
CONFIDENTIAL 
Statistical Analysis Plan 
D-US-60090-001 
 
Version 2.0, 17 December 2020 
Page 46 of 48 
 
APPENDIX C: ASSESSMENT OF DISEASE RESPONSE USING IRECIST 
The principles used to establish objective tumor response are largely unchanged from RECIST 1.1, but 
the major change for iRECIST is the concept of resetting the bar if RECIST 1.1 progression is followed at 
the next assessment by tumor shrinkage. iRECIST define iUPD on the basis of RECIST 1.1 principles; 
however, iUPD requires confirmation, which is done on the basis of observing either a further increase in 
size (or in the number of new lesions) in the lesion category in which progression was first identified in 
(ie, target or non-target disease), or progression (defined by RECIST 1.1) in lesion categories that had not 
previously met RECIST 1.1 progression criteria. However, if progression is not confirmed, but instead 
tumor shrinkage occurs (compared with baseline), which meets the criteria of iCR, iPR, or iSD, then the 
bar is reset so that iUPD needs to occur again (compared with nadir values) and then be confirmed (by 
further growth) at the next assessment for iCPD to be assigned. If no change in tumor size or extent from 
iUPD occurs, then the timepoint response would again be iUPD. This approach allows atypical responses, 
such as delayed responses that occur after pseudoprogression, to be identified, further understood, and 
better characterized. 
Table C-1: 
Comparison Between RECIST 1.1 and iRECIST 
 
RECIST 1.1 
iRECIST 
Definition of measurable 
and non-measurable 
disease; numbers and site 
of target disease  
Measurable lesions are 10 mm in 
diameter (15 mm for nodal 
lesions); maximum of 5 lesions (2 
per organ); all other disease is 
considered non-target (must be 10 
mm in short axis for nodal disease) 
No change from RECIST 1.1; however, new lesions are 
assessed as per RECIST 1.1 but are recorded separately 
on the case report form (but not included in the sum of 
lesions for target lesions identified at baseline) 
CR, PR, or SD 
Cannot have met criteria for 
progression before CR, PR, or SD 
Can have had iUPD (1 or more instances), but not iCPD, 
before iCR, iPR, or iSD 
Confirmation of CR or 
PR 
Required 
As per RECIST 1.1  
Confirmation of SD 
Not required 
Not required 
New lesions 
Result in progression; recorded but 
not measured 
New lesions should be assessed and categorized as 
measurable or non-measurable using RECIST 1.1. New 
lesions result in iUPD, but iCPD is only assigned on the 
basis of this category if at the next assessment, additional 
new lesions appear or an increase in size of new lesions is 
seen (5 mm for the sum of new lesion target or any 
increase in new lesion non-target); the appearance of new 
lesions, when none have previously been recorded, can 
also confirm iCPD.  
Confirmation of 
progression 
Not required (unless equivocal) 
The next imaging assessment should be performed at 4 
weeks but 8 weeks after iUPD. Progression is confirmed 
if the next imaging assessment confirms a further increase 
in size of at least 5 mm in the lesion category in which 
progression was first identified, or progression in a lesion 
category that had not previously met RECIST 1.1 
progression criteria, or development of new lesions. 
However, the criteria for iCPD (after iUPD) are not 
considered to have been met if iCR, iPR, or iSD criteria 
(compared with baseline and as defined by RECIST 1.1) 
are met at the next assessment after iUPD. The status is 
then reset and iCR, iPR, or iSD should be documented. 
Consideration of clinical 
status 
Not included in assessment 
Clinical stability is considered when deciding whether 
treatment is continued after iUPD 
Abbreviations: CR, complete response; iCPD, confirmed progression assigned using iRECIST; iCR, complete response 
assigned using iRECIST; iPR, partial response assigned using iRECIST; iSD, stable disease assigned using iRECIST; iUPD, 
unconfirmed progression assigned using iRECIST; PR, partial response; RECIST, Response Evaluation Criteria in Solid 
Tumors; SD, stable disease. 


IPSEN GROUP 
CONFIDENTIAL 
Statistical Analysis Plan 
D-US-60090-001 
 
Version 2.0, 17 December 2020 
Page 47 of 48 
 
Table C-2: 
Assignment of Timepoint Response Using iRECIST 
 
Timepoint response with no previous 
iUPD in any category 
Timepoint response with previous 
iUPD in any category*  
Target lesions: iCR; non-target lesions: 
iCR; new lesions: no 
iCR 
iCR 
Target lesions: iCR; non-target lesions: 
non-iCR/non-iUPD; new lesions: no 
iPR 
iPR 
Target lesions: iPR; non-target lesions: 
non-iCR/non-iUPD; new lesions: no 
iPR 
iPR 
Target lesions: iSD; non-target lesions: 
non-iCR/non-iUPD; new lesions: no 
iSD 
iSD 
Target lesions: iUPD with no change, or 
with a decrease from last timepoint; 
non-target lesions: iUPD with no 
change, or decrease from last timepoint; 
new lesions: yes 
Not applicable 
New lesions confirm iCPD if new 
lesions were previously identified and 
they have increased in size (≥5 mm in 
sum of measures for new lesion target or 
any increase for new lesion non-target) 
or number; if no change is seen in new 
lesions (size or number) from last 
timepoint, assignment remains iUPD 
Target 
lesions: 
iSD, 
iPR, 
iCR; 
non-target lesions: iUPD; new lesions: 
no 
iUPD 
Remains 
iUPD 
unless 
iCPD 
is 
confirmed on the basis of a further 
increase in the size of non-target disease 
(does not need to meet RECIST 1.1 
criteria for unequivocal progression) 
Target 
lesions: 
iUPD; 
non-target 
lesions: non-iCR/non-iUPD, or iCR; 
new lesions: no 
iUPD 
Remains 
iUPD 
unless 
iCPD 
is 
confirmed on the basis of a further 
increase in sum of measures ≥5 mm; 
otherwise, assignment remains iUPD 
Target 
lesions: 
iUPD; 
non-target 
lesions: iUPD; new lesions: no 
iUPD 
Remains 
iUPD 
unless 
iCPD 
is 
confirmed based on a further increase in 
previously identified target lesion iUPD 
in sum of measures ≥5 mm or non-target 
lesion iUPD (previous assessment need 
not 
have 
shown 
unequivocal 
progression) 
Target 
lesions: 
iUPD; 
non-target 
lesions: iUPD; new lesions: yes 
iUPD 
Remains 
iUPD 
unless 
iCPD 
is 
confirmed on the basis of a further 
increase in previously identified target 
lesion iUPD sum of measures ≥5 mm, 
previously identified non-target lesion 
iUPD 
(does 
not 
need 
to 
be 
unequivocal), or an increase in the size 
or number of new lesions previously 
identified 
Target 
lesions: 
non-iUPD 
or 
progression; non-target lesions: non-
iUPD or progression; new lesions: yes  
iUPD 
Remains 
iUPD 
unless 
iCPD 
is 
confirmed on the basis of an increase in 
the size or number of new lesions 
previously identified  
Target lesions, non-target lesions, and new lesions defined according to RECIST 1.1 principles; if no pseudoprogression occurs, 
RECIST 1.1 and iRECIST categories for complete response, partial response, and stable disease would be the same. *Previously 
identified in assessment immediately before this timepoint. “i” indicates immune responses assigned using iRECIST. 
iCR=complete response. iPR=partial response. iSD=stable disease. iUPD=unconfirmed progression. non-iCR/non-
iUPD=criteria for neither CR nor PD have been met. iCPD=confirmed progression. RECIST=Response Evaluation Criteria in 
Solid Tumours. 


 
 
 
 
Table C-3: Scenarios of assignments of best overall response using iRECIST 
 
Timepoint response 1 
Timepoint response 2 
Timepoint response 3 
Timepoint response 4 
Timepoint response 5 
iBOR 
Example 1 
iCR 
iCR, iPR, iUPD, or NE 
iCR, iPR, iUPD, or 
NE 
iUPD 
iCPD 
iCR 
Example 2 
iUPD  
iPR, iSD, or NE 
iCR 
iCR, iUPD, or NE 
iCR, iPR, iSD, iUPD, 
iCPD, or NE 
iCR 
Example 3 
iUPD 
iPR 
iPR, iSD, iUPD, or 
NE 
iPR, iSD, iUPD, NE, 
or iCPD 
iPR, iSD, iUPD, NE, 
or iCPD 
iPR 
Example 4 
iUPD 
iSD or NE 
iPR 
iPR, iSD, iUPD, or 
NE 
iPR, iSD, iUPD, 
iCPD, or NE 
iPR 
Example 5 
iUPD 
iSD 
iSD, iUPD, or NE 
iSD, iUPD, iCPD, or 
NE 
iSD, iUPD, iCPD, or 
NE 
iSD 
Example 6 
iUPD 
iCPD 
Any 
Any 
Any 
iCPD 
Example 7 
iUPD 
iUPD (no iCPD) 
iCPD 
Any 
Any 
iCPD 
Example 8 
iUPD 
NE 
NE 
NE 
NE 
iUPD 
Eight examples are presented for patients with target disease at baseline, but many more scenarios exist following the same principles. Table assumes a randomised 
study in which confirmation of complete response or partial response is not required. For patients with non-target disease only at baseline, only iCR or non-complete 
response or non-progression of disease can be assigned at each timepoint (not shown in the table for ease of presentation). “i” indicates immune responses assigned 
using iRECIST. iBOR=best overall response. iCR=complete response. iPR=partial response. NE=not evaluable. iUPD=unconfirmed progression. iCPD=confirmed 
progression. iSD=stable disease. RECIST=Response Evaluation Criteria in Solid Tumours. 
Source: Seymour L, et al. 2017.