Clinical trial NCT02567656
Conditions: Lymphoma, T-Cell, Peripheral Lymphoma, T-Cell, Cutaneous
Keywords: CTCL PTCL RP6530
Sponsor: Rhizen Pharmaceuticals SA
Start date: 2015-09-01; Completion date: 2018-12-10
Enrollment: 58 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate the safety, PK and efficacy of RP6530, a dual PI3K delta/gamma inhibitor in patients with relapsed and refractory T-cell Lymphoma.

Detailed description:
Safety: Treatment-Emergent AE; Treatment-Related AE, SAE and Clinical significant AE; Dose Limiting Toxicities (DLT). PK: Peak Plasma Concentration (Cmax), Area under the plasma concentration versus time curve (AUC), Time of Maximum concentration observed (Tmax). Efficacy: Overall Response Rate (ORR), Progression Free Survival (PFS), Overall Survival (OS) and Duration of Response.

Arms: arm 1: RP6530 administered orally twice a day.
Interventions: intervention 1: RP6530
Intervention descriptions: intervention 1: Tablet starting at 200 mg

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL  
 
Page 1 of 97 
                      PROTOCOL NO. RP6530-1401 
 
  
A Phase I/Ib, Dose Escalation Study to Evaluate Safety and Efficacy of 
RP6530, a dual PI3K δ/γ inhibitor, in Patients with Relapsed or Refractory T-
cell Lymphoma 
 
 
 
 
This document is a confidential communication of Rhizen Pharmaceuticals SA.  Acceptance of this 
document constitutes agreement by the recipient that no unpublished information contained herein shall 
be published or disclosed without prior written approval. 
 
 
 
 
PROTOCOL NUMBER: 
RP6530-1401 
TRIAL DRUG: 
RP6530 
IND NUMBER  
124584 
 
SPONSOR: 
 
  
 
PRINCIPAL INVESTIGATOR  
 
 
 
SPONSOR’S MEDICAL EXPERT 
 
 
 
VERSION : 
 
Version 7.0,  Dated 23 May 2018 


Protocol No. RP6530-1401 
 
Rhizen Pharmaceuticals SA 
Version 7,  Dated 23 May 2018 
CONFIDENTIAL  
 
Page 2 of 97 
Clinical Trial Protocol Statement of Compliance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This clinical trial shall be conducted in compliance with the protocol, as referenced herein, 
and all applicable local, national, and international regulatory requirements to include, but 
not be limited to: 
 
 
International Conference on Harmonization (ICH) Guidelines on Good Clinical 
Practice (GCP) 
 
Ethical principles that have their origins in the Declaration of Helsinki  
 
<Food and Drug Administration (FDA) Code of Federal Regulation (CFR): 
o 
Title 21CFR Part 50 & 45 CFR Part 46, Protection of Human Subjects 
o 
Title 21CFR Part 54, Financial Disclosure by Clinical Investigators 
o 
Title 21CFR Part 56, Institutional Review Boards 
o 
Title 21CFR Part 312, Investigational New Drug Application 
o 
Title 45 CFR Parts 160, 162, and 164, Health Insurance Portability and 
Accountability Act (HIPAA) 
 
As the PI/Co-PI/Investigator, I understand that my signature on the protocol constitutes my 
agreement and understanding of PI responsibilities to conduct the clinical trial in 
accordance to the protocol and applicable regulations.  Furthermore, it constitutes my 
understanding and agreement that any changes initiated by myself, without prior 
agreement in writing from the Sponsor, shall be defined as a deviation from the protocol, 
and shall be formally documented as such. 
 
 
As the Sposnor’s Medical Expert, I understand that my signature constitutes agreement and 
understanding of acceptance of the defined and contracted sponsor responsibilities to the 
CRO and the Study PI/Co-PI as defined by the protocol, applicable clinical trial agreements 
(CTA), and/or business contracts, but does not in any capacity relieve me of my 
responsibilities as the Sponsor.  Additionally, my signature constitutes my understanding 
and agreement that any changes to the protocol, CTA, or contracts shall be implemented 
timely with my review and approval prior to implementation. 
 


Protocol No. RP6530-1401 
 
Rhizen Pharmaceuticals SA 
Version 7,  Dated 23 May 2018 
CONFIDENTIAL  
 
Page 3 of 97 
Amendment history  
A Phase I/Ib, Dose Escalation Study to Evaluate Safety and Efficacy of 
RP6530, a dual PI3K δ/γ inhibitor, in Patients with Relapsed or Refractory T-
cell Lymphoma 
Amendment#
/date  
Reference to 
section  
Summary  
Rationale 
Amendment 
1/27 Jan 2014 
-Section 4.1: 
Inclusion criteria 
# 2 & synopsis 
Inclusion criteria # 2 is updated to: 
Disease status defined as: 
 
Refractory to or relapsed after 
≥ 1 prior treatment lines.  
 
Patients are not eligible for 
transplantation or any standard therapy 
and / or approved known to be life 
prolonging or life saving (patients who 
are eligible for transplantation or any 
standard and /or approved therapy 
known to be life prolonging or life-
saving and have declined 
transplantation or any standard and /or 
approved therapy known to be life 
prolonging or life saving are eligible 
for the study) 
In order to accommodate 
the use of approved 
therapies prior to 
enrollment of patients on 
the study, the inclusion 
criterion is updated as per 
the directive of regulatory 
authority.  - 
Amendment 
1/31 Jan 2015 
Section 6.2: 
Adverse 
event/SAE 
causality 
assessment &  
synopsis 
The causality assessment is updated as follows: 
For this study, the causality will be assessed as 
related and not related.  
Related: All toxicities should be considered to 
be related to RP6530 unless there is a clear 
alternative explanation.   
Not related: If there is no temporal association, 
or another etiology has been identified as the 
cause, or the trial treatment cannot be implicated 
based upon the current information. 
As a part of causality 
assessment, the updated 
criterion will be used to 
determine the relationship 
of adverse event with 
study drug as per the 
directive of regulatory 
authority.   
Amendment 
1/31 Jan 2015 
Section 6.6: Dose 
Limiting toxicity 
&  synopsis 
The following sentence is added for safety 
assessment. 
All toxicities should be considered to be 
related to RP6530 unless there is a clear 
alternative explanation. A toxicity will be 
considered dose-limiting if it occurs during the 
first Cycle (4-weeks) treatment with RP6530 and 
is considered related to RP6530. 
As a part of causality 
assessment, the updated 
criterion will be used to 
determine the relationship 
of adverse event with 
study drug as per the 
directive of regulatory 
authority.   
 
 


Protocol No. RP6530-1401 
 
Rhizen Pharmaceuticals SA 
Version 7,  Dated 23 May 2018 
CONFIDENTIAL  
 
Page 4 of 97 
Amendment#/d
ate  
Reference to 
section  
Summary  
Rationale 
Amendment 
2/21 May 2015 
Section 3.3.1: 
Dose 
Escalation 
procedure  
The dose escalation criteria and optimal dose 
are clarified. 
If two of the first 3 patients in a cohort 
experience a DLT, that dose level will be 
defined as exceeding MTD, no further dose 
escalation will occur.  The previous dose level 
will be considered the MTD and will be 
expanded to further elucidate safety, to define 
PK, and to evaluate efficacy. 
An optimal dose is defined as the threshold dose 
at which the study drug is clinically active / 
efficacious (shows complete response or partial 
response) in a specific disease population and is 
at or below the maximum tolerated dose. 
The dose escalation 
criteria and optimal dose 
are clarified as requested 
by the Clinical Research 
Committee (CRC) of 
MDACC.   
 
Section 3.6.1 
Dosage form 
and strengths 
of IMP 
The strengths of tablet is corrected to 200 mg 
and 400 mg. 
Correction of typo error. 
 
Section 3.8 
Study stopping 
rule 
Frequency of safety monitoring by DRG in 
expansion cohort is clarified.  
The DRG will continue to monitor toxicity for 
serious adverse events as well as for toxicity 
trends that may be of concern at interval of 3 
months from initiation of expansion cohort to 
completion of the study. Toxicity will be 
monitored across cohorts combined together, as 
the expansion will be done at the specific dose 
(either MTD or optimal dose). 
Frequency of monitoring 
safety in expansion cohort 
is clarified as requested by 
the Clinical Research 
Committee (CRC) of 
MDACC.   
 
Section D: 
Schedule of 
assessment  
The table of “schedule of assessment” is 
simplified and typo errors are corrected to 
match the text with study protocol 
- 
Amendment 3/ 
20 January 
2016 
Synopsis 
Dose Level -1 is corrected to 100 mg BID 
Correction of typo error. 
 
Contact 
information  
Clinical laboratory information has been updated 
Protocol clarification 
 
Section 4.1 
Inclusion 
criteria 
Inclusion criteria # 9 is corrected.  
Female patients of child-bearing potential, and 
all male partners must consent to use a medically 
acceptable method of contraception throughout 
the study period and for 4 weeks plus 5T1/2 (48 
hrs) after the last dose of RP6530. A barrier 
method of contraception must be included. 
Correction of typo error 
 
Section 8.2 
Screening  
The following sentence is updated.  
Patient registration will be done as per site’s 
practice. 
 
Sites 
will 
assign 
a 
patient 
identification number and dose level. 
Protocol clarification as 
study is expanded to other 
sites. 


Protocol No. RP6530-1401 
 
Rhizen Pharmaceuticals SA 
Version 7,  Dated 23 May 2018 
CONFIDENTIAL  
 
Page 5 of 97 
Amendment#/d
ate  
Reference to 
section  
Summary  
Rationale 
 
Section 8.3 
Laboratory 
investigations 
The sentence updated is updated to add local 
laboratory facilities. 
The investigations will be performed at MDACC 
laboratory/local laboratory or central laboratory 
as decided by sponsor. 
Sentence is updated to 
extend the study to the 
other sites 
 
Section 8.10 
Correlative/ 
Exploratory 
biomarkers 
The title is updated.  
 
 
Typo correction. 
 
Section 9.2 
Sample size 
determination 
and synopsis 
The sentence is updated as 
This trial will enroll up to 58 patients at 5-10 
sites 
New sites will be added to 
expedite recruitment 
 
Amendment 4/ 
25 April 2016 
Section 3.3.1 
Dose escalation 
procedure 
The additional cohort RP6530 800 mg with food 
(Cohort 3a) is added to dose escalation cohorts.  
Patients of subsequent cohorts (cohort 4 and 5) 
to receive the study drug after food. 
Dosing recommendations 
are in line with the 
findings of food effect 
study that suggests 
increased bio-availability 
of the study drug if 
administered after food as 
compared to fasting state. 
 
Section 3.3.2 
Intra dose 
escalation 
The following sentence is added in intra dose 
escalation 
At the discretion of treating investigator, dose 
escalation may be done in patient who received 
lower doses (de-escalation) due to safety reason. 
Protocol clarification 
 
Section 3.6.3 
Preparation 
and 
administration 
of 
investigational 
product  
Dosing recommendations are added for drug 
administration after food.  
In case of fasting cohorts, patients should 
swallow RP6530 tablets whole with a full glass 
(approximately 8 ounces) of water in a fasting 
state. In fed cohorts, RP6530 tablets will be self-
administered orally twice daily after food (30 
minutes after breakfast and dinner).  
Dosing recommendations 
are updated.  
 
Section 4.1 
Inclusion 
criteria and 
synopsis 
Inclusion criteria #2 
Disease status defined as: 
 Refractory to or relapsed after ≥ 1 prior 
treatment lines.  
 Patients are not eligible for transplantation or 
any standard therapy and / or approved 
therapy known to be life prolonging or life 
saving (patients who are eligible for 
transplantation or any standard and /or 
approved therapy known to be life prolonging 
or life saving and have declined 
transplantation or any standard and /or 
approved therapy known to be life prolonging 
or life saving are eligible for the study) 
is updated to 
Disease status defined as: 
Protocol clarification 
 
 
 
 


Protocol No. RP6530-1401 
 
Rhizen Pharmaceuticals SA 
Version 7,  Dated 23 May 2018 
CONFIDENTIAL  
 
Page 6 of 97 
Amendment#/d
ate  
Reference to 
section  
Summary  
Rationale 
 Refractory to or relapsed after ≥ 1 prior 
standard therapy and/or FDA approved 
therapy.   
 
Section 5.2 
Concomitant 
medication 
The initiation or escalation of growth factor 
therapy is modified as 
Patients who have been on stable erythropoietin 
or darbepoetin therapy for two weeks preceding 
trial treatment may remain on the same dose 
during the first month. Growth factor therapy, if 
initiated in the first month for the treatment of 
study drug related AE (e.g. RP6530 related 
neutropenia), such patients will be discontinued. 
Protocol clarification 
 
Section 6.1: 
Adverse events 
Adverse events section is updated.   
All Grade 3 and grade 4 AE s irrespective of 
causality constitute clinically significant AE. 
Protocol clarification 
 
Section 6.4.: 
Recording of 
AE’s and SAE 
The reporting of persistent and recurrent AE’s is 
updated as follows 
If a persistent AE becomes more severe or 
lessens in severity, it should be recorded at once 
with highest grade of severity on a SAE Report 
Form and/or AE CRF.   
Protocol clarification 
 
Section 6.6.1 
Determination 
of dose limiting 
toxicity 
Minimum safety requirement for DLT is updated 
as follow. 
Minimum safety requirements will be met if, 
during Cycle 1 of treatment, 
 
The patient receives at least 80% of planned 
doses of RP6530 doses OR received 
RP6530 for the first 21 days continuously; 
 
Completes all required safety evaluations (at 
least for three visits after the first dose); 
 
And is observed for at least 28 days 
following the first dose of RP6530 in case of 
related adverse event. 
Protocol clarification 
 
Section 6.7 
Dose 
modifications 
The following sentences is updated in the dose 
modification section. 
If serum creatinine >3 x baseline or >3 x ULN, 
hold dose until ≤ grade 1. Monitor serum 
creatinine at least twice a week until resolution 
to ≤ grade 2, and then at least one week until it 
resolves to ≤ grade 1 
The following note is added 
Note: 
In 
the 
event 
of 
unrelated 
haematological/non-haematological 
toxicity 
(e.g. toxicity due to underlying disease condition 
or co-morbidity), the dose modification or dose 
delay will be done at the discretion of PI/CO-PI 
after evaluating the safety of the patient and need 
for dose modification 
Protocol clarification 


Protocol No. RP6530-1401 
 
Rhizen Pharmaceuticals SA 
Version 7,  Dated 23 May 2018 
CONFIDENTIAL  
 
Page 7 of 97 
Amendment#/d
ate  
Reference to 
section  
Summary  
Rationale 
 
Section 8.6 
Skin biopsy & 
Appendix D 
The following statement is updated to clarify the 
evaluation of TCR gene rearrangement in disease 
assessment. 
Clonality of TCR gene rearrangement will be 
evaluated as part of standard of care and will be 
an optional 
Protocol clarification 
 
Section 8.9 
Pharmacodyna
mics & 
Appendix D 
The statement is updated as 
PD samples (pAKT) will be performed on C1D1 
(pre-dose and 1 hr later), C1D8 (pre-dose) and 
C1D22 (pre-dose); C2D1 (pre-dose) and C3D1 
(pre-dose) and/ at EOT in five Sezary syndrome 
patients. 
Protocol clarification 
 
Section 8.10 
Correlative/ 
Exploratory 
biomarkers/ 
assessment & 
Appendix D 
The sentence is updated as  
Correlative biomarkers (e.g. sIL2R CTACK 
(PTCL); CD30 (MF), IL-31 and IL-32 (CTCL)) 
will be performed at screening, C3D1 (pre-dose 
and 1 hr later); at EOT and/ or to confirm a 
response. Blood will be collected for these 
biomarkers, serum aliquots will be prepared and 
shall be stored at below -700C until analysis. The 
decision to analyse the serum samples will be 
taken at later stage only if required or deemed 
necessary by the investigator/sponsor. 
Protocol clarification. 
 
 
Section 9.2 
Sample size 
determination 
and synopsis 
The sentence is updated as 
The actual number of dose cohorts will depend 
upon the MTD/optimal dose (or recommended 
dose). 
Protocol clarification 
 
- 
Correction of typo errors.  
- 
Amendment 4/ 
20 June 2016 
Section 
Contact 
Information 
The change of PI at MDACC.  
Dr. Mandeleine Duvic to Dr. Auris Huen  
Adminsitrative Change 
Appendix D 
Chemistry Panel I includes Total bilirubin, ALP, 
AST, ALT, GGT, LDH and Serum electrolytes 
(Sodium, Potassium, Bicarbonate, Chloride, 
Magnesium, Phosphorus and Calcium). 
Protocol clarification. 
Appendix D 
Lymph node biopsy or aspirate: The lymph node 
will be required to perform only if the diagnosis 
is not confirmed at the baseline; and if required 
at other time points.  
Protocol clarification 
Amendment 5/ 
18 April 2017 
Section 4.1: 
Inclusion 
criteria # 2 & 
synopsis 
Inclusion criteria # 2 is updated to: 
Disease status defined as: 
 
Refractory to or relapsed after ≥ 1 prior 
treatment lines.  
The inclusion criterion is 
updated as per the 
directive of regulatory 
authority.   


Protocol No. RP6530-1401 
 
Rhizen Pharmaceuticals SA 
Version 7,  Dated 23 May 2018 
CONFIDENTIAL  
 
Page 8 of 97 
Amendment#/d
ate  
Reference to 
section  
Summary  
Rationale 
 
Patients 
who 
are 
not 
eligible 
for 
transplantation or any standard and / or 
approved therapy known to be life 
prolonging or life saving (patients who may 
be eligible for transplantation or any 
standard and /or approved therapy but have 
declined therapy, or in the investigators 
opinion based on the patient’s condition, an 
investigational therapy may benefit more 
than existing approved therapies are 
eligible for the study).   
 
Section: 
Contact 
information  
Change of Medical monitor. Neil Sankar, MD 
will be the medical monitor of the study.   
Administrative change  
 
Section 3.2 and 
3.3: Trial 
Design  
Dose Escalation schedule is updated and the dose 
of Dose Expansion is defined.  
RP6530 800 mg BID 
(Fasting) is considered as a 
MTD dose in patients with 
T-cell lymphoma. 
Therefore, this dose will 
be used for Dose 
Expansion.  
 
Section 6.3 
RP6530 Dose 
Modifications 
for Non-
Hematologic 
Toxicities 
 
Algorithm (Appendix M) for monitoring liver 
enzymes has been added.  
 
Grade III elevation of ALT 
and/or AST have been 
observed with RP6530 
treatment in Dose 
Escalation. Most 
transaminase elevations 
were reversible with dose 
interruption. Multiple lines 
of evidence from literature 
suggest that this 
hepatotoxicity was 
immune mediated.  
In in view of this, frequent 
monitoring of liver 
enzymes is recommended 
in patient presenting with 
transaminitis. Steroid can 
be initiated by the 
investigator after clinical 
evaluation of patient. 
 
Section 8: Trial 
assessment and 
treatment and 
Appendix D 
The procedures to be performed in Dose 
Expansion is defined. 
Protocol clarification  


Protocol No. RP6530-1401 
 
Rhizen Pharmaceuticals SA 
Version 7,  Dated 23 May 2018 
CONFIDENTIAL  
 
Page 9 of 97 
Amendment#/d
ate  
Reference to 
section  
Summary  
Rationale 
Amendment 
6, Dated 23 
May 2018 
 
 
Section 8: 
Design of trial 
The criteria for study closure is defined as 
follow:  
The study will end when all ongoing subjects 
have reached their third tumor assessment on 
Cycle 8/Day 1 (C8D1) or have discontinued 
treatment due to any reason, whichever is 
earlier.  At the end of the study, all ongoing 
patients will be given the opportunity to enroll 
in an open-label compassionate use study 
protocol. 
Protocol clarification  
Section 8: Trial 
assessment and 
treatment and 
Appendix D 
The post Cycle 8 procedures related to safety, 
efficacy and drug administration has been 
clarified. 
 
Clarification for laboratory investigations added. 
Protocol clarification  
 
Administrative changes or safety updates added. 
Administrative change 
 
 
 
 
 
 
 
 


Protocol No. RP6530-1401 
 
Rhizen Pharmaceuticals SA 
Version 7,  Dated 23 May 2018 
CONFIDENTIAL  
 
Page 10 of 97 
 
Clinical Trial Protocol Approval Page 
A Phase I/Ib, Dose Escalation Study to Evaluate Safety and Efficacy of 
RP6530, a dual PI3K δ/γ inhibitor, in Patients with Relapsed or Refractory T-
cell Lymphoma 
 
 
 
PROTOCOL NUMBER: 
 
RP6530-1401 
TRIAL DRUG: 
RP6530 
 
IND NUMBER: 
 
124584 
 
 
               
 
 
 
 
 
 
 
 
 
___________________________________________________ 
 
 
 
______________________________________________________________________________________ 
Sponsor’s Medical Expert  
 
 
Signature 
 
 
Date             
 
 
 
 
 
 
 
  
___________________________________________________ 
 
 
 
______________________________________________________________________________________ 
Sponsor’s Representative   
 
 
Signature 
 
 
Date             
 
 
 
 
 
 
 
 
          
_____________________________________________________ 
 
 
 
______________________________________________________________________________________ 
Bio-statistician 
 
 
 
 
Signature 
 
 
Date             
 
 


Protocol No. RP6530-1401 
 
Rhizen Pharmaceuticals SA 
Version 7,  Dated 23 May 2018 
CONFIDENTIAL  
 
Page 11 of 97 
RP6530-1401 
Protocol Acceptance Form 
 
A Phase I/Ib, Dose Escalation Study to Evaluate Safety and Efficacy of 
RP6530, a dual PI3K δ/γ inhibitor, in Patients with Relapsed or Refractory T-
cell Lymphoma 
 
 
 
PROTOCOL NUMBER: 
 
RP6530-1401 
TRIAL DRUG: 
RP6530 
IND NUMBER: 
124584 
FINAL: 
 Version 7, Dated 23 May 2018 
 
 
 
 
 
 
 
         Principal Investigator 
 
Signature 
 
Dated     
 
 
  
 
 
 
 
 
 
      
 
 
 
 
 
 
  
 
 
 
 


Protocol No. RP6530-1401 
 
Rhizen Pharmaceuticals SA 
 Version 7, Dated 23 May 2018 
CONFIDENTIAL  
 
Page 12 of 97 
PROTOCOL SYNOPSIS 
Title of Trial: 
A Phase I/Ib, Dose Escalation Study to Evaluate Safety and Efficacy of RP6530, 
a dual PI3K δ/γ inhibitor, in Patients with Relapsed or Refractory T-cell 
Lymphoma 
IND Number  
124584 
Protocol 
Number: 
 RP6530-1401 
Sponsor: 
 Rhizen Pharmaceuticals SA 
Study Duration 
Approximately 10 months to accrue, plus follow-up  
Trial Population 
and Trial 
Centers: 
This study will be conducted in relapse/refractory T-cell lymphoma patients at  5-
10 US sites.  
Rationale: 
Phosphoinositide-3-kinases (PI3Ks) are pivotal in various cellular functions 
including cell proliferation and survival, cell differentiation, intracellular trafficking 
and immunity. The delta (δ) and gamma (γ) isoforms of PI3K are highly expressed 
in cells of hematopoietic origin, and often dysregulated in various hematologic 
malignancies. Because these isoforms contribute to the development, maintenance, 
transformation, and proliferation of immune cells, dual targeting of PI3K δ and γ 
represents a promising approach in the treatment of various lymphomas. RP6530 is 
a novel, highly specific dual PI3K δ/γ inhibitor with nanomolar inhibitory potency 
at the enzyme and cellular level. Besides, RP6530 is effective in inhibiting Akt 
phosphorylation and inducing apoptosis in various lymphoma and leukemic cell 
lines and patient derived primary CTCL cells. 
Study objectives  Primary Objective  
 
To evaluate the safety and the maximum tolerated dose (MTD) of RP6530   
in patients with relapsed/refractory T-cell lymphoma (PTCL/CTCL).  
 
To evaluate the pharmacokinetics (PK) of RP6530. 
Secondary Objectives 
 
To examine the pharmacodynamic (PD) effects of RP6530. 
 
To assess the overall response rate (ORR) and duration of response (DoR) 
in patients with relapsed/refractory T-cell lymphoma. 
Exploratory Objectives 
 
Correlation of treatment outcomes with biomarkers which include but are 
not limited to quantitative and qualitative measurements of cytokines, 
chemokines and aberrations indicative of PI3K function and RP6530 
efficacy. 
Study End 
Points 
 
Primary Endpoint  
 
AE, SAE, clinically significant AE and dose limiting toxicities (DLT). 
 
PK parameters (including AUC (0-∞), AUC (0- ), Cmax, tmax, λz, and t½) of RP6530 
Secondary end points  
 
Inhibition of pAKT by RP6530. 
 
ORR as defined as sum of CR and PR rates; and DoR. 
Exploratory end points 
 
Correlative biomarkers (e.g. serum cytokines and chemokines). 
Study Design 
This is a two part Phase 1/1b study. The first part is a Phase 1 dose escalation, 3+3 
design, open-label, MTD determination study of RP6530 in patients with 
relapsed/refractory T-cell lymphoma (PTCL/CTCL). The second part is Phase 1b, 
dose expansion, open label study to be conducted once the MTD/optimal dose has 
been confirmed in dose escalation phase. 20 patients of each indication will be 
enrolled (20 for PTCL and 20 for CTCL). Tablet RP6530 will be administered orally 


Protocol No. RP6530-1401 
 
Rhizen Pharmaceuticals SA 
 Version 7, Dated 23 May 2018 
CONFIDENTIAL  
 
Page 13 of 97 
twice a day in 28-days cycle in absence of disease progression, unacceptable 
toxicity, or withdrawal from treatment. 
 
Phase I Dose Escalation: 
Sequential dose escalation will begin with Cohort 1. A minimum of three patients 
of either CTCL or PTCL will be entered into each opened dose level (cohort).  The 
first cohort of patients will receive RP6530 at 200 mg twice a day (BID).  Dose 
levels will be increased in successive increments according to the dose escalation 
scheme in the Table below. Dose escalation will continue until the MTD/optiomal 
dose has been identified or as determined by the DRG based on the available 
safety, PK and/or efficacy data. Dose determination will be documented 
appropriately. 
 
Dose Escalation Schedule 
Dose Level 
Dose (RP6530)  
Dosing 
recommendation  
Patients (n) 
 1* 
         200 mg BID  
Fasting 
3-6 
2 
        400 mg BID 
Fasting  
3-6 
3 
        800 mg BID 
Fasting  
3-6 
3a 
        800 mg BID  
After food  
3-6 
*If not tolerated or DLT occurs in over 33% of patients treated, a dose level of -1 (i.e. 100 
mg BID) will be tested. 
** In fasting cohorts, patients will fast 2 hours prior to study drug administration and 1 
hour after administration. In Fed cohort (After food), patients to take study after food (30 
minutes after breakfast and dinner).  
Note:  
 
The actual number of dose cohorts explored will depend upon the MTD and the 
safety profile observed during the conduct of the trial. Intermediate dose levels 
and alternative dosing schedules may be explored if deemed appropriate. 
 
Intra-subject dose escalation will be performed once the higher dose is 
considered safe and tolerable.   
 
Phase Ib, dose expansion: 
Once the MTD/optimal dose has been confirmed, patients who complete the Dose 
Escalation Phase will be permitted to enter the expansion cohorts (Phase Ib).  
Additional CTCL and PTCL patients may be enrolled to reach a maximum of 58 
patients (including the Phase I patients) in each of the CTCL and PTCL groups.  
 
The DRG may recommend to the Sponsor early termination of a study group if none 
of the first 10 patients achieve an objective response (PR or >), or </= 6 of the first 
20 patients achieve an objective response (PR or >), by the second efficacy 
assessment which is estimated on Cycle 8/Day 1 (C8D1).   
 
Dose Expansion Schedule 
Dose Level 
Dose (RP6530) 
Patients (n) 
CTCL 
 RP6530 800 mg 
Fasting  
20  
PTCL 
 RP6530 800 mg 
Fasting  
20  


Protocol No. RP6530-1401 
 
Rhizen Pharmaceuticals SA 
 Version 7, Dated 23 May 2018 
CONFIDENTIAL  
 
Page 14 of 97 
Number of 
Patients: 
The study will enroll approximately 58 patients; up to 18 during the dose 
escalation phase and 40 patients in the expansion phase.    
Note: The total number of patienst in phase I may exceed depending on MTD. 
Trial Drug(s), 
Dose, and Mode 
of 
Administration: 
RP6530: Dosing will begin on Cycle 1/Day 1 (C1D1) with continuous oral twice 
daily dosing (BID) in 28 days cycle. The dose and schedule of RP6530 will be 
determined during the dose escalation phase of the study, depending on PK and 
safety assessments.   
RP6530 will be self-administered by the patients. Tablet (s) of relevant strength 
should be taken at approximately the same time each day. In case of fasting state,  
patients will fast 2 hours prior to study drug administration and 1 hour after 
administration. In case of Fed state (After food), patients to take study after food (30 
minutes after breakfast and dinner).  
 
The expected duration of subject participation in the study will be 8 months. 
Treatment will be continued in patients experiencing clinical benefit for 2 years 
unless progression of disease or toxicity warranting discontinuation of therapy. The 
decision to continue the treatment will be taken by PI-Co-PI  after consultation with 
Sponsor on case to case basis. 
 
The study will end when all ongoing subjects have reached their third tumor 
assessment on Cycle 8/Day 1 (C8D1) or have discontinued from the study for any 
reason, whichever is earlier. At the end of the study, all ongoing patients with no 
evident disease progression will be given the opportunity to enroll in an open-label 
compassionate use study protocol and will be followed up. 
Baseline Lab 
Evaluation 
(Local Lab) 
 
CBC with differential 
 
Serum chemistry 
 
Serology to rule out active Hepatitis B, C or HIV infection  
 
Serum pregnancy test 
Instrumental 
Tests 
 
Computed tomography (CT) (MRI/PET scan as required) at screening. disease 
will be assessed on C3D1 (± 7 days) and C5D1 (± 7 days)  and approximately 
12 weeks thereafter (± 7 days) and/ or at the EOT.  Assessment will be 
performed thereafter if warranted, at the disctetion of PI/Co-PI. 
 
Bone marrow biopsy at screening and EOT and as indicated by study protocol. 
 
Skin biopsy at screening, on C3D1 (± 7 days) and/or to confirm a complete 
response. 
Assessment of 
Response  
PTCL patients will be evaluated according to the International Working Group 
Revised Response Criteria for Malignant Lymphoma (IWG) Cheson et al. 2007). 
Bone marrow disease alone may be used to assess response, as determined by the 
morphology of repeat bone marrow biopsy. Assessment of CTCL response and 
progression will be evaluated according to the Response Criteria in Mycosis 
Fungoides and Se´zary Syndrome by the International Society for Cutaneous 
Lymphomas (ISCL), the United States Cutaneous Lymphoma Consortium 
(USCLC), and the Cutaneous Lymphoma Task Force of the European Organisation 
for Research and Treatment of Cancer (EORTC) ISCL/EORTC crietria. For skin 
scoring, the modified Severity Weighted Assessment Tool (mSWAT) will be 
used. For local index lesion skin scoring, the Composite Assessment of Index 
Lesion Severity will be used. Additional disease specific crieteria will be used if 
deemed necessary. 


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Dose-Limiting 
Toxicity  
 
Toxicity will be assessed according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) v4.0 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE). 
All toxicities should be considered to be related to RP6530 unless there is a 
clear alternative explanation. A toxicity will be considered dose-limiting if it 
occurs during the first cycle (4 weeks) of treatment with RP6530 and is considered 
possibly related to RP6530.  Dose-limiting toxicities will be defined as the 
following: 
 Hematological DLTs: 
 
Grade 4 Anaemia  
 
Grade 4 neutropenia (absolute neutrophil count [ANC] <500/µL) for 
>7 days, or Grade ≥3 febrile neutropenia (ANC <1000/µL with fever 
>38.5ºC [101ºF] 
 
Grade 4 thrombocytopenia for >7 days, or grade ≥3 thrombocytopenia 
associated with bleeding 
 Non-Hematological DLTs: 
 
Grade ≥3 non-hematologic toxicity with exception of:  
o Grade ≥3 diarrhea or nausea that does not resolve to ≤ Grade 2 within 
48 hours despite treatment; and  
o If ≥1.5 ULN of bilirubin or >3 ALT/AST elevation that does not 
resolve to ≤ Grade 1 within 7 days 
 Treatment delay of ≥14 days due to unresolved toxicity 
 Non-hematologic toxicity of Grade 2 (at any time during treatment) that in the 
judgment of the DRG, is dose-limiting. 
 For certain toxicities such as laboratory assessments without a clear clinical 
correlate (e.g. lipase increase without signs of a clinical pancreatitis) a 
discussion between the Investigator and Medical Monitor may take place if this 
adverse event (AE) should be assessed as DLT necessitating dose reduction. 
Inclusion 
Criteria: 
1. Histologically confirmed T cell Non-Hodgkin Lymphoma (T-NHL) as 
approved by the Medical Monitor or PI/Co-PI.  
2. Disease status defined as: 
 Refractory to or relapsed after ≥ 1 prior treatment lines.  
 Patients who are not eligible for transplantation or any 
standard and / or approved therapy known to be life 
prolonging or life saving (patients who may be eligible for 
transplantation or any standard and /or approved therapy 
but have declined therapy, or in the investigators opinion 
based on the patient’s condition, an investigational therapy 
may benefit more than existing approved therapies are 
eligible for the study).  
3. Patients with a measurable or evaluable disease. 
 In case of radiologically measurable lesions, the longest 
diameter should be ≥ 2 cm in PTCL patients. 
 PTCL patients with non-measurable lesions but assessable 
disease (e.g. marrow disease without other radiographically 
measurable disease) can be enrolled in dose-escalation phase as 
approved by PI/Co-PI. 
 


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4. Adequate organ system function, defined as follows: 
 Patients with haemoglobin levels and/or neutrophil and platelet 
counts under these values will be eligible in case abnormalities 
are due to tumor dissemination or infiltration and according to 
physician's discretion and  under his direct responsibility 
a. Hemoglobin ≥8 g/dL 
b. Absolute neutrophil count (ANC) ≥0.75 x 109/L  
c. Platelets ≥50 x 109/L 
 Total bilirubin ≤1.5 times the upper limit of normal (ULN)   
 Alanine aminotransferase (ALT) and aspartate aminotransferase 
(AST) ≤2.5 x ULN without liver involvement or 5 x the ULN if 
there is known liver involvement. 
 Creatinine  2.0 mg/dL OR calculated creatinine clearance 
50 mL/min as calculated by the Cockcroft-Gault method 
5. ECOG performance status ≤2. 
6. Life expectancy of at least 12 weeks. 
7. Patients must be 18 years of age. 
8. Ability to swallow and retain oral medication. 
9. Female patients who are not of child-bearing potential, and female 
patients of child-bearing potential  who have a negative serum 
pregnancy test within 72 hours prior to initial trial treatment.  Female 
patients of child-bearing potential, and all male partners must consent 
to use a medically acceptable method of contraception throughout the 
study period and for 4 weeks plus 5T1/2 (48 hrs) after the last dose of 
RP6530.  A barrier method of contraception must be included.    
10. Male patients willing to use adequate contraceptive measures throughout the 
study period and for  12 weeks plus 5T1/2 (48 hrs) after the last dose of 
RP6530. 
11. Willingness and ability to comply with trial and follow-up procedures. 
12. Ability to understand the nature of this trial and give written informed consent. 
Exclusion 
Criteria: 
 
1. Any cancer therapy (i.e., chemotherapy, radiation therapy, immunotherapy, 
biologic therapy, hormonal therapy, surgery and/or tumor embolization) in the 
last 3 weeks or the last 5T1/2 of the agent, whichever is shorter. Limited 
palliative radiation <2 weeks. 
2. Autologous hematologic stem cell transplant within 3 months of study entry.  
Allogeneic hematologic stem cell transplant within 12 months. Active graft-
versus-host disease.    
3. Active HBV, HCV or HIV infection.  
4. Use of an investigational drug in the last 4 weeks prior to the first dose of 
RP6530.    
5. Therapy with GS-1101 (CAL-101, idelalisib), IPI-145, TGR-1202 or any drug 
that specifically inhibits PI3K/ mTOR (including temsirolimus, everolimus), 
AKT or BTK Inhibitor (including Ibrutinib) in last 6 months.  
6. Patient has received wide field radiotherapy (including therapeutic 
radioisotopes such Yttrium-90) ≤ 28 days or limited field radiation for 
palliation ≤ 14 days prior to starting RP6530 or has not recovered from side 
effects of such therapy. 
 


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7. 
Ongoing immunosuppressive therapy including systemic corticosteroids 
(prednisone or equivalent ≤10 mg daily allowed as clinically warranted).  
Patients are allowed to use topical or inhaled corticosteroids. 
8. 
Known history of drug-induced liver injury, alcoholic liver disease, non-
alcoholic steatohepatitis, primary biliary cirrhosis, ongoing extrahepatic 
obstruction caused by stones, cirrhosis of the liver or portal hypertension. 
9. 
Patients with uncontrolled Diabetes Type I or Type II (HbA1c >8% assessed 
locally).  
10. Any severe and/or uncontrolled medical conditions or other conditions that 
could affect their participation in the study such as: 
 Symptomatic, or history of documented congestive heart failure 
(New York Heart Association functional classification III-IV) 
 QTcF > 470 msec 
 Angina not well-controlled by medication  
 Poorly controlled or clinically significant atherosclerotic 
vascular disease including cerebrovascular accident (CVA), 
transient ischemic attack (TIA), angioplasty, cardiac or vascular 
stenting in the past 6 months 
 Active or uncontrolled severe infections requiring IV antibiotics   
 Patients with hemophilia or Von Willebrand’s disease should be 
excluded. 
11. Herbal preparations/medications must be discontinued 7 days prior to first 
dose of study drug. 
12. Presence of other active cancers, or history of treatment for invasive cancer 
≤3 years.  Patients with stage I cancer who have received definitive local 
treatment at least 3 years previously, and are considered unlikely to recur are 
eligible.  All patients with previously treated in situ carcinoma (i.e. non-
invasive) are eligible, as are patients with history of non-melanoma skin 
cancer. 
13. Women who are pregnant or lactating. 
14. Psychological, familial, sociological, or geographical conditions that do not 
permit compliance with the protocol.  
15. Concurrent condition that in the investigator’s opinion would jeopardize 
compliance with the protocol. 
16. Inability or unwillingness to comply with study and/or follow-up procedures 
outlined in the protocol.   
Statistical 
Methodology: 
 
This is an open-label, dose-escalation study to determine the MTD (or 
recommended dose based on available safety, PK and response data) to support of 
dose determination for further clinical studies, and preliminary information on the 
safety profile; and to evaluate PK profile and anti-tumor activity of RP6530 given 
as a single agent in patients with T-cell lymphoma.  
This trial will enroll approximately 58 patients. The actual number of dose 
escalations will depend upon the MTD/optimal dose (or recommended dose). 
Biomarker 
Assessments: 
During the treatment blood samples will be taken for exploratory evaluation of 
relevant biomarkers.  The analyses for biomarkers are exploratory, and will not be 
used to guide treatment decisions.  The results may be pooled with data from other 
studies to generate hypotheses to be tested in future studies. 
 
 
 


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CONTACT INFORMATION 
SPONSOR: 
Rhizen Pharmaceuticals SA 
Fritz-Courvoisier 40, 
Ch-2300 La Chaux-de-Fonds,  
Switzerland. 
Tel +41 32 580 0113 
Fax +41 32 580 0175 
PRINCIPAL 
INVESTIGATOR   
STUDY SITE  
Auris Huen, MD 
Assistant Professor of Medicine and Dermatology, Division of Internal 
Medicine,  The University of Texas MD Anderson Cancer Center,  
Houston, TX 
TEL: 1 713- 745-113 
FAX: 1 713- 745-3597  
EMAIL:  aohuen@mdanderson.org 
SPONSOR 
REPRESENTATIVE 
Ajit Nair, PhD 
Rhizen Pharmaceuticals SA 
Fritz-Courvoisier 40, 
Ch-2300 La Chaux-de-Fonds,  
Switzerland. 
Tel +41 32 580 0113 
Fax +41 32 580 0175 
EMAIL: an@rhizen.com 
SPONSOR’S MEDICAL 
EXPERT  
Prajak Barde, MD 
Rhizen Pharmaceuticals SA 
Fritz-Courvoisier 40, 
Ch-2300 La Chaux-de-Fonds,  
Switzerland. 
Tel: +1 (301) 250-5591 
Fax +41 32 580 0175 
EMAIL: pjb@rhizen.com  
STATISTICIAN   
Michael Chen, PhD 
Consultant Statistician,  
Tel: +01 908 500 9334 
Fax: +41 32 967 9596 
CENTRAL CLINICAL 
LABORATORY FOR 
PK 
NorthEast Bioanalytical Laboratories 
925 Sherman Avenue, Hamden,  
CT 06514, USA  
 
 


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List of Abbreviations 
ADME 
absorption, distribution, metabolism, excretion 
AE 
adverse events 
ALL 
acute lymphoblastic leukemia 
ALP 
alkaline phosphatase 
ALT (SGOT) 
Alanine aminotransferase 
ANC 
absolute neutrophil count 
AST (SGPT) 
Aspartate aminotransferase 
ATP 
adenosine triphosphate 
AUC 
area under the curve 
AUC0-t 
 
area under the plasma-concentration time curve from zero up to 
the last measureable concentration 
AUClast 
area under the concentration time curve at last dose 
BID 
twice daily 
B-NHL 
B-non-hodgkins lymphoma 
BSA 
bovine serum albumin 
BTK 
bruton's tyrosine kinase 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CLL 
chronic lymphocytic leukemia 
Cmax 
peak drug concentration 
CRF 
case report form 
CSF 
colony-stimulating factor 
CTCL 
cutaneous T-Cell Lymphoma 
CTCAE 
Common Terminology Criteria for Adverse Events 
CT 
computerized tomography 
CVA 
cerebro vascular accident 
DRG 
Data Review Group  
DHEA 
Dehydroepiandrosterone 
DLT 
dose limiting toxicity 
DoR 
duration of response 
EC50 
the dose of a drug that is pharmacologically effective for a 50% 
response in a biological system 
ECG 
Electrocardiogram 
ECHO 
Echocardiography (EK-o-kar-de-OG-rah-fee) 
ECOG PS 
eastern cooperative oncology group performance status 
EORTC 
European Organisation For Research and Treatment of Cancer  
FACS 
fluorescence activated cell sorter 
FSH 
follicular stimulating harmone 
GCP 
good clinical practices 
GGT 
gamma glutamyl transpeptidase  
HBV 
hepatitis B virus 
HbA1c 
glycated hemoglobin 
HCV 
hepatitis C virus 
HDL 
high-density lipoprotein 
HIV 
human immune deficiency virus 
HNSTD 
Highest Non-Severely Toxic Dose 
HTRF 
homogeneous time resolved fluorescence 
IB 
investigator brochure  


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ICH 
International Conference on Harmonization 
IEC 
Independent ethics committee 
IMP 
investigational medicinal product 
ISF 
investigator site file 
ISCL 
International Society For Cutaneous Lymphomas 
ITT 
intent-to-treat 
IUD 
intrauterine device 
IUS 
intrauterine system 
LDH 
 lactate dehydrogenase 
LDL 
low-density lipoprotein 
LLN 
Lower Limit of Normal  
MTD 
maxmum tolerated dose 
MDACC 
MD Anderson Cancer Center  
MRI 
Magnetic Resonance Imaging  
MTT 
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide 
MF 
Mycosis Fungoides  
NCI 
national cancer institute 
nM 
nano molar 
NOAEL 
no-observed-adverse effect level 
NYHA 
new 20hos heart association 
ORR 
20hospho response rate 
pAKT 
20hosphor AKT 
PD 
Pharmacodynamics 
PET 
positron emission tomography 
PDGF 
platelet derived growth factor 
PFS 
progression-free survival 
PI 
principle investigator 
PI3K 
phosphoinositide-3-kinase 
Pis 
20hosphor inositid lipids  
PK 
Pharmacokinetics 
PP 
per protocol 
PR 
partial response 
PT/INR 
prothrombin Time/international Normalized Ratio 
PTCL 
Peripheral T cell Lymphoma 
QA 
quality assurance 
QTcF 
fridericia’s (QTcF) formulas 
SAE 
serious adverse events 
SAP 
statistical analysis plan 
SAS 
statistical analysis software 
SDV 
source document verification 
SD 
Stable disease  
SS 
Sezary Syndrome  
STD10 
severely toxic dose in 10% of animals 
SOP 
standard operating procedures 
mSWAT 
Modified Severity Weighted Assessment Tool  
TIA 
transient ischemic attack 
TLS 
tumor lysis syndrome 
TKI 
tyrosine kinase inhibitor 
T-NHL 
T-non-hodgkins lymphoma 
TSH 
thyroid stimulating harmone 
ULN 
upper limit of normal 


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Table of content 
  
1. 
INTRODUCTION.............................................................................................................. 26 
1.1 
Background ........................................................................................................ 26 
1.2 
RP6530 ............................................................................................................... 26 
1.3 
Summary of RP6530 Preclinical Evaluations .................................................... 27 
1.3.1 
In Vitro Activity .................................................................................... 27 
1.3.2 
In Vivo Activity..................................................................................... 29 
1.3.3 
Toxicology............................................................................................. 30 
1.3.4 
Clinical experience ................................................................................ 31 
1.3.5 
Clinical pharmacokinetics ..................................................................... 31 
1.4 
Rationale ............................................................................................................ 31 
1.4.1 
Rationale for the Trial ........................................................................... 31 
1.4.2 
Rationale for the Starting Dose ............................................................. 32 
2. 
TRIAL OBJECTIVES....................................................................................................... 33 
2.1 
Primary Objective .............................................................................................. 33 
2.2 
Secondary Objectives......................................................................................... 33 
2.3 
Exploratory Objectives ...................................................................................... 33 
3. 
TRIAL DESIGN................................................................................................................. 33 
3.1 
Trial End Points ................................................................................................. 33 
3.1.1 
Primary Endpoint .................................................................................. 33 
3.1.2 
Secondary end points............................................................................. 33 
3.1.3 
Exploratory end points .......................................................................... 33 
3.2 
Design of trial .................................................................................................... 33 
3.3 
Part 1: Phase 1, dose Escalation ......................................................................... 35 
3.3.1 
Dose escalation procedure ..................................................................... 35 
3.3.2 
Intra-subject dose escalation ................................................................. 36 
3.3.3 
Alternative Dosing Cohorts ................................................................... 36 
3.4 
Part 2: Phase 1b, dose expansion ....................................................................... 36 
3.5 
Randomization and Blinding ............................................................................. 36 
3.6 
Investigational Medicinal Product ..................................................................... 36 
3.6.1 
Dosage form and Strenghts ................................................................... 36 


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3.6.2 
Labeling, Packaging and Supply ........................................................... 37 
3.6.3 
Preparation and Administration of Investigational Products ................ 37 
3.6.4 
Accountability of Investigational Products ........................................... 37 
3.6.5 
Precautions and Risks Associated with Investigational Products ......... 37 
3.7 
The expected duration of subject participation and follow-up .......................... 38 
3.8 
Study stopping rules ........................................................................................... 38 
4. 
SELECTION AND WITHDRAWAL of SUBJECTS .................................................... 39 
4.1 
Inclusion Criteria ............................................................................................... 39 
4.2 
Exclusion Criteria .............................................................................................. 40 
4.3 
Discontinuation from Trial Treatment ............................................................... 41 
5. 
TREATMENT OF SUBJECTS ........................................................................................ 42 
5.1 
Administration of RP6530 ................................................................................. 42 
5.2 
Concomitant Medications .................................................................................. 42 
5.3 
Prohibited Medications ...................................................................................... 43 
5.4 
Procedures for monitoring subject compliance. ................................................. 44 
6. 
ASSESSMENT OF SAFETY ............................................................................................ 44 
6.1 
Adverse Events .................................................................................................. 44 
6.1.1 
Definitions of Adverse Events .............................................................. 44 
6.1.2 
Recording of Adverse Events ................................................................ 44 
6.1.3 
Handling of Adverse Events.................................................................. 44 
6.2 
Adverse Event/Serious Adverse Event Causality Assessment .......................... 45 
6.3 
Serious Adverse Events ..................................................................................... 45 
6.3.1 
Definitions of Serious Adverse Events ................................................. 45 
6.3.2 
Serious Adverse Event Reporting by Investigators ............................... 46 
6.3.3 
Sponsor SAE Reporting Requirements ................................................. 46 
6.4 
Recording of Adverse Events and Serious Adverse Events .............................. 47 
6.4.1 
Diagnosis vs. Signs and Symptoms ....................................................... 47 
6.4.2 
Persistent or Recurrent Adverse Events ................................................ 47 
6.4.3 
Abnormal Laboratory Values ................................................................ 47 
6.4.4 
Deaths .................................................................................................... 47 
6.4.5 
Hospitalization, Prolonged Hospitalization, or Surgery ........................ 48 
6.4.6 
Pre-Existing Medical Conditions .......................................................... 48 
6.4.7 
Pregnancy, Abortion, Birth Defects/Congenital Anomalies ................. 48 


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6.4.8 
New Cancers.......................................................................................... 48 
6.4.9 
Lack of Efficacy .................................................................................... 48 
6.5 
Protocol-Defined Events of Special Interest ...................................................... 48 
6.6 
Dose-Limiting Toxicity ..................................................................................... 49 
6.6.1 
Determination of Dose-Limiting Toxicity ............................................ 50 
6.6.2 
Maximum Tolerated Dose (MTD) ........................................................ 50 
6.7 
Dose Modifications ............................................................................................ 50 
6.7.1 
Criteria for Starting RP6530 New Cycle ............................................... 51 
6.7.2 
RP6530 Dose Modifications for Hematologic Toxicity........................ 51 
6.7.3 
RP6530 Dose Modifications for Non-Hematologic Toxicities ............. 52 
7 
ASSESSMENT OF EFFICACY ....................................................................................... 53 
7.1 
Specification of the efficacy parameters. ........................................................... 53 
7.2 
Response Evaluations and Measurements ......................................................... 53 
8 
TRIAL ASSESSMENTS AND TREATMENT ............................................................... 54 
8.1 
Overview ............................................................................................................ 54 
8.2 
Screening............................................................................................................ 55 
8.3 
Laboratory Investigations .................................................................................. 55 
8.4 
12-Lead Electrocardiograms .............................................................................. 56 
8.5 
Bone Marrow Biopsy/Aspiration ....................................................................... 56 
8.6 
Skin Biopsy ........................................................................................................ 56 
8.7 
Radiological Evaluations ................................................................................... 56 
8.8 
Pharmacokinetic Assessments ........................................................................... 57 
8.9 
Pharmacodynamics ............................................................................................ 57 
8.10 
Correlative Assessments/Exploratory Biomarkers ............................................ 57 
8.11 
Archived Tumor Tissue ..................................................................................... 57 
8.12 
Trial Treatment Period ....................................................................................... 57 
8.13 
Response Assessment ........................................................................................ 58 
8.14 
End of Trial Treatment....................................................................................... 58 
8.15 
Early Patient Termination / Patient Withdrawal ................................................ 58 
9 
STATISTICAL CONSIDERATIONS ............................................................................. 58 
9.1 
General Considerations ...................................................................................... 58 
9.2 
Determination of Sample Size ........................................................................... 58 
9.3 
Statistical Analyses ............................................................................................ 58 


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9.3.1 
Demographic and Baseline Characteristics ........................................... 59 
9.3.2 
Safety Analyses ..................................................................................... 59 
9.3.3 
Efficacy Analyses .................................................................................. 59 
9.3.4 
Pharmacokinetic Analyses .................................................................... 59 
10 
ETHICAL, FINANCIAL, AND REGULATORY CONSIDERATIONS ..................... 60 
10.1 
IRB/IEC Approval ............................................................................................. 60 
10.2 
Regulatory Approval .......................................................................................... 60 
10.3 
Insurance and Indemnity .................................................................................... 60 
10.4 
Informed Consent............................................................................................... 60 
10.5 
Confidentiality ................................................................................................... 61 
10.5.1 
Patient Confidentiality ........................................................................ 61 
10.5.2 
Investigator and Staff Information ...................................................... 61 
11 
RECORD RETENTION AND DOCUMENTATION OF THE TRIAL ...................... 62 
11.1 
Amendments to the Protocol .............................................................................. 62 
11.2 
Documentation Required to Initiate Trial .......................................................... 62 
12 
DATA HANDLING AND RECORD KEEPING ............................................................ 62 
12.1 
Data Collection .................................................................................................. 64 
12.2 
Trial Monitoring, Auditing, and Inspecting ....................................................... 64 
12.3 
Quality Assurance and Quality Control ............................................................. 64 
12.4 
Disclosure and Publication Policy ..................................................................... 65 
13 
REFERENCES ................................................................................................................... 65 
14. APPENDIX ......................................................................................................................... 68 
Appendix A. 
ECOG Performance Status Scale ....................................................................... 68 
Appendix B: 
New York Heart Association (NYHA) Classifications ..................................... 69 
Appendix C: 
Contraceptive Guidelines and Pregnancy .......................................................... 70 
Appendix D: 
Schedule of Assessments (Dose Escalation and Dose Expansion) .................... 72 
Appendix E: 
Response Criteria for Malignant Lymphoma .................................................... 81 
Appendix F: Ann Arbor staging system ....................................................................................... 86 
Appendix G: Recommended evaluation for MF/SS ptients ......................................................... 87 
Appendix H: ISCL/EORTC staging of MF and SS patients ........................................................ 88 
Appendix I: Modified Severity Weighted Assessment Tool ........................................................ 90 
Appendix J: Composite Assessment of Index Lesion Severity .................................................... 91 
Appendix K: Definition of Response in CTCL patients ............................................................... 92 


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Appendix L: Body Surface area assessment note for CTCL patients ........................................... 95 
Appendix M: Monitoring of Liver enzymes ................................................................................. 96 
 
 
List of Figures 
Figure 1: PI3K isoform enzyme assays           
 Figure 2: PI3K isoform cell-based assays ................ 27 
Figure 3. Reduction of pAKT by RP6530 in cell lines by Western blotting .......................................... 28 
Figure 4. RP6530 In vivo efficacy .................................................................................................... 29 
Figure 5: Induction of pAKT in Patient Derived Cells ........................................................................ 29 
Figure 6: Induction of Apoptosis in Patient Derived Cells .................................................................. 30 
Figure 7: Study design and dose escalations ...................................................................................... 34 
 
List of Tables 
Table 1: Inhibition of leukemic cell growth ....................................................................................... 28 
Table 2: Dose Escalation Schedule ................................................................................................... 35 
Table 3: Dose Expansion Schedule ................................................................................................... 36 
Table 4: Dose Modifications for Hematologic Toxicity ...................................................................... 51 
Table 5: Dose Modifications for Non-Hematologic Toxicities ............................................................ 52 
 
 
 


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1. INTRODUCTION 
1.1 Background  
Phosphoinositide-3 kinase (PI3K) belongs to a class of intracellular lipid kinases that 
phosphorylate the 3 position hydroxyl group of the inositol ring of phosphoinositide lipids (PIs) 
generating lipid second messengers. While α and β isoforms are ubiquitous in their distribution, 
expression of δ and γ is restricted to circulating hematogenous cells and endothelial cells.  
 
The scientific evidence for PI3K involvement, in particular the δ and γ isoforms in various cellular 
processes stems from studies using small molecule inhibitors and gene-targeting approaches. 
Although PI3Kδ expression has been assigned to B-cells and PI3Kγ is associated with T-
lymphocytes and neutrophils, there appears to be a significant synergy rather than a redundancy 
between the two isoforms in various leukemias and lymphomas. In addition dual inhibition is 
expected to result in better targeted destruction of abnormal lymphocytes. In relapsed/refractory 
T-cell lymphomas for instance, blockade of the PI3K δ/γ isoforms at clinically achievable 
concentrations could potentially prevent T-cell activation/proliferation and alteration of tumor 
microenvironment with the former attributed to the γ and the latter to the δ isoform. Simultaneous 
inhibition of PI3K δ/γ isoforms was shown to prolong survival in a mouse model of T-cell acute 
lymphoblastic leukemia. Dual targeting of PI3K δ/γ therefore is strongly implicated as an 
intervention strategy in leukemias/lymphomas that are hard to treat by conventional means due to 
the added anti-inflammatory potential that helps modulate the tumor microenvironment. 
 
Many PI3K inhibitors are in clinical development including PI3K δ specific inhibitor Idelalisib 
(by Gilead; now approved by USFDA for CLL and FL)1-6 and PI3K δ and γ inhibitor IPI-145 (by 
Infinity Pharmaceuticals)7. While Idelalisib and IPI-145 have reported ALT/AST elevation and 
neutropenia as major side effects, IPI-145 has additionally reported opportunistic infections. 
RP6530 has greater safety margin, with several fold selectivity over α and β isoforms with 
equipotency against PI3K δ and γ isoforms. Based on the 28-day tolerability studies in rat and dog, 
monitoring of liver and thyroid parameters is advised since these were the major target organs 
noted during repeat dose toxicity studies in rats and dogs. 
 
1.2 RP6530 
RP6530 is a highly specific and orally available dual PI3K δ/γ inhibitor with nanomolar inhibitory 
potency and several fold selectivity over the α and β PI3K isoforms.  Chemically, RP6530 is an 
isoflavone substituted adenine.  
The specificity of RP6530 towards PI3K δ and γ is evidenced by >1000 and >100 fold selectivity 
over α and β isoforms in an enzyme based assay.  PI3K δ and γ isoforms are expressed in 
hematopoietic cells and contribute to their development, maintenance, transformation and 
proliferation. Although PI3K δ expression has been assigned to B-cells while PI3K γ is associated 
with T-lymphocytes and neutrophils, there appears to be a significant synergy rather than a 
redundancy between the two isoforms in various leukemia’s and lymphomas. Dual targeting of 
PI3K δ/γ therefore is strongly implicated as an intervention strategy in leukemia/lymphomas that 
are hard to treat by conventional means.  
 


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1.3 Summary of RP6530 Preclinical Evaluations 
1.3.1 In Vitro Activity 
Potency of RP6530 against human PI3K δ and γ was evaluated in a HTRF based enzyme assay in 
the presence of 100 µM ATP. Selectivity over the other two isoforms, namely, α, and β were also 
determined8-11.  Data demonstrated the specificity of RP6530 towards PI3K δ and γ with >10000 
and >100-fold selectivity over α and β isoforms, indicating that the primary mode of action of this 
compound is via dual inhibition of the δ and γ isoforms (Figure 1).  Functional selectivity of 
RP6530 in a 245 Kinase Panel12 indicated >50 fold selectivity over other tyrosine and 
serine/threonine kinases. 
 
Cellular specificity towards PI3Kδ and γ was determined in an anti-IgM induced human B cell 
proliferation13 and complement component 5a (c5a) induced pAKT in RAW macrophages14 
wherein potency of RP6530 was equivalent to the enzyme assay. PI3K α or β-mediated 
phosphorylation of AKT by platelet-derived growth factor (PDGF)15 or lysophosphotidic acid16 in 
3T3 fibroblasts mediated through α or β, isoforms of PI3K was determined by Western blotting. 
Results were in line with enzyme inhibition data with the fold-selectivity being maintained for α 
and β (Figure 2). 
Figure 1: PI3K isoform enzyme assays            
Figure 2: PI3K isoform cell-based assays 
 
 
 
 
 
 
 
 
 
Proliferation of immortalized T and B-leukemic cells representative of various indications was 
determined by a MTT assay17 (Table 1). Cells were incubated with RP6530 for different time-
periods (72 -96 h) based on their doubling time.  Data demonstrated the ability of RP6530 to inhibit 
leukemic cell proliferation albeit with different potencies based on the cell type.  
 
Overall, a 50% growth inhibition for majority of B, T, and monocytic cell lines was achieved at a 
concentration between 0.5 -7.5 μM of RP6530. 
 
Subsequent to cell viability, the effect of RP6530 on AKT phosphorylation18-22 and induction of 
apoptosis was determined23-27 (Figure 3).  AKT, a serine threonine kinase mediates the downstream 
effects of PI3K activity and modulates several cell processes including survival and growth. 
Enzyme Assay
-4
-2
0
2
4
6
0
20
40
60
80
100
120
PI3K
PI3K
PI3Kδ
PI3Kγ
IC50 (nM)
24.5
33.2
Log Conc (nM)
% inhibition
Cell-based Assays
-2
0
2
4
6
0
20
40
60
80
100
120
PI3K
PI3K
PI3Kδ
PI3Kγ
EC50 (nM)
44.0
22.4
Log Conc (nM)
% inhibition


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Reduction of pAKT by RP6530 in representative cell lines was determined by Western blotting 
using a phospho-AKT (Ser473) antibody.  
 
 
Figure 3. Reduction of pAKT by RP6530 in cell lines by Western blotting 
 
 
 
 
 
 
 
 
 
 
Table 1: Inhibition of leukemic cell growth 
Cell Line 
Disease 
Cell Type 
Organ 
GI50 (nM) 
Daudi 
Burkitt’s Lymphoma 
B lymphoblast 
Peripheral Blood 
8424 
KG-1 
Acute Myelogenous 
Leukemia 
Macrophage 
Bone Marrow 
1741 
MM-S 
immunoglobulin A lambda 
myeloma 
B lymphoblast 
Peripheral Blood 
1180 
Raji 
Burkitt’s Lymphoma 
B lymphoblast 
Maxilla 
6937 
SU-DHL 
Diffuse large cell lymphoma 
Anaplastic large 
cell lymphoma 
Pleural Effusion 
2519 
TOLEDO 
Diffuse large cell 
lymphoma/Non-Hodgkin’s 
B-cell lymphoma 
B lymphocyte 
Peripheral Blood 
3480 
CCRF-
CEM 
Acute lymphoblastic 
leukemia 
T-llymphoblast 
Peripheral Blood 
7632 
Jurkat 
Acute T-cell leukemia 
T lymphocyte 
Peripheral Blood 
2077 
MOLT-4 
ALL 
T lymphoblast 
Peripheral Blood 
3024 
HuT-78 
Sezary Syndrome 
Cutaneous T-
lymphoblast 
Peripheral Blood 
4643 
HuT-102 
Lymphoma/Mycosis 
Fungoides 
Cutaneous T-
lymphoblast 
Peripheral Blood 
2239 
pAKT
10
100
300
1000
10000
0
20
40
60
80
100
120
Jurkat
MOLT-4
CCRF-CEM
HuT-78
HuT-102
RP6530 (nM)
% inhibition


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1.3.2 In Vivo Activity 
Xenograft 
In vivo efficacy of RP6530 was evaluated in a subcutaneous mouse MOLT-4 xenograft model29 
representative of human T-cell acute lymphoblastic leukemia. Oral administration of 50 
mg/kg/BID RP6530 over a 18-day period resulted in a significant delay in tumor growth28. 
 
Figure 4. RP6530 In vivo efficacy 
 
 
 
 
 
 
 
 
 
 
 
Ex-Vivo Pharmacology 
RP6530 inhibited pAKT in primary CTCL cells (Figure 5) with an EC50 of 198.2 nM30. 
Additionally, the compound caused a dose-dependent induction in apoptosis29 (Figure 6).   
Figure 5: Induction of pAKT in Patient Derived Cells 
  
 
 
 
 
                     
 
 
 
 
 
 
 
Tumor Volume
0
5
10
15
20
0
500
1000
1500
2000
2500
3000
3500
Vehicle
RP6530 50 mg/kg/PO/BID
Ara-C (50 mg/kg)
*(P<0.05)
*
Treatment Day
(mm3)
pAKT in patient derived cells
1
10
100
1000
10000
100000
0
10
20
30
40
50
60
70
A29
M7
A
0
M9
J11
J19
J27
RP6530 (nM)
% Inhibition


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Figure 6: Induction of Apoptosis in Patient Derived Cells 
 
 
 
 
 
 
 
 
 
 
 
1.3.3 Toxicology  
To assess the safety and toxicity of RP6530 a 28-day repeat dose study with a 14-day recovery 
period was conducted in Rat and beagle dogs, to evaluate the potential reversibility of findings and 
to support the use in humans.  
 
Once daily oral administration (by Gavage) of RP6530 was well tolerated in rat at dose levels of 
5, 20, and 100 mg/kg/day for 28 days. At the terminal euthanasia (Day 29/30) thyroid gland 
enlargement was a test article-related gross pathology finding in males at 100 mg/kg/day.  
Follicular cell hyperplasia in the thyroid glands and hepatocellular hypertrophy in the liver were 
test article-related histopathology findings in males and females at 100 mg/kg/day. Following the 
14-day recovery period (Day 43), test article-related findings observed at Day 29/30 were 
diminished or absent.  Target organ effects were observed at levels of 100 mg/kg/day and consisted 
of thyroid and liver. Based on these results, the no-observed-adverse-effect level (NOAEL) was 
considered to be 20 mg/kg/day and the Highest Non-Severely Toxic Dose (HNSTD) in the rat30. 
 
Toxicokinetics of RP6530 were characterized in plasma of male and female rat after a single and 
repeat dose administration for 28 days.  Peak concentrations were achieved between 0.5 and 4.0 
h post dose with terminal t1/2 ranging from 2.04 to 6.18 h. Increase in half-life was observed 
with increasing doses, with no significant accumulation.    
 
Once daily oral administration (as Capsule) of RP6530 was well tolerated in dogs at dose levels 
of 3, 10 and 30 mg/kg/day.  At terminal euthanasia (Day 30/31), small thymuses correlating with 
decreased organ weight and lymphoid depletion were observed in males of the 10 and 30 
mg/kg/day and females of the 30 mg/kg/day groups.  Following the 14-day recovery period (Day 
44), no test article-related gross pathology or organ weight changes were observed. The liver was 
identified as a target organ at 30 mg/kg/day in males and females.  Based on these results, the no 
NOAEL was 10 mg/kg and the HNSTD was 30 mg/kg/day for the dog31. 
 
Apoptosis in patient derived cells
0
10
100
300
1000
10000
0
20
40
60
80
B
Total PI+
Total AnnV+
PI+AnnV+
RP6530 (nM)
% Cells


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Toxicokinetics of RP6530 were characterized in plasma of male and female dog after single and 
repeat dose administration for 28 days. Peak concentrations were achieved between 1.6 and 8.5 h 
post dose with terminal t1/2 ranging from 1.98 to 9.37 h.  Increase in half-life was observed with 
increasing doses, with no significant accumulation.    
 
Based on the favorable results of pre-clinical and toxicological studies, this first-in-man study is 
being undertaken to explore the safety, efficacy, and MTD/optimal dosing of RP6530 in patients 
with haematolgical malignancy in compliance with ICH GCP guidelines.  
Refer to the RP6530 Investigator’s Brochure (IB) for detailed information on toxicology studies 
conducted to date. 
 
1.3.4 Clinical experience  
In human, RP6530 is being evaluated in two ongoing clinical trials: A Phase I Dose Escalation Study 
Evaluating the Safety and Efficacy of RP6530, a dual PI3K δ/γ inhibitor, in Patients with Relapsed 
or Refractory Hematologic Malignancies (European study: Protocol Number RP6530-1301) and 
A Phase I/Ib, Dose Escalation Study to Evaluate Safety and Efficacy of RP6530, a dual PI3K δ/γ 
inhibitor, in Patients with Relapsed or Refractory T-cell Lymphoma (USA study: Protocol number 
RP6530-1401). In addition, an open label, randomized, single dose, crossover study was 
undertaken to evaluate food effects on relative bioavailability of RP6530 administered in fasting 
and fed conditions in healthy volunteers (Protocol no: RP6530-1501).  
 
In the European study, RP6530 has been safe and well tolerated up to 1200 mg BID and 800 mg 
TID. There have been no dose-limiting toxicities (DLT). In the US study, a total of 19  patients 
were treated at 200 mg BID (n=4), 400 mg BID (n=4), 800 mg BID (Fasting) (n=5) and 800 mg 
BID (Fed) (n=6) in dose escalation part of the study. RP6530 demonstrated acceptable safety and 
tolerability profile up to 800 mg BID (fasting). Reported SAEs were assessed not related to 
RP6530 but attributed to the disease under study/concomitant disease conditions. Three DLTs 
(transaminitis, neutropenia and skin rash each) were reported in RP6530 800 mg BID (fed) cohort, 
therefore this dose is defined as exceeding MTD. RP6530 800 mg BID (Fasting) is considered as 
a MTD dose in patients with T-cell lymphoma.    
 
1.3.5 Clinical pharmacokinetics 
In the European study, maximum systemic exposures assessed by AUC0-t (r2 = 0.99) as 
determined on Cycle 1/Day 1 (C1D1) at 25, 50, 100, 200, 400, 600, 800, 1200 mg BID, 600 and 
800 mg TID. Dose related exposure observed across the doses. On Day 29, no accumulation 
observed. Steady state pharmacokinetic parameters of RP6530 as determined on Cycle 2/Day 1 
(C2D1) revealed no accumulation.  Similar findings were reported in US study. The healthy 
volunteer (food effect) study showed that administration of RP6530 after a high-fat meal increases 
the bioavailability of RP6530.    
 
1.4 Rationale  
1.4.1 
Rationale for the Trial 
The δ isoform of PI3K is highly expressed in cells of hematopoietic origin, and strongly implicated 
in various hematologic malignancies. The γ isoform is associated with T-lymphocytes and 
neutrophils; there appears to be a significant synergy rather than a redundancy between the two 


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isoforms in various leukemias and lymphomas.  As T-cell lymphomas (both CTCL and PTCL) are 
unmedical need, dual targeting of PI3K δ/γ therefore is strongly implicated as an intervention 
strategy in leukemia/lymphomas that are hard to treat by conventional means. RP6530 is a highly 
specific and orally available, PI3K δ and γ inhibitor with nanomolar inhibitory potency, and several 
fold selectivity over the alpha and beta isoforms.  Inhibition of PI3K δ and/or γ signaling with 
RP6530 in numerous non-clinical assays has demonstrated:  
 Potent inhibition of Anti-IgM induced human B-cell proliferation; 
 Potent inhibition of PI3Kδ and γ dependent CD63 surface expression in human whole blood 
basophils;  
 Potent reduction of AKT phosphorylation in several B-cell and T-cell cell-lines.  
 In vivo efficacy in a mouse T-cell leukemia Xenograft model 
 Ex-vivo activity in malignant patient derived primary CTCL cells 
 High oral bioavailability and high clearance of RP6530 support twice daily dosing in humans. 
 
1.4.2 Rationale for the Starting Dose 
Based on the favorable results of pre-clinical and toxicological studies, this first-in-man, Phase I, 
3+3 dose escalation study has been initiated in Europe in patients with relapsed and/or refractory 
hematologic malignancies (Study RP6530-1301). Patients received starting dose of 25 mg BID 
(50 mg/day).   
 
As the safety of 200 mg BID was established in European study, it was reasonable to consider 200 
mg BID dose as the starting dose in proposed Phase I study in relapse/refractory T-cell lymphoma. 
Presence of anti-tumor activity will be a real benefit to this patient population who have limited 
choice of treatment.  
 


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2. TRIAL OBJECTIVES 
2.1 Primary Objective  
 
To evaluate the safety and the maximum tolerated dose (MTD) of RP6530 in 
patients with relapsed/refractory T-cell lymphoma (CTCL/PTCL). 
 
To evaluate the pharmacokinetic (PK) effects of RP6530. 
 
2.2 Secondary Objectives 
 
To examine the pharmacodynamic (PD) effects of RP6530. 
 
To assess and the overall response rate (ORR) and duration of response (DoR) in 
patients with relapsed/refractory T-cell lymphoma. 
 
2.3 Exploratory Objectives 
 
Correlation of treatment outcomes with biomarkers which include but are not 
limited to quantitative and qualitative measurements of cytokines, chemokines and 
aberrations indicative of PI3K function and RP6530 efficacy. 
 
3. TRIAL DESIGN 
3.1 Trial End Points 
3.1.1 Primary Endpoint  
 
AE, SAE, clinically significant AE and dose limiting toxicities (DLT). 
 
PK parameters (including AUC (0-∞), AUC (0- ), Cmax, tmax, λz, and t½) of RP6530 
 
3.1.2 Secondary end points  
 
Inhibition of pAKT by RP6530. 
 
ORR as defined as sum of CR and PR rates; and DoR. 
 
3.1.3 Exploratory end points 
 
Correlative biomarkers (e.g. serum cytokines and chemokines). 
 
3.2 Design of trial 
This is a two part Phase 1/1b study. The first part is a Phase 1 dose escalation, 3+3 design, open-
label, MTD determination study of RP6530 in patients with relapsed/refractory T-cell lymphoma 
(PTCL/CTCL). The second part is Phase 1b, dose expansion, open label study to be conducted 
once the MTD/optimal dose has been confirmed in dose escalation phase. 20 patients of each 
indication will be enrolled (20 for PTCL and 20 for CTCL). RP6530 will be administered orally 
twice a day in 28-days cycle in absence of disease progression, unacceptable toxicity, or 
withdrawal from treatment.  
 
 
 
 
 
 
 
 


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Figure 7: Study design and dose escalations   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (n=3-6) 
• 
RP6530 (200mg) 
Cohort 2 (n=3-6) 
• 
RP6530 (400mg) 
Cohort 3 (n=3-6) 
• 
RP6530 (800mg) 
PD, AE,  
Non-compliance, 
withdrawal 
Stop 
Therap
y 
Follow-up 
for survival 
and disease 
status 
0/3 or 1/6 patients have a 
DLT escalate to Cohort 2 
0/3 or 1/6 patients have a 
DLT escalate to Cohort 3 
2/6 patients have a DLT 
de-escalate to Cohort 1 
2/6 patients have a DLT 
de-escalate to Cohort 2 
 
If 2/6 patients have a 
DLT in cohort -1, study 
will be terminated 
Dose Expansion  
 
CTCL (n=20): RP6530 800 mg 
BID Fasting 
 
 
PTCL (n=20): RP6530 800 mg 
BID Fasting 
Cohort -1 
• 
RP6530 (100 mg) 
2/6 patients have a DLT 
de-escalate to Cohort -1 
Coort 4 (n=3-6) 
• 
RP6530 (800mg) 
(Fed) 
2/6 patients have a DLT 
de-escalate to Cohort 3 
0/3 or 1/6 patients have a 
DLT escalate to Cohort 4 


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3.3 Part 1: Phase 1, dose Escalation  
3.3.1 Dose escalation procedure 
Sequential dose escalation will begin with Cohort 1. A minimum of three patients of either CTCL 
or PTCL will be entered into each opened dose level cohort. The first cohort of patients will receive 
RP6530 200 mg twice a day (BID).  Dose levels will be increased in successive increments 
according to the dose escalation scheme in the Table 2. Dose escalation will continue until the 
MTD/optiomal dose has been identified or as determined by the DRG based on the available safety, 
PK and/or efficacy data. Dose determination will be documented appropriately. 
 
Table 2: Dose Escalation Schedule 
Dose Level 
RP6530 PO BID 
Dosing recommendation   
Patients (n) 
 1* 
        200 mg BID 
Fasting 
3-6 
2 
        400 mg BID 
Fasting  
3-6 
3 
        800 mg BID 
Fasting  
3-6 
3a 
        800 mg BID 
After food  
3-6 
*If not tolerated or DLT occurs in over 33% of patients treated, a dose level of Dose Level -1 
(i.e. 100 mg BID) will be tested. 
 
** In fasting cohorts, patients will fast 2 hours prior to study drug administration and 1 hour after 
administration. In Fed cohort (After food), patients to take study drug after food (30 minutes 
after breakfast and dinner).  
 
Notes:  
 The first 28-days of safety follow up data as confirmed by the Investigator(s), and C1D1 PK 
data is essential for dose-escalation decisions.    
 Dose escalation may occur if no patient within a three-patient cohort experiences a DLT as 
defined in Section 6.6. If one of three patients within a 3-patient cohort experiences a DLT, an 
additional three patients will be treated at the same dose level.  If one of six patients within a 
dose level experiences a DLT, dose escalation will continue.  If two or more of six patients 
within a dose level experience a DLT, that dose level will be defined as exceeding MTD, no 
further dose escalation will occur.  The previous dose level will be considered the MTD and 
will be expanded to further elucidate safety, to define PK, and to evaluate efficacy. 
 If two of the first 3 patients in a cohort experience a DLT, that dose level will be defined as 
exceeding MTD, no further dose escalation will occur.  The previous dose level will be 
considered the MTD and will be expanded to further elucidate safety, to define PK, and to 
evaluate efficacy. 
 The actual number of dose cohorts explored will depend upon the MTD and the safety profile 
observed during the conduct of the trial.  Intermediate dose levels and dosing schedules may 
be explored if deemed appropriate. 
 An optimal dose is defined as the threshold dose at which the study drug is clinically active / 
efficacious (shows complete response or partial response) in a specific disease population and 
is at or below the maximum tolerated dose. 
 


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3.3.2 Intra-subject dose escalation  
Individual patients may be considered for treatment at a dose level of RP6530 higher than the dose 
to which they were initially assigned. For a patient to be treated at a higher dose level of RP6530, 
the patient must not have experienced a DLT at the assigned dose and tolerated the lower dose for 
at least one cycle of therapy. The patient must have undergone a disease evaluation and been found 
appropriate to continue on study. The new higher dose must be a dose that has completed 
evaluation and has not exceeded the MTD. There is no limit to the number of times a patient may 
have their dose of RP6530 increased.  However, the rules remain the same as listed above. At the 
discretion of the treating investigator(s), the dose escalation may be done in patient who received 
lower doses (de-escalation) due to safety reason.   
     
3.3.3 Alternative Dosing Cohorts 
Depending on the nature and the timing of the toxicities encountered and the pharmacokinetic data 
from continuous daily dosing of RP6530, alternative dosing regimens and schedules may be 
examined.  If in the opinion of the DRG, observed toxicities (DLTs and/or non-dose limiting 
adverse events of concern) are likely to have resulted from a continuous exposure to the study drug 
or cumulative effect, alternative dosing regimens or schedules may be explored.  The DRG will 
determine the alternative schedule, based on PK data, nature and timing of toxicities, and the 
required recovery periods for the observed toxicities encountered. Dose escalation would proceed 
with an alternative schedule to determine the MTD/optimal dose.   
 
3.4 Part 2: Phase 1b, dose expansion  
Once the MTD/optimal dose has been confirmed, patients who complete the Dose Escalation 
Phase will be permitted to enter the expansion cohorts (Phase Ib). Additional CTCL and PTCL 
patients may be enrolled to reach a maximum of 58 patients (including the Phase I patients) in 
each of the CTCL and PTCL groups.  
 
Table 3: Dose Expansion Schedule 
Dose Level 
RP6530 PO BID 
Patients (n) 
CTCL 
 MTD (RP6530 800 mg Fasting) 
20  
PTCL 
 MTD (RP6530 800 mg Fasting)  
20  
 
3.5 Randomization and Blinding 
This is a non-randomised, open label study.  
 
3.6 Investigational Medicinal Product 
3.6.1 Dosage form and Strenghts  
Investigational Product 
Dosage form and strength 
Manufacturer 
 RP6530 
200 mg and 400 mg tablets  
Alembic Pharmaceuticals 
and 
WuXi 
AppTec. 
Shanghai 
Additional information can be found in the current RP6530 Investigator Brochure. 
 


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3.6.2 Labeling, Packaging and Supply 
RP6530 will be made available by XXXXXXXXXXXX and XXXXXXXX. Shanghai and 
supplied through Rhizen Pharmaceuticals SA to the study site.  All trial drugs must be kept in a 
secure place under appropriate storage conditions.  Storage conditions for RP6530 are included in 
the RP6530 Investigator’s Brochure and on the product label. 
 
3.6.3 Preparation and Administration of Investigational Products 
RP6530 will be available as 30 tablets per bottle. At each visit, patients will be dispensed sufficient 
RP6530 drug supplies until the next visit. Study drug compliance should be reviewed with the 
patient at the beginning of each new treatment cycle.  Missed doses should be documented.   
 
RP6530 tablets will be self-administered by the patients.  RP6530 will be administered orally twice 
daily. In case of fasting cohorts, patients should swallow RP6530 tablets whole with a full glass 
(approximately 8 ounces) of water in a fasting state. In fed cohorts, RP6530 tablets will be self-
administered orally twice daily after food (30 minutes after breakfast and dinner). RP6530 tablets 
should NOT be crushed/opened or chewed.   
 
3.6.4 Accountability of Investigational Products 
The PI (or designee) is responsible for accountability of all used and unused trial drug supplies at 
the site.The study monitor will verify receipt of investigational product at the site during 
monitoring visit(s), and will conduct an inventory of remaining clinical trial supplies at the site 
close-out visit.  All trial drug inventories must be made available for inspection by the monitor, 
sponsor representatives and regulatory agency inspectors upon request.  
 
Returned or expired trial drugs can be destroyed according to local institutional policy with 
sponsor pre-approval of a site-specific destruction policy. Certificate(s) of destruction must be 
filed at the site and in Trial Master File. 
 
3.6.5 Precautions and Risks Associated with Investigational Products 
Monitoring of liver enzymes and levels of TSH, T3, and T4 in subjects receiving RP6530 is 
recommended based on target organ toxicity. Patients should be monitored for increased 
ALT/AST, skin rash, neutropenia as these events are reported with RP6530. Monitor patients for 
signs and symptoms of these events and interrupt RP6530 for Grade 3 or higher event. In addition, 
enteritis (colitis), pneumonia/pneumonitis as these events are reported with other PI3K inhibitors.  
 
RP6530  may  cause  serious  infections  that  may  include  sepsis  and  other  infections. Monitor 
patients for signs and symptoms of infection and interrupt RP6530 for Grade 3 or higher infection. 
RP6530 elicit no photo instability upon exposure to ultraviolet (UV) radiations. However, in 
absence of an in-vitro data, possibility of phototoxicity with RP6530 cannot be ruled out. 
Therefore, patients should be warned about the possible photosensitivity and advised to be careful 
with the UV exposure while on RP6530 treatment. Patients should be recommended to wear loose-
fitting clothes that protect skin from sun exposure, in case they need to be outdoors. If sunburn 
like reaction or skin eruption occurs, patients should contact study physician. 
 


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RP6530 800 mg BID (Fasting) is considered as a MTD dose in patients with T-cell lymphoma. 
Refer to the current Investigator Brochure for details of the risks associated with the use of 
RP6530, and instructions on how to manage patients. 
 
RP6530 demonstrated moderate to high inhibition of CYP3A4 enzymes. Therefore, concomitant 
administration of RP6530 with CYP3A4 substrates (e.g. calcium channel blockers, warfarin, 
carbamazepine, macrolide antibiotics, lovastatin, simvastatin, terfenadine) may reduce clearance 
of these drugs increasing the risk of adverse events.  
 
Similarly, as RP6530 is metabolized by CYP3A4/5 and CYP2C9, there is possibility of drug 
interaction with inhibitors or inducers of CYP3A4 and CYP2C9. If concomitant treatment of these 
drugs are clinically warranted, careful observation of the patient is advised. Raised INR has been 
reported with concomitant warfarin administration. Therefore, use of heparin or warfarin is 
generally avoided. Low molecular weight heparin (LMWH) is advised for prophylaxis and 
treatment of venous thrombosis. In absence of reproductive toxicity and genotoxicity data, the 
study participants should be advised to follow post treatment contraceptive measures. 
 
3.7 The expected duration of subject participation and follow-up 
The expected duration of subject participation in the study will be 8 months. Treatment will be 
continued in patients experiencing clinical benefit for 2 years unless progression of disease or 
toxicity warranting discontinuation of therapy. The decision to continue the treatment will be 
taken by PI/Co-PI  after consultation with Sponsor on case to case basis. 
 
The study will end when all ongoing subjects have reached their third tumor assessment on Cycle 
8/Day 1 (C8D1) or have discontinued from the study for any reason, wheichever is earlier.  At the 
end of the study, all ongoing patients with no evident disease progression will be given the 
opportunity to enroll in an open-label compassionate use study protocol and will be followed up. 
 
3.8 Study stopping rules 
Stopping rule for dose escalation:  
The DRG (PI, Co-PI, Medical Monitor and Sponsor Representative) will be in charge of reviewing 
safety data following the final treatment dose (Day 28 of Cycle 1) of the last patient in each cohort, 
and will decide whether or not it is possible to proceed to the next cohort according to the dose 
escalation procedure described in Section 3.3  In order to ensure safety and limit toxicity for 
enrolled patients, dose modifications will be performed according to the procedure described in 
Section 6.7. 
 
Suspension of Patient Enrollment: 
In the event of one (1) death attributed to the study drug, study accrual will be suspended 
pending further investigation, and will only be resumed at the recommendation of the DRG.  The 
DRG will have discretion to terminate the trial if an additional death occurs that can be attributed 
to the study drug. 
 
 
Phase Ib:  
Once the MTD/optimal in the Phase I dose-escalation have been established, the Phase Ib 
expansion part of the study will open after review of safety, PK and/or efficacy data by the DRG. 


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The DRG will continue to monitor toxicity for serious adverse events as well as for toxicity trends 
that may be of concern at interval of 3 months from initiation of expansion cohort to completion 
of the study. Toxicity will be monitored across cohorts combined together, as the expansion will 
be done at the specific dose (either MTD or optimal dose). The DRG may recommend to the 
Sponsor early termination of a study group if none of the first 10 patients achieve an objective 
response (PR or >), or </= 6 of the first 20 patients achieve an objective response (PR or >) by the 
second efficacy assessment performed before or on Cycle 8/Day 1 (C8D1).   
 
Study stopping:  
Sponsor reserves the right to terminate the study in the interest of patient safety, for non-
compliance with the protocol, lack of recruitment or any other administrative reasons. The sponsor 
and PIs will notify the regulatory authority and respective IRB respectively if the trial terminates 
early, with  a justification for the early termination. 
 
 
4. SELECTION AND WITHDRAWAL of SUBJECTS  
4.1 Inclusion Criteria 
Patients must meet the following criteria in order to be included in this clinical trial: 
1. Histologically confirmed T cell Non-Hodgkin Lymphoma (T-NHL) as approved by the 
Medical Monitor or PI/Co-PI.  
2. Disease status defined as: 
 
Refractory to or relapsed after ≥ 1 prior treatment lines.  
 
Patients who are not eligible for transplantation or any standard and / or approved 
therapy known to be life prolonging or life saving (patients who may be eligible for 
transplantation or any standard and /or approved therapy but have declined therapy, 
or in the investigators opinion based on the patient’s condition, an investigational 
therapy may benefit more than existing approved therapies are eligible for the 
study).   
3. Patients with a measurable or evaluable disease. 
 
In case of radiologically measurable lesions, the longest diameter should be ≥ 2cm 
in PTCL patients. 
 
PTCL patients with non-measurable lesions but assessable disease (e.g. marrow 
disease without other radiographically measurable disease) can be enrolled in dose-
escalation phase as approved by PI/Co-PI. 
4. Adequate organ system function, defined as follows: 
 
Patients with haemoglobin levels and/or neutrophil and platelet counts under these 
values will be eligible in case abnormalities are due to tumor dissemination or 
infiltration and according to physician's discretion  and under his direct 
responsibility. 
a. 
Hemoglobin ≥8 g/dL 
b. 
Absolute neutrophil count (ANC) ≥0.75 x 109/L  
c. 
Platelets ≥50 x 109/L 
 
Total bilirubin ≤1.5 times the upper limit of normal (ULN)   
 
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x 
ULN if no liver involvement or 5 x the ULN if known liver involvement. 


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 
Creatinine  2.0 mg/dL OR calculated creatinine clearance 50 mL/min as 
calculated by the Cockcroft-Gault method 
5. ECOG performance status ≤2. 
6. Life expectancy of at least 12 weeks. 
7. Patients must be 18 years of age. 
8. Ability to swallow and retain oral medication. 
9. Female patients who are not of child-bearing potential or female patients of child-
bearing potential  who have a negative serum   pregnancy test within 72 hours prior to 
initial trial treatment. Female patients of child-bearing potential, and all male partners 
must consent to use a medically acceptable method of contraception throughout the 
study period and for 4 weeks plus 5T1/2 (48 hrs) after the last dose of RP6530. A 
barrier method of contraception must be included.   
10. Male patients willing to use adequate contraceptive measures throughout the study period 
and for 12 weeks plus 5T1/2 (48 hrs) after the last dose of RP6530.  
11. Willingness and ability to comply with trial and follow-up procedures. 
12. Ability to understand the nature of this trial and give written informed consent. 
 
Note: The EORTC classification of CTCLs will be used to classify patients. CTCL includes other 
variants other than MF (e.g. Gamma delta cutaneous T-cell lymphoma or subcutaneous or 
panniculitic like T-cell lymphoma and CD8 positive T-cell lymphoma). PTCL includes patients 
with predominantly nodal disease (systemic involvement) but some patients (e.g.. AITCL or 
ATCL) may have skin lesions.  Patient having both skin and node lesions will be placed into one 
of the group (CTCL or PTCL) as approved by PI/Co-PI.  
 
There are a number of FDA-approved drugs for relapsed/resistant CTCL and/or PTCL. These 
include romedepsin, denileukin diffitox, vorinostat, bexarotene, mechlorethamine gel, pralatrexate 
and belinostat. Investigator should make accommodations for the use of such approved therapies 
prior to enrollment on the study. 
 
4.2 Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from trial entry: 
1. Any cancer therapy (i.e., chemotherapy, radiation therapy, immunotherapy, biologic therapy, 
hormonal therapy, surgery and/or tumor embolization) in the last 3 weeks or the last 5T1/2 of 
the agent, whichever is shorter. Limited palliative radiation <2 weeks. 
2. Autologous hematologic stem cell transplant within 3 months of study entry.  Allogeneic 
hematologic stem cell transplant within 12 months.  Active graft-versus-host disease.    
3. Active HBV, HCV or HIV infection.   
4. Use of an investigational drug in the last 4 weeks prior to the first dose of RP6530 
5. Treatment with GS-1101 (CAL-101, idelalisib), IPI-145, TGR-1202 or any drug that 
specifically inhibits PI3K/ mTOR (including temsirolimus, everolimus), AKT or BTK 
Inhibitor (including Ibrutinib) in last 6 months. 
6. Patient has received wide field radiotherapy (including therapeutic radioisotopes such as 
Yttrium-90) ≤ 28 days or limited field radiation for palliation ≤ 14 days prior to starting 
RP6530 or has not recovered from side effects of such therapy. 


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7. Ongoing immunosuppressive therapy including systemic corticosteroids (prednisone or 
equivalent ≤10 mg daily allowed as clinically warranted).  Patients are allowed to use topical 
or inhaled corticosteroids. 
8. Known history of drug-induced liver injury, alcoholic liver disease, non-alcoholic 
steatohepatitis, primary biliary cirrhosis, ongoing extrahepatic obstruction caused by stones, 
cirrhosis of the liver or portal hypertension. 
9. Patients with uncontrolled Diabetes Type I or Type II (HbA1c >8% assessed locally).  
10. Any severe and/or uncontrolled medical conditions or other conditions that could affect their 
participation in the study such as: 
 Symptomatic, or history of documented congestive heart failure (New York Heart 
Association functional classification III-IV [see Appendix B]) 
 QTcF > 470 msec 
 Angina not well-controlled by medication  
 Poorly controlled or clinically significant atherosclerotic vascular disease 
including cerebrovascular accident (CVA), transient ischemic attack (TIA), 
angioplasty, cardiac or vascular stenting in the past 6 months 
 Active or uncontrolled severe infections requiring IV antibiotics  
 Patients with hemophilia or even Von Willebrand’s disease should be excluded.   
11. Herbal preparations/medications must be discontinued 7 days prior to first dose of study 
drug. 
12. Presence of other active cancers, or history of treatment for invasive cancer  3 years.  
Patients with stage I cancer who have received definitive local treatment at least 3 years 
previously, and are considered unlikely to recur are eligible.  All patients with previously 
treated in situ carcinoma (i.e. non-invasive) are eligible, as are patients with history of non-
melanoma skin cancer. 
13. Women who are pregnant or lactating. 
14. Psychological, familial, sociological, or geographical conditions that do not permit 
compliance with the protocol.  
15. Concurrent condition that in the investigator’s opinion would jeopardize compliance with the 
protocol. 
16. Inability or unwillingness to comply with study and/or follow-up procedures outlined in the 
protocol. 
 
4.3 Discontinuation from Trial Treatment 
Patients will be discontinued from trial treatment for any of the following reasons: 
 
Disease progression 
 
Irreversible or intolerable toxicity or abnormal laboratory values related to drug 
toxicity 
 
Consent withdrawal  
 
Patient requests to discontinue treatment 
 
Pregnancy (See Section 6.5) 
 
Inability of the patient to comply with trial requirements 
 
Conditions requiring therapeutic intervention not permitted by the protocol 
 
Intercurrent illness (at the investigator’s discretion) 
 
Non-compliance/lost to follow-up 
 
Discontinuation of the study by the Sponsor 


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If a patient withdraws from treatment during Cycle 1 due to any reason other than DLT and does 
not meet the minimum requirements for inclusion in the MTD-determining population described 
in Section 6.6.1 that patient will be replaced. Decision of discontinuation should be taken on case 
to case basis after discussion with medical monitor. 
 
After withdrawal from protocol treatment, patients must be followed for AEs for 30 calendar days 
after their last dose of trial drug.  All new AEs occurring during this period must be reported and 
followed until resolution, unless, in the opinion of the investigator, these values are not likely to 
improve because of the underlying disease.  In this case, the investigators must record his or her 
reasoning for this decision in the patients’ medical records and as a comment on the Case Report 
Form (CRF). 
 
All patients who have CTCAE grade 3 or 4 laboratory abnormalities at the time of withdrawal 
must be followed until the laboratory values have returned to grade 1 or 2, unless it is, in the 
opinion of the investigator, not likely that these values are to improve because of the underlying 
disease.  In this case, the investigator must record his or her reasoning for making this decision in 
the patients’ medical records and as a comment on the CRF.  
 
5. TREATMENT OF SUBJECTS  
5.1 Administration of RP6530 
RP6530 will be dosed continuously twice a day in 28-days cycle. The dose and schedule of RP6530 
will be determined during the dose escalation phase of the study.  RP6530 will be self-administered 
by the patient. Tablet (s) of relevant strenghs should be taken at approximately the same time each 
day. Patients should be instructed to swallow RP6530 tablets as a whole with a full glass 
(approximately 8 ounces) of water in a fasting state (fasting cohorts); and with food in fed cohorts 
(30 minutes after breakfast and dinner); and should not chew or crush them.  Patients will fast 2 
hours prior to study drug administration and 1 hour after administration.  On days of study visits, 
the morning dose to be adminsisted at the clinic. In dose expansion, RP6530 should be 
administered in a fasting state.  
 
If a dose of RP6530 is missed, it should be taken as soon as possible the same day.  If it is missed 
for the entire day, it should not be replaced.  If vomiting occurs, no attempt should be made to 
replace the vomited dose. Study drug compliance should be reviewed with the patient at the 
beginning of each new treatment cycle. Missed doses should be documented. No routine 
prophylactic antiemetics or premedications will be given.  However, these medications may be 
administered for symptoms when they occur, and may be given prophylactically afterwards.  
 
5.2 Concomitant Medications 
Patients will be instructed not to take any additional medications during the course of the study 
without prior consultation with the research team. At each visit, the patient will be asked about 
any new medications he/she is taking or has taken after the start of the study drug. 
 Use of erythropoietin replacement or bisphosphonates is considered supportive care, and 
their use is permitted if initiated >2 weeks prior to trial treatment.   


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 Use of antimicrobial or anti-viral prophylaxis can be used according to local standard 
practice; PCP and Zoster prophylaxis is strongly recommended unless there is known 
adverse events from the prophylactic therapy in the individual.  
 Initiation or escalation of growth factor therapy (erythropoietin, GM-CSF, G-CSF) is not 
allowed during the first month of study treatment.  However, patients who have been on 
stable erythropoietin or darbepoetin therapy for two weeks preceding trial treatment may 
remain on the same dose during the first month.  Growth factor therapy, if initiated in the 
first month for the treatment of study drug related AE (e.g. RP6530 related neutropenia), 
such patients will be discontinued. Growth factor therapy is allowed after the first month 
as are changes in the dose level of erythropoietin and darbepoetin.  
 Transfusions may be given, based on standard criteria and clinical judgment. 
 Patients are permitted to receive palliative radiation therapy on study after Cycle 1 at the 
discretion of the treating physician for existing bone lesions if there is no evidence of 
progressive disease elsewhere.  
 Prophylactic antiemetics will be withheld until the patient has experienced ≥ CTCAE grade 
1 nausea or vomiting. The patient may then receive prophylactic antiemetics at the 
discretion of the investigator.  Premedications for hypersensitivity (allergic reactions) will 
not be administered prophylactically.   
 If in the opinion of the investigator the risk of tumor lysis syndrome (TLS) is significant, 
allopurinol may be given prophylactically. 
 RP6530 demonstrated moderate to high inhibition of CYP3A4 enzymes. Therefore, 
concomitant administration of RP6530 with CYP3A4 substrates (e.g. calcium channel 
blockers, carbamazepine, macrolide antibiotics, lovastatin, simvastatin, terfenadine) may 
reduce clearance of these drugs increasing the risk of adverse events. Similarly, as RP6530 
is metabolized by CYP3A4/5 and CYP2C9, there is possibility of drug interaction with 
inhibitors or inducers of CYP3A4 and CYP2C9. If concomitant treatment of CYP3A4 
substrates are clinically warranted, careful observation of the patient is advised, particularly 
during treatment initiation. Raised INR has been reported with concomitant warfarin 
administration. Therefore, use of heparin or warfarin is generally avoided. Low molecular 
weight heparin (LMWH) is advised for prophylaxis and treatment of venous thrombosis. 
 
5.3 Prohibited Medications 
The following treatments are prohibited while on clinical trial:   
 Other investigational drug treatments or study participation, radiation therapy (except as 
described above), hormonal therapy for cancer, cancer immunotherapy or other biologic 
therapy excluding trial drugs. 
 Herbal preparations/medications are not allowed throughout the trial.  Examples include:  
St. John’s wort, Kava, ephedra (ma huang), ginko biloba, dehydroepiandrosterone 
(DHEA), yohimbe, saw palmetto, and ginseng.  Patients should stop using these herbal 
medications at least 7 days prior to the first dose of study drug. 
Note: Discontinuation of patient who received concomitant/prohibited medication will be taken 
by the PI/Co-PI in consultation with Medical Monitor on case to case basis, after evaluating the  
clinical benefit and acceptable/minimal clinical risk  
 


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5.4 Procedures for monitoring subject compliance. 
Subjects will be asked to maintain a diary to record drug administration. Subjects will be asked to 
bring any unused study drug to the research center at their next visit.  Research personnel will 
count and record the number of used and unused study drug tablets at each visit and reconcile with 
the subject diary.  The study coordinator will question the patient regarding adherence to the dosing 
regimen, record the number of tablets and strengths returned, the date returned and determine 
treatment compliance before dispensing new medication to the study patient.  Compliance below 
80% will require counseling of the patient by study site personnel.  
 
6. ASSESSMENT OF SAFETY 
6.1 Adverse Events 
The PI is responsible for collecting and reporting adverse events (see 6.1.2).  It is Sponsor 
responsibility to report relevant SAEs to the applicable regulatory body. 
 
6.1.1 Definitions of Adverse Events  
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An adverse event (AE) can therefore be any unfavourable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product. All Grade 3 and grade 4 AEs irrespective of causality constitute 
clinically significant AE.   
 
6.1.2 Recording of Adverse Events 
All adverse events of any patient during the course of the trial will be reported in the case report 
form, and the investigator will give his or her opinion as to the relationship of the adverse event to 
trial drug treatment (i.e., whether the event is related or unrelated to trial drug administration).  If 
the adverse event is serious, it should be reported immediately to Sponsor.  Other untoward events 
occurring in the framework of a clinical trial are also to be recorded as AEs (i.e., AEs that occur 
prior to assignment of trial treatment that are related to a protocol-mandated intervention, including 
invasive procedures such as biopsies, medication washout, or no treatment run-in). 
 
All AEs regardless of seriousness or relationship to RP6530 (study drug), spanning from the first 
dose of study drug until 30 calendar days after the last dose of study drug, discontinuation or 
completion of protocol-specific treatment as defined by the protocol for that patient, are to be 
recorded in the CRF. The data review group (DRG), comprise of PI/Co-PI, Medical Monitor and 
sponsor representative, will be constituted to review safety data on ongoing basis.  
 
6.1.3 Handling of Adverse Events 
All adverse events resulting in discontinuation from the trial should be followed until resolution 
or stabilization.  Patients must be followed for AEs for 30 calendar days after discontinuation or 
completion of protocol-specific treatment.  All new AEs occurring during this period must be 
reported and followed until resolution unless, in the opinion of the investigator, the adverse event 
or laboratory abnormality/ies are not likely to improve because of the underlying disease.  In this 
case, the investigators must record his or her reasoning for this decision in the patient’s medical 


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record and as a comment on the CRF. After 30 days of completion of protocol-specific treatment 
or discontinuation, only AEs, SAEs, or deaths assessed by the investigator as treatment related are 
to be reported. 
 
6.2 Adverse Event/Serious Adverse Event Causality Assessment  
Causality is assessing the relationship of the trial treatment to the adverse event. For this study, the 
causality assessment will be categorized as related and not related.  
Related: All toxicities should be considered to be related to RP6530 unless there is a clear 
alternative explanation.   
Not related:  If there is no temporal association, or another etiology has been identified as the 
cause, or the trial treatment cannot be implicated based upon the current information. 
 
6.3 Serious Adverse Events 
6.3.1 Definitions of Serious Adverse Events 
The definitions of serious adverse events (SAEs) are given below.  The principal investigator is 
responsible for ensuring that all staff involved in the trial are familiar with the content of this 
section. 
An SAE or reaction is defined as any untoward medical occurrence that: results in death, is 
immediately life-threatening, requires at least a 24-hour in-patient hospitalization or prolongation 
of existing hospitalization, results in persistent or significant disability/incapacity, or is a 
congenital anomaly/birth defect. 
 
The definition of SAE also includes any important medical event.  Medical and scientific judgment 
should be exercised in deciding whether expedited reporting is appropriate in other situations, such 
as important medical events that may not be immediately life-threatening or result in death or 
hospitalization, but may jeopardize the patient or may require intervention to prevent one of the 
other outcomes listed in the previous definition.  These should also usually be considered serious.  
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or 
development of drug dependency or drug abuse. Progression of malignancy (including fatal 
outcomes), if documented by use of appropriate method (for example, as per Cheson et al. 2007 
Revised Response Criteria for Malignant Lymphoma), should not be reported as a serious adverse 
event.  
 
Treatment within or admission to the following facilities is not considered to meet the criteria of 
“in-patient hospitalization” (although if any other SAE criteria are met, the event must still be 
treated as an SAE and immediately reported): 
 Emergency Department or Emergency Room 
 Outpatient or same-day surgery units 
 Observation or short-stay unit 
 Rehabilitation facility 
 Hospice or skilled nursing facility 
 Nursing homes, Custodial care or Respite care facility 
Hospitalization during the trial for a pre-planned surgical or medical procedure (one which was 
planned prior to entry in the trial), does not require reporting as a serious adverse event to the 
Sponsor. 


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6.3.2 Serious Adverse Event Reporting by Investigators 
It is important to distinguish between “serious” and “severe” adverse events, as the terms are not 
synonymous.  Severity is a measure of intensity; however, an AE of severe intensity need not 
necessarily be considered serious.  For example, nausea which persists for several hours may be 
considered severe nausea, but may not be considered an SAE.  On the other hand, a stroke which 
results in only a limited degree of disability may be considered only a mild stroke, but would be 
considered an SAE.  Severity and seriousness should be independently assessed when recording 
AEs on the CRF and SAEs on the SAE Report Form. 
 
Adverse events classified by the treating investigator as serious require expeditious handling and 
reporting to Sponsor in order to comply with regulatory requirements.  Serious adverse events may 
occur at any time from the signing of the informed consent form through the 30-day follow-up 
period after the last trial treatment.  Sponsor/sponsor representative must be notified of all SAEs, 
regardless of causality, within 1 day of the first knowledge of the event by the investigator.   
 
To report an SAE, the SAE Report Form should be completed with the necessary information.  All 
SAEs occurring from the signing of consent until 30 calendar days of last trial treatment must be 
reported to the Sponsor as SAEs on the SAE Report and followed until resolution (with autopsy 
report if applicable). 
 
Deaths and other SAEs occurring >30 calendar days after last trial treatment that are deemed 
‘possibly’ or ‘probably’ related to RP6530 must be reported as SAEs on the SAE Report within 1 
day of first knowledge of the event by the treating physician or research personnel (with an autopsy 
report if available). 
Deaths occurring >30 calendar days after last trial treatment and not attributed to trial treatment 
(e.g., disease progression) need not be reported as SAEs, but simply captured on the appropriate 
CRF. 
 
The SAE report should be sent to the Sponsor/Sponsor representative via fax or e-mail. The 
detailed SAE reporting process will be provided to the sites in the SAE reporting guidelines 
contained in the study reference manual. Transmission of the SAE report should be confirmed by 
the site personnel submitting the report. Follow-up information for SAEs and information on non-
serious AEs that become serious should also be reported to Sponsor as soon as it is available; these 
reports should be submitted using the SAE Report Form.   
Investigators must report SAEs and follow-up information to their responsible Institutional Ethics 
committee (IEC) according to the policies of the responsible IEC. 
 
6.3.3 Sponsor SAE Reporting Requirements 
Sponsor/Sponsor representative is responsible for reporting relevant SAEs to the competent 
authority, other applicable regulatory authorities, and participating investigators, in accordance 
with ICH guidelines, FDA regulations, and/or local regulatory requirements. 
 
Sponsor/sponsor representative is responsible for reporting unexpected fatal or life-threatening 
events associated with the use of the trial drugs to the regulatory agencies and competent 
authorities via telephone or fax within 7 calendar days after being notified of the event.  The 


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Sponsor will report all related unexpected SAEs including non-death/non-life-threatening related 
unexpected SAEs associated with the use of the trial medications to the FDA by a written safety 
report within 15 calendar days of notification. Reporting to the IRB/IEC will be done according to 
institutional policy.  
 
6.4 Recording of Adverse Events and Serious Adverse Events 
Investigators should use correct medical terminology/concepts when recording AEs or SAEs on 
the SAE Report Forms and AE CRF.  Avoid colloquialisms and abbreviations. All AEs, including 
those that meet SAE reporting criteria, should be recorded on the AE CRF; AEs that meet the 
definition of an SAE should additionally be reported following the procedures noted in above 
sections.  
 
6.4.1 Diagnosis vs. Signs and Symptoms 
All AEs should be recorded individually in the patient’s own words (verbatim) unless, in the 
opinion of the Coordinating Investigator or designated physician, the AEs constitute components 
of a recognized condition, disease, or syndrome.  In the latter case, the condition, disease, or 
syndrome should be named rather than each individual sign or symptom.  If a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome at the time 
of reporting, each individual event should be recorded as an AE or SAE as appropriate on the 
relevant form(s) (SAE Report Form and/or AE CRF).  If a diagnosis is subsequently established, 
it should be reported as follow-up information is available.  If a diagnosis is determined subsequent 
to the reporting of the constellation of symptoms, the signs/symptoms should be updated to reflect 
the diagnosis. 
 
6.4.2 Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution, between patient evaluation 
timepoints.  Such events should only be recorded once on the SAE Report Form and/or the 
AE CRF.  If a persistent AE becomes more severe or lessens in severity, it should be recorded at 
once with highest grade of severity on a SAE Report Form and/or AE CRF.   
A recurrent AE is one that occurs and resolves between patient evaluation timepoints, and 
subsequently recurs. All recurrent AEs should be recorded separately on an SAE Report Form 
and/or AE CRF. 
 
6.4.3 Abnormal Laboratory Values 
Any grade 3 or 4 laboratory abnormalities or any clinically significant grade 1 or 2 hematology or 
biochemistry laboratory value(s) should be recorded as an AE.  If an abnormal laboratory value or 
vital sign is associated with clinical signs and/or symptoms, the sign or symptom should be 
reported as an AE, and the associated laboratory value or vital sign should be considered additional 
information that must be collected on the relevant CRF.  If the laboratory abnormality is a sign of 
a disease or syndrome, only the diagnosis needs to be recorded on the SAE Report Form or AE 
CRF. 
6.4.4 Deaths 
Deaths that occur during the protocol-specified AE reporting period that are attributed by the 
investigator solely to progression of disease will be recorded on the “Trial Discontinuation” CRF.  


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All other on-trial deaths, regardless of attribution, will be recorded on an SAE Report and 
expeditiously reported to the Spoonsor. 
 
When recording a serious adverse event with an outcome of death, the event or condition that 
caused or contributed to the fatal outcome should be recorded as the single medical concept on the 
SAE report and Adverse Event page of the CRF.  If the cause of death is unknown and cannot be 
ascertained at the time of reporting, record “Death NOS” on the CRF Adverse Event page.   
 
6.4.5 Hospitalization, Prolonged Hospitalization, or Surgery 
Any AE that results in hospitalization of >24 hours or prolonged hospitalization should be 
documented and reported as an SAE unless specifically instructed otherwise in this protocol.  
There are some hospitalization scenarios that do not require reporting as an SAE when there is no 
occurrence of an AE. (see Section 06.3.1)  
 
6.4.6 Pre-Existing Medical Conditions 
A pre-existing medical condition is one that is present at the start of the trial.  Such conditions 
should be recorded on the General Medical History CRF. A pre-existing medical condition should 
be recorded as an AE or SAE only if the frequency, severity, or character of the condition worsens 
during the trial.  When recording such events on an SAE Report Form and/or AE CRF, it is 
important to convey the concept that the pre-existing condition has changed by including 
applicable descriptors. 
 
6.4.7 Pregnancy, Abortion, Birth Defects/Congenital Anomalies 
Pregnancy, abortion, birth defects, and congenital anomalies are events of special interest.  Please 
refer to pregnancy section 6.5 for specific instructions. 
 
6.4.8 New Cancers 
The development of a new primary cancer should be regarded as an AE and will generally meet at 
least one of the serious criteria.  New primary cancers are those that are not the primary reason for 
the administration of the study treatment and have developed after the inclusion of the patient into 
the study.  They do not include new lesions of the original cancer.  Symptoms of metastasis or the 
new lesions itself should not be reported as an AE/SAE, as they are considered to be disease 
progression. 
 
6.4.9 Lack of Efficacy 
When there is deterioration in the condition for which the study treatment is being used, there may 
be uncertainty as to whether this is lack of efficacy or an AE.  In such cases, unless the sponsor or 
reporting physician considers the study treatment contributed to the deterioration of the condition, 
the deterioration should be considered lack of efficacy and not an AE. 
 
6.5 Protocol-Defined Events of Special Interest 
The following are events of special interest, and will need to be reported expeditiously. 
 
 


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Pregnancy, Abortion, Birth Defects/Congenital Anomalies: 
Female patients who are not of child-bearing potential (see Appendix C) or female patients of 
child-bearing potential  who have a negative serum   pregnancy test within 72 hours prior to initial 
trial treatment are eligble for the study. Female patients of child-bearing potential (see Appendix 
C), and all male partners must consent to use a medically acceptable method of contraception 
throughout the study period and for 4 weeks plus 5T1/2 (48 hrs) after the last dose of RP6530. A 
barrier method of contraception must be included.    
During the course of the trial, all female patients of childbearing potential (the definitions of 
“women of childbearing potential” are listed in Appendix C) must contact the treating investigator 
immediately if they suspect that they may be pregnant (a missed or late menstrual period should 
be reported to the treating investigator).   
 
If an investigator suspects that a patient may be pregnant prior to administration of trial drug(s), 
the trial drug(s) must be withheld until the result of the pregnancy test is confirmed.  If a pregnancy 
is confirmed, the patient must not receive any trial drug(s), and must be discontinued from the 
trial.   
 
If an investigator suspects that a patient may be pregnant after the patient has been receiving trial 
drug(s), the trial drug(s) must immediately be withheld until the result of the pregnancy test is 
confirmed.  If a pregnancy is confirmed, the trial drug(s) must be immediately and permanently 
stopped, the patient must be discontinued from the trial, and the investigator must notify the 
Medical Monitor and Sponsor Representative as soon as possible.  If a patient becomes pregnant 
while enrolled in the trial, a Pregnancy Form should be completed and faxed to the Sponsor.    
Congenital anomalies/birth defects always meet SAE criteria, and should therefore be 
expeditiously reported as an SAE, using the previously described process for SAE reporting.  A 
Pregnancy Form should also have been previously completed, and will need to be updated to reflect 
the outcome of the pregnancy. 
 
RP6530 Overdose 
Symptomatic and non-symptomatic overdose must be reported in the CRF.  Any accidental or 
intentional overdose with the trial treatment that is symptomatic, even if not fulfilling a seriousness 
criterion, is to be reported to the Sponsor immediately (within one  day) using the corresponding 
screens in the CRF, and following the same process described for SAE reporting, if the overdose 
is symptomatic. 
 
6.6 Dose-Limiting Toxicity  
Toxicity will be assessed utilizing the National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI CTCAE) v4.0 (http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE). 
All toxicities should be considered to be related to RP6530 unless there is a clear alternative 
explanation. A toxicity will be considered dose-limiting if it occurs during the first cycle (4-weeks) 
treatment with RP6530 and is considered related to RP6530.  Dose-limiting toxicities will be 
defined as the following: 


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 Hematological DLTs: 
 Grade 4 anaemia 
 Grade 4 neutropenia (absolute neutrophil count [ANC] <500/µL) for >7 days, or Grade 
≥3 febrile neutropenia (ANC <1000/µL with fever >38.5ºC [101ºF] 
 Grade 4 thrombocytopenia for >7 days, or grade ≥3 thrombocytopenia associated with 
Grade >2 bleeding 
 Non-Hematological DLTs: 
 Grade ≥3 non-hematologic toxicity with exception of:  
o Grade ≥3 diarrhea or nausea that does not resolve to ≤ Grade 2 within 48 hours despite 
treatment; and  
o If  ≥1.5 ULN of bilirubin or >3 ALT/AST elevation that does not resolve to ≤ Grade 1 
within 7 days.  
 Treatment delay of ≥14 days due to unresolved toxicity. 
 Non-hematologic toxicity of Grade 2 (at any time during treatment) that, in the judgment of the 
DRG, is dose-limiting. 
 For certain toxicities such as laboratory assessments without a clear clinical correlate (e.g. lipase 
increase without signs of a clinical pancreatitis) a discussion within DRG may take place if this 
AE should be assessed as DLT necessitating dose reduction.  
 
6.6.1 Determination of Dose-Limiting Toxicity 
The patient population used for determination of MTD will consist of patients who have met the 
minimum safety evaluation requirements of the study, and/or who have experienced a DLT.  
Minimum safety requirements will be met if, during Cycle 1 of treatment,  
 Patient receives at least 80% of planned doses of RP6530 doses or received RP6530 for the 
first 21-days continuously;  
 Patient completes all required safety evaluations (at least for three visits after the first dose);  
 Patiet is observed for at least 28 days following the first dose of RP6530 in case of related 
adverse event.  
Patients who experience a DLT will be considered evaluable regardless of the number of doses 
received.  
Patients who discontinue treatment early due to disease progression or withdrawal will have all 
end-of-treatment safety evaluations performed as described in the Appendix D.  If a patient 
withdraws from treatment during Cycle 1 due to any reason other than DLT and does not meet the 
minimum requirements for inclusion in the MTD-determining population described above, that 
patient will be replaced.  
 
6.6.2 Maximum Tolerated Dose (MTD) 
The MTD is the highest dose at which ≤1 of 6 patients experience a DLT during 1 cycle (28 days) 
of therapy.  If 2 or more patients in a dosing group experience a DLT, the MTD has been exceeded. 
 
6.7 Dose Modifications 
Patients 
should 
be 
assessed 
for 
toxicity 
using 
the 
NCI 
CTCAE 
v4.0 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE) grading scale.  Patients who experience either a 
DLT or an adverse event meeting DLT criteria (that occurs after the DLT assessment window) 


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will be allowed to delay dosing in order to recover from the toxicity. Patients may resume RP6530, 
provided that the toxicity has resolved to Grade ≤2 or baseline. If study drug is delayed >2 weeks 
because of an adverse event, treatment may not be resumed until the strategy has been discussed 
with the Medical Monitor and continuation of treatment has been agreed upon. 
 
At the discretion of the Investigator, a dose re-escalation may be permitted for patients who were  
dose reduced upon resuming RP6530. Holidays from study drug are discouraged. Any patient in 
whom similar toxicity recurs at the reduced dose should be discontinued from further RP6530 
treatment.  Exceptions to this discontinuation rule, on the basis of ongoing clinical benefit and 
acceptable/minimal clinical risk), a patient may be allowed following a careful assessment and 
discussion of risk versus benefit with the patient by the investigator and with approval from the 
Medical Monitor. 
 
6.7.1 Criteria for Starting RP6530 New Cycle  
Criteria for continuing treatment beyond the first cycle will be at the discretion of the treating 
Investigator. In the absence of unacceptable toxicities or disease progression, patients may 
continue treatment with RP6530 as long as:  
 Absolute neutrophil count has returned to baseline, or >750/µL.  Platelet count is  
>50,000/µL.  
 Recovered from grade 3-4 non-hematologic toxicity to grade 1 or baseline (excluding 
alopecia). Treatment may be delayed for up to 2 weeks to recover from toxicity.  
 No clinical or radiographic evidence of disease progression.  
 If treatment is delayed > 2 weeks, because of an adverse event, treatment may not be 
resumed until the strategy has been discussed with the Medical Monitor and continuation 
of treatment has been agreed upon. 
 
6.7.2 RP6530 Dose Modifications for Hematologic Toxicity 
Table 4: Dose Modifications for Hematologic Toxicity 
Worst CTCAE Grade Toxicity 
Action to be Taken 
HEMATOLOGIC  
Neutropenia (ANC) 
Grade 1  
(ANC < LLN - 1.5 x 109/L) 
Maintain dose level 
Grade 2  
(ANC < 1.0-1.5 x 109/L) 
Maintain dose level 
Grade 3  
(ANC < 0.5-1.0 x 109/L) 
Hold* dose until resolved to ≤ Grade 2 or baseline, consider growth 
factor support, then reduce by 1 dose level.  If the ANC is <1 X 109/L 
(1000/µL) before therapy, the patient is not evaluable for toxicity, and 
the dose shall not be modified as long as ANC >0.5 X 109/L. 
Grade 4  
(ANC < 0.5 x 109/L) 
Hold* dose until resolved to ≤ Grade 2 or baseline, consider growth 
factor support, then reduce by 1 dose level.  If the ANC is <1 X 109/L 
(1000/µL) before therapy, the patient is not evaluable for toxicity, and the 
dose shall be held until resumption of baseline ANC is achieved; consider 
growth factor support, reduce drug by one dose level. 


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Grade 3 Febrile neutropenia  
(ANC < 1.0 x 109/L, fever ≥ 38.5°C) 
Hold* dose until resolved to ≤ Grade 2 or baseline, consider growth factor 
support, then reduce by 1 dose level***.   If the ANC is <1 X 109/L 
(1000/µL) before therapy, the patient is not evaluable for toxicity, and the 
dose shall not be modified as long as ANC >0.5 X 109/L. 
Thrombocytopenia 
Grade 1 (PLT < LLN - 75 x 109/L) 
Maintain dose level 
Grade 2 (PLT < 75 - 50 x 109/L) 
Maintain dose level.  
Grade 3 (PLT < 50-25 x 109/L) 
Hold** dose until to ≤ Grade 2 or baseline, then reduce by 1 dose level if 
warranted***.  
Grade 4 (PLT < 25 x 109/L) 
Hold** dose until to ≤ Grade 2 or baseline, then reduce by 1 dose level if 
warranted***.  
 *  If study drug is delayed >2 weeks because of an adverse event, treatment should not be resumed  until the 
strategy has been discussed with the Medical Monitor and continuation of treatment agrred upon. 
** Patient receiving concomitant medication (e.g. anticoagulants, antiplatelets, aspirin, or low molecular weight 
heparin) must be discussed with the Medical Monitor for continued management. 
*** Further dose reduction can be done in consultation with medical monitor. 
 
 
6.7.3 RP6530 Dose Modifications for Non-Hematologic Toxicities 
The dose reduction guidelines for non-hematologic toxicities are shown in Table 5.  
Table 5: Dose Modifications for Non-Hematologic Toxicities  
NON-HEMATOLOGIC  
Action to be Taken 
Renal* 
If serum creatinine >3 x baseline or >3 x ULN, hold dose until 
≤ grade 1. Monitor serum creatinine at least twice a week until 
resolution to  ≤ grade 2, and then at least one week until it 
resolves to ≤ grade 1  
Hepatic* 
Please refer the algorithm for dose modification. (Annexure M). 
Cardiac 
If a QTcF >500 msec has been demonstrated, hold dose: 
For all patients with a new QTcF >500 msec, occurring at any 
time during the study as identified by the investigator, an 
immediate evaluation of that ECG will be obtained and 
confirmed. 
The patient will be monitored hourly with ECGs until the QTcF 
<500 msec and the QTcF has returned to <30 msec from 
baseline.  Immediate attention to potassium and magnesium and 
other clinical factors such as oxygenation and ischemia will be 
addressed.  A plasma sample will be drawn to assess the 
concentrations of study drug, magnesium and potassium at the 
time when the QTcF is first noted to be >500 msec. 
OTHER NON-HEMATOLOGIC  
Action to be Taken   
Grade  1 or 2 
None 
Grade 3 CTCAE  
Hold* dose until toxicity Grade ≤1 , then reduce by 1 dose level.  
If toxicity remains grade 3 toxicity 
for longer than 2 weeks 
 Contact medical monitor 


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* If study drug is delayed >2 weeks because of an adverse event, treatment should not be resumed until the strategy 
has been discussed with medical monitor and continuation of treatment agreed upon. 
 
Note: In the event of unrelated hematological/non-hematological toxicity (e.g. toxicity due to 
underlying disease condition or co-morbidity), the dose modification or dose delay will be done 
at the discretion of PI/Co-PI after evaluating the safety of the patient and need for dose 
modification. 
 
7 
ASSESSMENT OF EFFICACY 
7.1 Specification of the efficacy parameters. 
PTCL patients will be evaluated by PI according to the International Working Group Revised 
Response Criteria for Malignant Lymphoma (Cheson et al. 2007 (Appendix E)32. Bone marrow 
disease alone may be used for disease assessment. In this case, response would be CR or non-CR 
only, determined by the morphology of repeat bone marrow biopsy.  
 
CTCL response and progression will be evaluated by PI according to the Response Criteria in 
Mycosis Fungoides and Se´zary Syndrome by the International Society for Cutaneous Lymphomas 
(ISCL), the United States Cutaneous Lymphoma Consortium (USCLC), and the Cutaneous 
Lymphoma Task Force ofthe European Organisation for Research and Treatment of Cancer 
(EORTC) criteria (Appendix K)33. Patients with non-measurable lesions but assessable disease 
will be evaluated using appropriate diagnostic modality as approved by PI/Co-PI. Similarly, 
patient having both skin and node lesions will be evaluated appropriately to assess the response. 
Additional measurement/evaluations will be performed for a specific indication if deemed 
necessary.  
 
7.2 Response Evaluations and Measurements 
At baseline PTCL and CTCL will be staged and diagnosis will be confirmed by an expert 
hematologist and dermato-oncologist respectively. Clinical assessments will include ECOG 
performance status, lymph nodes, organomegaly, and “B” symptoms. The staging of PTCL and 
CTCL patients will be done according to Ann Arbor (Appendix F) and ISCL/EORTC criteria 
(Appendix H) 34 respectively. 
 
CTCL: Recommended evaluation/initial staging of the patient with CTCL (MF /SS) is given 
Appendix G. For the definition of patch, plaque, and tumor should be as outlined in Appendix I. 
For study eligibility, the histopathologic diagnosis should be confirmed by a skin biopsy. These 
patients 
will 
have 
half 
body global 
and 
up 
to 
5 selected 
representative 
index 
lesions photographed at baseline, at C3D1, End of treatment (EOT), at PR/CR/PD and as required 
as per the discretion of PI/Co-PI. The pre-treatment evaluation and scoring of response parameters 
(Refer  
If grade 3 toxicity lasts 2 weeks 
and resolves to ≤ grade 1  
Hold* dose until toxicity Grade ≤1 
Exception  
Grade ≥3 diarrhea or nausea that does not resolve to Grade ≤2 
within 48 hours of treatment, reduce one dose level. 
Recurrence of grade 3 of  toxicity 
Reduce one dose level or more or discontinue treatment after 
discussion with medical monitor* 
Grade 4 CTCAE 
Hold* dose until toxicity Grade ≤1 , then reduce by 1 dose level  
Recurrence of grade 4 toxicity 
Discontinue study drug 


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Appendix L) can be done at baseline/screening. These scores will constitute the comparison values 
for all response measurements during the study. For skin scoring, the modified Severity Weighted 
Assessment Tool (mSWAT) will be used. For local index lesion skin scoring, Composite 
Assessment of Index Lesion Severity (Appendix J) will be used. Appendix K will be used for the 
definition of response in skin, lymph node, viscera and blood of patients with MF/SS. CTCL 
patients (sub-cutaneous or panniculitic like) with subcutaneous lesions which cannot be measured 
by mSWAT will be assessed by change in their positron emission tomography (PET)- computed 
tomography (CT) PET-CT avid lesions.  
 
In CTCL patients with other than presumed stage IA disease, or selected patients with limited T2 
disease and the absence of adenopathy or blood involvement, computed tomography (CT) scans 
of chest, abdomen, and pelvis alone ± FDG-PET scan are recommended to further evaluate any 
potential lymphadenopathy, visceral involvement, or abnormal laboratory tests. MRI may be 
substituted if clinically indicated, but the modality chosen to evaluate each individual patient 
should be the same throughout the duration of the study. 
 
PTCL: In these patients, bone marrow biopsy and CT scan of the thorax, abdomen, and pelvis 
will be performed. Bulky disease will be defined by the presence of tumor mass >5cm in the 
longest diameter. CT scans of the chest, abdomen and pelvis are required only for patients with 
measureable disease. Other scans may be performed (e. g, head CT) if clinically indicated or if the 
area is a site of known disease. PET-CT will be used to assess response in FDG-avid histologies. 
The product of the perpendicular diameters of a single node can be used to identify progressive 
disease.35 CT scans will be also performed at the end of treatment if the patient is discontinued for 
reasons other than disease progression and a previous assessment has not been performed within 
30 days. 
 
In both indications, the disease will be assessed by PI at baseline and at C3D1 (± 7 days) and C5D1 
(± 7 days)  and approximately 12 weeks thereafter (± 7 days) and/ or at the EOT.  Assessment will 
be performed thereafter if warranted, at the disctetion of PI/Co-PI. All patients who discontinue 
study drugs will have an End of Treatment (See Appendix D) visit within 30 days from the last 
dose of study drug. The frequency outlined is the minimum required for study participation. 
Patients who progress according to the corresponding criteria will receive no further treatment. 
Patients who respond to the treatment (i.e., CR, PR or SD) may remain on trial. All disease specific 
assessments are to be completed as applicable to disease type. The modality chosen should be the 
same throughout the duration of the study.  
 
 
8 TRIAL ASSESSMENTS AND TREATMENT 
8.1 Overview 
A cycle of treatment is scheduled to last 4 weeks (28 calendar days).  Patients will visit the study 
center according to the schedule of assessments shown in Appendix D.  In dose expansion, all 


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visits to be performed on monthly interval; patients will be visiting hospital on Day 1 of each cycle 
(e.g. Day 1 of Cycle 1, Cycle 2, and Cycle 3… etc). 
 
Multiple procedures may be scheduled at the same time point relative to RP6530 dosing.  Priority 
should be given to PK collection at the time specified followed by collection of PD samples.  Vital 
signs should be performed prior to specimen collections. 
 
8.2 Screening  
The informed consent must be obtained ≤28 days prior to initiation of treatment before any 
protocol-specific procedures are performed. Patient registration will be done as per site’s practice.  
Sites will assign a patient identification number and dose level. Screening assessments described 
in Appendix D will be collected, reviewed, and determined to be acceptable by the site PI or 
designee after obtaining informed consent and ≤7 calendar days prior to the initiation of treatment.  
If these initial examinations are obtained within 72 hours (or as otherwise noted) of Cycle/1 Day 
1, they do not have to be repeated.  Rescreening can be done at the discretion of PI. Scans to 
document measurable or evaluable disease should be performed ≤4 weeks prior to initiation of 
treatment.  
 
During screening active Active HBV, HCV or HIV infection should be ruled out.  To be considered 
negative for active infection will be used:  
 HBV: HBc antibody should be negative or if HBc antibody is positive, HBVDNA should be 
undetectable 
 HCV: HCV antibody should be negative or if HCV antibody is positive, HCVDNA should 
be undetectable 
 HIV: HIV antibody should be negative. (HIV 1/ 2 antibody should be negative unless 
positive result is considered false positive by PI) 
 
8.3 Laboratory Investigations 
The CBC plus differential, platelets, biochemistry test, PT/INR will be perfomed as mentioned in  
Annexure D. Blood drawn for these tests will be specified in informed consent form (ICF). The 
investigations will be performed at local laboratory. The additional details will be provided in 
laboratory manual.  
1. All laboratory investigations should preferably be done in fasting condition prior to 
administration of RP6530. 
2. TSH, free T3 and free T4 should be performed as part of thyroid function testing and recorded 
in the eCRF. Total T3 and total T4, if performed as a Standard of Care (SOC), it should be 
recorded as an additional test in the eCRF. 
3. Serum bicarbonate should be performed as part of the electrolyte assessment. If carbon dioxide 
(CO2) is performed as SOC, it should be recorded as an additional test in the eCRF. 
4. Blood Urea Nitrogen (BUN) is preferred; if not available, Urea may be tested as per 
institutional practice. 
5. PT/INR: PT should be recorded in seconds. Both PT and INR results are to be entered in the 
eCRF field separated. 
6. Routine urinalysis should include at minimum pH, urobilinogen, ketones, glucose, protein, 
RBC, WBC, nitrites and caste. Additional parameters should be included if clinically relevant 
per Investigator judgement.  


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8.4 12-Lead Electrocardiograms 
There is no preclinical evidence of QTc liability with RP6530 to date.  In Dose escalation, a single 
ECG will be performed at screening and C1D1 pre-dose.  Post-dose ECGs will be performed in 
conjunction with the 1 hr, 2hr and 4hr post-dose PK collection on C1D1; and on C1D8 (pre-dose),  
C1D15 (pre-dose), and C1D22 (pre-dose).  On C2D1, ECGs will be obtained pre-dose and then 
one hour post-dose coinciding with the PD collection. In Dose Expansion, a single ECG will be 
performed at screening, C1D1 pre-dose and C2D1 pre-dose and one hour post-dose.  
 
Additional ECGs will be obtained if clinically indicated. Triplicate ECGs will be performed to 
confirm the significant changes of single ECG. All ECGs will be performed on local equipment.  
 
8.5 Bone Marrow Biopsy/Aspiration 
PTCL: Patients entering the study with low grade lymphoma must have a morphology and flow 
cytometry performed ≤3 months prior to study entry and/or to confirm a complete response.  
Patients with high grade lymphoma must have a morphology and flow cytometry  performed ≤28 
days prior to study entry and/or to confirm a complete response.  
 
Patients without measurable disease but assessable disease (e.g. marrow disease without other 
radiographically measurable disease) will have have a bone marrow biopsy at screening /baseline 
and on C3D1 (± 7 days) and C5D1 (± 7 days)  and approximately 12 weeks thereafter (± 7 days) 
and/or to confirm a complete response. 
 
CTCL: Patients with predominantly blood involvement (as confirmed by flow cytometry) will 
have a bone marrow biopsy at screening /baseline (unless it has been shown to be negative within 
the last 6 months) and as indicated to confirm a complete response occurring at all other 
sites. Specific molecular exams for some particular malignancies will be performed according to 
institutional diagnostic guidelines. 
 
8.6 Skin Biopsy 
CTCL: skin biopsy should be performed at screening, on C3D1 (± 7 days) and/or to confirm a 
complete response at the most indurated area if only one biopsy. Immunophenotyping to include 
at least the following markers: CD3, CD4, CD7, CD8 and Ki67. CD30 may also be indicated in 
cases where lymphomatoid papulosis, anaplastic lymphoma, or large-cell transformation is 
considered. Clonality of TCR gene rearrangement will be performed as part of standard of care 
and will be an optional. This information will be sought from patient’s previous report. 
PTCL: Skin assessment will be performed at the time of screening in case of skin lesion. 
 
8.7 Radiological Evaluations 
A CT scan (chest, abdomen, pelvis) and other radiological evaluations (X-RAY/MRI/Ultrasound) 
will be provided by the patients at the time of screening prior to therapy. PET-CT will be used to 
assess response in FDG-avid histologies. These evaluations should have been performed within 
28 days of screening. Efficacy evaluation would be done at C3D1 (± 7 days) and C5D1 (± 7 days)  
and approximately 12 weeks thereafter (± 7 days). Patients will be restaged after radiological 
evaluations. Refer section 7.2 for additional details.     
 


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8.8 Pharmacokinetic Assessments 
Extensive PK sample collection is applicable to Dose Escalation. Pre-dose sample will be collected 
in Dose Expansion at the start of each cycle (e.g. C1D1, C2D1,…). No PK assessments are 
required beyond Cycle 8. The PK parameters (including AUC (0-∞), AUC (0- ), Cmax, tmax, λz, and t½) 
of RP6530 following will be assessed by analysis of RP6530 plasma concentrations during the 
dose escalation phase of the study. Exploratory analysis will be performed if deemed essential. 
Please refer Annexure D for PK blood samples. Plasma samples will be collected and stored at -
70 °C at the clinic and shipped to Bioanalytical Laboratory: NorthEast Bioanalytical Laboratories, 
925 Sherman Avenue, Hamden, CT 06514, USA. See laboratory manual for PK processing 
instructions. 
 
8.9 Pharmacodynamics 
The PD samples (to estimate pAKT) will be performed on C1D1 (pre-dose and 1 hr later), C1D8 
(pre-dose) and C1D22 (pre-dose); C2D1 (pre-dose) and C3D1 (pre-dose) and/ at EOT in five 
sezary syndrome (SS) patients at MDACC only. pAKT will not be performed in dose expansion. 
The analyses for pharmacodynamic biomarkers (inhibition of pAKT) are exploratory, and will not 
be used to guide treatment decisions.  The results may be pooled with data from other studies to 
generate hypotheses to be tested in future studies. Whole blood samples will be collected, cells 
will be extracted and stored at -70°C, until analyzed. See laboratory manual for PD processing 
instructions. 
 
8.10 
Correlative Assessments/Exploratory Biomarkers 
Correlative serum biomarkers (e.g. sIL2R CTACK (PTCL); CD30 (MF), IL-31 and IL-32 
(CTCL)) will be performed at screening, C3D1 (pre-dose and 1 hr later); at EOT and/ or to confirm 
a response. Blood will be collected for these biomarkers, serum aliquots will be prepared and shall 
be stored at below -700C until analysis. The decision to analyse the serum samples will be taken 
at later stage only if required or deemed necessary by the investigator/sponsor.  
 
The analyses of correlative biomarkers are exploratory evaluation, and will not be used to guide 
treatment decisionsin the dose escalation and expanded cohort of the study. See laboratory manual 
for biomarker processing instructions. 
 
8.11 
Archived Tumor Tissue 
Archival tissues will be collected from all patients, if the tissue sample  available.  Institutional 
procedure will be followed for processing and archieval of tumor tissue.  
 
8.12 
Trial Treatment Period 
In Dose Escalation, patients will visit the study center weekly (± 1 day) in during cycle 1 and 2 for 
safety assessment. All visits should occur as close as possible to the protocol specified time. 
Complete listings of the assessments that will be performed at each visit during the trial treatment 
period are specified in Appendix D. Patients will return to the study center weekly during cycles 
1 and 2 for safety assessments.  During Cycles 3 and 4 patients will return to the study center on 
Days 1 (± 3 day) and Day 15 (± 3 day) of each cycle for assessments and study drug.  Patients 
continuing on study after Cycle 4 will return to the study center on Day 1 (± 3 day)  of each 
subsequent cycle for study drug and safety assessments. In Dose Expansion, all visits to be 
performed on monthly interval.  


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8.13 
Response Assessment 
Response will be assessed at C3D1 (± 7 days) and C5D1 (± 7 days)  and approximately 12 weeks 
thereafter (± 7 days) and/ or at the EOT.  Assessment will be performed thereafter if warranted, at 
the disctetion of PI/Co-PI. Patients with progressive disease or unacceptable toxicity should be 
discontinued from the trial; patients with stable disease or response to therapy will continue 
treatment.  The assessments to be performed at this time are specified in Appendix D. 
 
8.14 
End of Trial Treatment 
Patients are permitted to continue treatment with RP6530 until disease progression, or the patient 
is discontinued due to unacceptable toxicity or decision to discontinue treatment by the patient or 
the trial physician. Follow-up evaluations required after treatment ends are specified in Appendix 
D. If treatment is discontinued because of toxicity or any other reason(s) at a treatment visit and 
no trial treatment is administered, that visit may fulfill the End of Trial Treatment Visit. 
 
After withdrawal from or completion of protocol treatment, patients must be followed for any new 
adverse events for 30 calendar days after the last dose of trial drug. 
 
8.15 
Early Patient Termination / Patient Withdrawal 
Patients who discontinue treatment early due to disease progression or withdrawal will be asked 
to have all end-of-treatment safety evaluations performed as described in the protocol (see 
Appendix D).  If a patient withdraws from treatment during Cycle 1 due to any reason other than 
DLT and does not meet the minimum requirements for inclusion in the MTD-determining 
population described in Section 6.6.1, that patient will be replaced. 
 
9 STATISTICAL CONSIDERATIONS   
The sections of the Statistical Considerations described the statistical methods to be used to 
analyze the safety and efficacy as described in the objectives. These methods may be revised and 
updated due to reasons such as regulatory requirements or need for further clarifications. The final 
analysis plan will be documented in a formal statistical analysis plan (SAP) that must be finalized 
before database lock. The SAP will include details on how variables will be derived, how missing 
data will be handled, and how censoring procedures will be applied to time to event related 
variables as well as the details on statistical methods to be used for safety and efficacy analyses. 
The final clinical study report will discuss deviations from the SAP, if any. 
 
9.1 General Considerations 
This is an open-label, Phase I, dose-escalation study of the PI3K δ/γ inhibitor RP6530.  This trial 
is designed to determine the MTD (or recommended dose)  to support further clinical studies, and 
preliminary information on the safety profile and PK profile and anti-tumor activity of RP6530 
given as a single agent.   
 
9.2 Determination of Sample Size 
This trial will enroll up to 58 patients at 5-10 sites.  The actual number of dose cohorts will depend 
upon the MTD/ optimal dose (or recommended dose) . 
 
9.3 Statistical Analyses 
All statistical analyses will be performed using SAS 9.1 or higher. 


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9.3.1 Demographic and Baseline Characteristics 
Demographics and baseline characteristics will be summarized using descriptive statistics for 
continuous variables, and frequencies and percentages for categorical variables. 
 
9.3.2 Safety Analyses 
The safety population will include all patients who will receive at least one dose of study 
medication. The safety endpoints will include: 
 Incidence of DLTs   
 Incidence of AEs and AEs considered to be drug-related 
 Incidence of grade 3 and grade 4 AEs 
 Incidence of SAEs 
 Laboratory values 
 ECG/vital signs 
The safety endpoints will be listed and/or summarized by dose cohort.  No inferential statistical 
analyses will be performed. 
The analyses of safety will be based on the frequency of adverse events and their severity for 
patients in each portion who received at least one dose of study treatment. Worst toxicity grades 
per patient will be tabulated for select adverse events and laboratory measurements by using NCI 
CTCAE criteria v4.0. 
 
9.3.3 Efficacy Analyses 
Two populations will be used in the efficacy analyses, Intent-to-Treat (ITT) and Per Protocol (PP) 
populations. The ITT population will include all safety population who provide efficacy 
assessment. PP population will include all ITT population without major protocol violations.    
The efficacy endpoints will include: 
 Overall response rate (ORR) 
 Duration of Response (DoR) 
 
These variables will be analyzed/summarized based on the ITT population as well as the PP 
population as appropriate.  The percentages of CR, CR+PR, and CR+PR+SD will be presented, as 
will the median duration of response.  The 95% confidence intervals of these percentages may also 
be presented.   
Additional analyses may also be performed as appropriate. 
These analyses will be performed from time to time for presentation/publication purposes. 
 
9.3.4 Pharmacokinetic Analyses 
The following PK parameters will be derived: 
 
AUC, Cmax, Tmax, T1/2 
These variables will be summarized by n, mean, standard deviation, median, minimum, and 
maximum by dose.  The geometric means will also be presented for AUC and Cmax. 
 
 
 


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10 ETHICAL, FINANCIAL, AND REGULATORY CONSIDERATIONS 
 
This trial will be conducted according to the standards of Good Clinical Practice outlined in the 
ICH E6 Tripartite Guideline, and CFR Title 21 part 312, applicable government regulations, 
institutional research policies and procedures and any other local applicable regulatory 
requirement(s).  
 
10.1 
IRB/IEC Approval 
The trial protocol, ICF, IB, available safety information, patient documents (e.g., subject diary), 
patient recruitment procedures (e.g., advertisements), information about payments (i.e., PI 
payments) and compensation available to the patients and documentation evidencing the PI’s 
qualifications should be submitted to the IRB/IEC for ethical review and approval if required by 
local regulations, prior to the trial start.   
 
The PI/Sponsor/CRO and/or designee will follow all necessary regulations to ensure appropriate, 
initial, and ongoing, IRB/IEC trial review. The PI/Sponsor (as appropriate) must submit and, where 
necessary, obtain approval from the IRB/IEC for all subsequent protocol amendments and changes 
to the informed consent document.  Investigators will be advised by the sponsor or designee 
whether an amendment is considered substantial or non-substantial and whether it requires 
submission for approval or notification only to an IRB/IEC. 
Safety updates for RP6530 will be prepared by the Sponsor or its representative as required, for 
submission to the relevant IEC. 
 
10.2 
Regulatory Approval 
As required by local regulations, the Sponsor will ensure all legal aspects are covered, and approval 
of the appropriate regulatory bodies obtained, prior to trial initiation. If required, the Sponsor will 
also ensure that the implementation of substantial amendment to the protocol and other relevant 
trial documents happen only after approval by the relevant regulatory authorities. 
Safety updates for RP6530 will be prepared by the Sponsor or its representative as required, for 
submission to the relevant regulatory authority.  
 
10.3 
Insurance and Indemnity 
Details of insurance and/or indemnity will be contained within the written agreement between the 
PI or site and the Sponsor. 
 
10.4 
Informed Consent 
Informed consent is a process by which a subject voluntarily confirms his or her willingness to 
participate in a particular trial, after having been informed of all aspects of the trial that are relevant 
to the subject's decision to participate.  Informed consent is documented by means of a written, 
signed and dated informed consent form. 
The informed consent form will be submitted for approval to the IEC that is responsible for review 
and approval of the trial.  Each consent form must include all of the relevant elements currently 
required by the US FDA, as well as local county authority or state regulations and national 
requirements. 
 


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Before recruitment and enrollment into the trial, each prospective candidate will be given a full 
explanation of the trial.  Once the essential information has been provided to the prospective 
candidate, and the investigator is sure that the individual candidate understands the implications 
of participating in this trial, the candidate will be asked to give consent to participate in the trial 
by signing an informed consent form.  A notation that written informed consent has been obtained 
will be made in the patient’s medical record.  A copy of the signed informed consent formwill be 
provided by the investigator to the patient.   
 
If an amendment to the protocol substantially alters the trial design or the potential risks to the 
patients, the patient’s consent to continue participation in the trial should be obtained. 
 
10.5 
Confidentiality 
10.5.1 Patient Confidentiality 
Confidentiality of patient’s personal data willbe protected in accordance with the Health  
Insurance Portability and Accountability Act of 1996 (HIPAA) and national data protection laws,  
as applicable. HIPAA regulations require that, in order to participate in the trial, a patient must  
sign an authorization from the trial that he or she has been informed of following: 
a. What protected health information (PHI) will be collected from patients in this trial; b. Who will 
have access to that information and why; c. Who will use or disclose that information; d. The 
information collected about the research trial will be kept separate from the patient’s medical 
records, but the patient will be able to obtain the research records after the conclusion of the trial; 
e. Whether the authorization contains an expiration date; and f. The rights of a research patient to 
revoke his or her authorization.  
 
In the event that a patient revokes authorization to collect or use his or her PHI, the investigator, 
by regulation, retains the ability to use all information collected prior to the revocation of patient 
authorization.  For patients that have revoked authorization to collect or use PHI, attempts should 
be made to obtain permission to collect at least vital status (i.e., that the patient is alive) at the end 
of their scheduled trial period. 
 
In compliance with ICH GCP guidelines and applicable parts of 21 CFR, it is a requirement that 
the investigator and institution permit authorized representatives of Sponsor, the regulatory 
authorities and the IEC direct access to review the patient’s original medical records at the site for 
verification of trial-related procedures and data.  
 
Measures to protect confidentiality include: only a unique trial number and initials will identify 
patients on the CRF or other documents submitted to the Sponsor. This information, together with 
the patient’s date of birth, will be used in the database for patient identification. Patient names or 
addresses will not be entered in the CRF or database. No material bearing a patient’s name will be 
kept on file by Sponsor. Patients will be informed of their rights within the ICF. 
 
10.5.2 Investigator and Staff Information 
Personal data of the investigators and sub-investigators may be included in the site database, and 
shall be treated in compliance with all applicable laws and regulations. When archiving or 
processing personal data pertaining to the investigator or sub-investigator, the site shall take all 
appropriate measures to safeguard and prevent access to this data by any unauthorized party. 


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11 RECORD RETENTION AND DOCUMENTATION OF THE TRIAL 
11.1 
Amendments to the Protocol 
Amendments to the protocol shall be planned, documented and signature authorized prior to 
implementation.   
If an amendment to the protocol is required, the amendment will be originated and documented by 
the Sponsor. All amendments require review and approval of Rhizen Pharmaceutical.  The written 
amendment must be reviewed and approved by the Sponsor, and submitted to the IEC at the 
investigator’s facility for the board’s approval. 
 
Amendments specifically involving change to trial design, risk to patient, increase to dosing or 
exposure, subject number increase, addition or removal of new tests or procedures, shall be 
reviewed and approved by the IRB/IEC at the investigator’s facility. 
 
The amendment will be submitted formally to the FDA by the Sponsor as applicable, after 
IRB/IEC approval and specifically when an increase to dosing or patient exposure and/or subject 
number has been proposed; or, when the addition or removal of an Investigator is necessitated. 
Items requiring a protocol amendment with IRB/IEC and/or FDA approval include, but are not 
limited to, the following: 
 
Change to trial design  
 
Risk to patient 
 
Increase to dose or patient exposure to drug  
 
Subject number increase  
 
Addition or removal of tests and / or procedures  
 
Addition/removal of a new Investigator  
It should be further noted that, if an amendment to the protocol substantially alters the trial design 
or the potential risks to the patients, their consent to continue participation in the trial should be 
obtained. 
 
11.2 
Documentation Required to Initiate Trial 
Before the trial may begin, documentation required by  US FDA will be provided by the Sponsor.  
Documents at a minimum required to begin a trial in the US include, but are not limited to: a 
signature-authorized protocol and contract; a copy of the official IRB approval ofthe trial and the 
IRB members list; current Curricula Vita for the principal investigator and any associate 
investigator(s) who will beinvolved in the trial; indication of appropriate accreditation for any 
laboratories to be used in the trial and a copy of the normal ranges for tests to be performed by that 
laboratory; original Form FDA 1572 (Statement of Investigator), appropriately completed and 
signed; a copy of the IRB-approved consent form containing permission for audit by 
representatives of Sponsor, the IRB, and the FDA; financial disclosure forms for all investigators 
listed on Form FDA 1572; site qualification reports, where applicable; verification of Principal 
Investigator acceptability from local and/or national debarment list(s).  
 
12 DATA HANDLING AND RECORD KEEPING  
The PI must maintain a list of appropriately qualified persons to whom he/she has delegated trial 
duties and should ensure that all persons assisting in the conduct of the trial are informed of their 
obligations. All persons authorized to make entries and/or corrections on the CRFs are to be 


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included on this document. All entries in the patient’s CRF are to be supported by source 
documentation where appropriate. 
 
Source documents are the original documents, data, records and certified copies of original records 
of clinical findings, observations and activities from which the patient’s CRF data are obtained. 
These can include, but are not limited to, hospital records, clinical and office charts, laboratory, 
medico-technical department and pharmacy records, diaries, microfiches, ECG traces, copies or 
transcriptions certified after verification as being accurate and complete, photographic negatives, 
microfilm or magnetic media, X-rays, and correspondence. 
 
The PI and trial staff are responsible for maintaining a comprehensive and centralized filing system 
(Site Trial File/SSF or Investigator Site File (ISF)) of all trial-related (essential) documentation, 
suitable for inspection at any time by representatives from the Sponsor and/or applicable regulatory 
authorities.  The ISF/SSF must consist of those documents that individually or collectively permit 
evaluation of the conduct of the trial and the quality of the data produced.  The ISF/SSF should 
contain as a minimum all relevant documents and correspondence as outlined in ICH GCP and 21 
CFR Part 312.57, including key documents such as the IB and any amendments, protocol and any 
amendments, signed ICFs, copies of completed CRFs, IRB/IEC approval documents, Financial 
Disclosure forms, patient identification lists, enrollment logs, delegation of authority log, staff 
qualification documents, laboratory normal ranges, records relating to the trial drug including 
accountability records.  Drug accountability records should, at a minimum, contain information 
regarding receipt, shipment, and disposition.  Each form of drug accountability record, at a 
minimum, should contain PI name, date drug shipped/received, date, quantity and batch/code, or 
lot number for identity of each shipment.  In addition, all original source documents supporting 
entries in the CRF must be maintained and be readily available. 
 
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial and as required by the applicable regulatory 
requirement(s). The investigator/institution should take measures to prevent accidental or 
premature destruction of these documents 
 
The Investigator shall maintain adequate records of drug disposition, case histories and any other 
trial-related records as per 21 CFR Part 312.62 for no less than 2 years after the last marketing 
application has been approved by FDA; or, in the event that the marketing application has not been 
approved by FDA, for no less than 2 years after the last shipment / delivery of the drug for 
investigational use is discontinued and FDA has been notified of the discontinuation. 
 
To enable evaluations and/or audits from regulatory authorities or from the Sponsor or its 
representative, the investigator additionally agrees to keep records, including the identity of all 
participating patients (sufficient information to link records e.g., CRFs and medical records), all 
original, signed informed consent forms, and copies of all CRFs, SAE Reporting forms, source 
documents, detailed records of treatment disposition, and related essential regulatory 
documents.  The documents listed above must be retained by the investigator for as long as needed 
to comply with national and international regulations (generally 2 years after discontinuing clinical 
development 
or 
after 
the 
last 
marketing 
approval).  
Sponsor 
will 
notify 
the 
investigator(s)/institutions(s) when the trial-related records are no longer required.   


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If the investigator relocates, retires, or for any reason withdraws from the trial, both site and 
sponsor should be prospectively notified.  The trial records must be transferred to an acceptable 
designee, such as another investigator, another institution, or to sponsor.  The investigator must 
obtain the sponsor written permission before disposing of any records, even if retention 
requirements have been met.  All trial files will be maintained by the Sponsor/Sponsor 
Representative/CRO throughout the trial, and will be transferred to the Sponsor at the conclusion 
of the trial. 
 
12.1 
Data Collection 
The data will be captured in Case Record Form (CRF).  The CRF is clinical trials data management 
tool that provides investigational sites a standardised and validated, remote, electronic data capture 
system for the collection of clinical trial data.  All data requested on the CRF must be supported 
by and be consistent with the patient’s source documentation. All missing data must be explained. 
When a required laboratory test, assessment, or evaluation has not been done or an “Unknown” 
box is not an option on the CRF, a note should be created verifying that the field was “Not Done” 
or “Unknown”. For any entry errors made, the error(s) must be corrected, and a note explaining 
the reason for change should be provided.  
 
The principal investigator will sign and date each casebook attesting to his/her responsibility for 
the quality of all data included therein, and that the data represent a complete and accurate record 
of each subject's participation in the study.  
 
Clinical data management will be performed in accordance with applicable standards. Data 
cleaning procedures will be performed with the objective of removing errors and inconsistencies 
in the data which would otherwise impact on the analysis and reporting objectives, or the 
credibility of the Clinical Study Report. Adverse events, medical history and concomitant 
medications will be coded using industry standard dictionaries (MedDRA and WHO Drug).  
 
12.2 
Trial Monitoring, Auditing, and Inspecting 
The investigator will permit trial-related monitoring, quality audits, and inspections by the sponsor, 
government regulatory authorities, the Sponsor or its representative(s) of all trial-related 
documents (e.g., source documents, regulatory documents, data collection instruments, case report 
forms).  The investigator will ensure the capability for inspections of applicable trial-related 
facilities.  The investigator will ensure that the trial monitor or any other compliance or QA 
reviewer is given access to all trial-related documents and trial-related facilities.   
Participation as an investigator in this trial implies the acceptance of potential inspection by 
government regulatory authorities, the sponsor or its representative(s). At the Sponsor’s discretion 
Source Document Verification (SDV) may be performed on all data items or a percentage thereof. 
 
12.3 
Quality Assurance and Quality Control 
Each trial site shall be required to have Standard Operating Procedures (SOP’s) to define and 
ensure quality assurance/control processes for trial conduct, data generation & collection, 
recording of data/documentation and reporting according to the protocol, GCP and any applicable 
local, national or international regulations. 
 


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12.4 
Disclosure and Publication Policy 
All information provided regarding the trial, as well as all information collected/documented 
during the course of the trial, will be regarded as confidential.  The Sponsor reserves the right to 
release literature publications based on the results of the trial.  Results from the trial will be 
published/presented as per the Sponsor’s publication strategy. 
 
Inclusion of the investigator in the authorship of any multi-center publication will be based upon 
substantial contribution to the design, analysis, interpretation of data, drafting and/or critically 
revising any manuscript(s) derived from the trial.  The investigator acknowledges that the trial is 
part of a multi-center trial and agrees that any publication by the investigator of the results of the 
trial conducted at research site shall not be made before the first multi-center publication.  In the 
event there is no multi-center publication within fifteen (15) months after the trial has been 
completed or terminated at all trial sites, and all data has been received, the investigator shall have 
the right to publish its results from the trial, subject to the notice requirements described herein 
and subject to acknowledgement of the Sponsor as appropriate.  Investigator shall provide the 
Sponsor thirty days to review a manuscript or any poster presentation, abstract or other written or 
oral material which describes the results of the trial for the purpose only of determining if any 
confidential or patentable information is disclosed thereby. If the Sponsor requests in writing, the 
investigator shall withhold any publication or presentation an additional sixty (60) days solely to 
permit the Sponsor to seek patent protection and to remove any site Confidential Information from 
all publications.  
  
 
13 REFERENCES 
 
1 
Herman SE, Gordon AL, Wagner AJ, et al. Phosphatidylinositol 3-kinase-delta 
inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic 
leukemia by antagonizing intrinsic and extrinsic cellular survival signals. Blood 2010; 
116:2078-2088 
2 
Lannutti BJ, Meadows SA, Herman SE, et al. CAL-101, a p110delta selective 
phosphatidylinositol-2-kinase inhibitor for the treatment of B-cell malignancies, 
inhibits PI3K signaling and cellular viability. Blood. 2011; 117:591-594 
3 
Hoellenriegel J, Meadows SA, Sivina M, et al. The phosphoinositide-3-kinase delta 
inhibitor, CAL-101, inhibits B-cell receptor signaling and chemokine networks in 
chronic lymphocytic leukemia. Blood. 2011; 118; 3603-3612 
4 
Ikeda H, Hideshima T, Fulciniti M, et al. PI3k/p110 (delta) is a novel therapeutic 
target in multiple myeloma. Blood. 2010; 1460-1468 
5 
Coutre SE, et al. Phase I study of CAL-101, an isoform selective inhibitor of 
phosphotidylinositol-3-kinase P110d, in patients with previously treated chronic 
lymphocytic leukemia J.Clin Oncol. 2011; 29,451s (suppl;abstr 6631) 
6 
Idelalisib. Prescribing information  
http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206545lbl.pdf  
7 
Flinn et al. 2012. Clinical Safety and Activity in a Phase-1 Trial of IPI-145, a Potent 
Inhibitor of Phosphoinositide-3-Kinase-δ,γ, in Patients with Advanced Hematological 
Malignancies. American Haematology Association Annual Meeting 
8 
PI3Kδ Enzyme Assay (Study No. IVT-6530-HPI3K-D-1) 


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9 
PI3Kγ Enzyme Assay (Study No. IVT-6530-HPI3K-G-2) 
10 
PI3Kα Enzyme Assay (Study No. IVT-6530-HPI3K-A-29) 
11 
PI3Kβ Enzyme Assay (Study No. IVT-6530-HPI3K-B-30) 
12 
SelectScreen®Z′-LYTE Kinase Screening (SSBK10755_26985) 
13 
Anti-IgM induced human B cell proliferation (Study No. IVT-6530-BCP-41) 
14 
c5a induced AKT Phosphorylation in 3T3 cells (Study No. IVT-6530-CAG-33) 
15 
PDGF induced AKT Phosphorylation in 3T3 cells (Study No. IVT-6530-PAA-34) 
16 
LPA induced AKT Phosphorylation in 3T3 cells (Study No. IVT-6530-LAB-34) 
17 
Leukemic Cell Proliferation Assay (Study No. IVT-6530-LPA-54) 
18 
AKT phosphorylation in Jurkat cells (Study No. IVT-6530-APJ-36) 
19 
AKT phosphorylation in MOLT-4 cells (Study No. IVT-6530-APM-39) 
20 
AKT phosphorylation in CCRF-CEM cells (Study No. IVT-6530-APC-40) 
21 
AKT phosphorylation in HuT-78 cells (Study No. IVT-6530-APH78-37) 
22 
AKT phosphorylation in HuT-102 cells (Study No. IVT-6530-APH102-38) 
23 
Induction of Capase-3 in Jurkat cells (Study No. IVT-6530-CSP-JUR-12) 
24 
Induction of Capase-3 in MOLT-4 cells (Study No. IVT-6530-CSP-MOLT-10) 
25 
Induction of Capase-3 in CCRF-CEM cells (Study No. IVT-6530-CSP-CCRF-20) 
26 
Induction of Capase-3 in HuT-78 cells (Study No. IVT-6530-CSP-HuT 78-18) 
27 
Induction of Capase-3 in HuT-102 cells (Study No. IVT-6530-CSP-HuT 102-19) 
28 
MOLT-4 Xenograft in Nude Mice (Incozen-CP-006)  
29 
T-cell Patient blood sample analysis (Yale Medical University, USA) 
30 
A 28-day Repeat Dose Study by oral gavage in Wistar Rat with 14-day recovery 
period (20040303) 
31 
A 28-day Repeat Dose Study by oral capsule in dogs with 14-day recovery period 
(Study No. 20040304)  
32 
Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, Coiffier  
B, Fisher RI, Hagenbeek A, Zucca E, Rosen ST, Stroobants S, Lister TA, Hoppe RT,  
Dreyling M, Tobinai K, Vose JM, Connors JM, Federico M, Diehl V; International 
Harmonization Project on Lymphoma. Revised response criteria for malignant 
lymphoma. J Clin Oncol. 2007 Feb 10;25(5):579-86. 
33 
Olsen EA, Whittaker S, Kim YH, Duvic M, Prince HM, Lessin SR, et al; International 
Society for Cutaneous Lymphomas; United States Cutaneous Lymphoma Consortium; 
Cutaneous Lymphoma Task Force of the European Organisation for Research and 
Treatment of Cancer. Clinical end points and response criteria in mycosis fungoides 
and Sézary syndrome: a consensus statement of the International Society for 
Cutaneous Lymphomas, the United States Cutaneous Lymphoma Consortium, and the 
Cutaneous Lymphoma Task Force of the European Organisation for Research and 
Treatment of Cancer. J Clin Oncol. 2011 Jun 20;29(18):2598-607. 
34 
Olsen E, Vonderheid E, Pimpinelli N, Willemze R, Kim Y, Knobler R et al; 
ISCL/EORTC. Revisions to the staging and classification of mycosis fungoides and  
Sezary syndrome: a proposal of the International Society for Cutaneous Lymphomas  
(ISCL) and the cutaneous lymphoma task force of the European Organization of 
Research and Treatment of Cancer (EORTC). Blood. 2007 Sep 15;110(6):1713-22. 1. 
35 
Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, Lister 
TA. Recommendations for Initial Evaluation, Staging, and Response Assessment of 


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Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification. J Clin Oncol. 
2014 Aug 11. 


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14. 
APPENDIX 
 
Appendix A. 
ECOG Performance Status Scale 
 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Normal activity. Fully active, able to carry on all pre-disease performance without restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous activity, but ambulatory and able to 
carry out work of a light or sedentary nature (e.g., light housework, office work). 
2 
In bed < 50% of the time.  Ambulatory and capable of all self-care, but unable to carry out any work 
activities.  Up and about more than 50% of waking hours. 
3 
In bed > 50% of the time.  Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or 
chair. 
5 
Dead 


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Appendix B: 
New York Heart Association (NYHA) Classifications 
Class 
Functional Capacity 
Objective Assessment 
I 
Patients with cardiac disease but without resulting limitations of physical 
activity.  Ordinary physical activity does not cause undue fatigue, 
palpitation, dyspnea, or anginal pain. 
No objective evidence of 
cardiovascular disease. 
II 
Patients with cardiac disease resulting in slight limitation of physical 
activity.  They are comfortable at rest.  Ordinary physical activity results in 
fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of minimal 
cardiovascular disease. 
III 
Patients with cardiac disease resulting in marked limitation of physical 
activity.  They are comfortable at rest.  Less than ordinary activity causes 
fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of moderately 
severe cardiovascular disease. 
IV 
Patients with cardiac disease resulting in inability to carry on any physical 
activity without discomfort.  Symptoms of heart failure or the anginal 
syndrome may be present even at rest.  If any physical activity is 
undertaken, discomfort is increased. 
Objective evidence of severe 
cardiovascular disease. 
Source:  The Criteria Committee of New York Heart Association.  Nomenclature and Criteria for Diagnosis of Diseases of the Heart 
and Great Vessels.  9th Ed. Boston, MA:  Little, Brown & Co; 1994:253-256. 


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Appendix C: 
Contraceptive Guidelines and Pregnancy 
Women Not of Childbearing Potential are Defined as Follows: 
Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural 
(spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor 
symptoms) or six months of spontaneous amenorrhea with serum FSH levels > 40 mIU/mL] or have had surgical 
bilateral oophorectomy (with or without hysterectomy) at least six weeks ago. In the case of oophorectomy alone, 
only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is 
she considered not of child bearing potential. 
Contraceptive Guidelines for Women of Child-Bearing Potential: 
 Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, must use 
highly effective contraception during the study and for 5 T1/2 (48 hrs) plus an additional 4 weeks after stopping 
treatment. The highly effective contraception is defined as either: 
1. 
True abstinence: When this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception. 
2.  
Sterilization:  have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at 
least six weeks ago.  In case of oophorectomy alone, only when the reproductive status of the woman has 
been confirmed by follow up hormone level assessment. 
3.  
Male partner sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the 
ejaculate). For female subjects on the study, the vasectomised male partner should be the sole partner for that 
patient. 
4.  
Use of a combination of any two of the following (a+b): 
a)   Placement of an intrauterine device (IUD) or intrauterine system (IUS). 
b)  Barrier methods of contraception: Condom or Occlusive cap (diaphragm or   cervical/vault caps) with 
spermicidal foam/gel/film/cream/vaginal suppository. 
 
The following are unacceptable forms of contraception for women of childbearing potential:  
 Oral contraception, injected or implanted hormonal methods are not allowed as RP6530 may  potentially 
decrease the effectiveness of hormonal contraceptives. 
 IUD progesterone T  
 Female condom  
 Natural family planning (rhythm method) or breastfeeding  
 Fertility awareness  
 Withdrawal  
 Cervical shield 


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Appendix C: Contraceptive Guidelines and Pregnancy (Cont.) 
Women of child-bearing potential must have a negative serum or urine pregnancy test ≤ 72 hours prior to 
initiating treatment. 
Fertile Males: 
Fertile males, defined as all males physiologically capable of conceiving offspring must use condom during 
treatment, for 5 T1/2 (48 hrs) plus additional 12 weeks after stopping treatment and should not father a child in 
this period.   
Pregnancies 
To ensure patient safety, each pregnancy in a patient on study treatment must be reported to Rhizen 
Pharmaceuticals SA within 24 hours of learning of its occurrence. The pregnancy should be followed up for 3 
months after the termination of the pregnancy to determine outcome, including spontaneous or voluntary 
termination, details of the birth, and the presence or absence of any birth defects, congenital abnormalities, or 
maternal and/or newborn complications. 
Pregnancy should be recorded on a Clinical Study Pregnancy Form and reported by the investigator to Rhizen 
Pharmaceuticals SA.  Pregnancy follow-up should be recorded on the same form and should include an 
assessment of the possible relationship to the Rhizen Pharmaceuticals SA  study treatment of any pregnancy 
outcome. Any SAE experienced during pregnancy must be reported on the SAE Report Form. 
Pregnancy outcomes must be collected for the female partners of any males who took study treatment in this 
study. Consent to report information regarding these pregnancy outcomes should be obtained from the mother. 


Protocol No. RP6530-1401 
 
Rhizen Pharmaceuticals SA 
 Version 7, Dated 23 May 2018 
CONFIDENTIAL  
 
Page 72 of 97 
Appendix D: 
Schedule of Assessments (Dose Escalation and Dose Expansion) 
PART 1: DOSE ESCALATION 
Cycle  
 
Cycle 1 
Cycle 2 
Cycle C3 
Cycle C4 
C5 
C6 
C7 
C8 
EOT25 
Day  
D-28 
to 0 
D1 
D8 
D15 
D22 
D1 
D8 
D15 
D22 
D1 
D15 
D1 
D15 
D1 
D1 
D1 
D1 
D1 
Window period  
 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
+30 
Study Days  
D-28 
to 0 
1 
8 
15 
22 
29 
36 
43 
50 
57 
71 
85 
99 
113 
141 
169 
197 
- 
Dose escalation visits  
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PROCEDURE  
Informed Consent1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics2  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vitals4  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height and weight5  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG Performance Status 
X 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
LABORATORY TEST/EVALUATIONS   
Complete blood count7   
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry panel I8  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry panel II9  
X 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Serology (HIV, HBV,   HCV)
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PT/INR10 
X 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
 
 
X 
HbA1c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinanalysis (routine) 
X 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Pregnancy test11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGs12 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
PK blood samples13 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Biomarker samples14 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
PD samples (pAKT)15 
- 
X 
X 
- 
X 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
Archived tumor tissue16 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DISEASE ASSESSMENT  


Protocol No. RP6530-1401 
 
Rhizen Pharmaceuticals SA 
 Version 7, Dated 23 May 2018 
CONFIDENTIAL  
 
Page 73 of 97 
Staging17 
X 
- 
- 
- 
- 
- 
- 
- 
- 
X 
- 
- 
- 
X 
- 
- 
 
X 
Radiological Examination18 
X 
- 
- 
- 
- 
- 
- 
- 
- 
X 
- 
- 
- 
X 
- 
- 
X 
X 
Skin lesion assessment19  
X 
- 
- 
- 
- 
- 
- 
- 
- 
X 
- 
- 
- 
X 
- 
- 
X 
X 
Skin biopsy20 
X 
- 
- 
- 
- 
- 
- 
- 
- 
X 
- 
- 
- 
- 
- 
- 
- 
- 
Immunophenotyping and 
TCR gene rearrangement21  
X 
- 
- 
- 
- 
- 
- 
- 
- 
X 
- 
- 
- 
- 
- 
- 
- 
- 
Photograph of skin lesion22 
X 
- 
- 
- 
- 
- 
- 
- 
- 
X 
- 
- 
- 
 
- 
- 
 
X 
Bone marrow, lymph node 
biopsy /Aspirate23 
X 
- 
- 
- 
- 
- 
- 
- 
- 
-23a 
- 
- 
- 
-23a 
- 
- 
-23a 
X 
DRUG ADMINISTRATION & SAFETY EVALUATION  
Drug administration24 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
Drug dispensing  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
Drug compliance  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
AE evaluation and reporting  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SAE evaluation and reporting 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication 
review 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Diary evaluation  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 


Protocol No. RP6530-1401 
 
Rhizen Pharmaceuticals SA 
 Version 7, Dated 23 May 2018 
CONFIDENTIAL  
 
Page 74 of 97 
 
Note:  
1. 
Patient should be re-consented in case informed consent is not obtained ≤28 days prior to the initiation of trial treatment.   
2. 
Demographic profile will include age, sex and race. 
3. 
Detailed history will be taken at screening that includes history of cancer, past history, no of prior therapies and prior medication (in last 4weeks); and 
other medical history. Abbreviated history will be taken at all subsequent visits.  
4. 
Vitals will include pulse (sitting/supine); blood pressure (sitting/supine); respiratory rate and oral temperature. (Note: Pulse rate and blood pressure can be 
recorded in sitting OR supine position depending on convenience of patient and ease of measurement.) 
5. 
Weight will be measured at all visits. Height to be measured at screening only.  
6. 
Physical examination will include lymph node and systemic examination. Complete physical examination will be done at screening visit. At subsequent 
visits, abbreviated examination will be done. 
7. 
This will include Hb, complete blood count, reticulocyte count, total leucocyte and differential count and platelet count. Additional investigations will be 
performed if clinically indicated. Hematology must be done ≤7 days prior to initiation of treatment. However, if these initial examinations are obtained 
within 72 hours of C1D1; they do not have to be repeated.      
8. 
Chemistry Panel I includes Total bilirubin, ALP, AST, ALT, GGT, LDH and Serum electrolytes (Sodium, Potassium, Bicarbonate/CO2, Chloride, 
Magnesium, Phosphorus and Calcium). These tests must be done ≤7 days prior to initiation of treatment. However, if these initial examinations are 
obtained within 72 hours of C1D1; they do not have to be repeated. These test will be performed at supplementary visits if clinically indicated.       
9. 
Chemistry Panel II includes blood glucose, urea or blood urea nitrogen, creatinine, albumin, globulin, total protein, Total Cholesterol, TG, LDL and HDL, 
TSH, free T3 and free T4. These tests must be done ≤7 days prior to initiation of treatment. However, if these initial examinations are obtained within 72 
hours of C1D1; they do not have to be repeated. These test will be performed at supplementary visits if clinically indicated. (Note: Total protein and albumin 
tests will be performed; and globulin will be calculated by deducting value of albumin from total protein)   
10. This test must be done ≤7 days prior to initiation of treatment. However, if initial examination is obtained within 72 hours of C1D1; this should not be 
repeated. This test will be performed at supplementary visits if clinically indicated.       
11. This is required for women of child bearing potential. A serum pregnancy test will be performed at screening and baseline (within 72 hours) of dosing. 
Urine pregnancy test will be performed at other visits as indicated.  
12. A single ECG will be performed at screening and C1D1 pre-dose.  Post-dose ECGs will be performed in conjunction with the 1 hr, 2hr and 4hr post-dose 
PK collection on C1D1; and on C1D8 (pre-dose),  C1D15 (pre-dose), and C1D22 (pre-dose).  On C2D1, ECGs will be obtained pre-dose and then one 
hour post-dose coinciding with the PD collection. Additional ECGs will be obtained if clinically indicated.  Triplicate ECGs will be performed to confirm 
the significant changes of single ECG. All ECGs will be performed on local equipment.  
13. PK blood sample collection time points: C1D1 at pre-dose, 0.5, 1, 2, 4, 6, 8 hrs post dose; and C1D8 and C1D15 at predose; C2D1 at pre-dose, 0.5, 1, 2, 4, 
6, 8 hrs post dose and C2D8 and C2D15 at pre-dose; C3D1 and C3D15 at pre-dose; C4D1 and C4D15 at pre-dose; Cycle 5 and beyond at predose. 
Window period for PK sampling will be defined in laboratory manual.  No PK assessments are required beyond Cycle 8. 
14. Correlative serum biomarkers (e.g. sIL2R CTACK (PTCL); CD30 (MF); IL-31 and IL-32 (CTCL)) will be performed at screening, C3D1 (pre-dose and 1 
hr later); at EOT and/ or to confirm a response. Blood will be collected for these biomarkers, serum aliquots will be prepared and will be banked for 
analysis at later stage.    
15. PD samples (pAKT) will be performed on C1D1 (pre-dose and 1 hr later), C1D8 (pre-dose) and C1D22 (pre-dose); C2D1 (pre-dose) and C3D1 (pre-dose) 
and/ at EOT in 5 sezary syndrome patients.   
16. Archival tumor samples will be collected during the trial, if available.      
17. Ann-Arbor staging system should be applied in patients with other types of NHL; ISCL/EORTC criteria should be used for CTCL. Patients will be 
restaged C3D1 (± 7 days) and C5D1 (± 7 days)  and approximately 12 weeks thereafter (± 7 days) and/ or at the EOT.   
18. CT scan (of the chest, abdomen, and pelvis) and other radiological evaluations (X-RAY/MRI/Ultrasound) will be performed at the time of screening within 
28 days of screening. PET-CT will be used to assess response in FDG-avid histologies. In CTCL patients with other than presumed stage IA disease, or 
selected patients with limited T2 disease and the absence of adenopathy or blood involvement, CT scans of chest, abdomen, and pelvis alone ± FDG-PET 


Protocol No. RP6530-1401 
 
Rhizen Pharmaceuticals SA 
 Version 7, Dated 23 May 2018 
CONFIDENTIAL  
 
Page 75 of 97 
scan are recommended to further evaluate any potential lymphadenopathy, visceral involvement, or abnormal laboratory tests. In patients unable to safely 
undergo CT scans, MRI may be substituted. PTCL patients will be evaluated according to the IWG Revised Response Criteria for Malignant Lymphoma. 
Assessment of CTCL response and progression will be evaluated according to the Response Criteria in Mycosis Fungoides and Se´zary Syndrome by the 
ISCL/EORTC criteria. In both CTCL and PTCL, disease will be assessed at C3D1 (± 7 days) and C5D1 (± 7 days) and approximately 12 weeks thereafter 
(± 7 days) and/ or at the EOT.  Assessment will be performed thereafter if warranted, at the discretion of PI/Co-PI. 
19. The assessment of skin lesion will be performed at the time of screening in CTCL patients. The assessments will be performed in PTCL if applicable. For 
skin scoring, the modified Severity Weighted Assessment Tool (mSWAT) will be used. For local index lesion skin scoring, Composite Assessment of 
Index Lesion Severity will be used. The disease will be assessed at C3D1 (± 7 days) and C5D1 (± 7 days) and approximately 12 weeks thereafter (± 7 
days) and/ or at the EOT.  Assessment will be performed thereafter if warranted, at the discretion of PI/Co-PI. 
20. Skin biopsy will be performed in CTCL patients at screening, on C3D1 (± 7 days) and/or to confirm a complete response. In CTCL patients, skin biopsy 
should be performed at the most indurated area if only one biopsy. 
21. Immunophenotyping to include at least the following markers: CD3, CD4, CD7, CD8 and Ki67. CD30 may also be indicated in cases where lymphomatoid 
papulosis, anaplastic lymphoma, or large-cell transformation is considered. Clonality of TCR gene rearrangement will be evaluated as part of standard of 
care and will be an optional. Immunophenotyping will be performed at screening, on C3D1 (± 7 days) and/or to confirm a complete response.  
22. CTCL patients will have half body global and up to 5 selected representative index lesions photographed at baseline, at C3D1, End of treatment (EOT), 
at PR/CR/PD and as required as per the discretion of PI/Co-PI. 
23. Bone marrow biopsy: PTCL patients entering the study with low grade lymphoma must have a morphology and flow cytometry performed ≤3 months prior 
to study entry and/or to confirm a complete response.  Patients with high grade lymphoma must have a morphology and flow cytometry performed ≤28 
days prior to study entry and/or to confirm a complete response. The lymph node will be required to perform only if the diagnosis is not confirmed at the 
baseline; and if required at other time points. 
23a PTCL patients without measurable disease but assessable disease (e.g. marrow disease without other radiographically measurable disease) will have 
a bone marrow biopsy at screening /baseline and on C3D1 (± 7 days) and C5D1 (± 7 days) and approximately 12 weeks thereafter (± 7 days) and/or to 
confirm a complete response. CTCL patients with predominantly blood involvement (confirmed by flow cytometry) will have a bone marrow biopsy at 
screening /baseline (unless it has been shown to be negative within the last 6 months) and as indicated to confirm a complete response occurring at all other 
sites. Specific molecular exams for some particular malignancies will be performed according to institutional diagnostic guidelines. If bone marrow 
aspirate is available, it will be processed and shipped according to the laboratory manual. Bone marrow disease alone may be used for disease assessment. 
In this case, response would be CR or non-CR only, determined by the morphology of repeat bone marrow biopsy. 
Post Cycle 8, disease assessments should be performed at 12 weekly intervals (± 7 days), and/ or at the EOT. For example, the appropriate radiological 
investigation (e.g. CT scan, PET-CT or PET) will be performed in PTCL patients at C11D1, C14D1, C17D1, C20D1, etc. Similarly, mSWAT and/or 
CAILS and radiological assessment (as required) will be performed in CTCL patients on this schedule.  
24. The study drug RP6530 will be administered orally twice a day in 28-days of cycle. The drug administration will be monitored on C1D1 and C2D1 
followed by PK evaluation. On other days, the treatment can be administered at home. The treatment period is at least 8 months. Treatment will be 
continued in patients experiencing clinical benefit for 2 years unless progression of disease or toxicity warranting discontinuation of therapy. The decision 
to continue the treatment will be taken by PI/Co-PI after consultation with Sponsor on case to case basis.  
Beyond Cycle 8, all visits will be monthly. During these monthly visits, RP6530 will be dispensed, medication compliance will be monitored and AEs will 
be assessed. Efficacy assessments will be done at scheduled visit. An End of treatment (EOT) visit will be performed within 30 days after treatment ends. 
 Safety assessments: Ongoing safety assessment is to occur during the monthly visits and AEs are to be reported as required by the protocol. There is no 
specific safety labs or evaluations to be done as per protocol. As part Standard of care, laboratory evaluations can be done and recorded per Investigator’s 
discretion. Adverse events (AEs, SAEs and deaths) will be recorded and reported for 30 calendar days after discontinuation or completion of protocol-
specific treatment. After the 30 day reporting period, only AEs, SAEs, or deaths assessed by the investigator as treatment related are to be reported. 
 Efficacy assessments: Disease assessments should be performed at 12 weekly intervals (± 7 days), and/ or at the EOT. For example, the appropriate 
radiological investigation (e.g. CT scan, PET-CT or PET) will be performed in PTCL patients at C11D1, C14D1, C17D1, C20D1, etc. Similarly, mSWAT 
and/or CAILS and radiological assessment (as required) will be performed in CTCL patients on this schedule.  


Protocol No. RP6530-1401 
 
Rhizen Pharmaceuticals SA 
 Version 7, Dated 23 May 2018 
CONFIDENTIAL  
 
Page 76 of 97 
 Other assessments: No other assessments (e.g. PK) are required beyond Cycle 8.  
 Drug dispensing: Patients will be dispensed 30 days of drug supply at the beginning of each cycle. At each visit, documentation of study drug 
accountability, compliance and any subject retraining given on proper dose administration must be available in the source notes.   
25. All patients will undergo the end-of-treatment assessments listed within 30 days after treatment ends.  Patients must be followed for adverse events for 30 
calendar days after the last dose of study drug. 
26. All visits will be ambulatory except C1D1 and C2D1 that involve extended hospital stay for PK assessment.  
 
 
 
 
 
 
 
 


Protocol No. RP6530-1401 
 
Rhizen Pharmaceuticals SA 
 Version 7, Dated 23 May 2018 
CONFIDENTIAL  
 
Page 77 of 97 
PART 2: DOSE EXPANSION  
Cycle 
 
C1 
C2 
C3 
C4 
C5 
C6 
C7 
C8 
EOT25 
Day  
D-28 to 0 
D1 
D1 
D1 
D1 
D1 
D1 
D1 
D1 
D1 
Window period  
 
±1 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
+30 
Study Days  
D-28 to 0 
1 
29 
57 
85 
113 
141 
169 
197 
- 
PROCEDURES 
Informed Consent1 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Demographics2  
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Medical history3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vitals4  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height and weight5  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
LABORATORY TEST/EVALUATIONS 
Complete blood count7   
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry panel I8  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry panel II9  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serology (HIV, HBV, HCV) 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
PT/INR10 
X 
X 
X 
X 
X 
 
 
 
 
X 
HbA1c 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Urinalysis (routine) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGs12 
X 
X 
X 
- 
- 
- 
- 
- 
- 
- 
PK blood samples13 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Biomarker samples14 
X 
- 
- 
X 
- 
- 
- 
- 
- 
X 
PD samples (pAKT)15 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Archived tumor tissue16 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
DISEASE ASSESSMENTS 
Staging17 
X 
- 
- 
X 
- 
X 
- 
- 
 
X 
Radiological Examination18 
X 
- 
- 
X 
- 
X 
- 
- 
X 
X 
Skin lesion assessment19 
X 
- 
- 
X 
- 
X 
- 
- 
X 
X 
Skin biopsy20 
X 
- 
- 
X 
- 
- 
- 
- 
- 
- 


Protocol No. RP6530-1401 
 
Rhizen Pharmaceuticals SA 
 Version 7, Dated 23 May 2018 
CONFIDENTIAL  
 
Page 78 of 97 
Immunophenotyping and 
TCR gene rearrangement21  
X 
- 
- 
X 
- 
- 
- 
- 
- 
- 
Photograph of skin lesion22 
X 
- 
- 
X 
- 
 
- 
- 
 
X 
Bone marrow/ lymph node 
biopsy /Aspirate23 
X 
- 
- 
-23a 
- 
-23a 
- 
- 
-23a 
X 
DRUG ADMINISTRATION AND SAFETY EVALUATION 
Drug administration24 
- 
X 
X 
X 
X 
X 
X 
X 
X 
- 
Drug dispensing  
- 
X 
X 
X 
X 
X 
X 
X 
X 
- 
Drug compliance  
- 
 
X 
X 
X 
X 
X 
X 
X 
- 
AE evaluation and reporting  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SAE evaluation and reporting 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication  
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Diary evaluation  
- 
 
X 
X 
X 
X 
X 
X 
X 
- 
Foot Notes:  
1. 
Patient should be re-consented in case informed consent is not obtained ≤28 days prior to the initiation of trial treatment.   
2. 
Demographic profile will include age, sex and race. 
3. 
Medical history: Detailed history will be taken at screening that includes history of cancer, past history, no of prior therapies and prior medication (in last 
4weeks); and other medical history. Abbreviated history will be taken at all subsequent visits.  
4. 
Vitals will include pulse (sitting/supine); blood pressure (sitting/supine); respiratory rate and oral temperature. (Note: Pulse rate and blood pressure can be 
recorded in sitting OR supine position depending on convenience of patient and ease of measurement.) 
5. 
Weight will be measured at all visits. Height to be measured at screening only.  
6. 
Physical examination will include lymph node and systemic examination. Complete physical examination will be done at screening visit. At subsequent 
visits, abbreviated examination will be done. 
7. 
Complete blood count will include Hb, complete blood count, reticulocyte count, total leucocyte and differential count and platelet count. Additional 
investigations will be performed if clinically indicated. Hematology must be done ≤7 days prior to initiation of treatment. However, if these initial 
examinations are obtained within 72 hours of C1D1; they do not have to be repeated.      
8. 
Chemistry Panel I includes Total bilirubin, ALP, AST, ALT, GGT, LDH and Serum electrolytes (Sodium, Potassium, Bicarbonate/CO2, Chloride, 
Magnesium, Phosphorus and Calcium). These tests must be done ≤7 days prior to initiation of treatment. However, if these initial examinations are obtained 
within 72 hours of C1D1; they do not have to be repeated. These tests will be performed at supplementary visits if clinically indicated.       
9. 
Chemistry Panel II includes blood glucose, urea or blood urea nitrogen, creatinine, albumin, globulin, total protein, Total Cholesterol, TG, LDL and HDL, 
TSH, free T3 and free T4. These tests must be done ≤7 days prior to initiation of treatment. However, if these initial examinations are obtained within 72 


Protocol No. RP6530-1401 
 
Rhizen Pharmaceuticals SA 
 Version 7, Dated 23 May 2018 
CONFIDENTIAL  
 
Page 79 of 97 
hours of C1D1; they do not have to be repeated. These tests will be performed at supplementary visits if clinically indicated.  (Note: Total protein and 
albumin tests will be performed; and globulin will be calculated by deducting value of albumin from total protein) 
10. 
PT/INR must be done ≤7 days prior to initiation of treatment. However, if initial examination is obtained within 72 hours of C1D1; this should not be 
repeated. This test will be performed at supplementary visits if clinically indicated.       
11. 
Pregnancy test is required for women of child bearing potential. A serum pregnancy test will be performed at screening and baseline (within 72 hours) of 
dosing. Urine pregnancy test will be performed at other visits as indicated.  
12. 
ECG: A single ECG will be performed at screening, C1D1 pre-dose and C2D1 pre-dose and one hour post-dose. Additional ECGs will be obtained if 
clinically indicated.  Triplicate ECGs will be performed to confirm the significant changes of single ECG. All ECGs will be performed on local equipment.  
13. 
PK: C1D1 at pre-dose, C2D1 at pre-dose, C3D1 at pre-dose; C4D1 at pre-dose; Cycle 5 and beyond at predose. Window period for PK sampling will be 1 
hr pre-dose.  No PK assessments are required beyond Cycle 8. 
14. 
Correlative serum biomarkers (e.g. sIL2R CTACK (PTCL); CD30 (MF); IL-31 and IL-32 (CTCL)) will be performed at screening, C3D1 (pre-dose and 
1 hr later); at EOT and/ or to confirm a response. Blood will be collected for these biomarkers; serum aliquots will be prepared and will be banked for 
analysis at later stage.   
15. 
PD samples (pAKT): pAKT is not applicable to dose expansion  
16. 
Archival tumor samples will be collected during the trial, if available.      
17. 
Staging: Ann-Arbor staging system should be applied in patients with other types of NHL; ISCL/EORTC criteria should be used 
for CTCL. Patients will be restaged C3D1 (± 7 days) and C5D1 (± 7 days) and approximately 12 weeks thereafter (± 7 days) and/ 
or at the EOT 
18. 
Radiological assessment: PTCL: A CT scan (of the chest, abdomen, and pelvis) and other radiological evaluations (X-RAY/MRI/Ultrasound) will be 
performed at the time of screening within 28 days of screening. PET-CT will be used to assess response in FDG-avid histologies. In CTCL patients with 
other than presumed stage IA disease, or selected patients with limited T2 disease and the absence of adenopathy or blood involvement, CT scans of chest, 
abdomen, and pelvis alone ± FDG-PET scan are recommended to further evaluate any potential lymphadenopathy, visceral involvement, or abnormal 
laboratory tests. In patients unable to safely undergo CT scans, MRI may be substituted. PTCL patients will be evaluated according to the IWG Revised 
Response Criteria for Malignant Lymphoma. Assessment of CTCL response and progression will be evaluated according to the Response Criteria in 
Mycosis Fungoides and Sezary Syndrome by the ISCL/EORTC criteria. In both CTCL and PTCL, disease will be assessed at C3D1 (± 7 days) and C5D1 
(± 7 days) and approximately 12 weeks thereafter (± 7 days) and/ or at the EOT.  Assessment will be performed thereafter if warranted, at the discretion of 
PI/CoPI. 
19. 
Skin lesion assessment: The assessment of skin lesion will be performed at the time of screening in CTCL patients. The assessments will be performed in 
PTCL if applicable. For skin scoring, the modified Severity Weighted Assessment Tool (mSWAT) will be used. For local index lesion skin scoring, 
Composite Assessment of Index Lesion Severity will be used. The disease will be assessed at C3D1 (± 7 days) and C5D1 (± 7 days) and approximately 12 
weeks thereafter (± 7 days) and/ or at the EOT.  Assessment will be performed thereafter if warranted, at the discretion of PI/Co-PI 
20. 
Skin biopsy: Biopsy will be performed in CTCL patients at screening, on C3D1 (± 7 days) and/or to confirm a complete response. In CTCL patients, skin 
biopsy should be performed at the most indurated area if only one biopsy. 
21. 
Immunophenotyping to include at least the following markers: CD3, CD4, CD7, CD8 and Ki67. CD30 may also be indicated in cases where lymphomatoid 
papulosis, anaplastic lymphoma, or large-cell transformation is considered. Clonality of TCR gene rearrangement will be evaluated as part of standard of 
care and will be an optional. Immunophenotyping will be performed at screening, on C3D1 (± 7 days) and/or to confirm a complete response.  
22. 
Photograph of skin lesion: CTCL patients will have half body global and up to 5 selected representative index lesions photographed at baseline, at C3D1, 
End of treatment (EOT), at PR/CR/PD and as required as per the discretion of PI/Co-PI. 
23. 
PTCL patients entering the study with low grade lymphoma must have a morphology and flow cytometry performed ≤3 months prior to study entry and/or 
to confirm a complete response.  Patients with high grade lymphoma must have a morphology and flow cytometry performed ≤28 days prior to study entry 


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and/or to confirm a complete response. The lymph node will be required to perform only if the diagnosis is not confirmed at the baseline and if required at 
other time points. 
23a  
CTCL patients with predominantly blood involvement (confirmed by flow cytometry) will have a bone marrow biopsy at screening /baseline (unless it has 
been shown to be negative within the last 6 months) and as indicated to confirm a complete response occurring at all other sites. Specific molecular exams 
for some particular malignancies will be performed according to institutional diagnostic guidelines. If bone marrow aspirate is available, it will be processed 
and shipped according to the laboratory manual.   
24. 
The study drug RP6530 800 mg BID in fasting conditions will be administered orally twice a day in 28-days of cycle. The drug should be administered 
at hospital during hospital visits. On other days, the treatment can be administered at home. The treatment period is at least 8 months. Treatment will be 
continued in patients experiencing clinical benefit for 2 years unless progression of disease or toxicity warranting discontinuation of therapy. The decision 
to continue the treatment will be taken by PI-Co-PI after consultation with Sponsor on case to case basis. 
Beyond Cycle 8, all visits will be monthly. During these monthly visits, RP6530 will be dispensed, medication compliance will be monitored and AEs 
will be assessed. Efficacy assessments will be done at scheduled visit. An End of treatment (EOT) visit will be performed within 30 days after treatment 
ends. 
 
Safety assessments: Ongoing safety assessment is to occur during the monthly visits and AEs are to be reported as required by the protocol. There is 
no specific safety labs or evaluations to be done as per protocol. As part Standard of care, laboratory evaluations can be done and recorded per 
Investigator’s discretion. Adverse events (AEs, SAEs and deaths) will be recorded and reported for 30 calendar days after discontinuation or 
completion of protocol-specific treatment. After the 30 day reporting period, only AEs, SAEs, or deaths assessed by the investigator as treatment 
related are to be reported. 
 
Efficacy assessments: Disease assessments should be performed at 12 weekly intervals (± 7 days), and/ or at the EOT. For example, the appropriate 
radiological investigation (e.g. CT scan, PET-CT or PET) will be performed in PTCL patients at C11D1, C14D1, C17D1, C20D1, etc. Similarly, 
mSWAT and/or CAILS and radiological assessment (as required) will be performed in CTCL patients on this schedule.  
 
Other assessments: No other assessments (e.g. PK) are required beyond Cycle 8.  
 
Drug dispensing: Patients will be dispensed 30 days of drug supply at the beginning of each cycle. At each visit, documentation of study drug 
accountability, compliance and any subject retraining given on proper dose administration must be available in the source notes.   
25. 
All patients will undergo the end-of-treatment (EOT) assessments listed within 30 days after treatment ends.  Patients must be followed for adverse events 
for 30 calendar days after the last dose of study drug. 
26. 
All visits will be ambulatory. 


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Appendix E: 
Response Criteria for Malignant Lymphoma 
International Working Group Revised Response Criteria for Malignant Lymphoma (Cheson et. al. 2007) 
Complete Response (CR):  
The designation of CR requires the following: 
 
Complete disappearance of all detectable clinical evidence of disease and 
disease-related symptoms if present before therapy. 
 
Typically FDG-avid lymphoma: in patients with no pretreatment PET 
scan or when the PET scan is positive before therapy, a post-treatment 
residual mass of any size is permitted as long as it is PET negative. 
 
Variably FDG-avid lymphomas/FDG avidity unknown: in patients 
without a pretreatment PET scan, or if a pretreatment PET scan is 
negative, all lymph nodes and nodal masses must have regressed on CT to 
normal size (≤1.5 cm in their greatest transverse diameter for nodes >1.5 
cm before therapy). Previously involved nodes that were 1.1 to 1.5 cm in 
their long axis and more than 1.0 cm in their short axis before treatment 
must have decreased to ≤1.0 cm in their short axis after treatment. 
 
The spleen and/or liver, if considered enlarged before therapy on the basis 
of a physical examination or CT scan, should not be palpable on physical 
examination and should be considered normal size by imaging studies, 
and nodules related to lymphoma should disappear. However, 
determination of splenic involvement is not always reliable because a 
spleen considered normal in size may still contain lymphoma, whereas an 
enlarged spleen may reflect variations in anatomy, blood volume, the use 
of hematopoietic growth factors, or causes other than lymphoma. 
 
If the bone marrow is involved by lymphoma before treatment, the 
infiltrate must have cleared on repeat bone marrow biopsy. The biopsy 
sample on which this determination is made must be adequate (with a 
goal of >20 mm unilateral core). If the sample is indeterminate by 
morphology, it should be negative by immunohistochemistry. A sample 
that is negative by immunohistochemistry but that demonstrates a small 
population of clonal lymphocytes by flow cytometry will be considered a 
CR until data become available demonstrating a clear difference in patient 
outcome. 
 
Complete 
Response/Unconfirmed 
(CRu): 
The use of the above definition for CR and those below for PR eliminates the 
category of CRu. 
 
 


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Appendix E. Response Criteria for Malignant Lymphoma (continued) 
Partial Response (PR):  
 
The designation of PR requires all of the following: 
 
At least a 50% decrease in sum of the product of the diameters (SPD) of up 
to six of the largest dominant nodes or nodal masses. These nodes or masses 
should be selected according to all of the following: they should be clearly 
measurable in at least 2 perpendicular dimensions; if possible they should be 
from disparate regions of the body; and they should include mediastinal and 
retroperitoneal areas of disease whenever these sites are involved. 
 
No increase should be observed in the size of other nodes, liver, or spleen. 
 
Splenic and hepatic nodules must regress by ≥50% in their SPD or, for single 
nodules, in the greatest transverse diameter. 
 
With the exception of splenic and hepatic nodules, involvement of other 
organs is usually assessable and no measurable disease should be present. 
 
Bone marrow assessment is irrelevant for determination of a PR if the sample 
is positive before treatment. However, if positive, the cell type should be 
specified (e.g., large-cell lymphoma or small neoplastic B cells). Patients 
who achieve a CR by the above criteria, but who have persistent 
morphologic bone marrow involvement will be considered partial 
responders.  
When the bone marrow is involved before therapy and a clinical CR is 
achieved, but with no bone marrow assessment after treatment, patients 
should be considered partial responders. 
 
No new sites of disease should be observed. 
 
Typically FDG-avid lymphoma: for patients with no pretreatment PET scan 
or if the PET scan is positive before therapy, the post-treatment PET should 
be positive in at least one previously involved site. 
 
Variably FDG-avid lymphomas/FDG-avidity unknown: for patients without a 
pretreatment PET scan, or if a pretreatment PET scan is negative, CT criteria 
should be used. 
 
In patients with follicular lymphoma or mantle-cell lymphoma, a PET scan is only 
indicated with one or at most two residual masses that have regressed by more than 
50% on CT; those with more than two residual lesions are unlikely to be PET 
negative and should be considered partial responders. 
 


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Appendix E. 
Response Criteria for Malignant Lymphoma (continued) 
Stable Disease (SD):   
 
Stable disease (SD) is defined as the following: 
 
A patient is considered to have SD when he or she fails to attain the criteria 
needed for a CR or PR, but does not fulfill those for progressive disease (see 
Relapsed Disease [after CR]/Progressive Disease [after PR, SD]). 
 
Typically FGD-avid lymphomas: the PET should be positive at prior sites of 
disease with no new areas of involvement on the post-treatment CT or PET. 
 
Variably FDG-avid lymphomas/FDG-avidity unknown: for patients without 
a pretreatment PET scan or if the pretreatment PET is negative, there must be 
no change in the size of the previous lesions on the post-treatment CT scan. 
 
Relapsed Disease (after 
CR) / Progressive Disease 
(after PR, SD):   
 
Lymph nodes should be considered abnormal if the long axis is more than 1.5 cm 
regardless of the short axis. If a lymph node has a long axis of 1.1 to 1.5 cm, it 
should only be considered abnormal if its short axis is more than 1.0. Lymph nodes 
≤1.0 x ≤1.0 cm will not be considered as abnormal for relapse or progressive 
disease. 
 
Appearance of any new lesion more than 1.5 cm in any axis during or at the 
end of therapy, even if other lesions are decreasing in size. Increased FDG 
uptake in a previously unaffected site should only be considered relapsed or 
progressive disease after confirmation with other modalities. In patients with 
no prior history of pulmonary lymphoma, new lung nodules identified by CT 
are mostly benign. Thus, a therapeutic decision should not be made solely on 
the basis of the PET without histologic confirmation. 
 
At least a 50% increase from nadir in the SPD of any previously involved 
nodes, or in a single involved node, or the size of other lesions (e.g., splenic 
or hepatic nodules). To be considered progressive disease, a lymph node with 
a diameter of the short axis of less than 1.0 cm must increase by 50% and 
to a size of 1.5 x 1.5 cm or more than 1.5 cm in the long axis. 
 
At least a 50% increase in the longest diameter of any single previously 
identified node more than 1 cm in its short axis. 
 
Lesions should be PET positive if observed in a typical FDG-avid lymphoma 
or the lesion is PET positive before therapy unless the lesion is too small to 
be detected with current PET systems (< 1.5 cm in its long axis by CT). 
 


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Appendix E. 
Response Criteria for Malignant Lymphoma (continued) 
Measurable extranodal disease should be assessed in a manner similar to that for nodal disease. For these 
recommendations, the spleen is considered nodal disease.  Disease that is only assessable (e.g., pleural effusions, bone 
lesions) will be recorded as present or absent only, unless, while an abnormality is still noted by imaging studies or 
physical examination, it is found to be histologically negative.  
In clinical trials where PET is unavailable to the vast majority of participants, or where PET is not deemed necessary or 
appropriate for use (e.g., a trial in patients with MALT lymphoma), response should be assessed as above, but only using 
CT scans.  However, residual masses should not be assigned CRu status, but should be considered partial responses. 
 
Response Assessment: 
Response Definitions for Clinical Trials 
Response  
Definition 
Nodal Masses 
Spleen, Liver 
Bone Marrow 
CR 
Disappearance of all 
evidence of disease 
 FDG-avid or PET 
positive prior to 
therapy; mass of any 
size permitted if 
PET negative 
 Variably FDG-avid 
or PET negative; 
regression to normal 
size on CT 
Not palpable, nodules 
disappeared 
Infiltrate cleared on 
repeat biopsy; if 
indeterminate by 
morphology, 
immunohistochemistry 
should be negative 
PR 
Regression of 
measurable disease and 
no new sites 
 ≥50% decrease in 
SPD of up to 
6 largest dominant 
masses; no increase 
in size of other 
nodes 
 FDG-avid or PET 
positive prior to 
therapy; one or more 
PET positive at 
previously involved 
site 
 Variably FDG-avid 
or PET negative; 
regression on CT 
≥50% decrease in 
SPD of nodules (for 
single nodule in 
greatest transverse 
diameter); no increase 
in size of liver or 
spleen 
Irrelevant if positive 
prior to therapy; cell 
type should be 
specified 


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Appendix E. 
Response Criteria for Malignant Lymphoma (continued) 
 
Response Definitions for Clinical Trials (continued) 
Response  
Definition 
Nodal Masses 
Spleen, Liver 
Bone Marrow 
SD 
Failure to attain CR/PR 
or PD 
 FDG-avid or PET 
positive prior to 
therapy; PET 
positive at prior sites 
of disease and no 
new sites on CT or 
PET 
 Variably FDG-avid 
or PET negative; no 
change in size of 
previous lesions on 
CT 
— 
— 
Relapsed 
disease or 
PD 
Any new lesion or 
increase by ≥50% of 
previously involved 
sites from nadir 
 Appearance of a new 
lesion(s) >1.5 cm in 
any axis, ≥50% 
increase in SPD of 
more than one node, 
or ≥50% increase in 
longest diameter of a 
previously identified 
node >1 cm in short 
axis 
 Lesions PET 
positive if FDG-avid 
lymphoma or PET 
positive prior to 
therapy 
>50% increase from 
nadir in the SPD of 
any previous lesions 
New or recurrent 
involvement 
Abbreviations: CR, complete remission; FDG, [18F]fluorodeoxyglucose; PET, positron emission tomography; CT, 
computed tomography; PR, partial remission; SPD, sum of the product of the diameters; SD, stable disease; PD, 
progressive disease. 
 
Source:  Cheson BD, Pfistner B, Malik E, et al. Revised Response Criteria for Malignant Lymphoma. J Clin Oncol. 
2007;25:579-86. 


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86 
 
Appendix F: Ann Arbor staging system 
Stage I 
Either of the following means the disease is stage I: 
 
The lymphoma is in only 1 lymph node area or lymphoid organ such as the thymus (I). 
 
The cancer is found only in 1 area of a single organ outside of the lymph system (IE). 
 
 
Stage II 
Either of the following means the disease is stage II: 
 
The lymphoma is in 2 or more groups of lymph nodes on the same side of (above or below) the 
diaphragm (the thin band of muscle that separates the chest and abdomen). For example, this might 
include nodes in the underarm and neck area but not the combination of underarm and groin nodes 
(II). 
 
The lymphoma extends from a single group of lymph node(s) into a nearby organ (IIE). It may also 
affect other groups of lymph nodes on the same side of the diaphragm. 
 
 
Stage III 
Either of the following means the disease is stage III: 
 
The lymphoma is found in lymph node areas on both sides of (above and below) the diaphragm. 
 
The cancer may also have spread into an area or organ next to the lymph nodes (IIIE), into the spleen 
(IIIS), or both (IIISE). 
 
Stage IV 
Either of the following means the disease is stage IV: 
 
The lymphoma has spread outside of the lymph system into an organ that is not right next to an 
involved node. 
 
The lymphoma has spread to the bone marrow, liver, brain or spinal cord, or the pleura (thin lining 
of the lungs). 
Other modifiers may also be used to describe the lymphoma stage: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix G: Recommended evaluation for MF/SS ptients 
Recommended evaluation/initial staging of the patient with mycosis fungoides/Sézary syndrome 
 
Complete physical examination including 
 
Determination of type(s) of skin lesions 
o If only patch/plaque disease or erythroderma, then estimate percentage of body surface area 
involved and note any ulceration of lesions 
o If tumors are present, determine total number of lesions, aggregate volume, largest size lesion, 
and regions of the body involved 
 
Identification of any palpable lymph node, especially those >1.5 cm in largest diameter or firm, 
irregular, clustered, or fixed 
 
Identification of any organomegaly 
 
Skin biopsy 
 
Most indurated area if only one biopsy 
 
Immunophenotyping to include at least the following markers: CD2, CD3, CD4, CD5, CD7, CD8, 
and a B-cell marker such as CD20. CD30 may also be indicated in cases where lymphomatoid 
papulosis, anaplastic lymphoma, or large-cell transformation is considered. 
 
Evaluation for clonality of TCR gene rearrangement 
 
Blood tests 
 
CBC with manual differential, liver function tests, LDH, comprehensive chemistries 
 
TCR gene rearrangement and relatedness to any clone in skin 
 
Analysis for abnormal lymphocytes by either Sézary cell count with determination absolute number 
of Sézary cells and/or flow cytometry (including CD4+/CD7- or CD4+/CD26-) 
 
Radiologic tests 
 
In patients with T1N0B0stage disease who are otherwise healthy and without complaints directed to 
a specific organ system, and in selected patients with T2N0B0disease 
 
with limited skin involvement, radiologic studies may be limited to a chest X-ray or ultrasound of 
the peripheral nodal groups to corroborate absence of adenopathy 
 
In all patients with other than presumed stage IA disease, or selected patients with limited T2disease 
and the absence of adenopathy or blood involvement, CT scans of chest, abdomen, and pelvis 
alone±FDG-PET scan are recommended to further evaluate any potential lymphadenopathy, visceral 
involvement, or abnormal laboratory tests. In patients unable to safely undergo CT scans, MRI may 
be substituted. 
 
 
Lymph node biopsy  
 
Excisional biopsy is indicated in those patients with a node that is either ≥1.5 cm in diameter and/or 
is firm, irregular, clustered, or fixed 
 
Site of biopsy 
o Preference is given to the largest lymph node draining an involved area of the skin or if FDG-
PET scan data are available, the node with highest standardized uptake value (SUV). 
o If there is no additional imaging information and multiple nodes are enlarged and otherwise 
equal in size or consistency, the order of preference is cervical, axillary, and inguinal areas. 
 
Analysis: pathologic assessment by light microscopy, flow cytometry, and TCR gene rearrangement. 
 
 


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Appendix H: ISCL/EORTC staging of MF and SS patients 
TNMB 
Stages 
 
Description of TNMB 
Skin* 
  
    
T1 
 Limited patches, papules, and/or plaques covering < 10% of the skin surface; may further 
stratify into T1a (patch only) v T1b(plaque ± patch) 
    
T2 
 Patches, papules, or plaques covering ≥ 10% of the skin surface; may further stratify into 
T2a (patch only) v T2b (plaque ± patch) 
T3 
 One or more tumors (≥ 1 cm diameter) 
T4 
 Confluence of erythema covering ≥ 80% body surface area 
Node† 
  
N0 
 No clinically abnormal lymph nodes; biopsy not required 
N1 
 Clinically abnormal lymph nodes; histopathology Dutch grade 1 or NCI LN0-2 
N1a 
 Clone negative 
N1b 
 Clone positive 
N2 
 Clinically abnormal lymph nodes; histopathology Dutch Grade 2 or NCI LN3 
N2a 
 Clone negative 
N2b 
 Clone positive 
N3 
 Clinically abnormal lymph nodes; histopathology Dutch grade 3-4 or NCI LN4; clone positive 
or negative 
    
Nx 
 Clinically abnormal lymph nodes without histologic confirmation or inability to fully 
characterize the histologic subcategories 
Visceral 
 
M0 
 No visceral organ involvement 
M1 
 Visceral involvement (must have pathology confirmation and organ involved should be 
specified) 
Blood 
 
B0 
 Absence of significant blood involvement: ≤ 5% of peripheral blood lymphocytes are atypical 
(Sézary) cells 
B0a 
 Clone negative 
B0b 
 Clone positive 
B1 
 Low blood tumor burden: > 5% of peripheral blood lymphocytes are atypical (Sézary) cells 
but does not meet the criteria of B2 
B1a 
 Clone negative 
B1b 
 Clone positive 
    
B2 
 High blood tumor burden: ≥ 1,000/μL Sézary cells with positive clone‡; one of the following 
can be substituted for Sézary cells: CD4/CD8 ≥ 10, CD4+CD7- cells ≥ 40% or CD4+CD26- 
cells ≥ 30% 
 
Abbreviations: ISCL, International Society for Cutaneous Lymphomas; EORTC, European 
Organisation for Research and Treatment of Cancer; MF, mycosis fungoides; SS, Sézary 
syndrome; NCI, National Cancer Institute. 
 
↵* Patch = any size lesion without induration or significant elevation above the surrounding 
uninvolved skin: pokiloderma may be present. Plaque = any size lesion that is elevated or 
indurated: crusting or poikiloderma may be present. Tumor = any solid or nodular lesion ≥ 1 cm 
in diameter with evidence of deep infiltration in the skin and/or vertical growth. 


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 
↵† Lymph node classification has been modified from 2007 ISCL/EORTC consensus 
revisions1 to include central nodes. Lymph nodes are qualified as abnormal if > 1.5 cm in 
diameter. 
 
↵‡ The clone in the blood should match that of the skin. The relevance of an isolated clone in the 
blood or a clone in the blood that does not match the clone in the skin remains to be determined. 
 
Modified ISCL/EORTC Revisions to the Staging of MF/SS 
Stage  
T 
N 
M 
B 
IA 
1 
0 
0 
0,1 
IB 
2 
0 
0 
0,1 
IIA 
1.2 
1,2X 
0 
0,1 
IIb 
3 
0-2X 
0 
0,1 
IIIA 
4 
0-2X 
0 
0 
IIIB 
4 
0-2X 
0 
1 
IVA1 
1-4 
0-2X 
0 
2 
IVA2 
1-4 
3 
0 
0-2 
IVB 
1-4 
0-3X 
1 
0-2 
X clinically abnormal lymph nodes without histologic confirmation or inability to fully characterize 
histologic subcategories. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix I: Modified Severity Weighted Assessment Tool 
 
Body Region 
% BSA in Body 
Region 
Assessment of Involvement in Patient's 
Skin 
Patch* 
Plaque† 
Tumor‡ 
Head 
7 
Neck 
2 
 
 
 
Anterior trunk 
13 
Arms 
8 
 
 
 
Forearms 
6 
 
 
 
Hands 
5 
Posterior trunk 
13 
 
 
 
Buttocks 
5 
Thighs 
19 
 
 
 
Legs 
14 
Feet 
7 
 
 
 
Groin 
1 
Subtotal of lesion BSA 
 
 
 
 
    Weighting factor 
 
×1 
×2 
×4 
Subtotal lesion BSA × weighting 
factor 
 
 
 
 
 
NOTE. mSWAT score equals summation of each column line. 
 
Abbreviations: BSA, body surface area; mSWAT, modified Severity Weighted Assessment 
Tool. 
 
↵* Any size lesion without induration or significant elevation above the surrounding uninvolved 
skin; poikiloderma may be present. 
 
↵† Any size lesion that is elevated or indurated; crusting, ulceration, or poikiloderma may be 
present. 
 
↵‡ Any solid or nodular lesion ≥ 1 cm in diameter with evidence of deep infiltration in the skin 
and/or vertical growth. 
 
 
 
 
 
 
 


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Appendix J: Composite Assessment of Index Lesion Severity 
 
Clinical Sign and Degree or 
Size (scale of 0-8) 
Index Lesion 
1 
2 
3 
4 
5 
Erythema 
Scaling 
 
 
 
 
 
Plaque elevation 
Hypo- or hyperpigmentation 
 
 
 
 
 
Lesion size* 
Subtotal 
Total (sum of subtotals) 
 
NOTE. Cannot be used as skin assessment in global response score. Suggestions for 
improvement include using actual size of lesion versus categorical score for size and eliminating 
pigmentation as a clinical parameter. 
 
↵* Lesion size (cm2): 0: no measurable area; 1: > 0 to ≤ 4; 2: > 4 to ≤ 10; 3: > 10 to ≤ 16; 4: > 16 
to ≤ 25; 5: > 25 to ≤ 35; 6: > 35 to ≤ 45; 7: > 45 to ≤ 55; 8: > 55 to ≤ 70; 9: > 70 to ≤ 90; 10: > 90 
to ≤ 110; 11: > 110 to ≤ 130; 12: > 130 to ≤ 155; 13: > 155 to ≤ 180; 14: > 180 to ≤ 210; 15: > 
210 to ≤ 240; 16: > 240 to ≤ 270; 17: > 270 to ≤ 300; 18: > 300. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix K: Definition of Response in CTCL patients 
Response in Skin*  
Response 
Definition 
Complete 
response 
100% clearance of skin lesions* 
Partial response 
50%-99% clearance of skin disease from baseline without new tumors (T3) in patients 
with T1, T2 or T4 only skin disease 
Stable disease 
< 25% increase to < 50% clearance in skin disease from baseline without new tumors 
(T3) in patients with T1, T2, or T4 only skin disease 
Progressive 
disease† 
≥ 25% increase in skin disease from baseline or 
New tumors (T3) in patients with T1, T2 or T4 only skin disease or 
Loss of response: in those with complete or partial response, increase of skin score of 
greater than the sum of nadir plus 50% baseline score 
Relapse 
Any disease recurrence in those with complete response 
 
NOTE. Based on modified Severity Weighted Assessment Tool score. 
 
↵* A biopsy of normal appearing skin is unnecessary to assign a complete response. However, a 
skin biopsy should be performed of a representative area of the skin if there is any question of 
residual disease (persistent erythema or pigmentary change) where otherwise a complete 
response would exist. If histologic features are suspicious or suggestive of mycosis 
fungoides/Sézary syndrome (see histologic criteria for early mycosis fungoides7), the response 
should be considered a partial response only. 
 
↵† Whichever criterion occurs first. 
 
Response in Lymph node*  
 
Response 
Definition 
CR 
All lymph nodes are now ≤ 1.5 cm in greatest transverse (long axis) diameter by 
method used to assess lymph nodes at baseline or biopsy negative for lymphoma; in 
addition, lymph nodes that were N3classification and ≤ 1.5 cm in their long axis and > 
1 cm in their short axis at baseline, must now be ≤ 1 cm in their short axis or biopsy 
negative for lymphoma 
PR 
Cumulative reduction ≥ 50% of the SPD of each abnormal lymph node at baseline and 
no new lymph node > 1.5 cm in the diameter of the long axis or > 1.0 cm in the 
diameter of the short axis if the long axis is 1-1.5 cm diameter 
SD 
Fails to attain the criteria for CR, PR, and PD 
PD† 
≥ 50% increase in SPD from baseline of lymph nodes or 
Any new node > 1.5 cm in the long axis or > 1 cm in the short axis if 1-1.5 cm in the 
long axis that is proven to be N3 histologically or 
 
Loss of response: > 50% increase from nadir in SPD of lymph nodes in those with PR 


Protocol No. RP6530-1401 
 
Rhizen Pharmaceuticals SA 
 Version 7, Dated 23 May 2018 
CONFIDENTIAL  
 
Page 93 of 97 
Response 
Definition 
Relapse 
Any new lymph node > 1.5 cm in the long axis in those with CR proven to be 
N3 histologically 
 
Abbreviations: CR, complete response; PR, partial response; SPD, sum of the maximum linear 
dimension (major axis) × longest perpendicular dimension (minor axis); SD, stable disease; PD, 
progressive disease. 
 
↵* Peripheral and central lymph nodes. 
 
↵† Whichever criterion occurs first. 
 
Response in Viscera*  
Response 
Definition 
CR 
Liver or spleen or any organ considered involved at baseline should not be enlarged on 
physical exam and should be considered normal by imaging; no nodules should be 
present on imaging of liver or spleen; any post treatment mass must be determined by 
biopsy to be negative for lymphoma 
PR 
≥ 50% regression in any splenic or liver nodules, or in measureable disease (SPD) in 
any organs abnormal at baseline; no increase in size of liver or spleen and no new sites 
of involvement 
SD 
Fails to attain the criteria for CR, PR, or PD 
PD* 
> 50% increase in size (SPD) of any organs involved at baseline or 
 
New organ involvement or 
Loss of response: > 50% increase from nadir in the size (SPD) of any previous organ 
involvement in those with PR 
Relapse 
New organ involvement in those with CR 
 
Abbreviations: CR, complete response; PR, partial response; SPD, sum of the maximum linear 
dimension (major axis) × longest perpendicular dimension (minor axis); SD, stable disease; PD, 
progressive disease. 
 
↵* Whichever criterion occurs first. 
 
 
 
 
 
 
 


Protocol No. RP6530-1401 
 
Rhizen Pharmaceuticals SA 
 Version 7, Dated 23 May 2018 
CONFIDENTIAL  
 
Page 94 of 97 
Response in blood*  
 
Response 
Definition 
CR† 
B0 
PR‡ 
> 50% decrease in quantitative measurements of blood tumor burden from baseline in 
those with high tumor burden at baseline (B2) 
SD 
Fails to attain criteria for CR, PR, or PD 
PD§ 
B0 to B2 or 
 
> 50% increase from baseline and at least 5,000 neoplastic cells/μL36or 
 
Loss of response: in those with PR who were originally B2 at baseline, > 50% increase 
from nadir and at least 5,000 neoplastic cells/μL 
Relapse 
Increase of neoplastic blood lymphocytes to ≥ B1 in those with CR 
 
Abbreviations: CR, complete response; PR, partial response; SD, stable disease; PD, progressive 
disease. 
 
↵* As determined by absolute numbers of neoplastic cells/μL. 
 
↵† If a bone marrow biopsy is performed at baseline and determined to unequivocally be 
indicative of lymphomatous involvement, then to confirm a global CR where blood assessment 
now meets criteria for B0, a repeat bone marrow biopsy must show no residual disease or the 
response should be considered a PR only. 
 
↵‡ There is no PR in those with B1 disease at baseline as the difference within the range of 
neoplastic cells that define B1 is not considered significant and should not affect determination of 
global objective response. 
 
↵§ Whichever occurs first. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol No. RP6530-1401 
 
Rhizen Pharmaceuticals SA 
 Version 7, Dated 23 May 2018 
CONFIDENTIAL  
 
Page 95 of 97 
Appendix L: Body Surface area assessment note for CTCL patients 
 
 
 
 
 


Protocol No. RP6530-1401 
 
Rhizen Pharmaceuticals SA 
 Version 7, Dated 23 May 2018 
CONFIDENTIAL  
 
Page 96 of 97 
Appendix M: Monitoring of Liver enzymes 
 
Grade III elevation of ALT or AST [> 5 X the upper limit of normal (ULN)] have been observed with 
RP6530 treatment in Dose Escalation Part. Most transaminase elevations were reversible with dose 
interruption. Multiple lines of evidence from literature suggest that this hepatotoxicity was immune 
mediated. In in view of this, frequent monitoring of liver enzymes is recommended in patient 
presenting with transaminitis. Steroid can be initiated by the investigator after clinical evaluation 
of patient.  
 Grade ≥ 1 Transaminitis:  
o Maintain RP6530 dose and initiate prednisone 40 mg daily.  
o The frequency of monitoring should be weekly in any instance of ALT or AST >3 
X ULN (> Grade 1) until resolved.  
o Withhold RP6530 in case of development of grade 2 transaminitis or worsening 
of Grade 1 transaminitis while on steroids.  
 Grade ≥ 3 Transaminitis:  
o In of ALT/AST >5–20 X ULN (Grade 3), it is recommended to withhold RP6530 
and monitor ALT/AST twice a weekly until levels are Grade 1; once this occurs, 
RP6530 may be resumed at a reduced dose of 400 mg BID.  
o Wait for a week, initiate prednisone 1 mg/kg in case no improvement with 
discontinuation of RP6530 in 1 week.  
o Monitor ALT/AST twice a weekly until levels are Grade 1; once this occurs, 
RP6530 may be resumed at a reduced dose of 400 mg BID and taper steroid.  
o For patients with grade ≥3 transaminitis without immediate response to steroids, 
mycophenolate mofetil could be considered after 7 days of steroids.                                   
o If ALT/AST elevation >20 X ULN occurs, RP6530 should be permanently 
discontinued. 
o In case of recurrence of transaminitis at reduced doses, discontinue RP6530 
permanently after assessing risk versus benefit.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
          


Protocol No. RP6530-1401 
 
Rhizen Pharmaceuticals SA 
 Version 7, Dated 23 May 2018 
CONFIDENTIAL  
 
Page 97 of 97 
 
ALT/AST 
Grade ≥1  
Continue RP6530 
± Steroid (40 mg) 
(Monitor: once a week) 
Grade 1 worsening 
Grade 2 ALT/ AST 
RP6530 discontinue 
± Steroid (40 mg) 
(Monitor: once a week) 
Resolved 
Resolved 
Grade 3 ALT/ AST 
(Follow Grade 3 
instructions) 
                      Grade ≥3   
Withhold RP6530 immediately 
± Start Steroid (1mg/ kg) 1 wk later in 
case of no improvement  
(Monitor: twice a week) 
No improvement 
Start 
Mycophenolate  
Mofetil after 7 days 
of steroid 
Grade  1 ALT/AST 
Restart RP6530 
at reduced dose 
± Taper steroid  
Recurrence 
Discontinue RP6530 
After risk benefit assessment

SAP_001.pdf: 
Protocol ID: RP6530-1401 
 
 
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Statistical Analysis Plan 
Protocol Title: 
A Phase I/Ib, Dose Escalation Study to Evaluate Safety and Efficacy of RP6530, a dual PI3K δ/γ inhibitor, 
in Patients with Relapsed or Refractory T-cell Lymphoma 
 
 
 
 
 
 
 
XXXXXX XXXXXXXXXXXXXXX XX 
 
 
 
Protocol: RP6530-1401 
(Reference Document: Protocol: Version 7 dated 23 May, 2018) 
 
 
Phase I/Ib  
 
 
 
 


Protocol ID: RP6530-1401 
 
 
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Statistical Analysis Plan (SAP) 
Signature Page 
 
Type of document 
Statistical Analysis Plan 
Identifier 
RP6530-1401 
Effective date 
12/Mar/2019 
Version number 
v1 
 
Supersedes 
version 
None 
 
 
 
 
Name (Author) 
Designation 
Signature and date 
 
 
 
Reviewed by: Name 
Designation 
Signature and date 
 
 
 
Approved by: Name 
Designation 
Signature and date 
 
 
 
Approved by: Name 
Designation 
Signature and date 
Revision History  
Version: 
SOP ID: 
Document Name:  
Reason for change:  


Protocol ID: RP6530-1401 
 
 
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List of Abbreviations 
 
% 
Percentage 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area Under the Curve 
AUEC 
Area Under Effect Curve 
BID 
Twice Daily 
BUN 
Blood Urea Nitrogen 
CI 
Confidence Interval 
CM 
Concomitant Medication 
CR 
Complete Response 
CRF 
Case Report Form 
CS 
Clinically Significant 
CT 
Computerized Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTCL 
cutaneous T-Cell Lymphoma 
CV 
Co-efficient of variance 
CVA 
Cerebrovascular Accident 
DLT 
Dose limiting Toxicities 
DoR 
Duration of Response 
DRG 
Data Review Group 
E 
Count of Event 
ECG 
Electrocardiogram 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
EORTC 
European Organization For Research and Treatment of Cancer 
EOS value 
End of Study value 
EOT 
End of Treatment 
ET 
Early Termination 
GCV 
Geometric Co-efficient of variance 
GGT 
Gamma Glutamyl Transpeptidase 
H1 
Alternative Hypothesis 
Hb 
Hemoglobin 
HbA1c 
Glycated hemoglobin 
HBV 
Hepatitis B virus 
HCT 
Hematocritw3 
HCV 
Hepatitis C virus 
HDL 
High-Density Lipoprotein 


Protocol ID: RP6530-1401 
 
 
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HIV 
Human Immune deficiency Virus 
Ho 
Null Hypothesis 
ICF 
Informed Consent Form  
IMP 
Investigational Medicinal Product 
ISCL 
International Society For Cutaneous Lymphomas 
ITT 
Intent-to-Treat 
LDH 
Lactate Dehydrogenase 
LDL 
Low-Density Lipoprotein 
LLT 
Lower Level Term 
Max 
Maximum 
MDACC 
MD Anderson Cancer Centre 
MedDRA 
Medical Dictionary 
MH 
Medical history 
Min 
Minimum 
MRI 
Magnetic Resonance Imaging 
mSWAT 
modified Severity Weighted Assessment Tool 
MTD 
Maximum Tolerated Dose 
n 
Number of patients with non-missing data 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NCS 
Not Clinically Significant 
ORR 
Overall Response Rate 
pAKT 
Phospho-AKT 
PD 
Pharmacodynamics 
PET 
positron emission tomography 
PI3K 
Phosphoinositide-3-Kinase 
PK 
Pharmacokinetics  
PLT 
Platelet 
PP 
Per-protocol 
PR 
Partial Response 
PT 
Preferred Term 
PT/INR 
Prothrombin Time/international Normalized Ratio 
PTCL 
Peripheral T cell Lymphoma 
Q1 
First quartile 
Q3 
Third quartile 
RBC 
Red Blood Cells 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SOC 
System Organ Class 
SS 
Sezary Syndrome 
TEAE 
Treatment Emergent Adverse Events 
TG 
Tri-Glycerides 
TIA 
Transient Ischemic Attack 
T-NHL 
T cell Non-Hodgkin Lymphoma 


Protocol ID: RP6530-1401 
 
 
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TSH 
Thyroid Stimulating Hormone 
ULN 
Upper Limit of Normal 
USCLC 
United States Cutaneous Lymphoma Consortium 
WBC 
White Blood Cells 
WHO 
World Health Organization 


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SAP 
Table of Contents 
1. 
Introduction .......................................................................................................... 9 
1.1 
Statistical Analysis Plan ................................................................................................ 9 
1.2 
Rationale for Study ........................................................................................................ 9 
2. 
Study Design and Objectives ............................................................................ 10 
2.1 
Study Objectives ..........................................................................................................10 
2.1.1 
Primary Objectives ................................................................................................................ 10 
2.1.2 
Secondary Objectives ........................................................................................................... 10 
2.1.3 
Exploratory Objectives .......................................................................................................... 11 
2.2 
Assessment of Objectives ............................................................................................11 
2.2.1 
Primary Endpoints ................................................................................................................. 11 
2.2.1.1 
Primary Safety Endpoints ............................................................................................... 11 
2.2.1.2 
Primary Pharmacokinetic Endpoints .............................................................................. 11 
2.2.2 
Secondary Endpoints ............................................................................................................ 12 
2.2.2.1 
Secondary Pharmacodynamic Endpoints ...................................................................... 12 
2.2.2.2 
Secondary Efficacy Endpoints ....................................................................................... 12 
2.2.2.3 
Exploratory Efficacy Endpoints ...................................................................................... 13 
2.3 
Change the Primary Objective during the conduct of the study ....................................13 
2.4 
Study Design ................................................................................................................13 
2.4.1 
Study Flow Chart ................................................................................................................... 15 
2.5 
Sample Size and Power Considerations ......................................................................15 
2.6 
Randomization .............................................................................................................16 
2.7 
Blinding ........................................................................................................................16 
3. 
General Analysis Requirements ....................................................................... 16 
3.1 
Study Duration .............................................................................................................16 
3.2 
Schedule of Study Visits, Visit windows and Procedures ..............................................17 
3.3 
Study Populations ........................................................................................................26 
3.3.1 
Inclusion Criteria .................................................................................................................... 26 
3.3.2 
Exclusion Criteria................................................................................................................... 27 
3.3.3 
Withdrawal / Discontinuation Criteria .................................................................................... 28 
3.4 
Treatment Assignment and Treatment Groups .............................................................29 
4. 
Statistical Methods ............................................................................................. 29 
4.1 
Analysis Datasets .........................................................................................................30 
4.1.1 
Safety Population .................................................................................................................. 30 


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4.1.2 
Intent to Treat Population ...................................................................................................... 30 
4.1.3 
Per Protocol Population ......................................................................................................... 30 
4.1.4 
Protocol Deviations ............................................................................................................... 31 
4.2 
Timing of Analysis ........................................................................................................31 
4.2.1 
Interim Analysis ..................................................................................................................... 31 
4.2.2 
Final Analysis ........................................................................................................................ 31 
4.3 
Methods for Handling Missing Data ..............................................................................31 
4.3.1 
Handling Missing Data Not Due to Dropouts ........................................................................ 32 
4.3.2 
Handling missing data Due to Dropouts ................................................................................ 32 
4.3.3 
Handling of Screen Failures / Ineligible Patients ................................................................... 32 
4.4 
Statistical Analysis .......................................................................................................32 
4.4.1 
Derived Data .......................................................................................................................... 32 
4.4.1.1 
Treatment Start Date ...................................................................................................... 32 
4.5 
Baseline Values ...........................................................................................................33 
4.5.1.1 
Date of Birth ................................................................................................................... 33 
4.5.1.2 
End of Study Value ........................................................................................................ 33 
4.5.1.3 
Clinical Laboratory Data ................................................................................................. 33 
4.5.2 
Patient Disposition ................................................................................................................. 33 
4.5.3 
Baseline Characteristics ........................................................................................................ 34 
4.5.3.1 
Demographics ................................................................................................................ 34 
4.5.3.2 
Medical History and Concomitant Illness (Pre-existing Conditions) .............................. 34 
4.5.3.3 
Prior Medications/Therapies .......................................................................................... 35 
4.5.3.4 
ECG ................................................................................................................................ 36 
4.5.3.5 
Serology ......................................................................................................................... 36 
4.5.3.6 
Pregnancy test ............................................................................................................... 36 
4.5.3.7 
Eastern Co-operative Oncology Group Performance Status ......................................... 36 
4.5.4 
Efficacy Analysis.................................................................................................................... 37 
4.5.4.1 
Secondary Efficacy Analysis .......................................................................................... 37 
4.5.4.2 
Safety Analysis ............................................................................................................... 41 
4.5.4.3 
Primary Safety Analysis ................................................................................................. 41 
4.5.4.4 
Secondary Safety Analysis ............................................................................................ 41 
4.5.4.5 
Adverse Events (AEs) .................................................................................................... 42 
4.5.4.6 
Deaths, Serious Adverse Events and Significant Adverse Events ................................ 45 
4.5.4.7 
Significant Events of Special Interest ............................................................................. 45 
4.5.4.8 
Vital Signs ...................................................................................................................... 46 
4.5.4.9 
Physical Examinations ................................................................................................... 47 
4.5.4.10 
Clinical Laboratory Evaluation ....................................................................................... 48 


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4.5.4.11 
Concomitant Medications ............................................................................................... 51 
4.5.4.12 
Electrocardiograms (ECG) ............................................................................................. 52 
4.5.5 
Pharmacokinetics and Pharmacodynamic Analysis.............................................................. 53 
4.5.5.1 
Pharmacokinetics Parameters ....................................................................................... 53 
4.5.5.2 
Pharmacodynamics Parameters .................................................................................... 53 
5. 
Evaluation of Treatment Compliance and Exposure ....................................... 53 
5.1 
Compliance to Study Drug ...........................................................................................53 
5.2 
Exposure to Study Drug ...............................................................................................55 
5.3 
Statistical Analytical Issues ..........................................................................................56 
5.3.1 
Changes in the Planned Analysis From Protocol .................................................................. 56 
6. 
Statistical Tables to be Generated .................................................................... 56 
7. 
Statistical Listings to be Generated ................................................................. 58 
8. 
Statistical Graphs to be Generated ................................................................... 60 
 


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1. 
Introduction 
1.1 
Statistical Analysis Plan 
The Statistical Analysis Plan (SAP) is intended to be a comprehensive and detailed description of the 
methods of data analyses proposed for patients enrolled in Phase I (Dose Escalation) and Phase Ib (Dose 
Expansion) part of the study.  
The first part of protocol (Phase I – dose escalation part) is designed to determine the Maximum Tolerated 
Dose (MTD) of RP6530 in patients with relapsed/refractory T-cell lymphoma (PTCL/CTCL). The second 
part of protocol (Phase Ib dose expansion part) is to be conducted once the MTD/optimal dose has been 
confirmed in dose escalation phase.  
Thus, the patient cohorts used for finding MTD will be analyzed under “Dose Escalation” Phase and the 
patient cohort enrolled in the study after finding MTD for the study will be analyzed under “Dose Expansion” 
Phase of the study. The patient list of “Dose Expansion” Phase will be provided by Data Management.  
The “Statistical Analysis Plan” of the study RP6530-1401 is distinct from the statistical section of the 
protocol. Any changes or additions to the statistical analysis / methods planned related to the efficacy or 
safety analysis from the protocol are explained in this SAP. Pharmacokinetic (PK) and Pharmacodynamics 
(PD) analyses will be performed by other stakeholders and hence the detailed analyses related to PK and 
PD are not included in this SAP. 
This SAP includes following contents that are related to statistical analysis of efficacy, safety data of the 
study:  
 
Include statements of the objectives of the trial, as stated in the protocol  
 
Clearly define all primary, secondary and exploratory end-points of the study  
 
Details of derived variables and censoring procedures (if applied)   
 
Define the analysis populations to be used for the statistical analyses  
 
Provide a full and detailed description of the statistical methods of analyses including details of 
handling of missing data, drop outs, derived variables, etc. 
The SAP may be changed over time due to reasons such as protocol amendments or regulatory feedback.  
The final SAP should be approved before data base lock. Deviations from the final approved SAP if any will 
be discussed in the clinical study report. 
1.2 
Rationale for Study 
The δ isoform of PI3K is highly expressed in cells of hematopoietic origin, and strongly implicated in various 
hematologic malignancies. The γ isoform is associated with T-lymphocytes and neutrophils; there appears 
to be a significant synergy rather than a redundancy between the two isoforms in various leukemia and 
lymphomas. As T-cell lymphomas (both CTCL and PTCL) are unmedical need, dual targeting of PI3K δ/γ 


Protocol ID: RP6530-1401 
 
 
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therefore is strongly implicated as an intervention strategy in leukemia/lymphomas that are hard to treat by 
conventional means. RP6530 is a highly specific and orally available, PI3K δ and γ inhibitor with nano-
molar inhibitory potency, and several fold selectivity over the alpha and beta isoforms.  
Based on the favorable results of pre-clinical and toxicological studies, the first-in-man, Phase I, 3+3 dose 
escalation study was initiated in Europe in patients with relapsed and/or refractory hematologic 
malignancies (Study RP6530-1301). Patients received starting dose of 25 mg BID (50 mg/day). 
As the safety of 200 mg BID was established in the European study (RP6530-1301), it was reasonable to 
consider 200 mg BID dose as the starting dose in proposed Phase I study in relapse/refractory T-cell 
lymphoma in the US study RP6530-1401. 
2. 
Study Design and Objectives 
Dose Escalation Phase: 
The first part is a Phase 1 dose escalation, 3+3 design, open-label, MTD determination study of RP6530 in 
patients with relapsed/refractory T-cell lymphoma (PTCL/CTCL). Up to 18 patients will be enrolled in the 
escalation phase of the study. There will be total 8 cycles in this part. RP6530 is self-administered by the 
patients orally twice a day in 28-days cycle in absence of disease progression, unacceptable toxicity, or 
withdrawal from treatment. These patients will be analyzed under “Dose Escalation” Phase of the study.  
Dose Expansion Phase: 
The second part is Phase 1b dose expansion, open label study to be conducted once the MTD/optimal 
dose has been confirmed in dose escalation phase. Additional 40 patients, 20 patients of each indication 
will be enrolled (20 for PTCL and 20 for CTCL) to reach a maximum of 58 patients (including the Phase I 
patients). There will be total 8 cycles in this part. These patients will be analyzed under “Dose Expansion” 
Phase of the study.  
2.1 
Study Objectives 
2.1.1 
Primary Objectives 
The primary objectives are: 
 
To evaluate the safety and the maximum tolerated dose (MTD) of RP6530 in patients with 
relapsed/refractory T-cell lymphoma (CTCL/PTCL)  
 
To evaluate the pharmacokinetic (PK) effects of RP6530  
2.1.2 
Secondary Objectives 
The secondary objectives are: 
 
To examine the pharmacodynamic (PD) effects of RP6530.  


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 
To assess and the Overall Response Rate (ORR) and Duration of Response (DoR) in patients with 
relapsed/refractory T-cell lymphoma. 
2.1.3 
Exploratory Objectives 
The Exploratory objectives of this study are: 
 
Correlation of treatment outcomes with biomarkers which include but are not limited to quantitative 
and qualitative measurements of cytokines, chemokines and aberrations indicative of PI3K function 
and RP6530 efficacy. 
2.2 
Assessment of Objectives 
2.2.1 
Primary Endpoints 
2.2.1.1 
Primary Safety Endpoints 
AEs, SAEs, Clinically Significant AEs and Dose Limiting Toxicities (DLT).  
All AEs including DLTs, regardless of seriousness or relationship to RP6530 (study drug), spanning from 
the first dose of study drug until 30 calendar days after the last dose of study drug, discontinuation or 
completion of protocol-specific treatment as defined in the protocol for that patient, are to be recorded in 
the CRF. 
The development of a new primary cancer should be regarded as an AE and will generally meet at least 
one of the serious criteria. 
Deaths that occur during the protocol-specified AE reporting period that are attributed by the investigator 
solely to progression of disease will be recorded on the “Trial Discontinuation” CRF. All other on-trial deaths, 
regardless of attribution, will be recorded on an SAE Report. 
Pregnancy, abortion, birth defects, congenital anomalies and overdose of RP6530 are protocol defined 
events of special interest and recorded as AE. Further Symptomatic and non-symptomatic overdose of 
RP6530 will be reported in the CRF. 
2.2.1.2 
Primary Pharmacokinetic Endpoints 
PK parameters: AUC (0-inf), AUC (0-tau), Cmax, tmax, λz, and t½ of RP6530  
PK analyses will be performed by a Clinical pharmacology CRO contracted by the Sponsor and PK report 
with TLFs will be provided by the sponsor to the XXXXXXXXXX for incorporation in the final CSR. Therefore, 
PK analysis is not applicable for this SAP. PK analysis will be documented in a separate SAP prepared by 
a Clinical pharmacology CRO.     


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2.2.2 
Secondary Endpoints 
2.2.2.1 Secondary Pharmacodynamic Endpoints 
Inhibition of pAKT by RP6530  
This secondary pharmacodynamic (PD) endpoint will be assessed using following PD parameters 
 
Change in pAKT at each cycle, Cycle j i.e at Cycle j – Day 8, Cycle j – Day 22 and Cycle j – Day 29 
from Cycle 1 dose 1 that is Pre-Dose 1. Where Cycle j = 1, 2, 3,……8. This will also be checked for 
association with the Survival or Tumor Response. 
This analysis will be done in five Sezary Syndrome (SS) patients at MDACC site only. The statistical 
analysis of PD will be performed by clinical pharmacology CRO contracted by the Sponsor and the PD 
report will be provided by sponsor to the XXXXXXXXXX for incorporation in the final CSR. Therefore, PD 
analysis is not applicable for this SAP. PD analysis will be documented in a separate SAP prepared by 
Clinical pharmacology CRO.     
2.2.2.2 Secondary Efficacy Endpoints 
Secondary efficacy endpoint of Overall Response Rate (ORR) and Duration of Response (DoR) will be 
assessed as below: 
 
Overall Response Rate (ORR) 
Overall Response is defined as the best response [e.g. Complete Response (CR) or Partial Response (PR), 
Stable disease (SD) or disease progression (PD)] documented in the PTCL/CTCL patients treated with 
RP6530. 
ORR is defined as percentage of patients with Complete or Partial Response at any time point during the 
study, as assessed by investigator. 
 
Duration of Response (DoR)  
Duration of Response (DoR), is applicable to patients who achieved CR or PR and it is defined as time from 
the first documented assessment of CR or PR until the documented tumor disease progression (date of the 
first occurrence of PD as per investigator’s tumor assessment response based on post-treatment 
radiological assessment (e.g. PET/CT scan) up to predefined cut-off date. The cut-off date is nothing but 
the last patient last visit date (LPLV) i.e. 10-Dec-2018 when last patient (D8) was moved to compassionate 
study protocol 
In PTCL & CTCL patients, disease will be assessed using imaging assessments at Screening and at 
subsequent scheduled visits it will be assessed with respect to this baseline assessment using imaging 
assessments at C3D1 (± 7 days) and C5D1 (± 7 days) and approximately 12 weeks thereafter (± 7 days) 
and/ or at the End of Treatment (EOT). Disease assessment will be performed thereafter if warranted, at 
the discretion of investigator. 


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For PTCL patients, CT assessment based tumor response provided by investigator in “Response” field of 
eCRF module “Restaging for PTCL patient” will be considered for the analysis of ORR and DoR. 
For CTCL patients, tumor response provided by investigator in “Global Response” field of eCRF module 
“Restaging for CTCL patient” (which takes into account of skin response + nodal response + visceral 
response and blood response) will be considered for the analysis of ORR and DoR. 
2.2.2.3 Exploratory Efficacy Endpoints 
Correlative biomarkers (e.g. serum cytokines and chemokines)  
The listing related to correlative markers will be generated by XXXXXXXXXX, if the data is transferred by 
sponsor to XXXXXXXXXXX DM team for integrating it with Data Management database. The analysis of 
correlative biomarkers will be performed and report will be provided by XXXXXX XXXXXXXXXX, XX. 
2.3 
Change the Primary Objective during the conduct of the study 
Not Applicable 
2.4 
Study Design  
Dose Escalation Phase: 
The first part of this study is a Phase 1 dose escalation, 3+3 design, open-label, MTD determination study 
of RP6530 in patients with relapsed/refractory T-cell lymphoma (PTCL/CTCL). 18 patients will be enrolled 
in the escalation phase of the study. RP6530 is self-administered by the patients orally twice a day in 28-
days cycle in absence of disease progression, unacceptable toxicity, or withdrawal from treatment 
Sequential dose escalation is with Cohort 1. A minimum of three patients of either CTCL or PTCL will be 
entered into each opened dose level cohort. The first cohort of patients received RP6530 200 mg twice a 
day (BID). Dose levels will be increased in successive increments according to the dose escalation scheme 
as given in below Table 1. Dose escalation will be continued until the MTD/optimal dose has been identified 
or as determined by the DRG based on the available safety, PK and/or efficacy data. Dose determination 
will be documented appropriately. 
Table 1 Dose Escalation Schedule 
Dose Level 
RP6530 PO BID  
Dosing recommendation** 
Patients (n) 
1* 
200 mg BID 
Fasting 
3-6 
2 
400 mg BID 
Fasting 
3-6 
3 
800 mg BID 
Fasting 
3-6 
3a 
800 mg BID 
After Food 
3-6 
*If not tolerated or DLT occurs in over 33% of patients treated, a dose level of Dose Level -1 (i.e. 100 mg BID) will be 
tested 
** In fasting cohorts, patients will fast 2 hours prior to study drug administration and 1 hour after administration. In Fed 
cohort (After food), patients to take study after food (30 minutes after breakfast and dinner) 


Protocol ID: RP6530-1401 
 
 
Confidential                                                                  Statistical Analysis Plan                                                            Page 14 of 60 
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Intra-subject dose escalation: 
Individual patients may be considered for treatment at a dose level of RP6530 higher than the dose to which 
they were initially assigned. For a patient to be treated at a higher dose level of RP6530, the patient must 
not have experienced a DLT at the assigned dose and tolerated the lower dose for at least one cycle of 
therapy. The patient must have undergone a disease evaluation and been found appropriate to continue 
on study. The new higher dose must be a dose that has completed evaluation and has not exceeded the 
MTD. There is no limit to the number of times a patient may have their dose of RP6530 increased. However, 
the rules remain the same as listed above. At the discretion of the treating investigator(s), the dose 
escalation may be done in patient who received lower doses (de-escalation) due to safety reason.  
During statistical analyses of Dose escalation phase, the patient data will be analyzed according to dose 
received / assigned initially (initial cohort assigned to the patient). 
Alternative Dosing Cohorts 
Depending on the nature and the timing of the toxicities encountered and the pharmacokinetic data from 
continuous daily dosing of RP6530, alternative dosing regimens and schedules may be examined. If in the 
opinion of the DRG, observed toxicities (DLTs and/or non-dose limiting adverse events of concern) are 
likely to have resulted from a continuous exposure to the study drug or cumulative effect, alternative dosing 
regimens or schedules may be explored. The DRG will determine the alternative schedule, based on PK 
data, nature and timing of toxicities, and the required recovery periods for the observed toxicities 
encountered. Dose escalation would proceed with an alternative schedule to determine the MTD/optimal 
dose. 
Dose Expansion Phase: 
Once the MTD/optimal dose has been confirmed, patients who complete the Dose Escalation Phase will 
be permitted to enter the expansion cohorts (Phase Ib). Additional 40 patients, 20 CTCL and 20 PTCL 
patients may be enrolled to reach a maximum of 58 patients (including the Phase I patients) in each of the 
CTCL and PTCL groups. There will be total 8 cycles in this part of the study. 
 
Table 2  Dose Expansion Schedule 
Dose Level 
RP6530 PO BID  
Patients (n) 
CTCL 
RP6530 800 mg Fasting 
20 
PTCL 
RP6530 800 mg Fasting 
20 


Protocol ID: RP6530-1401 
 
 
Confidential                                                                  Statistical Analysis Plan                                                            Page 15 of 60 
v1: 12/Mar/2019 
2.4.1 Study Flow Chart 
 
2.5 
Sample Size and Power Considerations 
Dose Escalation Phase: 
No formal sample size calculation is performed for this part of study. Sample size up to 18 is considered 
based on 3+3 dose escalation design of the dose escalation phase of this study 
Note: The total number of patients in phase I may exceed depending on MTD. 
Dose Expansion Phase: 
No formal sample size calculation is performed for this part of study. This trial will enroll up to 58 patients 
from 5-10 different sites, 40 patients (20 PTCL, 20 CTCL) of dose expansion phase and 18 patients of dose 
escalation phase will be considered for this part of the study. 


Protocol ID: RP6530-1401 
 
 
Confidential                                                                  Statistical Analysis Plan                                                            Page 16 of 60 
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2.6 
Randomization  
Not Applicable as this is a non-randomized, open label study. 
2.7 
Blinding 
Not Applicable as this is a non-randomized, open label study. 
3. 
General Analysis Requirements 
3.1 
Study Duration 
The study duration of each patient included in the study is approximately 8 months. The conduct of the 
study trial from Screening visit (Day -28 to 0) to End of Treatment visit, is provided in the visit schedule 
chart. 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol ID: RP6530-1401 
 
 
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3.2 
Schedule of Study Visits, Visit windows and Procedures 
Dose Escalation Phase: 
Table 3 Schedule of Assessment – Part 1 Dose Escalation 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle C4 
C5 
C6 
C7 
C8 
EOT25 
Day 
D-28 
to 0 
D1 
D8 
D15 
D22 
D1 
D8 
D15 
D22 
D1 
D15 
D1 
D15 
D1 
D1 
D1 
D1 
D1 
Window period 
 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±30 
Study Days 
D-28 
to 0 
1 
8 
15 
22 
29 
36 
43 
50 
57 
71 
85 
99 
113 
141 
169 
197 
- 
Dose escalation visits 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
PROCEDURE 
Informed Consent1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vitals4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height and weight5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG Performance 
Status 
X 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
LABORATORY TEST/EVALUATIONS 
Complete blood count7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry panel I8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry panel II9 
X 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Serology (HIV, HBV, 
HCV) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PT/INR10 
X 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
 
 
X 


Protocol ID: RP6530-1401 
 
 
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v1: 12/Mar/2019 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle C4 
C5 
C6 
C7 
C8 
EOT25 
Day 
D-28 
to 0 
D1 
D8 
D15 
D22 
D1 
D8 
D15 
D22 
D1 
D15 
D1 
D15 
D1 
D1 
D1 
D1 
D1 
Window period 
 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±30 
Study Days 
D-28 
to 0 
1 
8 
15 
22 
29 
36 
43 
50 
57 
71 
85 
99 
113 
141 
169 
197 
- 
HbA1c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis (routine) 
X 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Pregnancy test11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGs12 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
PK blood samples13 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Biomarker samples14 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
PD samples (pAKT)15 
- 
X 
X 
- 
X 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
Archived tumor tissue16 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DISEASE ASSESSMENT 
Staging17 
X 
- 
- 
- 
- 
- 
- 
- 
- 
X 
- 
- 
- 
X 
- 
- 
- 
X 
Radiological 
Examination18 
X 
- 
- 
- 
- 
- 
- 
- 
- 
X 
- 
- 
- 
X 
- 
- 
X 
X 
Skin lesion 
assessment19 
X 
- 
- 
- 
- 
- 
- 
- 
- 
X 
- 
- 
- 
X 
- 
- 
X 
X 
Skin biopsy20 
X 
- 
- 
- 
- 
- 
- 
- 
- 
X 
- 
- 
- 
- 
- 
- 
- 
- 
Immunophenotyping 
and TCR gene 
rearrangement21 
X 
- 
- 
- 
- 
- 
- 
- 
- 
X 
- 
- 
- 
- 
- 
- 
- 
- 
Photograph 
of 
skin 
lesion22 
X 
- 
- 
- 
- 
- 
- 
- 
- 
X 
- 
- 
- 
- 
- 
- 
- 
X 
Bone marrow, lymph 
node biopsy /Aspirate23 
X 
- 
- 
- 
- 
- 
- 
- 
- 
-23a 
- 
- 
- 
-23a 
- 
- 
-23a 
X 


Protocol ID: RP6530-1401 
 
 
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Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle C4 
C5 
C6 
C7 
C8 
EOT25 
Day 
D-28 
to 0 
D1 
D8 
D15 
D22 
D1 
D8 
D15 
D22 
D1 
D15 
D1 
D15 
D1 
D1 
D1 
D1 
D1 
Window period 
 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±30 
Study Days 
D-28 
to 0 
1 
8 
15 
22 
29 
36 
43 
50 
57 
71 
85 
99 
113 
141 
169 
197 
- 
DRUG ADMINISTRATION & SAFETY EVALUATION 
Drug administration24 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Drug dispensing 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Drug compliance 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE 
evaluation 
and 
reporting  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SAE 
evaluation 
and 
reporting 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication 
review 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Diary evaluation 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1. Patient should be re-consented in case informed consent is not obtained ≤28 days prior to the initiation of trial treatment. 
2. Demographic profile will include age, sex and race. 
3. Detailed history will be taken at screening that includes history of cancer, past history, no of prior therapies and prior medication (in last 4weeks); and other medical history. Abbreviated 
history will be taken at all subsequent visits. 
4. Vitals will include pulse (sitting/supine); blood pressure (sitting/supine); respiratory rate and oral temperature. 
5. Weight will be measured at all visits. Height to be measured at screening only. 
6. Physical examination will include lymph node and systemic examination. Complete physical examination will be done at screening visit. At subsequent visits, abbreviated examination 
will be done. 
7. This will include Hb, complete blood count, reticulocyte count, total leucocyte and differential count and platelet count. Additional investigations will be performed if clinically indicated. 
Hematology must be done ≤7 days prior to initiation of treatment. However, if these initial examinations are obtained within 72 hours of C1D1; they do not have to be repeated. 
8. Chemistry Panel I includes Total bilirubin, ALP, AST, ALT, GGT, LDH and Serum electrolytes (Sodium, Potassium, Bicarbonate, Chloride, Magnesium, Phosphorus and Calcium). 
These tests must be done ≤7 days prior to initiation of treatment. However, if these initial examinations are obtained within 72 hours of C1D1; they do not have to be repeated. These 
test will be performed at supplementary visits if clinically indicated. 


Protocol ID: RP6530-1401 
 
 
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9. Chemistry Panel II includes blood glucose, urea or blood urea nitrogen, creatinine, albumin, globulin, total protein, Total Cholesterol, TG, LDL and HDL, TSH, T3 and T4. These tests 
must be done ≤7 days prior to initiation of treatment. However, if these initial examinations are obtained within 72 hours of C1D1; they do not have to be repeated. These test will be 
performed at supplementary visits if clinically indicated. 
10. This test must be done ≤7 days prior to initiation of treatment. However, if initial examination is obtained within 72 hours of C1D1; this should not be repeated. This test will be 
performed at supplementary visits if clinically indicated. 
11. This is required for women of child bearing potential. A serum pregnancy test will be performed at screening and baseline (within 72 hours) of dosing. Urine pregnancy test will be 
performed at other visits as indicated. 
12. A single ECG will be performed at screening and C1D1 pre-dose. Post-dose ECGs will be performed in conjunction with the 1 hr, 2hr and 4hr post-dose PK collection on C1D1; and 
on C1D8 (pre-dose), C1D15 (pre-dose), and C1D22 (pre-dose). On C2D1, ECGs will be obtained pre-dose and then one hour post-dose coinciding with the PD collection. Additional 
ECGs will be obtained if clinically indicated. Triplicate ECGs will be performed to confirm the significant changes of single ECG. All ECGs will be performed on local equipment. 
13. PK blood sample collection time points: C1D1 at pre-dose, 0.5, 1, 2, 4, 6, 8 hrs post dose; and C1D8 and C1D15 at predose; C2D1 at pre-dose, 0.5, 1, 2, 4, 6, 8 hrs post dose and 
C2D8 and C2D15 at pre-dose; C3D1 and C3D15 at pre-dose; C4D1 and C4D15 at pre-dose; Cycle 5 and beyond at predose. Window period for PK sampling will be defined in laboratory 
manual.  
14. Correlative serum biomarkers (e.g. sIL2R CTACK (PTCL); CD30 (MF); IL-31 and IL-32 (CTCL)) will be performed at screening, C3D1 (pre-dose and 1 hr later); at EOT and/ or to 
confirm a response. Blood will be collected for these biomarkers, serum aliquots will be prepared and will be banked for analysis at later stage. 
15. PD samples (pAKT) will be performed on C1D1 (pre-dose and 1 hr later), C1D8 (pre-dose) and C1D22 (pre-dose); C2D1 (pre-dose) and C3D1 (pre-dose) and/ at EOT in 5 sezary 
syndrome patients. 
16. Archival tumor samples will be collected during the trial, if available. 
17. Ann-Arbor staging system should be applied in patients with other types of NHL; ISCL/EORTC criteria should be used for CTCL. Patients will be restaged C3D1 (± 7 days) and C5D1 
(± 7 days) and approximately 12 weeks thereafter (± 7 days) and/ or at the EOT. 
18. CT scan (of the chest, abdomen, and pelvis) and other radiological evaluations (X-RAY/MRI/Ultrasound) will be performed at the time of screening within 28 days of screening. PET-
CT will be used to assess response in FDG-avid histologies. In CTCL patients with other than presumed stage IA disease, or selected patients with limited T2 disease and the absence 
of adenopathy or blood involvement, CT scans of chest, abdomen, and pelvis alone ± FDG-PET scan are recommended to further evaluate any potential lymphadenopathy, visceral 
involvement, or abnormal laboratory tests. In patients unable to safely undergo CT scans, MRI may be substituted. PTCL patients will be evaluated according to the IWG Revised 
Response Criteria for Malignant Lymphoma. Assessment of CTCL response and progression will be evaluated according to the Response Criteria in Mycosis Fungoides and Se´zary 
Syndrome by the ISCL/EORTC criteria. In both CTCL and PTCL, disease will be assessed at C3D1 (± 7 days) and C5D1 (± 7 days) and approximately 12 weeks thereafter (± 7 days) 
and/ or at the EOT. Assessment will be performed thereafter if warranted, at the discretion of PI/Co-PI.  
19. The assessment of skin lesion will be performed at the time of screening in CTCL patients. The assessments will be performed in PTCL if applicable. For skin scoring, the modified 
Severity Weighted Assessment Tool (mSWAT) will be used. For local index lesion skin scoring, Composite Assessment of Index Lesion Severity will be used. The disease will be 
assessed at C3D1 (± 7 days) and C5D1 (± 7 days) and approximately 12 weeks thereafter (± 7 days) and/ or at the EOT. Assessment will be performed thereafter if warranted, at the 
discretion of PI/Co-PI.  


Protocol ID: RP6530-1401 
 
 
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20. Skin biopsy will be performed in CTCL patients at screening, on C3D1 (± 7 days) and/or to confirm a complete response. In CTCL patients, skin biopsy should be performed at the 
most indurated area if only one biopsy. 
21. Immunophenotyping to include at least the following markers: CD3, CD4, CD7, CD8 and Ki67. CD30 may also be indicated in cases where lymphomatoid papulosis, anaplastic 
lymphoma, or large-cell transformation is considered. Clonality of TCR gene rearrangement will be evaluated as part of standard of care and will be an optional. Immunophenotyping will 
be performed at screening, on C3D1 (± 7 days) and/or to confirm a complete response. 
22. CTCL patients will have half body global and up to 5 selected representative index lesions photographed at baseline, at C3D1, End of treatment (EOT), at PR/CR/PD and as required 
as per the discretion of PI/Co-PI. 
23. Bone marrow biopsy: Patients entering the study with low grade lymphoma must have a morphology and flow cytometry performed ≤3 months prior to study entry and/or to confirm 
a complete response. Patients with high grade lymphoma must have a morphology and flow cytometry performed ≤28 days prior to study entry and/or to confirm a complete response. 
The lymph node will be required to perform only if the diagnosis is not confirmed at the baseline; and if required at other time points. 
23a PTCL patients without measurable disease but assessable disease (e.g. marrow disease without other radiographically measurable disease) will have a bone marrow biopsy at 
screening /baseline and on C3D1 (± 7 days) and C5D1 (± 7 days) and approximately 12 weeks thereafter (± 7 days) and/or to confirm a complete response. CTCL patients with 
predominantly blood involvement (confirmed by flow cytometry) will have a bone marrow biopsy at screening /baseline (unless it has been shown to be negative within the last 6 months) 
and as indicated to confirm a complete response occurring at all other sites. Specific molecular exams for some particular malignancies will be performed according to institutional 
diagnostic guidelines. If bone marrow aspirate is available, it will be processed and shipped according to the laboratory manual. Bone marrow disease alone may be used for disease 
assessment. In this case, response would be CR or non-CR only, determined by the morphology of repeat bone marrow biopsy. 
24. The study drug RP6530 will be administered orally twice a day in 28-days of cycle. The drug administration will be monitored on C1D1 and C2D1 followed by PK evaluation. On other 
days, the treatment can be administered at home. The treatment period is at least 8 months. Treatment will be continued in patients experiencing clinical benefit for 2 years unless 
progression of disease or toxicity warranting discontinuation of therapy. The decision to continue the treatment will be taken by PI-Co-PI after consultation with Sponsor on case to case 
basis. 
25. All patients will undergo the end-of-treatment assessments listed within 30 days after treatment ends. Patients must be followed for adverse events for 30 calendar days after the 
last dose of study drug. 
26. All visits will be ambulatory except C1D1 and C2D1 that involve extended hospital stay for PK assessment. 
 
 
 
 
 


Protocol ID: RP6530-1401 
 
 
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Dose Expansion: 
Table 4 Schedule of Assessment – Part 2 Dose Expansion 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
Cycle 7 
Cycle 8 
EOT25 
Day 
D-28 to 0 
D1 
D1 
D1 
D1 
D1 
D1 
D1 
D1 
D1 
Window period 
 
±1 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
±30 
Study Days 
D-28 to 0 
1 
29 
57 
85 
113 
141 
169 
197 
- 
PROCEDURE 
 
 
 
 
 
 
 
 
 
 
Informed Consent1 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Demographics2 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Medical history3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vitals4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height and weight5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
LABORATORY TEST/ EVALUATION 
 
 
 
 
 
 
 
 
 
 
Complete blood count7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry panel I8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry panel II9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serology (HIV, HBV, HCV) 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
PT/INR10 
X 
X 
X 
X 
X 
- 
- 
- 
- 
X 
HbA1c 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Urinalysis (routine) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGs12 
X 
X 
X 
- 
- 
- 
- 
- 
- 
- 
PK blood samples13 
- 
X 
X 
X 
X 
X 
X 
X 
X 
- 
Biomarker samples14 
X 
- 
- 
X 
- 
- 
- 
- 
- 
X 
PD samples (pAKT)15 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 


Protocol ID: RP6530-1401 
 
 
Confidential                                                                                                           Statistical Analysis Plan                                                                                                      Page 23 of 60 
v1: 12/Mar/2019 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
Cycle 7 
Cycle 8 
EOT25 
Day 
D-28 to 0 
D1 
D1 
D1 
D1 
D1 
D1 
D1 
D1 
D1 
Window period 
 
±1 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
±30 
Study Days 
D-28 to 0 
1 
29 
57 
85 
113 
141 
169 
197 
- 
Archived tumor tissue16 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
DISEASE ASSESSMENT 
 
 
 
 
 
 
 
 
 
 
Staging17 
X 
- 
- 
X 
- 
X 
- 
- 
- 
X 
Radiological Examination18 
X 
- 
- 
X 
- 
X 
- 
- 
X 
X 
Skin lesion assessment19 
X 
- 
- 
X 
- 
X 
- 
- 
X 
X 
Skin biopsy20 
X 
- 
- 
X 
- 
- 
- 
- 
- 
- 
Immunophenotyping and TCR gene 
rearrangement21 
X 
- 
- 
X 
- 
- 
- 
- 
- 
- 
Photograph of skin lesion22 
X 
- 
- 
X 
- 
- 
- 
- 
- 
X 
Bone marrow, lymph node biopsy 
/Aspirate23 
X 
- 
- 
-23a 
- 
-23a 
- 
- 
-23a 
X 
DRUG ADMINISTRATION AND SAFETY EVALUATION 
 
 
 
 
 
 
 
 
Drug administration24 
- 
X 
X 
X 
X 
X 
X 
X 
X 
- 
Drug dispensing 
- 
X 
X 
X 
X 
X 
X 
X 
X 
- 
Drug compliance 
- 
- 
X 
X 
X 
X 
X 
X 
X 
X 
AE evaluation and reporting  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SAE evaluation and reporting 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication review 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Diary evaluation 
- 
- 
X 
X 
X 
X 
X 
X 
X 
X 
1. Patient should be re-consented in case informed consent is not obtained ≤28 days prior to the initiation of trial treatment. 
2. Demographic profile will include age, sex and race. 
3. Medical History: Detailed history will be taken at screening that includes history of cancer, past history, no of prior therapies and prior medication (in last 4weeks); and other medical 
history. Abbreviated history will be taken at all subsequent visits. 
4. Vitals will include pulse (sitting/supine); blood pressure (sitting/supine); respiratory rate and oral temperature. 


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5. Weight will be measured at all visits. Height to be measured at screening only. 
6. Physical examination will include lymph node and systemic examination. Complete physical examination will be done at screening visit. At subsequent visits, abbreviated examination 
will be done. 
7. Complete blood count will include Hb, complete blood count, reticulocyte count, total leucocyte and differential count and platelet count. Additional investigations will be performed if 
clinically indicated. Hematology must be done ≤7 days prior to initiation of treatment. However, if these initial examinations are obtained within 72 hours of C1D1; they do not have to be 
repeated. 
8. Chemistry Panel I includes Total bilirubin, ALP, AST, ALT, GGT, LDH and Serum electrolytes (Sodium, Potassium, Bicarbonate, Chloride, Magnesium, Phosphorus and Calcium). 
These tests must be done ≤7 days prior to initiation of treatment. However, if these initial examinations are obtained within 72 hours of C1D1; they do not have to be repeated. These 
test will be performed at supplementary visits if clinically indicated. 
9. Chemistry Panel II includes blood glucose, urea or blood urea nitrogen, creatinine, albumin, globulin, total protein, Total Cholesterol, TG, LDL and HDL, TSH, T3 and T4. These tests 
must be done ≤7 days prior to initiation of treatment. However, if these initial examinations are obtained within 72 hours of C1D1; they do not have to be repeated. These test will be 
performed at supplementary visits if clinically indicated. 
10. PT/INR test must be done ≤7 days prior to initiation of treatment. However, if initial examination is obtained within 72 hours of C1D1; this should not be repeated. This test will be 
performed at supplementary visits if clinically indicated. 
11. Pregnancy test is required for women of child bearing potential. A serum pregnancy test will be performed at screening and baseline (within 72 hours) of dosing. Urine pregnancy 
test will be performed at other visits as indicated. 
12. ECG: A single ECG will be performed at screening and C1D1 pre-dose. Post-dose ECGs will be performed in conjunction with the 1 hr, 2hr and 4hr post-dose PK collection on C1D1; 
and on C1D8 (pre-dose), C1D15 (pre-dose), and C1D22 (pre-dose). On C2D1, ECGs will be obtained pre-dose and then one hour post-dose coinciding with the PD collection. Additional 
ECGs will be obtained if clinically indicated. Triplicate ECGs will be performed to confirm the significant changes of single ECG. All ECGs will be performed on local equipment. 
13. PK: C1D1 at pre-dose, C2D1 at pre-dose, C3D1 at pre-dose; C4D1 at pre-dose; Cycle 5 and beyond at pre-dose. Window period for PK sampling will be 1 hr pre-dose. 
14. Correlative serum biomarkers (e.g. sIL2R CTACK (PTCL); CD30 (MF); IL-31 and IL-32 (CTCL)) will be performed at screening, C3D1 (pre-dose and 1 hr later); at EOT and/ or to 
confirm a response. Blood will be collected for these biomarkers, serum aliquots will be prepared and will be banked for analysis at later stage. 
15. PD samples (pAKT): pAKT is not applicable to dose expansion. 
16. Archival tumor samples will be collected during the trial, if available. 
17. Staging: Ann-Arbor staging system should be applied in patients with other types of NHL; ISCL/EORTC criteria should be used for CTCL. Patients will be restaged C3D1 (± 7 days) 
and C5D1 (± 7 days) and approximately 12 weeks thereafter (± 7 days) and/ or at the EOT. 
18. Radiological assessment: PTCL: A CT scan (of the chest, abdomen, and pelvis) and other radiological evaluations (X-RAY/MRI/Ultrasound) will be performed at the time of screening 
within 28 days of screening. PET-CT will be used to assess response in FDG-avid histologies. In CTCL patients with other than presumed stage IA disease, or selected patients with 
limited T2 disease and the absence of adenopathy or blood involvement, CT scans of chest, abdomen, and pelvis alone ± FDG-PET scan are recommended to further evaluate any 
potential lymphadenopathy, visceral involvement, or abnormal laboratory tests. In patients unable to safely undergo CT scans, MRI may be substituted. PTCL patients will be evaluated 
according to the IWG Revised Response Criteria for Malignant Lymphoma. Assessment of CTCL response and progression will be evaluated according to the Response Criteria in 


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Mycosis Fungoides and Se´zary Syndrome by the ISCL/EORTC criteria. In both CTCL and PTCL, disease will be assessed at C3D1 (± 7 days) and C5D1 (± 7 days) and approximately 
12 weeks thereafter (± 7 days) and/ or at the EOT. Assessment will be performed thereafter if warranted, at the discretion of PI/Co-PI. 
19. Skin lesion Assessment: The assessment of skin lesion will be performed at the time of screening in CTCL patients. The assessments will be performed in PTCL if applicable. For 
skin scoring, the modified Severity Weighted Assessment Tool (mSWAT) will be used. For local index lesion skin scoring, Composite Assessment of Index Lesion Severity will be used. 
The disease will be assessed at C3D1 (± 7 days) and C5D1 (± 7 days) and approximately 12 weeks thereafter (± 7 days) and/ or at the EOT. Assessment will be performed thereafter if 
warranted, at the discretion of PI/Co-PI. 
20. Skin biopsy: Biopsy will be performed in CTCL patients at screening, on C3D1 (± 7 days) and/or to confirm a complete response. In CTCL patients, skin biopsy should be performed 
at the most indurated area if only one biopsy. 
21. Immunophenotyping to include at least the following markers: CD3, CD4, CD7, CD8 and Ki67. CD30 may also be indicated in cases where lymphomatoid papulosis, anaplastic 
lymphoma, or large-cell transformation is considered. Clonality of TCR gene rearrangement will be evaluated as part of standard of care and will be an optional. Immunophenotyping will 
be performed at screening, on C3D1 (± 7 days) and/or to confirm a complete response. 
22. Photograph of skin lesion: CTCL patients will have half body global and up to 5 selected representative index lesions photographed at baseline, at C3D1, End of treatment (EOT), at 
PR/CR/PD and as required as per the discretion of PI/Co-PI. 
23. Bone marrow biopsy: Patients entering the study with low grade lymphoma must have a morphology and flow cytometry performed ≤3 months prior to study entry and/or to confirm 
a complete response. Patients with high grade lymphoma must have a morphology and flow cytometry performed ≤28 days prior to study entry and/or to confirm a complete response. 
The lymph node will be required to perform only if the diagnosis is not confirmed at the baseline; and if required at other time points. 
23a CTCL patients with predominantly blood involvement (confirmed by flow cytometry) will have a bone marrow biopsy at screening /baseline (unless it has been shown to be negative 
within the last 6 months) and as indicated to confirm a complete response occurring at all other sites. Specific molecular exams for some particular malignancies will be performed 
according to institutional diagnostic guidelines. If bone marrow aspirate is available, it will be processed and shipped according to the laboratory manual. 
24. The study drug RP6530 800 mg BID in fasting conditions will be administered orally twice a day in 28-days of cycle. The drug should be administered at hospital during hospital 
visits. On other days, the treatment can be administered at home. The treatment period is at least 8 months. Treatment will be continued in patients experiencing clinical benefit for 2 
years unless progression of disease or toxicity warranting discontinuation of therapy. The decision to continue the treatment will be taken by PI-Co-PI after consultation with Sponsor on 
case to case basis. 
25. All patients will undergo the end-of-treatment assessments listed within 30 days after treatment ends. Patients must be followed for adverse events for 30 calendar days after the 
last dose of study drug. 
26. All visits will be ambulatory.


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3.3 
Study Populations 
Patients will be screened to verify that they fulfill all of the eligibility criteria – Inclusion Criteria and Exclusion 
Criteria listed in the Protocol. Eligible patients will be dosed with the study treatment. Adherence to these 
criteria as specified in the protocol is essential. At Cycle 1 (Day 1), a patient is dosed if he or she fulfills all 
screening requirements during the past 28 days as reviewed against the inclusion and exclusion criteria of 
protocol.  
3.3.1 Inclusion Criteria 
Dose Escalation Phase and Dose Expansion Phase: 
Patients must meet the following criteria in order to be included in this clinical trial: 
1. Histologically confirmed T cell Non-Hodgkin Lymphoma (T-NHL) as approved by the Medical Monitor or 
PI/Co-PI. 
2. Disease status defined as:  
 
Refractory to or relapsed after ≥ 1 prior treatment lines. 
 
Patients who are not eligible for transplantation or any standard and / or approved therapy known 
to be life prolonging or lifesaving (patients who may be eligible for transplantation or any standard 
and /or approved therapy but have declined therapy, or in the investigators opinion based on the 
patient’s condition, an investigational therapy may benefit more than existing approved therapies 
are eligible for the study). 
3. Patients with a measurable or evaluable disease. 
 
In case of radiologically measurable lesions, the longest diameter should be ≥ 2cm in PTCL 
patients. 
 
PTCL patients with non-measurable lesions but assessable disease (e.g. marrow disease without 
other radiographically measurable disease) can be enrolled in dose-escalation phase as approved 
by PI/Co-PI. 
4. Adequate organ system function, defined as follows:  
 
Patients with haemoglobin levels and/or neutrophil and platelet counts under these values will be 
eligible in the case abnormalities are due to tumor dissemination or infiltration and according to 
physician’s discretion and under his direct responsibility.  
a. Hemoglobin ≥8 g/dL 
b. Absolute neutrophil count (ANC) ≥0.75 x 109/L 
c. Platelets ≥50 x 109/L 
 
Total bilirubin ≤1.5 times the upper limit of normal (ULN) 


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 
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x ULN if no liver 
involvement or 5 x the ULN if known liver involvement. 
 
Creatinine ≤2.0 mg/dL OR calculated creatinine clearance ≥ 50 mL/min as calculated by the 
Cockcroft-Gault method 
5. ECOG performance status ≤2.  
6. Life expectancy of at least 12 weeks. 
7. Patients must be ≥18 years of age. 
8. Ability to swallow and retain oral medication. 
9. Female patients who are not of child-bearing potential or female patients of child-bearing potential who 
have a negative serum pregnancy test within 72 hours prior to initial trial treatment. Female patients of 
child-bearing potential, and all male partners must consent to use a medically acceptable method of 
contraception throughout the study period and for 4 weeks plus 5T1/2 (48 hrs) after the last dose of RP6530. 
A barrier method of contraception must be included. 
10. Male patients willing to use adequate contraceptive measures throughout the study period and for 12 
weeks plus 5T1/2 (48 hrs) after the last dose of RP6530. 
11. Willingness and ability to comply with trial and follow-up procedures. 
12. Ability to understand the nature of this trial and give written informed consent. 
3.3.2 Exclusion Criteria 
Dose Escalation Phase and Dose Expansion Phase: 
Patients who meet any of the following criteria will be excluded from trial entry: 
1. Any cancer therapy (i.e., chemotherapy, radiation therapy, immunotherapy, biologic therapy, hormonal 
therapy, surgery and/or tumor embolization) in the last 3 weeks or the last 5T1/2 of the agent, whichever is 
shorter. Limited palliative radiation <2 weeks. 
2. Autologous hematologic stem cell transplant within 3 months of study entry. Allogeneic hematologic stem 
cell transplant within 12 months. Active graft-versus-host disease. 
3. Active HBV, HCV or HIV infection. 
4. Use of an investigational drug in the last 4 weeks prior to the first dose of RP6530 
5. Treatment with GS-1101 (CAL-101, idelalisib), IPI-145, TGR-1202 or any drug that specifically inhibits 
PI3K/ mTOR (including temsirolimus, everolimus), AKT or BTK Inhibitor (including Ibrutinib) in last 6 
months. 
6. Patient has received wide field radiotherapy (including therapeutic radioisotopes such as Yttrium-90) ≤ 
28 days or limited field radiation for palliation ≤ 14 days prior to starting RP6530 or has not recovered from 
side effects of such therapy. 


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7. Ongoing immunosuppressive therapy including systemic corticosteroids (prednisone or equivalent ≤10 
mg daily allowed as clinically warranted). Patients are allowed to use topical or inhaled corticosteroids. 
8. Known history of drug-induced liver injury, alcoholic liver disease, non-alcoholic steatohepatitis, primary 
biliary cirrhosis, ongoing extrahepatic obstruction caused by stones, cirrhosis of the liver or portal 
hypertension. 
9. Patients with uncontrolled Diabetes Type I or Type II (HbA1c >8% assessed locally). 
10. Any severe and/or uncontrolled medical conditions or other conditions that could affect their participation 
in the study such as: 
 
Symptomatic, or history of documented congestive heart failure (New York Heart Association 
functional classification III-IV [see Appendix B]) 
 
QTcF > 470 msec 
 
Angina not well-controlled by medication 
 
Poorly controlled or clinically significant atherosclerotic vascular disease including cerebrovascular 
accident (CVA), transient ischemic attack (TIA), angioplasty, cardiac or vascular stenting in the 
past 6 months 
 
Active or uncontrolled severe infections requiring IV antibiotics 
 
Patients with hemophilia or even Von Willebrand’s disease should be excluded. 
11. Herbal preparations/medications must be discontinued 7 days prior to first dose of study drug. 
12. Presence of other active cancers, or history of treatment for invasive cancer ≤ 3 years. Patients with 
stage I cancer who have received definitive local treatment at least 3 years previously, and are considered 
unlikely to recur are eligible. All patients with previously treated in situ carcinoma (i.e. non-invasive) are 
eligible, as are patients with history of non-melanoma skin cancer. 
13. Women who are pregnant or lactating. 
14. Psychological, familial, sociological, or geographical conditions that do not permit compliance with the 
protocol. 
15. Concurrent condition that in the investigator’s opinion would jeopardize compliance with the protocol. 
16. Inability or unwillingness to comply with study and/or follow-up procedures outlined in the protocol. 
3.3.3 Withdrawal / Discontinuation Criteria 
Dose Escalation Phase and Dose Expansion Phase: 
Patients will be discontinued from trial treatment for any of the following reasons: 
 
Disease progression 
 
Irreversible or intolerable toxicity or abnormal laboratory values related to drug toxicity 
 
Consent withdrawal 
 
Patient requests to discontinue treatment 


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 
Pregnancy  
 
Inability of the patient to comply with trial requirements 
 
Conditions requiring therapeutic intervention not permitted by the protocol 
 
Intercurrent illness (at the investigator’s discretion) 
 
Non-compliance/lost to follow-up 
 
Discontinuation of the study by the Sponsor 
After withdrawal from protocol treatment, patients will be followed for AEs for 30 calendar days after their 
last dose of trial drug. All new AEs occurring during this period must be reported and followed until 
resolution, unless, in the opinion of the investigator, these values are not likely to improve because of the 
underlying disease. In this case, the investigators must record his or her reasoning for this decision in the 
patients’ medical records and as a comment on the Case Report Form (CRF). 
All patients who have CTCAE grade 3 or 4 laboratory abnormalities at the time of withdrawal will be followed 
until the laboratory values have returned to grade 1 or 2, unless it is, in the opinion of the investigator, not 
likely that these values are to improve because of the underlying disease. In this case, the investigator must 
record his or her reasoning for making this decision in the patients’ medical records and as a comment on 
the CRF. 
3.4 
Treatment Assignment and Treatment Groups 
This is a study of a single study drug with no placebo or comparator drug. 
All patients will receive RP6530 as per drug and dose escalation schedule. 
Dose Escalation Phase: 
RP6530: Dosing will begin on Cycle 1/Day 1 (C1D1) with continuous oral twice daily dosing (BID) in 28 
days cycle. RP6530 will be self-administered by the patients. Tablet (s) of relevant strength should be taken 
at approximately the same time each day. In case of fasting state, patients will fast 2 hours prior to study 
drug administration and 1 hour after administration. In case of Fed state (After food), patients need to take 
study drug after food (30 minutes after breakfast and dinner). 
Dose Expansion Phase: 
Once MTD is decided in Dose Escalation Phase, the same dose will be used in Dose Expansion Phase. 
4. 
Statistical Methods 
Statistical analysis will be performed for Dose escalation and Dose Expansion phases of the study for 
CTCL, PTCL and for all patients (combined data). Three separate sets of Tables and Graphs will be 
generated as below depending on data availability. 
Set 1: All Patients (Combined CTCL and PTCL) 
Set 2: CTCL Patients 
Set 3: PTCL Patients 


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For Listings, only one Set for All Patients (Combined CTCL and PTCL) will be generated 
4.1 
Analysis Datasets 
The patient cohort used for finding MTD will be analyzed under “Dose Escalation” Phase and even if intra 
escalation of Dose happens the subject will be analyzed in the same cohort as per the first dose for safety 
and efficacy analysis. 
The patient cohort enrolled in the study after finding MTD for the study will be analyzed under “Dose 
Expansion” Phase of the study. The patient list of “Dose Expansion” Phase will be provided by Data 
Management as an external data along with data extracts.  
4.1.1 Safety Population 
Dose Escalation Phase and Dose Expansion Phase: 
The safety population will include all patients who have received at least one dose of study medication. 
This population will be used for safety analysis. 
4.1.2 Intent to Treat Population 
Dose Escalation Phase and Dose Expansion Phase: 
The ITT population will include all safety population who provide efficacy assessment as follows. 
 
For PTCL patients – efficacy assessment with respect to “Imaging / Scan/Bone Marrow Biopsy (i.e. 
“Bone Marrow Involvement” field in PTCL without measurable but assessable disease)” should be 
available on “RESTAGING” domain of eCRF 
 
For CTCL patients – efficacy assessment with respect to mSWAT score/global response should be 
available on “RESTAGING” domain of eCRF 
This population will be used for efficacy analysis. 
4.1.3 Per Protocol Population  
Dose Escalation Phase and Dose Expansion Phase: 
PP population will include all ITT population without major protocol violations. 
Major protocol deviations related to efficacy assessment and impacting outcomes / endpoints will therefore 
lead to exclusion patient from PP population.  Criteria for exclusion from PP population will be determined 
and documented prior to data base lock. 
This population will be used for efficacy analysis. 
 
 


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4.1.4 Protocol Deviations 
Dose Escalation Phase and Dose Expansion Phase: 
The major protocol deviations are those which may significantly affect the validity/interpretation of efficacy 
endpoints and may require exclusion of data / patient from the respective efficacy analysis. The review of 
all protocol deviations will be performed and the protocol deviations impacting statistical analysis of 
respective endpoint will be evaluated. The decision taken related to Data / Patient exclusion from respective 
analysis will be documented in “Protocol Deviation Listing”. 
Thus, final Protocol Deviation Listing will be used at analysis level to find the analysis populations of different 
endpoints and final Protocol Deviation Listing will be used to summarize major and minor protocol 
deviations. 
The summary of major protocol deviations (PD) will be provided by dose cohort using the safety population. 
Overall summary of Minor PD (all) by dose cohort will be provided using safety population. 
4.2 
Timing of Analysis 
4.2.1 Interim Analysis 
Dose Escalation Phase: 
There is no formal interim analysis planned for this part of the study. However, safety review will be 
performed at the end of each cohort to determine MTD/optimal dose. 
Dose Expansion Phase: 
There is no formal interim analysis planned for this part of the study.  
However, safety review will be performed at every 3 months to understand any safety concerns. 
4.2.2 Final Analysis 
The final analysis is applicable to all  dosed patients in the study (combining Dose Escalation and Expansion 
Phase). Data collected up to end of treatment for all endpoints will be analysed at the time of Final Analysis. 
The final analysis shall be done after the third assessment of last patient has been completed or before in 
case of early discontinuation and as per the predefined cut-off date of “Last patient Last Visit” (i.e. 
10-Dec-2018 when last patient (D8) was moved to compassionate study protocol) used for final database 
lock. The analysis will be started after final database lock is performed. 
4.3 
Methods for Handling Missing Data 
Dose Escalation Phase and Dose Expansion Phase: 
Values obtained at Unscheduled visits prior to administration of first dose of RP6530 (Pre-dose on C1D1) 
will be considered to derive Baseline values.  


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For “Tumor Assessment” response provided by investigator, the values obtained at the unscheduled visits 
Post Dose 1 (Post dose on C1D1) will be considered for analysis and also it will be provided in listings. If 
“PD” response is obtained at unscheduled visit for “Tumor Assessment” data then the result will be 
considered in the analysis. 
4.3.1 Handling Missing Data Not Due to Dropouts 
Dose Escalation Phase and Dose Expansion Phase: 
No imputation will be made for missing values, thus missing data will be treated as missing. 
4.3.2 Handling missing data Due to Dropouts 
The scheduled parameter values, in general, visit-specific evaluations will be taken as nominal visit value 
without any consideration of window days around the cycle days. 
4.3.3 Handling of Screen Failures / Ineligible Patients 
Study patients who are screened but do not meet the eligibility criteria (i.e., screening failures) or any other 
reason(s) for Screen Failure will be entered into a CRF. Screening numbers assigned to Patients who are 
screen failures will not be reused. Listing for Screen Failure patients will be provided with a reason of screen 
failure. 
4.4 
Statistical Analysis  
All statistical analysis relating to the study will be performed using statistical software, SAS version 9.2 or 
higher. The quantitative variables will be summarized using “Summary Statistics” - Number of patients, 
Missing data [n (Missing)], Mean, Standard Deviation, Median, Minimum (Min), Maximum (Max) and 95 % 
Confidence Interval (CI) wherever applicable. The qualitative variables will be summarized as number and 
percentage and if specified 95% CI will be presented. All analyses will be conducted on safety population 
unless stated otherwise.  All data used in summaries will be listed. 
All below sections are applicable to Dose Escaltion and Dose Expansion phases unless specified 
explicitely. 
4.4.1 
Derived Data 
4.4.1.1 
Treatment Start Date 
Treatment start date is the First dosing Date defined as the date when the patient has been confirmed as 
taken the study drug at the clinic/home (even if the patient has not taken the study drug at the clinic, and 
there is evidence of the patient taking at least one dose of the drug). 
For patients who did not take at least one dose of study drug yet randomized i.e. if “Treatment Start Date” 
(Treatment Start date is nothing but Date of Dispensing IMP as per eCRF as first dose is taken at site) field 


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is completely blank i.e. complete date is missing then the treatment start date will not be defined and will 
be kept blank. 
4.5 
Baseline Values 
Baseline value of any parameter other than plasma concentration is defined as the latest non-missing value 
of the parameter prior to administration of first dose of RP6530.   
Unscheduled values prior to administration of first dose of RP6530 (Pre-dose on C1D1) will be considered 
to derive Baseline values.  
If Plasma concentration value is missing for time t=0 (Pre-first dose value) then it will be set to 0. 
4.5.1.1 
Date of Birth 
For Date of Birth, if day and month are missing then the day/month will be imputed as 01/JAN and if only 
day is missing then 01 of that month will be imputed for “Day”. 
Age = [Date of Screening Visit – Date of Birth] / 365.25. The format used for presenting age will be ##.## 
If DOB is completely missing and “Age in years” is available then that Data will be used for analysis. 
4.5.1.2 
End of Study Value 
End of Study value (EOS value) of any parameter is defined as the latest non-missing assessment of the 
parameter post first dose administration of RP6530. Thus, in addition to scheduled visit assessments, early 
termination assessments and unscheduled visit assessments will also be used to derive End of Study value. 
If ‘End of treatment (EOT)’ is performed for any patient, then End of study value is not presented in listing 
however it is used for the analysis in table 
4.5.1.3 
Clinical Laboratory Data 
If a laboratory value for any laboratory parameter is being provided as <x.y (or >x.y), then for analysis 
purpose the numerical value will be imputed as x.y – 0.1 (or x.y + 0.1). 
4.5.2 
Patient Disposition 
The Number and percentage of patients who were screen failures; along with the reason for screen failure 
will be provided. The number and percentage of patients included in the study will be provided. 
A Patient is called a completer if he/she has completed the cycle 8, Day 1 visit, i.e. did not discontinue the 
study treatment prior to cycle 8. The withdrawal/discontinuation of subjects will be summarized along with 
reasons for discontinuation using safety populations. 
The summary of all protocol deviations (major/minor) will be provided using the safety population.  
The number and percentage of patients in each of analysis populations will also be provided using safety 
population. Listing will be provided for analysis population 


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4.5.3 Baseline Characteristics 
The baseline parameters will be the parameters assessed just prior to Cycle 1/ Day 1 dosing (prior to first 
dose intake) of the patient. 
At baseline Demography (age, gender, Race), Vital Signs, Physical Examination, Laboratory Evaluations, 
ECOG performance status, Outcome to last therapy (Relapse or refractory), median prior therapies  
smoking/alcohol status and Medical History will be summarized for safety population. 
4.5.3.1 
Demographics 
For this analysis, Safety population will be used.  
Demographic data will include Age (years), gender, race. The type of variable, and the corresponding 
analysis, is presented in the table below: 
Table 5 Details of Demographic Variables 
Variable 
Type of Variable 
Type of 
Analysis 
Unit of 
Measurements 
Formulae for Derived 
Variable 
Age 
(Derived 
variable) 
Quantitative 
Summary 
Statistics 
Years 
Age = [Date of 
Screening Visit (Day -28 
to Day 0) – Date of Birth] 
/ 365.25 
Format: Numeric field 
##.## 
Gender 
Qualitative 
Frequency and 
Percentage  
Not applicable 
-- 
Race 
Qualitative   
(Asian, 
White/Caucasian, Afro-
American, 
Hawaiian/Pacific 
Islander, Indo-
American) 
Frequency and 
Percentage  
Not applicable 
-- 
Quantitative Variable (Age) will be summarized as n, Mean, Standard Deviation, Median, Max, and Min and 
Qualitative variable (Gender and Race) will summarized as n (%) i.e. frequency and percentage. 
 
4.5.3.2 
Medical History and Concomitant Illness (Pre-existing Conditions) 
Medical History will be those medical events which would have occurred during past and stopped prior to 
dosing of RP6530 i.e. stop date of the condition should be < First dosing Date in the CRF. Pre-existing 
conditions (Concomitant Illness) are those medical events which are ongoing at the time of first dosing date 
with RP6530 i.e. stop date of condition should be ≥ first dosing date in CRF. If the stop date is missing or 
partial such that the stop date of the event could not be determined unambiguously with respect to first 
dosing date, the event will be considered as Pre-existing conditions. 


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Medical history and pre-existing conditions will be coded using the MedDRA dictionary, Version 18.1 or 
higher. The exact version of the dictionary will be mentioned in the footnote of the respective Listing and/or 
Table. Medical history and pre-existing conditions of all the patients will be summarized as n (%), E where 
n = Number of Patients with at least one Medical history/Pre-existing conditions (patients counted once if 
the patient reported one or more Medical history/Pre-existing conditions), % = (n / N) *100 where N=Number 
of patients in the safety Population and E = Count of Medical history/Pre-existing conditions (One patient 
may be counted more than once) by system organ class/preferred term. For this analysis, safety population 
will be used. If Any ‘System Organ Class’ is missing in MedDRA coding then ‘Code Not Available#’ will be 
used and If Preferred Term is missing in MedDRA coding then the same will be replaced by Medical 
Condition/ Surgical Procedure reported by investigator with followed by special character ‘#’. 
4.5.3.3 
Prior Medications/Therapies  
Medications will be coded as per the WHO DDE. Prior Medications will be summarized in one table and will 
be presented using WHO Drug Name (Preferred Term) as the 5th Level Term Chemical Substance, ATC 
Class as 3rd Level ATC and the ATC Class as the 1st Level ATC in the order ATC Level 1 within that ATC 
level 3 and then ATC Level 5. The version of the WHO DDE used will be ‘Version 2016’ or later. The exact 
version will be mentioned in the footnote of the respective Listing and/or Table. If WHO Drug Name 
(Preferred Term) is not coded then the same will be replaced by “Generic Term” and indicated by “#”. If 
‘ATC Level 1’ and ‘ATC Level 3’ is missing in WHO-DDE coding then ‘Code Not Available#’ will be used 
Prior medications will be classified as follows: 
o 
Prior medications stopped prior to First Dose of RP6530 i.e. [stop date of medication] should be < first 
dose date  
Medications that were stopped before the dose of RP6530 are referred to as Prior medications stopped 
before first dose.  
o 
Prior medications ongoing at the time of first dose i.e. Medication Start Date < first dose date </= Stop 
Date 
Medications that were started before the start of study drug and were continuing at the time of first dose of 
study drug i.e. post exposure RP6530 are referred to as Prior medications ongoing at the time of First Dose 
of RP6530. If the stop date is missing or partial such that the stop date of the medication could not be 
determined unambiguously with respect to date of first dose of study dose or if the start date is missing or 
partial and stop date of medication is after the date of first dose of study dose, then the medication will be 
considered as Prior medications ongoing at the time of first Dose of RP6530. 
Cancer Therapies that were given before the start of study drug i.e. cancer therapies prior to first dose of 
study drug are referred to as Prior therapies. Prior therapies will not be coded as per the WHO DDE so will 
be presented by term reported by investigator. 


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Prior medications for each of the above classifications and prior therapies will be summarized as n (%), E 
where n = Number of Patients with at least one Prior Medication/ Prior therapies (patients counted once if 
the patient reported one or more Prior Medication/ Prior therapies), % = (n / N) *100 where N=Number of 
patients in the safety Population and E = Count of Prior Medication / Therapy (One patient may be counted 
more than once) by ATC class and WHO Drug Name (Preferred Term) for prior medication and by therapy 
reported by investigator for prior therapies. For this analysis, safety population will be used. 
4.5.3.4 
ECG 
The abnormalities of ECG, if any, will be collected at Screening visit (Day -28 to Day 0) and cycle1/day1 
visit (before dose). The ECG results will be summarized as Normal/ Abnormal - Not clinically significant / 
Abnormal - clinically significant with frequency (n) and percentage (%) of patients using safety population. 
The last available value before dosing will be considered for analysis. 
Triplicate ECG will be performed for any visit, if 12-lead ECG result is found to be “Abnormal – CS” for 
respective visit. Thus, at analysis level, for each visit, derived “Final ECG Results” will be used for 
summarizing ECG data.  For each patient the “Final ECG Result for any visit” is nothing but the latest ECG 
result available either from 12-lead ECG or from Triplicate ECG for respective visit. The ECG results will 
be summarized as Normal/ Abnormal - Not clinically significant / Abnormal - clinically significant with 
frequency (n) and percentage (%) of patients using safety population. 
4.5.3.5 
Serology 
The Serology assessment (HBV, HCV, and HIV tests) will be performed at screening only. Serology 
response at baseline will be categorised as “Positive” and “Negative”. 
Different Serology tests will be summarized as frequency (n) and percentage (%) using safety population. 
4.5.3.6 
Pregnancy test 
Any pregnant patient who got dosed by mistake will be summarized with protocol violations for violating 
inclusion/exclusion criterion. 
If the patient becomes pregnant during the study then patient will be discontinued from the study. 
4.5.3.7 
Eastern Co-operative Oncology Group Performance Status 
The Eastern Cooperative Oncology Group performance status (ECOG PS) will be assessed at screening 
(Day -28 to 0) and cycle 1/day 1 (before dose) visit. The ECOG PS will be summarized with frequency (n) 
and percentage (%) of different performance scale as mention in below  
 
 
 


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Table 6 using the safety population.  
 
 
 
 
Table 6 Eastern Cooperative Oncology Group performance status 
ECOG 
Performance  
scale 
ECOG Performance Status 
0 
asymptomatic 
1 
symptomatic, fully ambulatory 
2 
symptomatic in bed less than 50% of day 
3 
symptomatic, in bed more than 50% of day but not bedridden 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
Note: If ECOG PS ≥ 2 during screening, then the patient will not be eligible for the study. 
4.5.4 Efficacy Analysis 
4.5.4.1 
Secondary Efficacy Analysis 
The evaluation of secondary efficacy endpoint is imaging-based tumor/skin based assessments by 
investigator in PTCL/CTCL patients treated with RP6530. All baseline imaging-based tumor assessments 
are to be performed on screening (Day -28 to 0) of the study. The disease will be assessed at subsequent 
scheduled visits using CT scan/skin assessment to re-evaluate with respect to this baseline assessment at 
visits Cycle 3/Day 1 (± 3 days), Cycle 5/Day 1 (± 3 days) and End of study treatment. Tumor Assessment 
will be performed thereafter if warranted, at the discretion of investigator. 
The secondary efficacy endpoints are Overall Response Rate (ORR) & Duration of Response (DoR). 
Intent to Treat (ITT) and Per-protocol population (PP) will be used for the secondary efficacy analysis. 
 
Overall Response Rate (ORR) 
ORR is defined as percentage of patients with Complete or Partial Response at any time point during the 
study, as assessed by investigator. 
ORR will be summarized as frequency, percentages along with two-sided 95%, using Clopper-Perason 
Exact method in SAS. 
 
Duration of Response (DoR) for Responders (CR/PR):   
DoR will be derived based on responders (i.e., patients who achieved CR or PR during the study) only in 
the following manner: 


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 
For responders who had PD (or died for any reason), DoR (in days) = (PD Date – First Response Date 
+ 1, where Date of Disease Progression Based on overall response visit date if not available then Date 
of Disease Progression mentioned on end of study CRF or Date of death  and the First Response Date 
is the date when CR or PR was first observed)+1 
 
For the rest responders, the DoR = (Date of visit when last scheduled tumor assessment response was 
provided by investigator which is showing documented CR/PR response irrespective of status of patient 
on “Participants Trial Completion Assessment Page”– Date of visit when tumor assessment response 
was provided by investigator which is showing documented CR/PR response first time) +1 
Duration of Response (DoR) is applicable to patients showing CR or PR and it is defined as time from the 
first documented assessment of CR or PR until the documented tumor disease progression (date of the 
first occurrence of PD as per investigator’s tumor assessment response based on post-treatment CT scan 
performed or Date of Disease Progression mentioned on end of study CRF up to predefined cut-off date. 
The cut-off date is nothing but the last patient last visit date till End of the study i.e. 10-Dec-2018 when last 
patient (D8) was moved to compassionate study protocol. If patient do not show the response CR or PR 
during the study, then the duration of response is considered as 0. For patients who complete the study 
and CR / PR response if still continues or if patient is discontinued due to any reason then DoR will be 
calculated using the date of visit when last scheduled tumor assessment response was provided by 
investigator which is showing documented CR/PR response (objective evidence of response). Duration of 
response will be calculated in days as follows: 
DoR for Responders (Days) = Min [Date of Disease Progression Based on overall response visit date if not 
available then Date of Disease Progression mentioned on end of study CRF] or (If Disease Progression is 
not observed then Date of visit when last scheduled tumor assessment response was provided by 
investigator which is showing documented CR/PR response irrespective of status of patient on “Participants 
Trial Completion Assessment Page”) – Date of visit when tumor assessment response was provided by 
investigator which is showing documented CR/PR response first time +1 
DoR (days) will be summarized descriptively as Minimum, Maximum and Median along with 95% CI for 
median. For calculating confidence interval for median normality is not assumed and distribution-free 95% 
confidence intervals for median will be calculated using following code in SAS: 
Title 'Analysis of Duration of Response (DoR)'; 
ods select Quantiles; 
proc univariate data=<<Dataset Name>> ciquantdf (alpha=0.05); 
   var <<Variable Name e.g. DoR>>; 
run; 
In PTCL & CTCL patients, disease will be assessed using imaging assessments at Screening and at 
subsequent scheduled visits it will be assessed with respect to this baseline assessment using imaging 
assessments at C3D1 (± 3 days) and C5D1 (± 3 days) and at the End of Treatment (EOT). Assessment 
will be performed thereafter if warranted, at the discretion of investigator. 


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For PTCL patients, imaging assessments based tumor response provided by investigator in “Response” 
field of eCRF module “Restaging for PTCL patient” will be considered for the analysis of ORR and DoR. 
For CTCL patients, tumor response provided by investigator in “Global Response” field of eCRF module 
“Restaging for CTCL patient” (which takes into account of skin response + nodal response + visceral 
response and blood response) will be considered for the analysis of ORR and DoR. 
Exploratory analysis of DoR for Responders (CR/PR) will also be performed considering Time of 
Duration till Discontinuation:-  
The calculation of DoR will remain same as above except for discontinued patients if documented tumor 
disease progression is not recorded after achieving the response (CR or PR) then for those patients the 
duration of response will be from the first assessment of CR or PR until the date of discontinuation. 
The formula used to calculate for DoR is modified as follows: 
DoR for Responders (CR/PR) [Days] = DoR for Responders (CR/PR) (Days) till Discontinuation = Min [Date 
of Disease Progression Based on overall response visit date if not available then Date of Disease 
Progression mentioned on end of study CRF] or (If patient discontinued without observing Disease 
Progression then Date of Discontinuation) or (If Date of Discontinuation is not available then Date of visit 
when last scheduled tumor assessment response was provided by investigator which is showing 
documented CR/PR response)– Date of visit when tumor assessment response was provided by 
investigator which is showing documented CR/PR response first time +1 
 
Other Secondary Endpoints  
In addition to ORR, the following analysis will also be performed. The percentage of subjects along with 
95% CI will be calculated using each scheduled tumor assessment time point responses provided by 
investigator along with Best Overall Response (BOR). BOR (Derived Variable – Derived once from 
Screening to EOT) is derived from all time point responses available up to EOT. The following hierarchy 
will be followed to derive BOR from all available time point tumor responses  
 
Complete response (CR),  
 
Partial Response (PR) 
 
Stable Disease (SD) 
 
Progression of Disease (PD), 
 
Not Evaluable 
 
Not Assessed 
All Listings related to Radiological Evaluations, Disease Evaluations, Morphology & Cytogenetic 
Evaluations, Disease Assessment for CTCL and PTCL Patients and Staging of PTCL and CTCL patients 
will be provided with respect to PTCL and CTCL patients wherever Applicable. 
In Disease Assessment of CTCL patient for skin mSWAT, Total Score will be calculated of Patch, Plaque 
and Tumor at analysis level for all body region by doing summation of  “Subtotal lesion BSA × Weighting 


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Factor” of Patch, Plaque and Tumor at each visit. Also Total of “Degree/Size of Index lesion 1-5” will be 
calculated at analysis Level. 
In Disease Assessment of CTCL patient for Radiological assessment of Lymph node, Total sum of Products 
of Measurements will be calculated at analysis level for all Tissue site by doing summation of “Products of 
measurements” of all Tissue site at each visit. 
In Disease Assessment of PTCL patient for dominant nodes and non-dominant nodes, Total sum of 
Products of Measurements will be calculated at analysis level for all Tissue site by doing summation of 
“Products of measurements” of all Tissue site at each visit. 
All Efficacy Listings will be presented for Safety Population and Tables will be presented for both FA and 
PP Population. 
Swimmer Plot and Water Fall Plot will be plotted for each efficacy evaluable patients using ITT population. 
For swimmer plot, treatment duration will be considered on x-axis and patient with Dose cohort on X-axis. 
Bar color will be presented with best tumor response. Following three parameters will be displayed in the 
swimmer plot. 
1. First Tumor response 
2. First CR/PR Response 
3. Continuation of treatment 
 
Water fall plot will be plotted for each evaluable patients using ITT population considering patient number 
on X-axis and % change from baseline on Y-axis. Bar colour will represent the Best response in the study. 
For % change from Nadir result, if value is captured with any special character then that special character 
will be removed and converted the result into numeric format and that numeric result will be used for the 
plotting of graph. Following points will be taken into consideration while plotting the Water Fall plot. 
1. For any patient, if BOR is present at only one visit then respective change from Nadir value is 
considered as change from baseline on Y-axis. If BOR is present for more than one visit then maximum 
value of % change from nadir will be used by ignoring the sign i.e. Minimum if the value is negative or 
maximum if the value is positive to select the respective change from Nadir value as change from 
baseline on Y-axis. 
2. For PTCL patient with “non-measurable lesion but assessable disease”, if “% change from Nadir” is 
blank and patient has “CR” response throughout the study then check the “Disease assessment” module 
of eCRF. In “Disease assessment” module, if “Bone Marrow Involvement” is marked as “No” then that 
patient will be presented in the graph followed by “#” and footnote will be added as “#Patient has “CR” 
response as positive bone marrow became negative”  
3. For any patient, if numeric variable of “% change from Nadir” is blank and in the character variable if 
the text is present as “This PD due to new lesion” and patient has “PD” response in the study then it will 
be considered as “Progression Disease” due to new lesion. This patient will be presented as “% change 


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from nadir” value 25% with patient number followed by “*”in the graph and footnote will be added as 
“*Patient has new lesion so % change from Nadir value is imputed with 25%.”  
4. For any patient, if character and numeric variable of “% change from Nadir” is blank and patient has 
“PD” response in the study then it will considered as “Progression Disease” as per the clinical judgement 
of investigator (Clinical progression). This patient will be presented as “% change from nadir” value 25% 
with patient number followed by “**”in the graph and footnote will be added as “**Patient has “clinical 
progression” so % change from Nadir value is imputed with 25%.” 
4.5.4.2 
Safety Analysis 
4.5.4.3 
Primary Safety Analysis 
Maximum Tolerated Dose (MTD): 
Patients who experienced DLT at 200 mg BID, at 400 md BID, at 800 mg BID will be presented with 
frequency and percentage against respective dose level. 
The Primary endpoints are based on Safety and Dose limiting Toxicities (DLT) of RP6530. 
Primary safety endpoint will be assessed as 
1. Number and percentage of patients reporting at least one Adverse Event (AE) during the study. 
2. Number and percentage of patients reporting at least one Serious Adverse Event (SAE) during the 
study. 
3. Number and percentage of patients reporting at least one grade 3 and grade 4 AE during the study. 
4. Number and percentage of patients reporting at least one drug related AE during the study. 
5. Number and percentage of patients reporting at least one clinically significant (CS) AE due to 
abnormal CS result as per investigator discretion for laboratory, Electrocardiogram (ECG) or vital 
signs during the study. 
The above safety endpoints will be summarized by dose cohort. Adverse Events (AEs) will be assessed at 
each scheduled day of each cycle i.e. AEs will be assessed from screening to till end of the treatment 
assessment. 
6. Number and percentage of patients who experienced at least one Dose Limiting toxicity (DLT) 
during the usage of RP6530 study treatment. The analysis will be summarized by dose cohort. 
For filtering of DLT data, the field on AE page “Reported as DLT” will be used. If this field is ticked 
then that patient is considered as “DLT” for that event.  
4.5.4.4 
Secondary Safety Analysis 
Not Applicable 


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4.5.4.5 
Adverse Events (AEs) 
Assessment of AE (Includes Serious Adverse Events, DLTs): 
An adverse event is any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or medical condition occurring after signing of the consent form i.e. Day -28 to 0, even if the event 
is not considered to be causally related to investigational products.  An AE can therefore be any unfavorable 
and unintended sign (including a new, clinically important abnormal laboratory finding), symptom, or 
disease, temporally associated with drug administration, whether or not related to the product. 
Adverse Events (AEs) will be coded using MedDRA, Version 18.1 or higher.  
All AEs including DLTs, regardless of seriousness or relationship to RP6530 (study drug), spanning from 
the first dose of study drug until 30 calendar days after the last dose of study drug, discontinuation or 
completion of protocol-specific treatment as defined in the protocol for that patient, are to be recorded in 
the CRF 
After 30 days of completion of protocol-specific treatment or discontinuation, only AEs, SAEs, or Deaths 
assessed by the investigator as treatment related are to be reported. 
DLTs will not be presented separately for Dose expansion Phase of the study and will be treated as AEs. 
DLT Assessment:   
DLT assessment is applicable only for Dose Escalation Phase. For Dose Expansion phase it will not be 
analyzed separately and will be part of AEs.  
DLT will be assessed according to the National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE) v4.0 (http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE). 
All toxicities should be considered to be related to RP6530 unless there is a clear alternative explanation. 
A toxicity is considered dose-limiting if it occurs during the first cycle (4 weeks) of treatment with RP6530 
and is considered related to RP6530. DLT is be defined as the following: 
A. Hematological DLTs: 
 
Grade 4 Anaemia 
 
Grade 4 neutropenia (absolute neutrophil count [ANC] <500/μL) for >7 days, or Grade ≥3 febrile 
neutropenia (ANC <1000/μL with fever >38.5ºC [101ºF] 
 
Grade 4 thrombocytopenia for >7 days, or grade ≥3 thrombocytopenia associated with Grade >2 
bleeding 
B. Non-Hematological DLTs: 
 
Grade ≥3 non-hematologic toxicity with exception of: 
o 
Grade ≥3 diarrhea or nausea that does not resolve to ≤ Grade 2 within 48 hours despite 
treatment; and 


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o 
If ≥1.5 ULN of bilirubin or >3 ALT/AST elevation that does not resolve to ≤ Grade 1 within 
7 days 
 
Treatment delay of ≥14 days due to unresolved toxicity 
 
Non-hematologic toxicity of Grade 2 (at any time during treatment) that in the judgment of the DRG, 
is dose-limiting. 
 
For certain toxicities such as laboratory assessments without a clear clinical correlate (e.g. lipase 
increase without signs of a clinical pancreatitis) a discussion between the Investigator and Medical 
Monitor may take place if this adverse event (AE) should be assessed as DLT necessitating dose 
reduction.  
Table for “DLT Assessment and Discontinued due to DLT” will be summarized using frequency and 
percentage. Following filtration rule will be followed for DLT assessment: 
1. DLT assessment will be applicable for Dose escalation cohorts.  
2. Cohort of Dose for the study group will be decided based on first dose received by patients at Cycle 1 
Day 1 visit (i.e. Dose details captured under “Trial Medication Dispensing” Domain of CRF) 
 
3. DLT evaluable population will be calculated based on following algorithm During Cycle 1 of treatment.  
 
Patient receives at least 80% of planned doses of RP6530 doses OR received RP6530 for the first 
21-days continuously; Following formula will be used to derive the number of days patient received 
the study drug 
Number of days patient received study drug =  (Date of EOT visit performed  if not available then 
Date of Withdrawal on EOT page in “PARTICIPANTS TRIAL COMPLETION ASSESSMENT” 
domain - Date of first Dose Dispense at cycle 1/Day 1) +1. 
For any patient if overall treatment duration is less than or equal to 22 days and overall compliance 
is less than 100% then that patient will not be considered for DLT assessment. 
AND 
 
Patient completes all required safety evaluations (at least for three visits after the first dose);    
 
Patients who experience a DLT will be considered evaluable regardless of the number of doses 
received. 
 
Patient with DLT and “Discontinued due to DLT” will be calculated based on following algorithm. 2. The 
patient will be assessed for “Adverse Event” occurrence in all visit using field “DLT assessment” will be 
filtered from AE page of CRF as follows:. 
For any patient, if “Reported as DLT” is marked as “Yes”, then that patient will be considered to have 
as “DLT”. 


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For any patient, if “Reported as DLT” is marked as “Yes” and “Dropped due to this AE?” is marked as 
“Yes”, then that patient will be considered as “Discontinued due to DLT”. 
Summary of AEs 
Adverse Events (AEs) will be coded using MedDRA, Version18.1 or higher. The version of the dictionary 
will be mentioned in the footnote of the respective Listing and/or Table. All AEs will be classified on the 
basis of Preferred Term and System Organ Class (SOC).  AE summaries will include SAEs. 
All safety analysis will be summarized over time. Listings for all the AEs and SAEs will be provided for each 
patient. Any AE will be summarized as n (%), E.  
Where,  
        n is the number of patients who experienced that particular AE  
       % Percentages w.r.t. number of patients who experienced event within particular category 
        E Number of times that particular AE experienced by patients.  
An overall summary of number of Patients within each of the categories described in the sub-section 
mentioned below will be provided. If Any ‘System Organ Class’ is missing in MedDRA coding then ‘Code 
Not Available#’ will be used and If Preferred Term is missing in MedDRA coding then the same will be 
replaced by AE term reported by investigator with followed by special character ‘#’. 
Analysis: 
Listings of TEAEs and Non-TEAEs will be provided 
The TEAEs will be summarized by each of the dose cohort (200 mg BID- Fasting, 400 mg BID- Fasting,  
800 mg BID- Fasting, 800 mg BID- After Food) as follows:  
 
Number and percentage of patients along with total number of events experiencing at least one TEAE 
will be tabulated by dose cohort. 
 
Number and percentage of patients along with total number of events experiencing treatment-emergent 
AEs by SOC and preferred term will be tabulated by dose cohort. 
 
Number and percentage of patients experiencing treatment-emergent AEs by preferred term (ignoring 
SOC) along with total number of events will be tabulated by dose cohort. 
 
Number and percentage of patients along with total number of events experiencing treatment-
emergent AEs within specific SOC/Preferred term by intensity (maximum intensity will be captured in 
the CRF) and separately by outcome, will be tabulated by dose cohort 
o 
Intensity Grade  
 
1 = Mild 
 
2 = Moderate 
 
3 = Severe 
 
4 = Life threatening 
 
5 = Death  
o 
Outcome  


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 
1 = Resolved 
 
2 = Resolving 
 
3 = Not Resolved 
 
4 = Resolved with Sequelae  
 
5 = Fatal 
 
6= Unknown 
 
Number and percentage of patients along with total number of events experiencing discontinuations 
due to treatment-emergent AEs will be tabulated by dose cohort. For filtering data related to 
discontinuations due to AE, the field on AE page “Dropped due to this AE?” will be used. If this field is 
ticked for “Yes” then the patient will be considered as discontinued due to AE. 
Number and percentage of patients along with total number of events experiencing drug-related treatment-
emergent AEs (assessed as Attribution =”Related”) will be tabulated by dose cohort. For filtering drug 
related AE data, the field on AE page “Attribution” will be used. If this field is ticked as “Related” and AE is 
Treatment Emergent AE then the respective AE will be considered as “Drug Related AE”. 
4.5.4.6 
Deaths, Serious Adverse Events and Significant Adverse Events 
Dose Escalation Phase and Dose Expansion Phase: 
Serious adverse events (SAEs) are those events recorded as “Serious” on the Adverse Events page of the 
(e)CRF. A summary of serious TEAEs by SOC and PT will be prepared. 
SAEs will be classified as Serious Treatment Emergent Adverse Events (TEAEs) and Serious Non-
Treatment Emergent Adverse Events (Non-TEAEs). 
For Serious Non-TEAEs only Overview Table will be presented. Separate Listings will also be provided for 
Serious Non-TEAEs. 
A summary of serious TEAEs will be analyzed by dose cohort, same as mentioned in section 4.5.5.3 
“Adverse Events (AEs)”. 
TEAEs leading to Death are those events whose outcome are recorded as “Fatal” on the Adverse Events 
page of the (e)CRF. A summary of TEAEs leading to death by SOC and PT will be prepared. 
4.5.4.7 
Significant Events of Special Interest 
The Events like pregnancy, Abortion, birth defects, and congenital anomalies are the events of special 
interest and will be analyzed separately as Significant Events of special interest. 
For filtering data related to Pregnancy, the study conclusion page will be used. If the reason for 
discontinuation in the study conclusion page is marked as “Pregnancy” then such patients will considered 
as having events of special Interest. 
For filtering data related to birth defects, and congenital abnormalities, if the SAE Criteria is marked as  
The analysis of these events will also be presented separately. These events will be summarized with 
frequency (total number of events) and percentage (Subjects who experienced only one event). 


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4.5.4.8 
Vital Signs  
Assessment: 
The Vital Signs parameters will be assessed at all scheduled visit from screening (Day -28 to Day 0) to End 
of study treatment in both part of study. Vital signs measurement will consist of the following assessments: 
 
Systolic Blood Pressure (mm of Hg) 
 
Diastolic Blood Pressure (mm of Hg) 
 
Pulse Rate (beats/ minute) 
 
Respiratory rate (breaths/ minute) 
 
Weight (kg) 
 
Height (m) only at screening 
 
Oral temperature (ºC) 
For other subsequent visits (except screening) all parameters will be recorded except Height. 
Findings Related to Vital Sign:  
All CS findings at screening or at cycle 1 day 1 (before dose) will be recorded as medical history or 
concomitant illness. Out of Normal range values of vital sign parameter will be flagged as Abnormal – CS, 
Abnormal – NCS. If this concomitant illness worsens during the study period after start of the treatment 
then it will be captured as AE. All CS findings in vital signs identified post screening will be captured as AE. 
Analysis: 
The quantitative Analysis of Vital Sign will be not be presented. Only shift analysis of qualitative results of 
vital sign will be presented. 
Out of range values of Vital Signs will be flagged as Abnormal - CS, and Abnormal - NCS in data listings.  
The number and percentage of patients who shift from abnormal or normal value at baseline to normal or 
abnormal at each post baseline visit will be summarized for each vital sign parameters. The abnormal 
values will be further classified as Abnormal – CS and Abnormal - NCS in shift table.  
The Reference Ranges considered for vital signs are as follows: 
 
Oral Temperature: 33.2-38.2 degree Celsius (both inclusive) 
 
Pulse rate: : 60 to 100 beats per minute (both inclusive) 
 
Respiratory rate: 12 to 18 breaths per minute (both inclusive) 
 
Blood Pressure (Systolic): 90 mm Hg ≤ Systolic BP ≤ 119 mm Hg 
 
Blood Pressure (Diastolic): 60 mm Hg ≤ Diastolic BP ≤ 79 mm Hg 
 
Weight: 35 kg to 92 kg (both inclusive) 


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Listing of abnormal values (CS/NCS) for vital sign parameters will be provided for patients for whom 
abnormal vital sign values are observed for that visit, for any vital sign parameter. 
Shift table for Vital Sign will be provided for each post baseline visit and EOS value w.r.t baseline visit. 
The shift analysis results will be presented as Normal, Abnormal- Clinically Significant (Abnormal – CS), 
Abnormal – Not Clinically Significant (Abnormal – NCS) and Not Done. Percentages will be calculated w.r.t. 
number of patients included in Safety population for each dose cohort. 
4.5.4.9 
Physical Examinations 
Assessment: 
Physical Examination will be performed at Screening Visit (Day -28 to Day 0) and all scheduled day of each 
cycle (Cycle 1 to Cycle 8). 
Physical examination will include lymph node and systemic examination. 
Physical Examination include General Appearance, Skin, Eyes, Ears, Nose & Throat , Head, Neck & 
Thyroid, Heart, Lungs, Chest, Abdomen, Extremities, Genitalia, Anorectal, Lymph Nodes, Muscular-
Skeletal, Neurological and Others.  
Findings Related to Physical Examination:  
Abnormal findings at screening or at cycle 1 day 1 (before dose) in physical examinations will be flagged 
as Clinically Significant (CS)/Not Clinically Significant (NCS) in data listings. All CS findings in physical 
examination at screening or at cycle 1 day 1 (before dose) are included as medical history or concomitant 
illness. If this concomitant illness worsens during the study period after start of the treatment then it will be 
captured as AE. All CS findings in physical examination identified post screening will be captured as AE. 
Analysis: 
Physical examination results will not be summarized visit wise. Patient wise listing of physical examination 
data (all visits) will be provided. 
Assessment of Physical Examination will include: 
1. General Appearance 
2. Skin 
3. Eyes, Ears, Nose & Throat 
4. Head, Neck & Thyroid 
5. Heart  
6. Lungs  
7. Chest (including Breast) 
8. Abdomen 
9. Extremities 
10. Genitalia 
11. Anorectal 


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12. Lymph Nodes 
13. Muscular-Skeletal 
14. Neurological 
15. Others 
Shift table for Physical Examination will be provided for each post baseline visits and EOS value w.r.t 
baseline visit. For Other Physical Examination Shift Table will not be provided 
The shift analysis results will be presented as Normal, Abnormal- Clinically Significant (Abnormal – CS), 
Abnormal – Not Clinically Significant (Abnormal – NCS) and Not Done. Percentages will be calculated w.r.t. 
number of patients included in Safety population for each dose cohort.  
Listing of abnormal values (CS/NCS) for Physical examination parameters will be provided for patients for 
whom abnormal physical examination results are observed for that visit, for any physical examination. 
4.5.4.10 
Clinical Laboratory Evaluation 
Assessments: 
Clinical laboratory tests constitute the assessments related to local laboratories. 
 
Haematology: 
o 
WBC 
o 
RBC 
o 
Hb 
o 
PT/INR 
o 
HCT 
o 
MCV 
o 
PLT 
o 
Neutrophils 
o 
Lymphocytes 
o 
Monocytes 
o 
Eosinophils 
o 
Basophils 
o 
Reticulocytes 
 
Biochemistry Panel I: 
o 
Total Bilirubin 
o 
ALK PHOS (ALP) 
o 
ALT 
o 
AST 
o 
Gamma-Glutamyl Transpeptidase (GGT) 
o 
LDH 
 
Biochemistry Panel II: 
o 
Glucose 
o 
HbA1C 
o 
BUN 
o 
Creatinine 


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o 
Albumin 
o 
Total Globulin 
o 
Total Protein 
o 
Total Cholesterol 
o 
Triglycerides 
o 
LDL 
o 
HDL 
o 
TSH 
o 
T3 
o 
T4 
 
Urinalysis: Physical parameter- 
o 
Appearance 
 
Urinalysis: Laboratory parameter- 
o 
Nitrate 
o 
Sodium 
o 
Potassium 
o 
Calcium 
o 
Phosphate 
o 
Protein 
o 
RBC 
o 
WBC 
o 
Casts 
o 
Glucose 
o 
Ketone bodies 
o 
Bilirubin 
o 
Urobilinogen 
o 
Creatinine 
o 
Specific Gravity 
o 
pH 
 
Serum Electrolytes: Laboratory parameter- 
o 
Bicarbonate 
o 
Sodium 
o 
Potassium 
o 
Calcium 
o 
Chloride 
o 
Magnesium 
o 
Phosphorous 
 
The laboratory tests included in the hematology and Chemistry panel I will be performed at screening visit 
and all scheduled day of each cycle. Any other laboratory assessment which is not defined in the protocol, 
will be done as required based on investigator’s discretion but these other laboratory assessments will not 
be analyzed and will be provided in listing. 


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Hematology panel includes Hemoglobin, complete blood count, reticulocyte count, total leucocyte, 
differential count and platelet count. 
Chemistry Panel I includes Total bilirubin, ALP, AST, ALT, GGT, LDH and Serum electrolytes (Sodium, 
Potassium, Bicarbonate, Chloride, Magnesium, Phosphorus and Calcium) 
Chemistry Panel II includes blood glucose, urea or blood urea nitrogen, creatinine, albumin, globulin, total 
protein, Total Cholesterol, TG, LDL and HDL, TSH, T3 and T4 and HbA1c. Total protein and albumin tests 
will be performed; and globulin will be calculated by deducting value of albumin from total protein. 
Haemetology, Chemistry Panel I, Chemistry Panel II t will be performed at screening visit and Day 1 of each 
cycle. For Dose Escalation Phase these tests additionally will be performed at Day 15 of cycle 1, 
Urinalysis will be performed on screening, Day 1 of each cycle.  
PT/INR will be performed on screening as well as on Day 1 of Cycle 1 to Cycle 4 and at the end of the 
treatment. For Dose Escalation Phase this test additionally will be performed at Day 15 of cycle 1, 
All Serology test (HIV, HBV, HCV) will be performed on screening visit only. 
Pregnancy test will be performed for women of child bearing potential. Serum Pregnancy test will be 
performed on screening / baseline and urine pregnancy test will be performed for all scheduled day of each 
cycle as indicated. 
Findings Related to Laboratory Abnormalities:  
Abnormal results for any of the laboratory evaluations at screening visit or at Cycle 1/Day 1 before dose 
and if clinically significant in the judgment of the investigator are to be reported as medical history or 
concomitant illness. Worsening of Pre-existing conditions from screening visit/ Visit 1(Day 0), if felt to be 
clinically significant in the judgment of the investigator, are to be recorded as AEs or SAEs. 
If Laboratory results are normal at screening visit/ Visit 1(Day 0) but abnormal and clinically significant at 
subsequent visits then it will be reported as an AE. 
Analysis: 
Laboratory parameters will be assessed at different applicable scheduled days of respective cycles as 
mentioned in visit scheduled chart in Table 3 for escalation phase and visit scheduled chart in Table 4 for 
expansion phase 
Laboratory parameter Total Globulin value will be calculated using the following formula and this calculated 
value of Total Globulin will be used for the statistical analysis. 
Total Globulin = Total Protein – Albumin 
The quantitative results of Laboratory variables (Hematology, Biochemistry Panel I, and Biochemistry 
Panel II) will not be analyzed.  
The Laboratory tests are performed in local laboratories so all laboratory results will be converted in SI unit 
and then SI converted value will be presented in listing. The clinical laboratory assessments will be analysed 


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using Observed Case approach for missing values i.e. missing data will be treated as missing. If a laboratory 
value has been provided as <x.y (or >x.y), the numerical value will be imputed as per section 4.5.1.3. For 
this analysis, Safety population will be used. 
Laboratory results, will be flagged as Normal, Abnormal- Clinically Significant (Abnormal – CS), Abnormal 
– Not Clinically Significant (Abnormal – NCS) as per the significance reported by investigator in eCRF, for 
abnormal laboratory values and presented in laboratory listing 
Moreover Abnormal laboratory values for Laboratory tests for whom CTCAE Grading are provided in 
CTCAE, Version 4.03, at each time point will also be classified in CTCAE Grade as “Grade 1”, “Grade 2”, 
“Grade 3”, “Grade 4” and “Grade 5”. If abnormal values cannot be graded as per CTCAE, Version 4.03 
grading then will be presented as “Cannot be graded”.  
The Flag “High” or “Low” will not be derived using normal reference ranges for urinalysis. The investigator’s 
reported qualitative results will be used directly for the analysis. 
Shift table for Laboratory test will be provided for each post baseline visits and EOS value w.r.t baseline 
visit. 
The shift analysis results will be presented as Normal, Abnormal- Clinically Significant (Abnormal – CS), 
Abnormal – Not Clinically Significant (Abnormal – NCS) and Not Done. Percentages will be calculated w.r.t. 
number of patients included in Safety population for each dose cohort. 
Clinically significant abnormal laboratory findings or other abnormal assessments that are detected during 
the study or are present at Screening and significantly worsen following the start of the study will be reported 
as AEs or SAEs. However, clinically significant abnormal laboratory findings or other abnormal 
assessments that are associated with the disease being studied, unless judged by the Investigator as more 
severe than expected for the patient’s condition, or that are present or detected at the start of the study and 
do not worsen, will not be reported as AEs or SAEs. The severity of this AE provided by investigator may 
not match with calculated CTCAE grading calculated at analysis level as investigator will assess value 
taking into consideration baseline laboratory values and his overall clinical judgement. 
The additional laboratory test will be presented in listings only it will not be analyzed in the table. 
Listing of abnormal values (CS/NCS) for laboratory parameters will be provided for patients for whom 
abnormal laboratory results are observed for that visit for any laboratory parameters.  
4.5.4.11 
Concomitant Medications 
Assessment: 
Medications/Therapies that were started on or after the treatment start date (Cycle 1, Day 1 Date) will be 
referred to as Concomitant Medications. If above conditions cannot be determined unambiguously, the 
medication/therapy will be considered Concomitant Medication.   


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Concomitant medications will be coded as per WHO DDE. The version of the WHO DDE used will be 
‘Version 2016’ or higher. The exact version will be mentioned in the footnote of the respective Listing and/or 
Table. 
Analysis: 
Concomitant Medication will be summarized using WHO Drug Name (Preferred Term) as the 5th Level Term 
Chemical Substance (ATC Level 5), ATC class as 3rd level ATC and Anatomical Therapeutic Chemical 
(ATC) Class as 1st Level ATC in the order ATC Level 1 within that ATC level 3 and then ATC Level 5.  If 
ATC Level 5 is missing in coded list then generic term as reported by investigator will be used and indicated 
by “#”.If Any ‘ATC Level 1’ and ‘ATC Level 3’ is missing in WHO-DDE coding then ‘Code Not Available#’ 
will be used 
Concomitant medications will be summarized as Number and percentage of patients classified as per 
Anatomical Therapeutic Chemical (ATC) Class 1st, ATC Class 3rd and WHO Drug Name (Preferred Term – 
5th level chemical substance term). Details of each medication such as, dose, frequency, route, etc. will be 
included in the data listing and will not be summarized. 
4.5.4.12 
Electrocardiograms (ECG) 
Assessment:-  
A standard Electrocardiogram (12 or 3 leads ECG) will be performed at screening and all scheduled day of 
cycle 1 i.e. Day 1, Day 8, Day 15, Day 22 and Day 1 of Cycle 2. 
For Dose Escalation Phase, a single ECG will be performed at screening and C1D1 pre-dose. Post-dose 
ECGs will be performed in conjunction with the 1 hr, 2hr and 4hr post-dose PK collection on C1D1; and on 
C1D8 (pre-dose), C1D15 (pre-dose), and C1D22 (pre-dose). On C2D1, ECGs will be obtained pre-dose 
and then one hour post-dose coinciding with the PD collection.  
For Dose Expansion Phase, a single ECG will be performed at screening, C1D1 pre-dose and C2D1 pre-
dose and one hour post-dose. 
Additional ECGs will be obtained if clinically indicated. Triplicate ECGs will be performed to confirm the 
significant changes of single ECG. All ECGs will be performed on local equipment. 
An overall evaluation will be done by the investigator. All ECGs must be evaluated by a qualified physician 
for the presence of abnormalities. Only clinically significant abnormalities will be reported as AEs after 
inclusion visit. 
Analysis: 
Final ECG results which will be derived from 12-lead ECG and Triplicate ECG results. 12-lead ECG and 
Triplicate ECG results will be captured as “Normal”, “Abnormal – CS” and “Abnormal – NCS”. These results 
will be used to derive Final ECG results as follows: 


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For any visit while deriving Final ECG results at analysis level, the 12-lead ECG result will be considered 
first.  
1. If 12-lead ECG result is “Normal” or “Abnormal – NCS” then final ECG results will remain same as 12-
lead ECG result.  
2. If 12-lead ECG result is “Abnormal – CS” then Triplicate ECG result will be checked as follows:  
a. If Triplicate ECG result is present for respective visit (Triplicate ECG performed) then final ECG 
results will be considered as results of Triplicate ECG for that visit. 
b. If Triplicate ECG result is not present for respective visit (Triplicate ECG not performed) then final 
ECG results will remain same as 12-lead ECG result for that visit. 
Final ECG results will be derived for each visit. However, Final ECG results will not be summarized visit 
wise. Patient wise listing of ECG data (all visits) will be provided. Shift table for ECG will be provided for 
each post baseline visits and EOS value w.r.t baseline visit. 
The shift analysis results will be presented as Normal, Abnormal- Clinically Significant (Abnormal – CS), 
Abnormal – Not Clinically Significant (Abnormal – NCS) and Not Done. Percentages will be calculated w.r.t. 
number of patients included in Safety population for each dose cohort.  
4.5.5 Pharmacokinetics and Pharmacodynamic Analysis 
4.5.5.1 
Pharmacokinetics Parameters 
The statistical analysis of PK will be performed by clinical pharmacology CRO contracted by the Sponsor 
and PK report will be provided by sponsor. Therefore, PK analysis is not applicable for this SAP. 
4.5.5.2 
Pharmacodynamics Parameters 
The statistical analysis of PD will be performed by clinical pharmacology CRO contracted by the Sponsor 
and PD report will be provided by sponsor. Therefore, PD analysis is not applicable for this SAP. 
5. 
Evaluation of Treatment Compliance and Exposure 
5.1 
Compliance to Study Drug 
Compliance to study treatment will be ascertained by total planned dose of RP6530 dispensed at each 
cycle i/Day j and total dose consumed at that particular cycle i/Day j.  
Listing of Treatment compliance will be provided along with planned dose and actual dose administered to 
each patient as <80%, 80%-100%, 100%-120% and >120%. Compliance to Treatment for the Study will be 
summarized based on following compliance categories: <80%, 80%-100%, 100%-120% and >120%. 
Compliance category at each cycle will be derived based on compliance calculation at each cycle. 
Calculation of Exposure of treatment / Compliance at any cycle will be calculated based on different 
following scenario, 


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Details of 
Tablet 
Return in 
next visit 
No. of 
tablets 
returned 
No. of tablets 
neither 
returned nor 
consumed 
Patient 
Compliance 
with study in 
next visit 
when Drug is 
dispensed 
Drug 
Exposure 
Calculation 
Compliance 
will be 
derived 
based on 
formula 
Compliance 
Category  
Data 
captured 
completely 
Data Present 
Data Present 
Yes 
Calculated 
using the 
formula  
Calculated 
using the 
formula  
Compliance Category 
will be derived based 
on calculated 
compliance 
Data 
captured 
completely 
Data Present 
Data Present 
No 
Calculated 
using the 
formula  
Calculated 
using the 
formula  
Compliance Category 
will be derived based 
on calculated 
compliance 
Data 
captured 
completely 
Data Present 
Data Present 
Data missing 
Calculated 
using the 
formula  
Calculated 
using the 
formula  
Compliance Category 
will be derived based 
on calculated 
compliance 
Data 
Missing 
Partially 
Data Present 
Data Not 
Present (Will be 
imputed as 0) 
Yes 
Calculated 
using the 
formula  
Calculated 
using the 
formula  
Compliance Category 
will be derived based 
on calculated 
compliance 
Data 
Missing 
Partially 
Data Present 
Data Not 
Present (Will be 
imputed as 0) 
No 
Calculated 
using the 
formula  
Calculated 
using the 
formula  
Compliance Category 
will be derived based 
on calculated 
compliance 
Data 
Missing 
Partially 
Data Present 
Data Not 
Present (Will be 
imputed as 0) 
Data missing 
Calculated 
using the 
formula  
Calculated 
using the 
formula  
Compliance Category 
will be derived based 
on calculated 
compliance 
Data 
Missing 
Partially 
Data Not 
Present (Will 
be imputed 
as 0) 
Data Present  
Yes 
Calculated 
using the 
formula  
Calculated 
using the 
formula  
Compliance Category 
will be derived based 
on calculated 
compliance 
Data 
Missing 
Partially  
Data Not 
Present (Will 
be imputed 
as 0) 
Data Present  
No 
Calculated 
using the 
formula  
Calculated 
using the 
formula  
Compliance Category 
will be derived based 
on calculated 
compliance 
Data 
Missing 
Partially  
Data Not 
Present (Will 
be imputed 
as 0) 
Data Present  
Data missing 
Calculated 
using the 
formula  
Calculated 
using the 
formula  
Compliance Category 
will be derived based 
on calculated 
compliance 
Data 
Missing 
Completely 
Data Not 
Present 
(Will not be 
imputed) 
Data Not 
Present 
(Will not be 
imputed) 
Yes 
Calculated 
using the 
formula  
Not 
calculated 
Compliance Category 
will be considered as 
“>=80% -<=100%” 
Data 
Missing 
Completely 
Data Not 
Present 
(Will not be 
imputed) 
Data Not 
Present 
(Will not be 
imputed) 
No 
Calculated 
using the 
formula  
Not 
calculated 
Compliance Category 
will be considered as 
“<80%” 
Data 
Missing 
Completely 
Data Not 
Present 
(Will not be 
imputed) 
Data Not 
Present 
(Will not be 
imputed) 
Data missing 
Calculated 
using the 
formula  
Not 
calculated 
Compliance Category 
will not be derived and 
kept  blank (missing) 
- 
Details of Tablet Return means “No. of tablets returned” Field and “No. of tablets neither returned nor consumed” 
field present on “TRIAL MEDICATION” page of CRF 
- 
If “No. of tablets returned” Field is non-missing and “No. of tablets neither returned nor consumed” field is missing 
then “No. of tablets neither returned nor consumed” field will be imputed with zero or vice versa 


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Compliance Formula -  
Compliance of study Drug for respective visits:-  
         Compliance to treatment at cycle i/Day j = {[Actual number of tablets taken at cycle i/Day j] / [Number 
of tablets planned to be administered at cycle i/Day j]}*100 
Where, 
Actual number of tablets taken at cycle i/Day j = [ Total number of RP6530 tablet dispensed at cycle 
i/Day j – Total number of RP6530 tablet returned at cycle i/Day j+1 – Total number of RP6530 tablet 
neither   returned nor consumed at cycle i/Day j+1]  
    Number of tablets planned to be administered at cycle i/Day j = Number of tablets to be taken per 
day for Cycle i/Day j* Number of planned days between the current cycle and the next cycle when 
drug accountability is performed 
Where, Number of planned days between the current cycle and the next cycle when drug accountability 
is performed will be calculated as follows, 
For except Last visit = (Date of Dose Dispense in next cycle i/Day j which is nothing but the date 
of tablets return of previous visit  - Date of Dose Dispense in current cycle i/Day j) 
For Last visit = (Date of EOT visit performed  if not available then Date of Withdrawal on EOT page 
in “PARTICIPANTS TRIAL COMPLETION ASSESSMENT” domain - Date of last Dose Dispense 
at cycle i/Day j) +1.  
 Overall Compliance of study Drug:-  
         Total Compliance to Treatment for the Study for patient y = [Compliance to treatment at cycle i/Day 
j for patient i + Compliance to treatment at cycle i/Day j+1 for patient i + …………………… + 
Compliance to treatment at last cycle/Day for patient y when dose is administered] / Total Number 
of cycles when dose of RP6530 administered to patient y  
Temporarily hold of study drug or dose reduction or discontinuation of study drug, if that happen during the 
middle of the cycle, will not be accounted in the calculation of the compliance during that cycle as the 
precise data is not available in eCRF; and thus, in overall compliance calculation. 
 
5.2 
Exposure to Study Drug 
Listing will be provided for administration details of RP6530 including start time of dosing, total calculated 
dose along with total dose administered at each cycle during patient participation in study (total duration of 
exposure for each patient and duration from previous dose).  
Duration of exposure/ Duration of treatment will be analyzed and tabulated for overall and cycle wise using 
following formula. Table will be summarized as n, Mean, Standard Deviation, Median, and Range (Max - 
Min) by using safety population. 


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Drug Exposure / Duration of Treatment Formula -  
Duration of Drug Exposure / Duration of Treatment for respective visits:-  
 Duration of Drug Exposure / Duration of Treatment at cycle i/Day j except Last visit = (Date of Dose 
Dispense in next cycle i/Day j which is nothing but the date of tablets return of previous visit  - Date 
of Dose Dispense in current cycle i/Day j) 
 Duration of Drug Exposure / Duration of Treatment for Last visit = (Date of EOT visit performed  if 
not available then Date of Withdrawal on EOT page in “PARTICIPANTS TRIAL COMPLETION 
ASSESSMENT” domain - Date of last Dose Dispense at cycle i/Day j) +1 
 
Duration of Drug Exposure / Duration of Treatment for overall visit:-  
 Duration of Drug Exposure / Duration of Treatment = (Date of EOT visit performed  if not available 
then Date of Withdrawal on EOT page in “PARTICIPANTS TRIAL COMPLETION ASSESSMENT” 
domain - Date of first Dose Dispense at cycle 1/Day 1) +1 
5.3 
Statistical Analytical Issues 
5.3.1 
Changes in the Planned Analysis From Protocol 
There is no change in any planned analysis from protocol 
6. 
Statistical Tables to be Generated 
Following are the minimum tables presented in Statistical analysis 
14.1 Demographic and Baseline Summary 
Table 14.1.1 Summary of Patient Disposition and Populations 
Table 14.1.2 Summary of Reasons for Screen Failures and Dropouts Prior to Dosing 
Table 14.1.3 Summary of Reason for Discontinuations 
Table 14.1.4 Summary of Major Protocol Deviations 
Table 14.1.5 Summary of Minor Protocol Deviations 
Table 14.1.6 Summary of Demographics and Other Baseline Characteristics 
Table 14.1.7 Summary of Surgical and Medical History by Dose Cohort 
Table 14.1.8 Summary of Concomitant/Current Illness at the Time of Start of the Treatment by Dose Cohort 
Table 14.1.9 Summary of Prior Medications Stopped before Treatment Start, by Dose Cohort by ATC Class 
Table 14.1.10 Summary of Prior Medications Ongoing at Treatment Start, by Dose Cohort by ATC Class 
Table 14.1.11 Summary of Prior Therapies, by Dose Cohort by ATC Class 
Table 14.1.12 Summary of Baseline Characteristics – Serology at Baseline by Dose Cohort 
Table 14.1.13 Summary of DLT Assessment by Dose Cohorts of Dose Escalation Phase 
14.2 Efficacy Analysis 


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14.2.1 Primary Efficacy Analysis …..Not Applicable 
14.2.2 Secondary Efficacy Analysis 
Table 14.2.2.1 Summary of Best Overall Response (BOR) – ITT Population 
Table 14.2.2.2 Summary of Best Overall Response (BOR) – PP Population 
Table 14.2.2.3 Summary of Overall Response Rate (ORR) by Dose Cohort 
Table 14.2.2.4 Summary of Duration of Response (DoR) by Dose Cohort 
Table 14.2.2.5 Summary of Duration of Response (DoR) in without Radiologically Documented Dieases 
Progression by Dose Cohort 
14.3 Safety Analysis 
14.3.1 Display of Adverse Events 
Table 14.3.1.1 Overview of Non-Treatment Emergent Adverse Events 
Table 14.3.1.2 Overview of Treatment Emergent Adverse Events by Dose 
Table 14.3.1.3 Summary of All Treatment Emergent Adverse Events by SOC and PT by Dose 
Table 14.3.1.4 Summary of Dose Limiting Toxicities by SOC and PT by Dose 
Table 14.3.1.5 Summary of Protocol Defined Events of Special Interest by SOC and PT by Dose 
Table 14.3.1.6 Summary of All Treatment Emergent Adverse Events by Intensity, Outcome for Each Dose 
Table 14.3.1.7 Summary of All Related Treatment Emergent Adverse Events by Intensity, Outcome for 
Each Dose 
Table 14.3.1.8 Summary of All Treatment Emergent Adverse Events Leading to Discontinuations by SOC 
and PT by Dose 
Table 14.3.1.9 Summary of Related Treatment Emergent Adverse Events Leading to Discontinuations by 
SOC and PT by Dose 
Table 14.3.1.10 Summary of All Treatment Emergent Adverse Events by Relatedness by Dose 
Table 14.3.1.11 Summary of Non Serious Treatment Emergent Adverse Events by Relatedness by Dose 
14.3.2 SAE Data and Listings of Deaths, Other Serious and Significant Events 
Table 14.3.2.1 Overview of Serious Treatment Emergent Adverse Events by Dose 
Table 14.3.2.2 Summary of Serious Treatment Emergent Adverse Events by SOC and PT by Dose 
Table 14.3.2.3 Summary of All Serious Treatment Emergent Adverse Events by Intensity, Outcome for 
Each Dose 
Table 14.3.2.4 Summary of All Related Serious Treatment Emergent Adverse Events by Intensity, Outcome 
for Each Dose 
Table 14.3.2.5 Summary of All Serious Treatment Emergent Adverse Events Leading to Discontinuations 
by SOC and PT by Dose 
Table 14.3.2.6 Summary of Related Serious Treatment Emergent Adverse Events Leading to 
Discontinuations by SOC and PT by Dose 
Table 14.3.2.7 Summary of All Fatal Serious Treatment Emergent by SOC and PT by Dose 


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Table 14.3.2.8 Summary of Serious Treatment Emergent Adverse Events by Relatedness by Dose 
Table 14.3.2.9 Summary of Grade 3 and Grade 4 Treatment Emergent Adverse Events (Signficant AE) by 
SOC and PT by Dose 
Table 14.3.2.10 Summary of Grade 3 and Grade 4 Treatment Emergent Adverse Events (Signficant AE) 
by Relatedness by Dose 
14.3.4 Laboratory Data and Abnormal Laboratory Value Listings 
Table 14.3.4.1 Summary of Abnormal Laboratory Results by Dose Cohort and CTCAE Grade 
Table 14.3.4.2 Summary of Shifts from Baseline to Each Post Baseline visits for Hematology Laboratory 
result by Dose Cohort 
Table 14.3.4.3 Summary of Shifts from Baseline to Each Post Baseline Visits for Biochemistry Laboratory 
result by Dose Cohort 
Table 14.3.4.4 Summary of Shifts from Baseline to Each Post Baseline Visits for Urinalysis Laboratory 
result by Dose Cohort 
Table 14.3.4.5 Summary of Shifts from Baseline to Each Post Baseline Visits for Serum Electrolyte 
Laboratory result by Dose Cohort 
14.3.5 Other Safety 
14.3.5.1 Vitals, Physical Examinations, ECG, ECOG, Pregnancy and Radiological Evaluation Data 
Table 14.3.5.1.1 Summary of Shifts from Baseline to Each Post Baseline Visits for Vital Sign result by Dose 
Cohort 
Table 14.3.5.1.2 Summary of Shifts from Baseline to Each Post Baseline Visits for Physical Examination 
result by Dose Cohort 
Table 14.3.5.1.3 Summary of Shifts from Baseline to Each Post Baseline Visits for ECG result by Dose 
Cohort 
14.3.5.2 Concomitant Medications 
Table 14.3.5.2.1 Summary of Concomitant Medications/Therapies, by Dose Cohort by ATC Class 
14.3.5.3 Drug Compliance Analysis 
Table 14.3.5.3.1 Drug Compliance – Safety Population 
Table 14.3.5.3.2 Duration of Exposure / Treatment – Safety Population 
7. 
Statistical Listings to be Generated 
14.3.2 Listing of Deaths, Other Serious and Significant Adverse Events 
Listing 14.3.2.1 Fatal SAEs 
Listing 14.3.2.2 Non-Fatal SAEs 
14.3.4 Abnormal Findings 
Listing 14.3.4.1 Abnormal Laboratory Values 
Listing 14.3.4.2 Abnormal Physical Examination Results 


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Listing 14.3.4.3 Abnormal Vital Signs Values 
16.2 Patient Data Listings 
16.2.1 Discontinued Patients 
Listing 16.2.1.1 Screen Failures and Drop out During Screening 
Listing 16.2.1.2 Eligibility Review 
Listing 16.2.1.3 Reasons for Withdrawal of Patient from the Study 
16.2.2 Protocol Deviations 
Listing 16.2.2.1 Protocol Deviations during the Study – Major 
Listing 16.2.2.2 Protocol Deviations during the Study – Minor 
16.2.3 Patients Excluded from the Efficacy Analysis 
Listing 16.2.3.1 Analysis Populations 
16.2.4 Demographic Data 
Listing 16.2.4.1 Demographic Data 
Listing 16.2.4.2 Baseline Disease Characteristics 
Listing 16.2.4.3 Medical History, Surgical History and Concomitant/Current Illnesses 
Listing 16.2.4.4 Prior Medication 
Listing 16.2.4.5 Prior Therapy 
Listing 16.2.4.6 Smoking and Alcohol Status 
Listing 16.2.4.7 Baseline Serology Assessment 
16.2.5 Compliance and Study Drug Exposure Data 
Listing 16.2.5.1 Study Drug Dose Exposure – Drug Dispensed Details 
Listing 16.2.5.2 Study Drug Dose Exposure – Drug Accountability 
Listing 16.2.5.3 Study Drug Compliance Visit Wise 
16.2.6 Efficacy Listings 
Listing 16.2.6.1 Radiological Examination 
Listing 16.2.6.2 Photographs for Disease Evaluation 
Listing 16.2.6.3 Bone Marrow Aspirate Specimen 
Listing 16.2.6.4 Morphology & Cytogenetic Evaluations 
Listing 16.2.6.5A Disease Characteristics – Staging, CTCL Patients 
Listing 16.2.6.5B Disease Characteristics – Staging, PTCL Patients 
Listing 16.2.6.6 Disease Assessment for CTCL Patients - Skin [Modified Severity Weighted Assessment 
Tool (mSWAT)] 
Listing 16.2.6.7 Disease Assessment for CTCL Patients - Skin (Composite Assessment of Index Lesion 
Severity)  
Listing 16.2.6.8 Disease Assessment for CTCL Patients - (Skin Biopsy and Immuno-phenotyping)  


Protocol ID: RP6530-1401 
 
 
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Listing 16.2.6.9 Disease Assessment for CTCL Patients - Radiological Assessment of Lymph Node 
Listing 16.2.6.10 Disease Assessment for CTCL Patients - Lymph Node, Visceral involvement and Blood 
involvement 
Listing 16.2.6.11 Disease Assessment for PTCL Patients - Lymphoma, Lesion 
Listing 16.2.6.12 Disease Assessment for PTCL Patients - Dominant Nodes 
Listing 16.2.6.13 Disease Assessment for PTCL Patients – Non-Dominant Nodes 
Listing 16.2.6.14 Disease Assessment for PTCL Patients – Extra-nodal Lesions 
Listing 16.2.6.15 Disease Assessment – Response 
Listing 16.2.6.16 Visit Wise Response 
16.2.7 Adverse Events Listings 
Listing 16.2.7.1 Non Treatment Emergent Adverse Events 
Listing 16.2.7.2 Treatment Emergent Adverse Events 
Listing 16.2.7.3 Treatment Emergent Adverse Events – Dose Limiting Toxicities 
Listing 16.2.7.4 Treatment Emergent Adverse Events – Significant AEs 
Listing 16.2.7.5 Treatment Emergent Serious Adverse Events 
16.2.8 Listings of Individual Laboratory Measurements by Patient 
Listing 16.2.8.1 Listing of Clinical Laboratory Normal Reference Ranges 
Listing 16.2.8.2 Clinical Laboratory Evaluations by Patients - Hematology 
Listing 16.2.8.3 Clinical Laboratory Evaluations by Patients - Biochemistry 
Listing 16.2.8.4 Clinical Laboratory Evaluations by Patients - Urinalysis 
Listing 16.2.8.5 Clinical Laboratory Evaluations by Patients - Additional Laboratory Tests 
Listing 16.2.8.6 Clinical Laboratory Evaluations by Patients - Serum Electrolyte 
16.2.9 Other Safety Listings 
Listing 16.2.9.1 12-Lead ECG Results 
Listing 16.2.9.2 ECOG Performance Status 
Listing 16.2.9.3 Physical Examination 
Listing 16.2.9.4 Vital Signs 
Listing 16.2.9.5 Pregnancy Test 
Listing 16.2.9.6 Concomitant Medication 
8. 
Statistical Graphs to be Generated 
14.3 Efficacy Figures 
Figure 14.3.1 Duration of Treatment in Efficacy Evaluable Patients – ITT Population 
Figure 14.3.2 Percent Change in Target Lesion – ITT Population