Clinical trial NCT04880863
Conditions: Non-small Cell Lung Cancer
Keywords: Advanced Metastatic Non small cell lung cancer EGFR ALK Docetaxel Naptumomab estafenatox Obinutuzumab NAP
Sponsor: NeoTX Therapeutics Ltd.
Start date: 2021-10-26; Completion date: 2024-01-30
Enrollment: 38 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Phase 2a Open-Label, Multicenter Trial of Naptumomab Estafenatox (NAP), following Obinutuzumab Pretreatment, on Days -13 and -12. NAP will be administered on Days 1-4 of treatment cycles 1-6, followed by docetaxel on Day 5. Starting cycle 7, NAP at a higher dose will be administered on Day 1 only and docetaxel on Day 2, in 21 days treatment cycles. When NAP is administered as monotherapy and not earlier than cycle 7, NAP will be administered on Day 1 only and cycles will be of 28 days treatment cycle.

Detailed description:
Patients must have received at least 1 and no more than 2 prior systemic regimens for the treatment of advanced/metastatic NSCLC. Patients were required to have progressed following treatment with both platinum-based chemotherapy and an anti-PD-(L)1 antibody administered either sequentially or concurrently. Entry into this trial was restricted to patients with incurable disease, including those whose disease had relapsed within 6 months after chemoradiotherapy for Stage III disease. Patients were to have available archival or fresh tissue collected for the retrospective determination of tumoral 5T4 levels.

Arms: arm 1: Subjects receive obinutuzumab, 1,000 mg, administered by IV infusion on Days -13 and -12 of the first treatment cycle in order to reduce the titer of anti-drug antibodies to NAP. NAP is administered by IV bolus on Days 1 - 4 of treatment cycles 1-6, followed by docetaxel on Day 5. Treatment cycles with the combination NAP/docetaxel are of 21 days in duration. Starting cycle 7, NAP at a higher dose is administered on Day 1 and docetaxel on Day 2, in 21 days treatment cycles. Once NAP is given as monotherapy and not earlier than C7, cycles are of 28 days of duration.
Interventions: intervention 1: NAP (Naptumomab estafenatox) intervention 2: Docetaxel intervention 3: Obinutuzumab
Intervention descriptions: intervention 1: Naptumomab estafenatox (NAP; ABR-217620) is a recombinant fusion protein consisting of a chimeric staphylococcal enterotoxin A/E (SEA/SEE) superantigen with several additional substitutions that are linked to a Fab moiety recognizing a tumor-associated glycoprotein, 5T4. NAP is administered at a dose of 10 μg/kg/day by IV bolus on Days 1 - 4 of treatment cycles 1-6. Starting cycle 7, NAP at a higher dose of 15 μg/kg is administered on Day 1. intervention 2: Docetaxel is administered in combination with the study drug, NAP, on Day 5 of the treatment cycles 1-6. Starting cycle 7, Docetaxel is administered in combination with the study drug, NAP, on Day 2. intervention 3: Obinutuzumab is administered as pre-medication on Day -13 and -12 of the first treatment cycle.

Protocol documents:
Prot_SAP_000.pdf: 
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PHASE 2a OPEN-LABEL, MULTICENTER TRIAL OF NAPTUMOMAB 
ESTAFENATOX (NAP) IN COMBINATION WITH DOCETAXEL FOLLOWING 
OBINUTUZUMAB PRETREATMENT IN SUBJECTS WITH CHECKPOINT 
INHIBITOR PRETREATED ADVANCED OR METASTATIC NON-SMALL CELL 
LUNG CANCER 
 
Investigational Treatment 
 
Naptumomab estafenatox (NAP) and docetaxel 
with obinutuzumab pre-treatment 
Clinical Trial Sponsor 
NeoTX Therapeutics Ltd,  
2 Pekeris Street 
 
Rehovot 7670202, Israel 
Phone: +972 (0)3 912 5853 
Protocol Number 
NT-NAP-102-1 
NCT Number 
NCT04880863 
IND Number 
152060 
Study Phase 
2a 
Protocol Version 
8.1 
Protocol Version Date 
25-Dec-22 
 
 
 
 
 
This document contains confidential information belonging to NeoTX.  Except as otherwise agreed to in writing, 
by accepting or reviewing this document, you agree to hold this information in confidence and not copy or 
disclose it to others (except where required by applicable law) or use it for unauthorized purposes.  In the event 
of any actual or suspected breach of this obligation, NeoTX must be promptly notified. 


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DOCUMENT HISTORY 
 
Document 
Version Date 
Summary of Main Changes and Rationale 
Original 
protocol 
25-NOV-2020 
 
Not applicable (N/A) 
Amendment 1 
(version 2) 
28-JAN-2021 
1. Updated COVID-19 guidance (appendix 15.7) 
2. Adding inclusion criterion to allow the inclusion of 
patients that already received COVID-19 vaccine, 
who completed all doses of the vaccine and at least 14 
days have passed since the last dose before receiving 
obinutuzumab pre-treatment (inclusion criterion #12). 
3. B cell level footnote was updated in the schedule of 
activities table, to clarify the timepoints for 
assessment. 
4. Removal of post-NAP treatment ECG test on C1D1 
and C4D1 and a change in the timepoint from C1D4 
to C1D5, after the completion of docetaxel 
administration. 
5. Allowing flexibility in the study drug NAP regimen, 
by allowing increase in dose on cycle 3 or 4 based on 
NAP plasma levels. 
 
Amendment 2 
(version 3) 
12-APR-2021 
1. Removal of the option to dose escalating to the 20 
µg/kg/day on Cycles 3 or 4 
2. Inclusion of NAP dose modifications in tabular 
format according to anticipated NAP toxicities and 
actions to be taken 
3. Inclusion of guidelines for identification and 
management of cytokine release syndrome 
4. Change of primary endpoint to ORR with a target of 
30% 
5. Specified patients receiving substrates of CYP 
enzymes for which small changes in concentration 
could lead to altered safety or efficacy should be 


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monitored closely and have doses adjusted as 
indicated 
6. Revised timing of ECG around the anticipated Tmax 
of NAP 
7. Inclusion of additional PK sampling on D4 of each 
NAP cycle  
8. Clarification that all assessments of Day 1, with the 
exception of PK sampling for NAP and cytokines, 
should be performed on the day of docetaxel 
treatment if NAP is discontinued due to an AE and 
treatment is continued with single agent docetaxel  
9. Reduction in the frequency of B-cell tests 
10. Correction of typographical discrepancies between the 
Schedule of Assessment (Section 6) and the 
Assessment (Section 7) sections 
11. Update of the format of subject identification/ 
numbering 
Amendment 3 
(version 4) 
27-APR-21 
1. Inclusion of the option to evaluate lower dose and/ or 
additional schedules of NAP, if the target response 
rate is achieved at 15 ug/kg/day 
2. Revision of section 5.2.4 Stability of Reconstituted 
and Diluted Naptumomab Estafenatox (NAP), to 
indicated that stability information on reconstituted 
and diluted NAP can be found in the IFU 
(Information For Use) and the Pharmacy Manual 
3. A clarification has been added regarding docetaxel 
dose adjustments, section 5.1.1  
4. Added clarifications under section 5.2.6 Dose 
Modifications for Naptumomab Estafenatox (NAP)  
5. Table 2 - Schedule of Assessments, note #15, has 
been clarified with additional assessments that should 
not be performed when docetaxel is administered as a 
monotherapy 
6. Removal of the statement in section 5.2.2 that every 
effort should be made to administer NAP over 


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approximately 5 minutes of injection. NAP will be 
administered as slow bolus injection 
Amendment 4 
(version 5) 
17-JUN-21 
1. Daily dose of NAP amended to 10 µg/kg/day 
2. The rationale for this change is updated in Section 
1.6: Dose Selection Rationale and Risk  
3. Section 5.2.6 Dose modifications was updated with 
the option to reduce the dose of NAP to 5 µg/kg/day 
where applicable 
Amendment 5 
(version 6) 
01-Feb-22 
1. Addition of abbreviations “EOD” and “GGT” 
2. A clarification has been added in exclusion criterion 
#13 that all prior treatments should be completed 21 
days prior to enrollment, which is D-13, 
obinutuzumab pre-treatment. 
3. Exclusion criterion #14 was previously omitted from 
section 4.2 while it was present in the synopsis. This 
discrepancy has been corrected and the criterion is 
added back in this amendment.  
4. Update of the rationale for daily dose of NAP at 10 
µg/kg/day with updated data from an ongoing P1 
study, in Section 1.6  
5. Removal of the sentence that treatment must begin 
within 72 hours after the approval of the patient’s 
eligibility form by the Medical Monitor, in section 4.3 
and section 6.  
6. New section (Premedication for docetaxel) has been 
added to clarify that if steroids are being initiated one 
day earlier of D5, it should be administered at least 1 
hour after NAP administration on D4 of each cycle, 
(section 5.1.1) 
7. Clarification on the time schedule for administration 
of pre-medications for NAP, in section 5.2.5 
8. NAP dose delay section has been updated with the 
information that in case of any obinutuzumab related 
toxicities of grade ≥2 that exist on the first scheduled 
day of NAP administration (C1D1), Cycle 1 of NAP- 


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docetaxel treatment may be delayed up to 7 days 
(section 5.2.7). 
9. Evaluation of disease (EOD): enlarging the time-
window allowed for imaging at screening to 3 weeks 
(instead of 2 weeks) prior to enrolment (D-13); and 
ongoing study imaging will be performed at the end 
of cycle 3 (63 days ± 7 days) instead of at the end of 
cycle 2, and every 9 weeks thereafter. A 
recommendation was also added to proceed 1-2 
additional treatment cycle(s) of NAP/docetaxel 
beyond progression in patients who demonstrate 
objective progression but who are clinically stable, at 
the discretion of the Investigator, followed by a 
confirmatory imaging after 4-8 weeks. 
10. Clarifications on the time to perform ECG, vital signs, 
PK and cytokines sampling (post NAP administration 
start time) in Schedule of Assessment (Section 6) and 
the Assessment (Section 7) sections. 
11. Correction of a discrepancy in the schedule of the B-
cell test between the Schedule of Assessment (Section 
6) and the Assessment (Section 7) sections.  
12. A new appendix has been added to provide guidance 
on the procedure and processing of samples, section 
14.8: Example for B cells quantitation procedure. 
13. A clarification on the types of tumor tissues which are 
not acceptable for biomarker test of 5T4 expression: 
bone samples, fine-needle aspiration, brushing, cell 
pellets and lavage, in sections 6 and 7. 
14. Correction of typographical discrepancies between the 
Schedule of Assessment (Section 6) and the 
Assessment (Section 7) sections  
15. Updated inclusion criterion #12 as well as appendix 
14.7 for COVID related guidance with updated data 
from the CDC website. A clarification has also been 
added to provide guidance on documenting 
information on COVID-19 in “Medical History” and 


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vaccinations in “Concomitant Medications”, in 
section 7.1. 
16. Addition of reference #23 in section 7.2.3 and section 
14. 
17. Addition of section 7.9.: “Unscheduled Visits”. 
18. Addition of section 10.6: “Protocol Deviations”. 
19. A clarification under section 8, that 
progression/worsening of underlying disease should 
not be considered as adverse event (AE or SAE).   
20. A typographical error in the amount of WFI in the 
synopsis has been corrected. 
21. A clarification on the pre-medications administered 
prior to obinutuzumab infusion and time of 
administration, in section 5.3.3. 
22. Added note to the table of assessments to follow the 
pre-medication guidelines for each of the study 
treatments. 
23. Provide detailed instructions on NAP administration 
in section 5.2.2. 
Amendment 6, 
version 7.0 + 
7.1 (correction 
of a 
discrepancy in 
ECG updated 
time points, 
section 7.2.4) 
17-Jul-22 
1. Updated dose reduction scheme has been 
implemented to adjust the reduction in percentage (by 
~25%) rather than in fixed increments.  
NAP may be reduced by one dose level for G3 AEs, 
and by two dose levels for G4, life-threatening AEs 
(with the exception of hematologic toxicity and 
laboratory findings). A second dose reduction is 
allowed for G3 AEs.    If the dose was reduced only 
once for a G3 AE (e.g., from 10 µg/kg/day to 5 
µg/kg/day) and is tolerated well with no recurrences 
or further NAP related AEs at the reduced dose, then 
at the PI discretion, the dose may be increased by one 
dose level in the following cycle.  
2. A clarification was added regarding a delay of a cycle 
due to docetaxel toxicity in section 5.1.2.  If NAP and 
docetaxel are to be delayed due to toxicity of 
docetaxel, the whole cycle of NAP and docetaxel may 
be delayed up to 6 weeks. Further delays should be 
discussed with the Medical Monitor. 


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3. Updated inclusion criterion #11: the collection of 
archival or fresh biopsies is mandatory to support the 
retrospective analysis of 5T4 level. 
4. The efficacy evaluation has been changed from 
RECIST to iRECIST due to the immune mediated 
mechanism of action of NAP (section 14.1 and 
throughout the protocol). Supporting this change, is a 
case of pseudo-progression that followed by a 
response. 
5. The schedule of disease assessment by imaging has 
been changed as follows: 
Ongoing study imaging will be performed at the end 
of cycle 2 (45 ± 7 days) and every 6 weeks (± 7 days) 
for the first 24 weeks and then every 9 weeks (± 7 
days) thereafter. This schedule should be maintained 
even if cycles are delayed.  Confirmatory scans will 
be performed after 6 weeks (± 7 days) during the first 
24 weeks and every 9 weeks thereafter.  
6. With the CDC guidance that recommends the 
administration of the vaccine to immunocompromised 
patients, it has been decided to remove the COVID-19 
related inclusion criterion (previously #12) and a 
clarification has been added to refer to the CDC 
guidelines for recommendations on the timing of the 
vaccine under section “14.7.2 Recommendations for 
the study patients regarding COVID-19 Vaccines”. 
7. Survival follow up time has been changed to allow 
longer overall survival assessment from ‘6 months 
after the last subject has been enrolled’ to ‘6 months 
following treatment completion of the last subject into 
the trial’. 
8. Due to accumulating data with NAP in several 
clinical trials, it has been decided to ease the burden 
of safety labs and remove the following tests: 
a) CBC and Serum Chemistry were previously 
collected on screening, day -12, and then on day 
1 and day 4 of each cycle. Day 15 is a safety 
follow up visit and remains unchanged. In this 
amendment the time-points have been changed to 
be collected at screening, day -12 and then day 1 
of each cycle but day 4 will be collected only on 
cycles 1, 2 and 3. Both will also be collected at 
EOT as previously done and as clinically 
indicated. 


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b) Urinalysis was previously collected on screening, 
day 1 of each cycle, day 15 and at EOT. This has 
been changed in this amendment to be collected 
at screening, C1D1, EOT and as clinically 
indicated. 
c) Coagulation panel was previously collected at 
screening, C1D4, C1D15, C4D1 and EOT visit. 
The tests during NAP treatments have been 
removed, however due to a known risk of 
Disseminated Intravascular Coagulation (DIC) 
related to obinutuzumab treatment, 2 new time-
points have been added at D-12 and at C1D1 
prior to NAP treatment (screening and EOT 
timepoints have not been changed).  
Changes are implemented on section 6: Study 
Procedures and section 7: Assessments. 
9. ECG was previously assessed at screening, at 5min 
(+3min) post NAP initiation time on: C1D1, C1D4, 
C4D1, C4D4, and at EOT visit. All timepoints during 
the treatment have been removed and ECG will be 
performed at screening, EOT and as clinically 
indicated throughout the study.  This revision is done 
under sections 6 & 7.  Rationale: Data from two 
ongoing clinical studies conducted with NAP (13 
patients in the current P2 study and 50 patients in an 
ongoing P1 study of NAP and durvalumab following 
pre-treatment of obinutuzumab), in addition to safety 
data from past clinical trials in over 300 patients 
treated with NAP, were reviewed for ECG 
assessments at various timepoints. Specific data from 
the current study were reviewed for ECGs at the time 
of the peak plasma levels of NAP, at the following 
timepoints: 
• 13 patients on C1D1 
• 13 patients on C1D4 
• 9 patients on C4D1 
• 8 patients on C4D4 
• 5 patients at End of Study visit 
No significant abnormalities and/ or shifts from 
baseline, including QTcF changes, were detected at 
any of those timepoints. 
In addition – neither AEs nor SAEs were identified to 
be related to any ECG abnormalities. Important to 
note, the challenge of multiple protocol procedures 


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required in the short timeframe post NAP 
administration. The ECG as well as PK sample 
collection and vital signs – all are requested at the 
same timepoint, which is a significant challenge for 
those taking care of the patients. 
10. Added clarifications (section 5.2.7) for dose delay of 
NAP between cycles, allowing 7 days delay for any 
reasons and the need to discuss with the Medical 
Monitor for any delays beyond the indicated window. 
A clarification was also added that the schedule of the 
imaging should be maintained even if cycles are 
delayed. 
11. A clarification has been included under section 7.3 
Efficacy Assessments, in cases that CT contrast agent 
is unavailable and for the general use of PET-CT in 
the study. 
12. Correction of a typographical error for vital signs 
collection after the end of the obinutuzumab infusion. 
Corrected to ‘every 30 minutes (± 5 min) for 1 hour 
after the end of the infusion’ instead of ‘1 hour after 
start of the infusion’. This correction is done under 
sections 6 & 7. 
13. A clarification has been added to section 7.2.5 
Laboratory Determinations, that if the b-cell test was 
missed in any of the visits, it is important to collect it 
in the next scheduled visit. 
Amendment 7, 
version 8.0 
12-Dec-22 
1. Collection of available results in patients’ medical 
history of NGS results, TMB (tumor mutational 
burden) and PD-L1 to better understand if these 
biomarkers can be predictive of response.  This 
addition is done under sections: “abbreviation”, 1.1, 
2.1.3, 2.2.3 and 3. Changes are also implemented in 
sections 6 and 7.  
2. Section 1.6: Dose Selection Rationale and Risk was 
updated with ongoing P1b study data and the study 
number in NIH website. 
3. Change in the regimen of NAP, starting cycle 7, to 
dose only on Day 1 instead of days 1-4. Starting 
Cycle 7, NAP may be increased to 15 μg/kg and will 
be administered on Day 1 followed by docetaxel on 
Day 2, in 21 days treatment cycles. Once docetaxel 
has been discontinued (either completed or stopped 
for toxicity), NAP as monotherapy will be given on a 
28-day cycle, but not earlier than C7. In patients 
whose NAP dose was reduced due to toxicities during 


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cycles 1-6, NAP dose will not be further increased in 
cycle 7. Rationale: After 6 cycles only a booster dose 
may be needed every cycle. Reducing days of NAP 
treatment will simplify the schedule and regimen of 
NAP. Dose increase to 15 μg/kg given only on day 1 
is not expected to increase NAP toxicity profile, as 
NAP related toxicities predominantly occur on cycles 
1-2 based on collected data with 15 μg/kg on days 1-
4. Changes are implemented in sections 1.6, 3, 5.1, 
5.2.2, 5.2.6, 6 and 7.  
4. NAP premedication in section 5.2.5:  IV fluids 
recommendations have been updated to avoid excess 
of IV fluid and paracetamol dose was adjusted to 
comply with standard paracetamol commercial doses 
(500-650mg).  
5. A Clarification has been added in section 4.5 that 
patients may be re-screened if failed previous 
screening. 
6. NAP administration time has been updated to allow to 
shorten the time if no IRRs ≥G2 occurred in a 
previous full cycle. A clarification that any IV fluids 
given simultaneously with NAP are prohibited has 
also been added. All changes implemented in section 
5.2.2.  
7. A clarification has been included under section 5.2.3 
on NAP dose calculation based on subject’s weight. 
8. NAP dose modification table in section 5.2.6 has been 
updated for cases of G3 or G4 NAP related 
hematologic AEs, the next cycle dose will be reduced 
only if has not been resolved to G2. 
9. Update of section 5.4, Prohibited concomitant 
medication, and section 7, Concomitant medications: 
Hematopoietic growth factors (e.g. G-CSF, 
erythropoietin) and approved COVID treatments (e.g. 
Paxlovid) are allowed during the study. 
10. Biomarkers collection schedule update:  
Addition of samples timepoints for PK, ADAs, Nab 
and HAMA: collection on day 1 of every 2 cycles 
after cycle 6.  Changes are done under sections 6 and 
7.5. 
11. Correction of typographical errors and other 
inconsistencies throughout the protocol. 
12. A flexibility in the time of collection of safety lab 
tests on Day 1 of each cycle to allow a broader 
window: up to 72 hours prior to any study drug 


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treatments instead of up to 15 minutes in CBC, serum 
chemistry, coagulation panel, pregnancy test, thyroid  
panel and symptom directed physical exam.  Changes 
are done under sections 6 and 7.5. 
13. Reducing number of CBC and chemistry tests. Day 4 
– CBC and chemistry are to be taken on Day 4 of 
cycle 1 only, with a broader window of up to 24 
hours, but after the NAP administration on day 3. 
Changes are done under sections 6 and 7.5. 
14. Evaluation of disease (EOD): Adding brain MRI at 
screening with further follow up if positive. This 
change is implemented in sections 6 and 7.3. 
15. Number of urinalysis tests was reduced and will be 
performed at the Screening visit only and then as 
indicated. Sections 6 and 7.2.5 were updated. 
16. Serum chemistry lab test was removed from Day -12. 
Updated in sections 6 and 7.2.5. 
17. Clarification in sections 6, 7.7 and 9.4, that EOT visit 
will be performed prior to start of any new anti-cancer 
treatment.  
18. Time of observation post NAP treatment has been 
updated as follows and implemented in sections 5.2.2, 
6 and 7.2.3: 
During cycle 1 (days 1-4) and cycle 2 Day 1 (C2D1), 
all subjects should be observed for 3 hours post 
injection of NAP at the site.  If no G3 or higher 
infusion related reactions occurred, time of 
observation can be shortened to 1 hour on further 
treatment days.  Subjects who experience any TEAEs 
during the observation period and/or any other 
medical condition requiring further monitoring at the 
discretion of the investigator, should be further 
observed as clinically appropriate. Subjects should be 
advised that in any case of severe and/or persistent 
fever, chills, or shortness of breath beyond 5-7 hours 
post NAP administration, they should seek a medical 
attention. Rationale:  Data from two ongoing clinical 
studies conducted with NAP (approximately 80 
patients) show that most of the infusion related 
reactions occurred during the first cycle (mostly days 
1 and 2) and on the first day of the second cycle. 
Patients who did not experience any infusion related 
reactions during these treatment days were less prone 
to experience any significant AEs on further treatment 
days. All those toxicities were manageable with 


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appropriate medical treatment, rapidly reversible and 
without long-term sequelae. Based on this experience, 
we can recommend on a shortened time of 
observation as described above. 
19. The exploratory objective and endpoint for Nab 
analysis was removed as method is still under 
development. 
20. Repeated thyroid function lab tests will continue after 
treatment discontinuation only in subjects with 
abnormal results at EOT. Subjects will be followed up 
until resolution or initiation of a new anti-cancer 
treatment. End of Study term was removed as it is no 
longer needed. Changes were implemented in Table 2 
and section 7.2.5. 
21. Day -12 treatment will be delayed if platelet count is 
below 75,000/µL, coagulation abnormalities and/or 
any signs and symptoms of bleeding or thrombosis 
are present. The second obinutuzumab dose can be 
delayed by Day -7. Any further delay in 
obinutuzumab dosing is to be discussed with the 
Medical Monitor. Implemented in section 5.3.4. 
22. Inclusion criterion #11 has been changed to add an 
exception “if discussed with the Medical Monitor”. 
Amendment 7, 
version 8.1 
25-Dec-22 
1. Additional corrections of typographical errors and 
other inconsistencies throughout the protocol. 
 


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TABLE OF CONTENTS 
LIST OF TABLES ..................................................................................................................................................... 16 
LIST OF FIGURES ................................................................................................................................................... 16 
ABREVIATIONS ...................................................................................................................................................... 17 
SIGNATURES ........................................................................................................................................................... 20 
PROTOCOL SYNOPSIS .......................................................................................................................................... 22 
1 INTRODUCTION ................................................................................................................................................ 35 
1.1 
BACKGROUND AND RATIONALE ................................................................................................................. 35 
1.2 
NAPTUMOMAB ESTAFENATOX (NAP) ......................................................................................................... 36 
1.3 
NAPTUMOMAB ESTAFENATOX (NAP) MECHANISM OF ACTION .................................................................. 36 
1.4 
PRE-CLINICAL ANTITUMOR ACTIVITY ........................................................................................................ 37 
1.5 
CLINICAL STUDIES ...................................................................................................................................... 39 
1.5.1 
Phase 1 Monotherapy Trial ................................................................................................................... 39 
1.5.2 
Phase 1 Trial in Combination with Docetaxel in NSCLC ...................................................................... 39 
1.5.3 
Phase 2/3 ............................................................................................................................................... 40 
1.6 
DOSE SELECTION RATIONALE AND RISK .................................................................................................... 40 
1.7 
OBINUTUZUMAB ......................................................................................................................................... 41 
1.8 
STUDY RATIONALE ..................................................................................................................................... 42 
2 STUDY OBJECTIVES AND ENDPOINTS ...................................................................................................... 43 
2.1 
STUDY OBJECTIVES .................................................................................................................................... 43 
2.1.1 
Primary Objective .................................................................................................................................. 43 
2.1.2 
Secondary Objectives ............................................................................................................................. 43 
2.1.3 
Exploratory Objectives .......................................................................................................................... 43 
2.2 
STUDY ENDPOINTS ...................................................................................................................................... 44 
2.2.1 
Primary Endpoints ................................................................................................................................. 44 
2.2.2 
Secondary Endpoints ............................................................................................................................. 44 
2.2.3 
Exploratory Endpoints ........................................................................................................................... 44 
3 STUDY DESIGN .................................................................................................................................................. 45 
4 STUDY POPULATION ...................................................................................................................................... 48 
4.1 
INCLUSION CRITERIA .................................................................................................................................. 48 
4.2 
EXCLUSION CRITERIA ................................................................................................................................. 49 
4.3 
ENROLLMENT ............................................................................................................................................. 52 
4.4 
SUBJECT IDENTIFICATION ........................................................................................................................... 52 
4.5 
SCREEN FAILURES ...................................................................................................................................... 52 
4.6 
SUBJECT DISCONTINUATION OR EARLY WITHDRAWAL AND REPLACEMENT .............................................. 52 
4.6.1 
Reasons for Treatment Discontinuation ................................................................................................ 52 
4.6.2 
Reasons for Study Discontinuation ........................................................................................................ 53 
5 STUDY DRUGS ................................................................................................................................................... 54 
5.1 
DOCETAXEL ................................................................................................................................................ 54 
5.1.1 
Premedication for Docetaxel ................................................................................................................. 54 
5.1.2 
Docetaxel Dose Adjustments ................................................................................................................. 54 


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5.2 
NAPTUMOMAB ESTAFENATOX (NAP; ABR-217620) ................................................................................. 55 
5.2.1 
Naptumomab Estafenatox (NAP) Packaging and Labeling ................................................................... 55 
5.2.2 
Naptumomab Estafenatox (NAP) Preparation and Administration ....................................................... 55 
5.2.3 
Naptumomab Estafenatox (NAP) Dilution ............................................................................................. 56 
5.2.4 
Stability of Reconstituted and Diluted Naptumomab Estafenatox (NAP) .............................................. 56 
5.2.5 
Premedication for Naptumomab Estafenatox (NAP) ............................................................................. 56 
5.2.6 
Dose Modifications for Naptumomab Estafenatox (NAP) ..................................................................... 57 
5.2.7 
Dose Delays for Naptumomab Estafenatox (NAP)/Docetaxel Combination ......................................... 60 
5.3 
OBINUTUZUMAB ......................................................................................................................................... 60 
5.3.1 
Obinutuzumab Packaging ...................................................................................................................... 61 
5.3.2 
Obinutuzumab Preparation ................................................................................................................... 61 
5.3.3 
Premedication for Obinutuzumab .......................................................................................................... 61 
5.3.4 
Obinutuzumab Administration ............................................................................................................... 61 
5.3.5 
Stability of Diluted Obinutuzumab ......................................................................................................... 62 
5.4 
PROHIBITED CONCOMITANT MEDICATION .................................................................................................. 63 
5.5 
LIFESTYLE RESTRICTIONS ........................................................................................................................... 64 
5.5.1 
Female subject of child-bearing potential ............................................................................................. 64 
5.5.2 
Male subjects with a female partner of childbearing potential ............................................................. 64 
5.5.3 
Additional Restrictions: All Subjects ..................................................................................................... 65 
6 STUDY PROCEDURES ...................................................................................................................................... 66 
7 ASSESSMENTS ................................................................................................................................................... 75 
7.1 
GENERAL ASSESSMENTS ............................................................................................................................. 75 
7.2 
SAFETY ASSESSMENTS ................................................................................................................................ 76 
7.2.1 
Physical Examination ............................................................................................................................ 76 
7.2.2 
ECOG Performance Score ..................................................................................................................... 76 
7.2.3 
Vital Signs .............................................................................................................................................. 76 
7.2.4 
ECG ....................................................................................................................................................... 79 
7.2.5 
Laboratory Determinations ................................................................................................................... 79 
7.3 
EFFICACY ASSESSMENTS ............................................................................................................................ 81 
7.4 
PHARMACOKINETIC ASSESSMENTS ............................................................................................................. 82 
7.5 
PHARMACODYNAMIC ASSESSMENTS .......................................................................................................... 82 
7.6 
TUMOR BIOPSY ........................................................................................................................................... 83 
7.7 
END OF TREATMENT/EARLY TERMINATION VISIT ...................................................................................... 83 
7.8 
LONG TERM FOLLOW-UP ............................................................................................................................ 83 
7.9 
UNSCHEDULED VISITS ................................................................................................................................ 83 
8 ADVERSE EVENTS REPORTING AND MEDICAL MANAGEMENT ...................................................... 83 
8.1 
ADVERSE EVENTS ....................................................................................................................................... 84 
8.2 
DEFINITION OF AN ADVERSE EVENT ........................................................................................................... 84 
8.3 
UNEXPECTED ADVERSE EVENT .................................................................................................................. 86 
8.4 
SEVERITY ASSESSMENT .............................................................................................................................. 86 
8.5 
CAUSALITY ASSESSMENT ........................................................................................................................... 87 
8.6 
SERIOUS ADVERSE EVENTS ........................................................................................................................ 87 
8.7 
HOSPITALIZATION ....................................................................................................................................... 88 
8.8 
SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTION (SUSAR) ........................................................... 89 
8.9 
SERIOUS ADVERSE EVENT REPORTING REQUIREMENTS ............................................................................. 89 


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8.10 REPORTING PERIOD .................................................................................................................................... 89 
8.11 ACTION TAKEN REGARDING THE STUDY DRUGS ........................................................................................ 90 
8.12 OUTCOME ................................................................................................................................................... 90 
8.13 RECORDING OF ADVERSE EVENTS .............................................................................................................. 90 
8.14 PREGNANCY ................................................................................................................................................ 91 
8.14.1 Maternal Exposure ................................................................................................................................ 91 
8.14.2 Paternal Exposure ................................................................................................................................. 92 
8.15 WITHDRAWAL DUE TO ADVERSE EVENTS .................................................................................................. 92 
9 STATISTICAL METHODS ............................................................................................................................... 93 
9.1 
ANALYSIS POPULATIONS ............................................................................................................................ 93 
9.2 
SAMPLE SIZE DETERMINATION ................................................................................................................... 93 
9.3 
EFFICACY ANALYSES .................................................................................................................................. 93 
9.4 
SAFETY ANALYSES ..................................................................................................................................... 94 
9.5 
PHARMACOKINETIC ANALYSIS ................................................................................................................... 95 
9.6 
PHARMACODYNAMIC ANALYSES ................................................................................................................ 95 
10 ETHICS ................................................................................................................................................................ 96 
10.1 INSTITUTIONAL REVIEW BOARD/ETHICS COMMITTEE ................................................................................ 96 
10.2 ETHICAL CONDUCT OF THE STUDY ............................................................................................................. 97 
10.3 SUBJECT INFORMATION AND CONSENT ....................................................................................................... 98 
10.4 SUBJECT RECRUITMENT .............................................................................................................................. 99 
10.5 REPORTING OF SAFETY ISSUES AND SERIOUS BREACHES OF THE PROTOCOL OR ICH GCP ........................ 99 
10.6 PROTOCOL DEVIATIONS ............................................................................................................................ 100 
10.7 PROTOCOL AMENDMENTS......................................................................................................................... 100 
10.8 SUBJECT IDENTIFICATION, ENROLLMENT, AND SCREENING LOGS ............................................................ 100 
10.9 PUBLICATION POLICY ..................................................................................................................................... 100 
11 QUALITY CONTROL AND QUALITY ASSURANCE ............................................................................... 101 
12 DATA HANDLING AND RECORD RETENTION ....................................................................................... 102 
12.1 ELECTRONIC CASE REPORT FORMS ................................................................................................................... 102 
12.2 RECORDS RETENTION ..................................................................................................................................... 102 
13 REFERENCES ................................................................................................................................................... 103 
14 APPENDICES .................................................................................................................................................... 106 
14.1 IRECIST GUIDELINES FOR DISEASE EVALUATION ................................................................................... 106 
14.2 CTCAE V5 ............................................................................................................................................... 106 
14.3 EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) PERFORMANCE STATUS ........................................ 106 
14.4 INFUSION RELATED REACTIONS AND CYTOKINE RELEASE SYNDROME GRADING (CTCAE V5) .............. 107 
14.5 INHIBITORS AND INDUCERS OF CYP3A4 .................................................................................................. 109 
14.6 HIGHLY EFFECTIVE METHODS OF CONTRACEPTION (<1% FAILURE RATE) ................................................. 111 
14.7 COVID-19 RELATED GUIDANCE .............................................................................................................. 112 
14.7.1 GUIDANCE FOR SUBJECTS ON STUDY WITH COVID-19 ............................................................................ 112 
14.7.2 RECOMMENDATIONS FOR THE STUDY PATIENTS REGARDING COVID-19 VACCINES ................................ 112 
14.8 EXAMPLE FOR B CELLS QUANTITATION PROCEDURE ................................................................................ 112 
 
 
 


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LIST OF TABLES 
Table 1. Schedule of Assessments: Cycle 1-6 ............................................................................................ 67 
Table 2. Schedule of Assessments: Subsequent Treatment Cycles for Cycle 7 Onward ............................ 71 
Table 3. PK Draws Timepoints ................................................................................................................... 82 
 
 
LIST OF FIGURES 
Figure 1.  Study Schema ............................................................................................................................. 27 
Figure 2.  Mechanism of action of NAP ..................................................................................................... 37 
Figure 3.  Synergistic anti-tumor activity of tumor targeted super antigen in combination with docetaxel 
against the B16 murine melanoma .............................................................................................................. 38 
 
 
 


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ABREVIATIONS 
Abbreviation 
Term 
ADA 
Anti-Drug Antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
APC 
Antigen-presenting cells 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CHMP 
Committee for Medicinal Products for Human Use 
CL 
Creatinine clearance 
CPI 
Checkpoint Inhibitor 
CR 
Complete Response 
CRF 
Case report form 
CRO 
Contract research organization  
CRS 
Cytokine release syndrome 
CSA 
Clinical study agreement 
CT 
Computed tomography 
CTA 
Clinical trial application 
CTCAE 
Common Terminology Criteria for Adverse Events 
DL 
Dose level 
DLT 
Dose-limiting toxicity 
DNA 
Deoxyribonucleic acid 
DoR 
Duration of Response 
EC 
Ethics committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDP 
Exposure during pregnancy 
EGFR 
Epidermal growth factor receptor 
EMA 
European Medicines Agency 
EOD 
Evaluation of Disease 
 
 
EOT 
End of treatment 


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Abbreviation 
Term 
FDA 
Food and Drug Administration (United States) 
FT4 
Free thyroxine 
FU 
Follow-up 
G 
Grade 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
HAMA 
Human Anti-Murine Antibodies 
HBc 
Hepatitis B core 
HbsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis C virus 
IB 
Investigator’s brochure 
ICH 
International Conference on Harmonization 
iCPD 
Immune confirmed progression disease 
ID 
Identification 
IHC 
Immunohistochemistry 
IFN-γ 
Interferon gamma 
INR 
International normalized ratio 
IO 
Immuno-oncology 
IP 
Investigational product 
iPR 
Immune partial response 
IRB 
Institutional review board 
iRECIST 
Immune Response evaluation criteria in solid tumors 
iSD 
Immune stable disease 
IUD 
Intrauterine device 
iUPD 
Immune unconfirmed progression disease 
IV 
Intravenous 
LDH 
Lactate dehydrogenase 
LFT 
Liver function test 
mAB 
Monoclonal antibody 
MHC 
Major histocompatibility complex 
MOA 
Mechanism of action 
MOH 
Ministry of Health 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
Nab 
Neutralizing Antibodies 
NAP  
Naptumomab estafenatox 
NGS 
Next Generation Sequencing 
NSCLC 
Non-small cell lung cancer 
ORR 
Objective Response Rate 


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Abbreviation 
Term 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cells 
PD 
Pharmacodynamics 
PD 
Progressive Disease 
PD-1 
Programmed death 1 
PD-L1 
Programmed death ligand 1 
PFS 
Progression-free survival 
PK 
Pharmacokinetics 
p.o. 
By mouth 
PR 
Partial response 
PS 
Performance Status 
PT 
Prothrombin time 
RECIST 
Response evaluation criteria in solid tumors 
RNA 
Ribonucleic acid 
RP2D 
Recommended Phase 2 dose 
R/R 
Relapsed/Refractory 
SAE 
Serious adverse event 
Sag 
Superantigen 
SAP 
Statistical analysis plan 
SCC 
Squamous Cell Carcinoma 
SD 
Stable disease 
SmPC 
Summary of Product Characteristics 
TEAE 
Treatment Emergent Adverse Event 
TMB 
Tumor mutational burden 
TNF- α 
Tumor necrosis factor alpha 
TRBV 
T cell receptor beta variable 
TSH 
Thyroid-stimulating hormone 
TTS 
Tumor-targeted superantigen 
ULN 
Upper limit of normal 
US 
United States 
USP 
United States Pharmacopeia 
WBC 
White blood cell 
WFI 
Water for injection 
 
 
 
 
 
 


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SIGNATURES 
 
Signature of Sponsor Representative 
 
PHASE 2 OPEN-LABEL, MULTICENTER TRIAL OF NAPTUMOMAB 
ESTAFENATOX (NAP) IN COMBINATION WITH DOCETAXEL FOLLOWING 
OBINUTUZUMAB PRETREATMENT IN SUBJECTS WITH CHECKPOINT 
INHIBITOR PRETREATED ADVANCED OR METASTATIC NON-SMALL CELL 
LUNG CANCER 
 
 
I have read and approve the protocol and appendices. My signature, in conjunction with the 
signature of the Investigator, confirms the agreement of both parties that the clinical trial will be 
conducted in accordance with the protocol and all applicable laws and regulations, including, but 
not limited to, the International Council on Harmonization (ICH) Guidelines for GCP and the 
ethical principles that have their origins in the Declaration of Helsinki, as well as all applicable 
privacy laws. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature : 
  
 
 
 
 
 
 
 
 
Ilana Lorber, MD 
 
 
Medical Director 
 
Date :  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Signature of Investigator 
 
PHASE 2 OPEN-LABEL, MULTICENTER TRIAL OF NAPTUMOMAB 
ESTAFENATOX (NAP) IN COMBINATION WITH DOCETAXEL FOLLOWING 
OBINUTUZUMAB PRETREATMENT IN SUBJECTS WITH CHECKPOINT 
INHIBITOR PRETREATED ADVANCED OR METASTATIC NON-SMALL CELL 
LUNG CANCER 
 
I declare that I have read and understood this study protocol. I agree to abide by this protocol 
(subject to any amendments agreed in writing between the Sponsor and Principal Investigator). 
Any changes in procedure will only be made, if necessary, to protect the safety, rights, or welfare 
of the subjects. I agree to treat all subjects entered in the study as per protocol and keep the 
appropriate records and documentation required. I will ensure that all staff participating in the 
study will be appropriately trained and informed about the study. 
 
Study NT-NAP-102-1 is being conducted in compliance with the protocol, International 
Conference on Harmonization Good Clinical Practice E6 (ICH-GCP), and the applicable 
regulatory requirements in the United States. Some of these requirements include: 
 
• 
U.S. Code of Federal Regulations applicable to clinical studies (45 CFR 46 and 21 CFR 
including parts 50 and 56 concerning informed consent and IRB regulations) 
 
It is agreed that the conduct and results of this study will be kept confidential. 
  
This trial will be conducted under an IND. It is agreed that the study will not be initiated without 
the approval of the Institutional Review Board (IRB).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Principal Investigator Name:  
 
 
 
 
 
 
 
Signature: 
 
 
 
 
 
 
 
 
 
Date:  
 
 
 
 
 
 
 
 
 
 
 
 


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PROTOCOL SYNOPSIS 
 
PROTOCOL TITLE 
PHASE 2a OPEN-LABEL, MULTICENTER, TRIAL OF NAP IN 
COMBINATION WITH DOCETAXEL FOLLOWING OBINUTUZUMAB 
PRETREATMENT IN SUBJECTS WITH CHECKPOINT INHIBITOR 
PRETREATED ADVANCED OR METASTATIC NON-SMALL CELL 
LUNG CANCER 
PROTOCOL NO. 
NT-NAP-102-1 
PHASE 
2a 
INVESTIGATIONAL 
TREATMENT 
NAP  
BACKGROUND AND 
RATIONALE 
Prior to the era of checkpoint inhibitors (CPIs), docetaxel given as a 
single agent was found to prolong survival vs. best supportive care, 
despite a marginal effect on response rate, in patients with NSCLC 
previously treated with a platinum-based combination chemotherapy 
regimen (1). More recently, PD-1 and PD-L1 inhibitors were shown to 
further improve overall survival (OS) vs. docetaxel (2)(3)(4)(5). OS, 
including squamous and non-squamous NSCLC, was about 12 months 
for the CPIs vs. about 9 months for docetaxel, while there was no 
difference in progression -free survival (PFS). At 12 months, however, 
the estimated PFS rates were generally around 20% for the CPIs and 
10% for docetaxel; the PFS rate at 6 months with docetaxel was 
approximately 30%. Overall, the response rates to CPIs varied 
between 14% and 20%, while the response rates to docetaxel varied 
between 9% and 13%. Docetaxel remains a standard of care for 
patients previously treated with CPIs. 
NAP is a recombinant protein with a Fab moiety targeting the 5T4 
antigen fused with a genetically engineered superantigen moiety (6). 
The 5T4 antigen is an oncofetal glycoprotein that is upregulated in 
most NSCLC (6)(7)(8). It is also present on stem cells. The 
superantigen is responsible for initiating the inflammatory reaction 
that leads to tumor cell kill. In a first step, the bridging of T cell 
receptors and MHC class 2 molecules by the superantigen results in 
the activation and expansion of T-cells, primarily in peripheral lymph 
nodes, outside of the immunosuppressive tumor environment. In the 
case of NAP, the superantigen has been specifically designed to bind 
very selectively to the subset of T-cells expressing the TCRVβ 6.4 
(TRBV 7-9) sequence on their T cell receptor, avoiding non-specific T 
cell over-stimulation. In a second step, the traffic of T-cells is 
redirected towards tumors expressing the 5T4 antigen bound to NAP, 


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resulting in tumor infiltration and, ultimately, tumor cell kill. This 
mechanism of action is unique. This is a native immune response with 
the tumor being recognized as a bacterial product. In preclinical in 
vivo models, a murine version of NAP was found to result in 
synergistic antitumor activity in combination with docetaxel and 
checkpoint inhibitors (9)(10)(11)(12). 
More than 300 patients have been treated with NAP, providing an 
extensive safety data base, but experience in NSCLC has been limited. 
In a small dose escalation trial of NAP and docetaxel in combination, 
one patient with an adenocarcinoma of the lung and liver metastases 
achieved a partial response for 10+ years. That patient had shown clear 
resistance to a prior docetaxel regimen (13). 
Antibodies binding to NAP (anti-SEA/E-120) may interfere with the 
exposure and activity of NAP. Low levels of anti-drug antibodies 
(ADAs) may be present at baseline, but these levels do increase after 
initial exposure to NAP, potentially resulting in significant reduction 
in NAP blood levels in subsequent treatment cycles. Obinutuzumab 
(14)(15), a new-generation, glycoengineered, humanized type 2 anti-
CD20 monoclonal antibody currently approved for the treatment of 
chronic lymphocytic leukemia and follicular lymphoma, depletes B 
cells and can eliminate the formation of ADAs, presumably without 
adversely impacting on T cell activation nor on dosing, activity or 
safety of NAP. In vitro studies have shown that T cells are activated 
and expand in similar frequencies when cultured with B cells, 
monocytes or both (16). In fact, CD14+ monocytes demonstrated a 
higher capacity to mediate the activation and expansion of TRBV7-9+ 
T cells as compared to B cells. These observations suggest that CD14+ 
monocytes alone can efficiently mediate NAP activation and 
expansion of TRBV7-9+ T cells in human blood. Hence, when given 
as a pretreatment, obinutuzumab, is expected to prevent the occurrence 
of ADAs and may result in more prolonged exposure to NAP, 
therefore potentially enhancing its antitumor activity. In this trial, 
obinutuzumab will be given once, over 2 days, on days -13 and -12 
prior to the first cycle of treatment with the combination of NAP and 
docetaxel. Additional administrations of obinutuzumab may be 
considered during the study based on biomarkers collected and B cell 
level.  
OBJECTIVES 
Primary Objectives 
• To describe the objective response rate (ORR) and duration of 
response (DOR) with the combination of NAP / docetaxel, 


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following obinutuzumab pre-treatment in subjects with 
checkpoint inhibitors pre-treated NSCLC 
 
Secondary Objectives 
• To describe the safety profile of the combination of NAP / 
docetaxel, following obinutuzumab pretreatment in subjects 
with relapsed/refractory (R/R) NSCLC  
• To evaluate the overall survival (OS) defined as the time from 
day 1 of treatment until death due to any cause 
• To assess the possible impact of prior taxane exposure on the 
antitumor activity of the NAP/docetaxel combination 
• To describe the effect of obinutuzumab pretreatment on the 
development of anti-drug antibodies and human anti-mouse 
antibodies to NAP  
• To describe blood levels over time of NAP when administered 
after B-cell suppression 
 
Exploratory Objectives 
• To evaluate and characterize the pharmacodynamic effect of 
NAP /docetaxel on biomarkers in the circulation in subjects pre-
treated with obinutuzumab  
 
• Clinical activity in relationship to biomarkers including 5T4, 
NGS results, TMB expression and PD-L1 level in the tumor. 
 
STUDY DESIGN 
This is an open-label, multicenter, phase 2a clinical trial of the 
combination of NAP /docetaxel following pretreatment with 
obinutuzumab in subjects with NSCLC who have progressive 
neoplastic disease despite having been treated with at most 2 prior 
systemic therapies, including a checkpoint inhibitor; approximately 35 
subjects will be entered for efficacy analysis of 28 evaluable subjects. 
Subjects will receive obinutuzumab, 1,000 mg, administered by IV 
infusion on Days -13 and -12 of the first treatment cycle, in order to 
reduce the titer of anti-drug antibodies to NAP. Additional 
administrations of obinutuzumab may be considered during the study 
based on biomarkers collected and B cell level. If an increase back to 
the normal level of B cell level is observed, additional biomarkers and 
PK level will be tested in the following visit. NAP will be 
administered in a dose of 10 μg/kg/day by IV bolus on Days 1 – 4 of 
treatment cycles 1-6, followed by docetaxel, 75 mg/m2 on Day 5. 


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Treatment cycles with the combination NAP/docetaxel will be 21 days 
in duration. Growth factors may be used at the discretion of the 
investigators. The combination of NAP and docetaxel will be given 
for a maximum of 8 cycles (unless, in the opinion of the investigator, 
the patient may derive benefit from continuing docetaxel). Starting 
Cycle 7, NAP at a higher dose of 15 μg/kg will be administered on 
Day 1 and docetaxel on Day 2, in 21 days treatment cycles. Once NAP 
is given as monotherapy and not earlier than C7, cycles will be of 28 
days of duration. In patients whose NAP dose was reduced due to 
toxicities during cycles 1-6, NAP dose will not be further increased in 
cycle 7. Dose increase to 15 μg/kg in advanced cycles is not expected 
to increase NAP toxicity profile, as NAP related toxicities 
predominantly occur on cycles 1-2, and this dose increase may 
overcome ADA formation with time. NAP as a single agent will be 
continued until disease progression, untoward toxicity or non-
compliance for a maximum of up to 24 months from day 1 of therapy.  
Subjects will be screened to assess eligibility within 14 days prior to 
entry. Subjects must have received at least 1 and no more than 2 prior 
systemic regimens for the treatment of advanced/metastatic NSCLC. 
Patients are required to have progressed following treatment with both 
platinum-based 
chemotherapy 
and 
an 
anti-PD-L1 
antibody 
administered either sequentially or concurrently. A prior PD-1/PD-L1 
inhibitor is, however, not required if there was prior exposure to 
targeted therapies for driver mutation positive tumors (e.g. EGFR or 
ALK inhibitors).  Entry into this trial is restricted to patients with 
incurable disease, including those who relapse within 6 months from 
chemoradiotherapy for Stage III disease. Subjects will have available 
archival or fresh tissue collected for the retrospective determination of 
tumoral 5T4 levels.  
Subjects will be assessed for the primary efficacy endpoint of 
objective response rate (ORR) according to the iRECIST criteria. 
Response duration is also a focus of interest in this study. In addition, 
disease control rate, combining the ORR with subjects demonstrating 
stable disease (SD), progression-free survival (PFS), PFS rate at 6 and 
12 months and overall survival (OS) will also be determined. If 
available, NGS results, TMB expression and PD-L1 levels will be 
collected for the expression of exploratory tumor biomarkers. 
Ongoing study imaging will be performed at the end of cycle 2 (45 ± 
7 days) and every 6 weeks for the first 24 weeks and then every 9 
weeks (± 7 days) thereafter. Confirmatory scans for responses (PR or 
CR) will be performed after 6 weeks (± 7 days) during the first 24 


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weeks and every 9 weeks thereafter. As NAP is known to induce an 
inflammatory reaction in the tumor, pseudo-progression may be 
observed and therefore, in patients who demonstrate objective 
progression but who are clinically stable, 1-2 additional treatment 
cycle(s) of NAP/docetaxel may be administered beyond progression 
at the discretion of the Investigator, followed by a confirmatory 
imaging as per the original schedule, every 6 weeks (± 7 days) 
during the first 24 weeks and every 9 weeks (± 7 days) thereafter.  
The safety of the combination of NAP /docetaxel following 
pretreatment with obinutuzumab in a B-cell suppressed setting will be 
assessed in all treated subjects including adverse events, the results of 
ECGs, results of laboratory determinations, findings on physical 
exams, vital signs and reporting of the ECOG Performance Score. All 
treatment emergent AEs (TEAEs), drug-related AEs, SAEs and drug-
related SAEs as well as hematology and chemistry lab results will be 
summarized using the worst grade per subject according to the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0. 
The pharmacokinetics of NAP will be based on plasma drug levels 
obtained at various timepoints after administration.  
The pharmacodynamics of the combination of NAP /docetaxel 
following pretreatment with obinutuzumab will be determined by 
measuring levels of cytokines (e.g., IL-2, IFNγ, IL-6 and TNFα) in 
serum. 
The immunogenicity of NAP will be assessed based on levels of anti-
drug antibodies and human anti-murine antibodies (HAMA) collected 
at various times after administration of NAP. Neutralizing antibodies 
(Nab) will be also collected and kept for future analysis.  
The primary efficacy endpoint of this trial is ORR. A Simon 2-stage 
design will be used with the following assumptions: H0=10%. H1= 
30%, α=0.05 and power=0.80. Accordingly, the target accrual is 29 
subjects. Subjects who discontinue from treatment for any reason will 
continue to be followed for survival (even if the subject receives 
subsequent anti-neoplastic therapy). Subjects will be followed for 
survival until 6 months after the last subject has completed study 
treatment. Subjects who discontinue from treatment for reasons other 
than progression will continue to be followed for progression by 
CT/MRI scans every 6 weeks for the first 24 weeks, every 9 weeks 
thereafter; if such a subject receives subsequent anti-neoplastic 


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therapy, further follow-up for progression will stop. A graphical 
description of the trial is depicted below (Fig. 1). 
 
+
 
* Starting Cycle 7, NAP at a higher dose of 15 μg/kg will be administered on Day 1 and docetaxel on Day 2, in 21 days 
treatment cycles. Once NAP is given as monotherapy and not earlier than C7, cycles will be of 28 days of duration. In patients 
whose NAP dose was reduced due to toxicities during cycles 1-6, NAP dose will not be further increased in cycle 7. 
 
Figure 1.  Study Schema 
PLANNED NUMBER 
OF SUBJECTS 
The trial will enroll approximately 35 subjects.  
PLANNED NUMBER 
OF STUDY SITES 
Approximately 10 study sites in the US will participate in the trial.  
ENROLLMENT 
CRITERIA 
Inclusion Criteria 
Subjects must meet ALL of the following criteria to be eligible for 
enrollment into the study: 
1. Subjects must be at least 18 years of age 
2. Subjects must have histologically and/or cytologically confirmed 
NSCLC  
3. Subjects must have incurable (advanced or metastatic) disease at 
the time of enrolment (Patients who relapse within 6 months from 
chemoradiotherapy for stage III disease are considered incurable) 
                                                        
                                             
       
      
              
       
                   
                     
                   
         
                          
                   
                              
  
                         
                            
                
                
 
   
                    
 
                
 
                     
 
   
 
                
            
                                                                                                                              
                  
                                                                                                                            
                       
                                                                     
*


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4. Subjects must have an Eastern Cooperative Oncology Group 
(ECOG) Performance Status of 0 or 1 
5. Subjects must provide signed informed consent prior to any study 
specific procedures that are not part of standard medical care.  
6. Subjects must have measurable neoplastic disease based on the 
iRECIST criteria 
7. Subjects must have received at least 1 and no more than 2 prior 
systemic regimens for the treatment of advanced/metastatic 
NSCLC. Patients are required to have progressed following 
treatment with both platinum-based chemotherapy and an anti-
PD-(L)1 
antibody 
administered 
either 
sequentially 
or 
concurrently. A prior PD-1/PD-L1 inhibitor is, however, not 
required if there was prior exposure to targeted therapies for  
driver mutation positive tumors (e.g. EGFR or ALK inhibitors).  
8. Subjects must have adequate hematologic and organ function:  
• WBC ≥3000/µL  
• Absolute neutrophil count ≥1500/µL  
• Platelets ≥100,000/µL 
• Hemoglobin ≥9.0 g/dL  
• Serum creatinine ≤1.5 mg/dL or calculated creatinine 
clearance (CL) >40 mL/min, as determined by Cockcroft-
Gault (using actual body weight) 
•  AST < 1.5 X ULN; ALT < 1.5 X ULN; Alk phos < 2.5 X 
ULN; bilirubin must be within normal limits 
• 
International Normalized Ratio (INR) or prothrombin time 
(PT) and activated partial thromboplastin time (aPTT) ≤1.5 X 
ULN unless subject is receiving anticoagulant therapy and the 
INR, PT or PTT is within therapeutic range of intended use of 
anticoagulants  
9. Subjects must be willing and able to comply with scheduled visits, 
procedures, drug administration plan, etc. as outlined in the 
protocol 
10. Subjects should have an estimated life expectancy of at least 12 
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11. Archival or fresh tumor tissue from a biopsy of a tumor lesion 
not previously irradiated must be provided for retrospective 5T4 
analysis, unless discussed with the Medical Monitor. 
 
Exclusion Criteria 
1. Subjects with active infection requiring treatment within 3 days of 
C1D1. 
2. Subjects with other active neoplastic disease requiring concurrent 
anti-neoplastic treatment 
3. Subjects with known, suspected or documented parenchymal 
brain metastases unless treated with surgery and/or radiation, with 
the subject neurologically stable and off pharmacologic doses of 
systemic 
glucocorticoids; 
subjects 
with 
leptomeningeal 
metastases are not eligible. Patients should have completed brain 
radiation for at least 14 days and be off steroids per exclusion 
criteria 7. 
4. Active or previously documented autoimmune or inflammatory 
disorders such as, but not limited to rheumatoid arthritis, systemic 
lupus erythematosus, uveitis, ulcerative 
colitis, 
Crohn’s 
syndrome, Wegener’s syndrome, multiple sclerosis, myasthenia 
gravis, scleroderma and sarcoidosis. The following are exceptions 
to this criterion:  
• Vitiligo or psoriasis not requiring systemic treatment (within 
the last 2 years)  
• Subjects with endocrinopathies (e.g. following Hashimoto 
syndrome) stable on hormone replacement or do not require 
any therapy. 
5. History of primary immunodeficiency 
6. Subjects with a history or prior allogeneic organ transplant 
7. The use of immunosuppressive agents within 28 days of 
enrolment (D-13; obinutuzumab pre-treatment) including, but not 
limited 
to, 
cyclosporine, 
mycophenolate, 
azathioprine, 
methotrexate, adalimumab, infliximab, vedolizumab, tofacitinib, 
dupilumab, 
rituximab, 
etc. 
Pharmacologic 
doses 
of 
glucocorticoids defined as glucocorticoid equivalents of >10 
mg/day of prednisone (with the exception of systemic steroids 
given as a premedication before each of the study medications, or 
used prior to administration of radiographic contrast material in 


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subjects with allergies) are not acceptable within 14 days prior to 
enrollment. Subjects are permitted to receive topical, intranasal, 
inhalational and intra-ocular glucocorticoids. 
8. Subjects who have uncontrolled inter-current illness, including but 
not limited to, ongoing or active infection, symptomatic 
congestive heart failure, uncontrolled hypertension, unstable 
angina pectoris, uncontrolled cardiac arrhythmia, active interstitial 
lung disease, serious chronic gastrointestinal conditions 
associated with diarrhea, or psychiatric illness/social situations 
and substance abuse that would limit compliance with study 
requirement, substantially increase risk of incurring AEs or 
compromise the ability of the subject to follow the dictates of the 
protocol.  
9. Subjects who have received a live attenuated vaccine within 28 
days prior to the first dose of obinutuzumab. 
10. Subjects with hepatitis B (positive HBV surface antigen 
[HBsAg]), hepatitis C (hepatitis C antibody) or HIV (HIV 
antibody). Subjects with a past or resolved HBV infection (defined 
as the presence of hepatitis B core antibody [anti-HBc] and 
absence of HBsAg) are eligible; subjects positive for hepatitis C 
(HCV) antibody who have completed a course of antiviral therapy 
are eligible if polymerase chain reaction (PCR) is negative for 
HCV RNA. 
11. Female subjects who are pregnant or breastfeeding.  
12. Male or female subjects of reproductive potential who are not 
willing to employ effective birth control from Screening to 90 
days after the last dose of study treatment. Highly effective 
methods of contraception are defined as one that results in a low 
failure rate (e.g., less than 1% per year) when used consistently 
and correctly.  
13. Prior 
treatment 
with 
chemotherapy 
or 
other 
systemic 
antineoplastic therapy within 21 days; experimental therapy 21 
days or 5 half-lives, whichever is shorter. All prior treatments 
should be completed 21 days prior to enrollment (D-13; 
obinutuzumab pre-treatment). 
14. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous 
anticancer therapy with the exception of alopecia, vitiligo, and the 
laboratory values defined in the inclusion criteria. 


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15. Subjects who have undergone major surgery or trauma within 4 
weeks of study entry (D-13; obinutuzumab pre-treatment).  
16. Subjects with Grade 2 neuropathy will be evaluated on a case-by-
case basis after consultation with the Medical Monitor. Subjects 
with neuropathy grade >2 are not eligible. 
17. Subjects who have been treated with one of the study drugs (NAP 
and/or docetaxel). 
18. Subjects with NYHA Class III or IV CHF, myocardial infarction 
or acute coronary syndrome within 6 months prior to study 
enrollment, ongoing angina pectoris, severe peripheral vascular 
disease, CVA within 6 months of study enrollment or any other 
concomitant medical disorder that might interfere with the 
subject’s participation in the trial or interpretation of the study 
data. 
19. Mean QT interval corrected for heart rate using Fridericia's 
formula (QTcF) ≥470 ms in women and ≥450 ms in men, 
calculated from 3 ECGs (within 15 minutes at 5 minutes apart).  
20. Subjects on strong inducers or inhibitors of CYP3A4. 
21. Known allergy or hypersensitivity to any of the study drugs or any 
of the study drug excipients (including kanamycin). 
22. Subjects 
with 
a 
history 
of 
progressive 
multifocal 
leukoencephalopathy (PML).  
INVESTIGATIONAL 
PRODUCTS 
Obinutuzumab will be supplied in a single-dose vial containing 1,000 
mg in 40 mL of preservative free solution. The obinutuzumab solution 
must be stored at 2 – 80 C.  
 
NAP will be supplied as 1.25 mg of a lyophilized powder in a 10 mL 
single-use glass vial to be reconstituted with 1.2 mL of WFI supplied 
in a second vial, after which the concentration of NAP will be 1 
mg/mL. The lyophilized NAP must be stored at 2 – 80 C. 
 
Docetaxel will be obtained commercially 
TREATMENT 
REGIMEN AND 
DURATION 
Treatment cycles will be 21 days in duration with NAP/docetaxel 
combination. Once NAP is given as monotherapy and not earlier than 
C7, cycles will be of 28 days of duration.  
 


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Obinutuzumab further diluted in normal saline is to be administered 
on Day -13 of the first cycle in a dose of 1,000 mg at a rate of 50 
mg/hr, with the rate of infusion increased in 50 mg/hr increments 
every 30 minutes to a maximum rate of 400 mg/hr. On Day -12 of the 
first cycle, obinutuzumab is to be administered in a second dose of 
1,000 mg. If no infusion reaction occurred during the previous 
infusion when the rate of administration was 100 mg/hr or faster, 
administer the second infusion starting with a rate of 100 mg/hr with 
the rate of infusion increased in 100 mg/hr increments every 30 
minutes to a maximum of 400 mg/hr.  Additional administrations of 
obinutuzumab may be considered during the study based on 
biomarkers collected and B cell level. 
 
NAP will be administered in a dose of 10 μg/kg daily X 4 on Days 1 
– 4 of  treatment cycles 1-6. NAP-docetaxel combination treatment 
will continue for a maximum of 8 cycles (unless, in the opinion of the 
investigator, the patient may derive benefit from continuing 
docetaxel). Starting Cycle 7, NAP at a higher dose of 15 μg/kg will be 
administered on Day 1 and docetaxel on Day 2, in 21 days treatment 
cycles. Once NAP is given as monotherapy and not earlier than C7, 
cycles will be of 28 days of duration. In patients whose NAP dose was 
reduced due to toxicities during cycles 1-6, NAP dose will not be 
further increased in cycle 7. NAP as a single agent will be continued 
until disease progression, untoward toxicity or non-compliance for a 
maximum of up to 24 months from day 1 of therapy. The reconstituted 
solution will be further diluted with a supplied diluent to reach the 
required dose for administration. Fully diluted NAP will be 
administered as an IV bolus injection.  
 
Docetaxel will be administered in a dose of 75 mg/m2 on day 5 of 
every 3 weeks cycle as an IV infusion over 1 hour for a maximum of 
8 cycles (unless, in the opinion of the investigator, the patient may 
derive benefit from continuing docetaxel) or until progression, 
untoward adverse reactions or non-compliance, whichever comes 
first. During cycles 1-6 docetaxel will be given on Day 5, and on Day 
2 if given in any further cycles.  
Premedication regimens before each of the study drugs will be 
detailed in the full protocol. 
STATISTICAL 
CONSIDERATIONS 
The primary endpoint is ORR. A subject is considered evaluable if 
there is at least one pre-treatment and one post-treatment tumor 


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AND SAMPLE SIZE 
DETERMINATION 
assessment (according to the iRECIST criteria) in the absence of 
eligibility and compliance issues. iRECIST requires the confirmation 
of progression and uses the terms iUPD (unconfirmed progression) 
and iCPD (confirmed progression). Confirmatory scans will be 
performed as per the original schedule, every 6 weeks (± 7 days) 
during the first 24 weeks and every 9 weeks (± 7 days) thereafter. 
Sample size is derived from a Simon’s Optimal two-stage design 
testing the null hypothesis H0: true ORR ≤ 0.10 versus the 
alternative H1: true ORR ≥ 0.30. With one-sided alpha = 0.05 and 
power = 0.80, 6 or more responses in a total of 29 subjects may be of 
further clinical interest. The trial may be stopped if there is a single 
responder or no responder in the first 10 patients. 
STATISTICAL 
ANALYSES 
Descriptive statistics will be used to describe the results of the trial. 
Continuous variables will be summarized by reporting the number of 
observations, mean, standard deviation, median, minimum and 
maximum. Categorical/discrete variables will be summarized using 
frequency tables showing the number and percentage of subjects 
within a particular category 
EFFICACY 
EVALUATION 
Overall response rate (ORR) is the proportion of subjects who achieve 
a best response of iCR or iPR by iRECIST. ORR will be calculated in 
all evaluable patients, and in all treated subjects. Immunotherapy may 
result in infiltration of immune cells leading to transient increase in 
the size in malignant lesions, or undetectable lesions becoming 
detectable. The criteria are identical to those of RECIST 1.1 in many 
respects but have been adapted to account for instances where an 
increase in tumor burden, or the appearance of new lesions, does not 
reflect true tumor progression. iRECIST requires the confirmation of 
progression, which should be done after 6 weeks (± 7 days) during the 
first 24 weeks and every 9 weeks thereafter. 
The ORR with corresponding exact 95% confidence intervals, will be 
summarized.  
Disease control rate, duration of response, progression free survival 
(PFS) and overall survival (OS) will be analyzed as well. 
Time-to-event data will be estimated and summarized using the 
Kaplan-Meier method. 
SAFETY 
EVALUATION 
Safety will be evaluated in all treated subjects.  
 


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The safety assessments will include treatment-emergent adverse 
events (TEAEs), volunteered, observed, and elicited by general 
questioning in a non-suggestive manner.  
TEAEs will be graded according to NCI CTCAE version 5.0, grouped 
by MedDRA preferred term, and summarized by worst grade severity 
per subject.  
Serious AEs will be tabulated and summarized.  
Other AEs leading to discontinuation of study therapy or any other 
premature interruption will be tabulated and summarized.  
Clinical laboratory results will be collected pretreatment through 30 
days after the last administration of any study treatment and prior to 
start of a new anti-cancer treatment.  
Clinically significant laboratory abnormalities, namely tests that result 
in treatment modification and/or require intervention, will be recorded 
as AEs.  
Where applicable, laboratory results will be classified according to the 
NCI CTCAE and will be summarized by worst grade per subject. 
Additional safety assessment will include physical examinations, vital 
signs, and ECG. 
No statistical tests will be performed for any of the safety assessments. 
PHARMACOKINETIC 
EVALUATION  
 
PK analysis will be performed on the PK population (i.e. enrolled 
subjects, with analyzable PK data and without relevant deviation 
interfering with the PK evaluations) 
PHARMACODYNAMIC 
EVALUATION  
 
The following parameters and the corresponding change from baseline 
will be measured and summarized by descriptive statistics and data 
listings for the NAP /docetaxel treatment:  
• Cytokine levels  
• B-cell levels 
• 
Anti-drug antibodies and human anti-murine antibodies (ADA 
and HAMA) 
 
 


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1 
INTRODUCTION 
1.1 
Background and Rationale 
Although the incidence of lung cancer has diminished over the last several years in many 
developed countries, most likely due to reductions in tobacco use, lung cancer remains one of the 
most frequently occurring malignancies. For 2020, it is estimated that there will be over 225,000 
new cases of lung cancer and over 135,000 deaths from lung cancer in the US; lung cancer remains 
the leading cause of cancer deaths in the US (17). Lung cancer also remains the most frequently 
reported cancer, and the leading cause of cancer deaths, worldwide (18). The most common type 
of lung cancer, non-small cell lung cancer (NSCLC), represents about 80% of all lung 
malignancies.  
For subjects with NSCLC whose tumors harbor known genetic mutations, agents targeted to these 
mutations have resulted in significant improvements in treatment. Third generation agents targeted 
to the epidermal growth factor receptor, such as osimertinib, result in objective response rates 
(ORR) of over 75% and produce progression-free survival (PFS) times of over 18 months (19). 
Unfortunately, most of these subjects ultimately relapse, as additional driver mutations evolve in 
their tumors.  
The checkpoint inhibitor class of agents has probably had the most impact on outcomes in subjects 
with NSCLC, both in the 1st and 2nd line settings. Marked improvement in response rates, durations 
of response, progression-free survival times and overall survival times have been demonstrated by 
several checkpoint inhibitors when compared to standard platinum-based doublet therapy or to 
docetaxel. The degree of improvement in many of these outcomes, however, is often dependent 
on tumor proportional PD-L1 scores or the extent of tumor mutational burden and not all subjects 
derive benefit (20). Low tumor mutational burden (TMB) and low expression of PD-L1 have been 
associated with a high level of resistance to these inhibitors (24, 25). Lack of neoantigens on the 
tumor surface believed to attribute to anti PD-(L)1 resistance. Low TMB is a surrogate for the lack 
of neoantigens. NAP targeting causing tumor cells being covered by a superantigen, activates, 
expands, and redirects a subset of T-cells towards the tumor and generating tumor inflammation. 
This mechanism of action may presumably overcome tumor resistance to anti PD-(L)1 treatment 
also in the setting of low TMB.   
Docetaxel as a single agent remains the standard of care for patients who have failed platinum-
based regimens, targeted agents and checkpoint inhibitors. As a single agent versus best supportive 
care, docetaxel was found to prolong survival, despite a marginal effect on response rate (1). In 
more contemporaneous studies comparing checkpoint inhibitors to docetaxel in patients failing 
platinum-based regimens, OS, including squamous and non-squamous NSCLC, was about 12 
months for the CPIs vs. about 9 months for docetaxel, while there was no difference in progression 
-free survival (PFS) (2)(3)(4)(5). At 12 months, however, the estimated PFS rates were generally 
around 20% for the CPIs and 10% for docetaxel; the PFS rate at 6 months with docetaxel was 
approximately 30%. Overall, the response rates to CPIs varied between 14% and 20%, while the 
response rates to docetaxel varied between 9% and 13%. Docetaxel remains a standard of care for 
patients previously treated with CPIs, but it is clear that there remains a need for additional novel 
therapies for the treatment of NSCLC. 


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1.2 
Naptumomab estafenatox (NAP) 
Naptumomab estafenatox (ABR-217620; NAP) was developed to activate and target subjects’ T-
cells to their own tumors, by fusing a superantigen (SAg) variant that activates T lymphocytes to 
the Fab moiety recognizing the tumor-associated oncofetal antigen 5T4, with the objective of 
eliciting a potent tumoricidal cytotoxic T cell response (6). The SAg moiety selectively engages 
the T cell receptor β variable (TRBV) 7-9. NAP has been engineered to have a low binding to 
human antibodies and to minimize killing of MHC class II positive cells. 
The 5T4 antigen is a 72 kDa oncofetal trophoblast transmembrane glycoprotein that is broadly 
expressed on tumor cells of solid tumors but has very low expression on normal adult tissues (7). 
It is also expressed on cancer stem cells which are hypothesized to be responsible for 
chemotherapeutic resistance and recurrence of cancer. Significant upregulation of 5T4 has been 
reported in many types of carcinomas (6)(7)(8). Studies have shown a homogenous 5T4 
expression, which in most cases is moderate to strong, in more than 95% of NSCLC tissue samples. 
The expression of 5T4 has been shown to influence adhesion, cytoskeletal organization, and 
motility, properties that might account for the 5T4 association with poorer clinical outcome in 
some cancers. The biology of 5T4 in normal and pathologic tissues is not well understood. No 
ligands or co-receptors have been identified for 5T4 to date and there is no evidence of circulating 
5T4 antigens. 
NAP ’s superantigen moiety represents the culmination of a long development program in which 
genetically engineered versions of superantigen were tested in the clinic until epitopes were found 
that can engage the immune system effectively without creating safety concerns such as cytokine 
storms. In pre-clinical and clinical studies, NAP has demonstrated recognition enhancement: it 
induced T cell expansion, activation and infiltration into the tumor without undo safety concerns 
(7). This effect of NAP makes it an ideal drug for combination with different cancer therapies 
including chemotherapy, checkpoint inhibitors and CAR T cells. 
 
1.3 
Naptumomab estafenatox (NAP) Mechanism of Action  
In the first phase of NAP treatment, T lymphocytes are activated and differentiate into effector 
cells (expansion phase, Fig. 2). In the second phase, the activated T cells localize and infiltrate to 
the tumor and mediate their anti-tumor actions (attack phase, Fig. 2). 
The expansion phase is mediated by the SAg moiety. Superantigens act as potent mitogens for 
human T cells. Unlike conventional antigens, these SAgs bind to MHC class II on antigen-
presenting cells (APC) outside of the conventional peptide-binding groove and stimulate T cells 
expressing specific TCR Vβ-chains, resulting in stimulation of a high proportion of T cells. SAgs 
activate both CD4 and CD8 T cells, and under certain circumstances CD4 T cells can also be 
cytotoxic to cells displaying the superantigen. Unlike the wild type superantigen, the SEA/E120 
moiety of NAP was designed to bind to a specific subset of T cells expressing TCRVβ 7.9 (TRBV 
7-9). NAP, via its SEA/E120 moiety, binds with intermediate/low affinity to the TCRVβ 7.9 and 
to MHC II, enabling the bridge between the T cell and APC. As a consequence, T cells are activated 


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and proliferate. Since only 2-5% of human T cells express TCR Vβ 7.9, this expansion phase is 
limited, ensuring a superior safety profile of the drug. 
In the second phase of NAP treatment, by binding to the 5T4 antigen on the tumor cells, NAP 
molecules act as guiding beacons for the SAg-activated T cells, directing them to the tumor 
microenvironment. The activated T cells bind to the cancer cells through TCR-SAg interaction 
which enables their activation and the resulting tumor killing by direct lysis of the engaged 5T4-
positive tumor cells and by indirect killing of the surrounding antigen-negative tumor cell variants 
by secretion of cytokines (paracrine effect) (6). NAP recognizes the 5T4 antigen with an affinity 
in the order of 1nM and induces T cell-mediated killing of tumor cells at concentrations around 10 
pM. 
 
 
Figure 2.  Mechanism of action of NAP 
 
1.4 
Pre-Clinical Antitumor Activity 
In vitro and in vivo studies have shown synergistic anti-cancer effect of NAP or NAP ’s surrogate 
murine molecule, C215Fab-SEA, in combination with checkpoint inhibitors (anti PD-(L)-1 and 
anti CTLA4) and cancer chemotherapeutic agents such as docetaxel (9)(10)(11)(12). Treatment of 
B16-C215 tumor bearing mice with the combination of C215Fab-SEA and docetaxel was found 
to be more effective in reducing the number of lung tumors as compared to mono therapies. 
Interestingly, it was shown that docetaxel at therapeutic doses did not interfere with superantigen 
induced T cell activation but rather appeared to enhance the response. Furthermore, C215Fab-SEA 
and docetaxel therapy synergistically prolonged long-term survival of the B16-C215 tumor bearing 
mice suggesting potential clinical benefit for the combined use (Fig. 3) (10). 


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Figure 3.  Synergistic anti-tumor activity of tumor targeted super antigen in combination with docetaxel 
against the B16 murine melanoma 
 
 


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1.5 
Clinical Studies 
1.5.1 Phase 1 Monotherapy Trial 
The safety and tolerability of NAP were assessed in a multicenter, multinational, open-label, phase 
1, dose-escalation study (N=39), involving single-agent NAP administered as a bolus injection in 
subjects with non-small cell lung cancer (N=20), renal cell carcinoma (N=11) or pancreatic cancer 
(N=8) at doses ranging from 0.5-27.4 µg/kg/day x 5 consecutive days (13).  
The pharmacokinetics of NAP showed a small volume of distribution (about 0.10 L/kg) and a low 
clearance (about 0.11 L/h/kg). The terminal half-life was determined to be about 1.1 h. Plasma 
concentrations seemed dose proportional. In most subjects, there was a low (0 - 100 pmol/mL) to 
intermediate (100 - 500 pmol/mL) increase in the levels of anti-SEA/E-120 antibodies prior to 
treatment cycle 2. There was a marked increase in the levels of blood cytokine levels 3 h after 
administration of NAP. Whereas the levels of IL-2 and IFN-γ were mainly increased during 
treatment cycle 1, the levels of IL-6 and IL-10 were also increased during treatment cycle 2. During 
treatment cycles 3 and 4, only effects on the levels of IFN-γ and IL-6 were detected. The TCR-Vβ 
profile from 15 subjects was determined at baseline and again on Day 12. A selective expansion 
of T cells expressing TCR-Vβ7.9 was observed on Day 12 compared to baseline. 
The most frequent adverse reactions were nausea, vomiting, diarrhea, hypotension, chills, and 
fever. The frequency and severity of AEs increased with increasing doses of NAP, but the majority 
of AEs (92%) were grade 1 or grade 2 in severity. Transient liver enzyme elevations were also 
encountered. Dose-limiting toxicities (DLTs) occurred at doses above 20 µg/kg/day x 5 and 
included fever, hypotension, liver toxicity and acute vascular leak syndrome. These DLTs were 
reversible with no significant long-term consequences during the entire follow-up duration of 5-6 
months. 
Fourteen subjects (36%) had stable disease (SD) on day 56: seven NSCLC (25%) and seven RCC 
(64%) subjects. The recommended phase 2 dosage was set at 15 μg/kg/day for subjects with RCC 
and 22 μg/kg/day for subjects with NSCLC and pancreatic cancer.  
 
1.5.2 Phase 1 Trial in Combination with Docetaxel in NSCLC 
Increasing doses of NAP (10.3, 16.5, 22 µg/kg) and docetaxel were administered to 13 subjects 
with advanced NSCLC. NAP was administered on Days 1 – 4 and docetaxel on Day 5 of each 
treatment cycle. Two patients achieved a partial response, and 5 achieved stable disease. One of 
the partial responders had demonstrated previous resistance to docetaxel and remained in 
remission for 10+ years. That patient had received NAP at the highest dose of 22 µg/kg. The most 
frequently reported AEs were fever, hypotension, nausea, chills tachycardia, neutropenia and 
asthenia. The majority (87%) of these AEs were grade 1 or grade 2 in severity. One subject 
required a dose reduction in docetaxel from 75 mg/m2 to 55 mg/m2 due to neutropenia. 
As with NAP monotherapy, there was a marked increase in the levels of blood cytokines 3 hours 
after administration. While IL-2 and IFNγ were primarily increased during Cycle 1, IL-6 and IL-
10 levels also increased during Cycle 2. Repeat tumor biopsies on treatment were obtained from 2 
subjects treated at the higher dose of NAP and demonstrated enhanced tumor-associated T-cell 
infiltration during NAP treatment; 1 of these subjects was the subject with the markedly prolonged 


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survival described above. Also, as with NAP monotherapy, the majority of subjects developed low 
to intermediate levels of anti-SEA/E-120 antibodies (13). 
 
1.5.3 Phase 2/3 
A randomized (1:1) phase 2/3 trial involving treatment of 513 subjects with renal cell carcinoma 
with NAP (15 µg/kg/day x 4 consecutive days on weeks 1, 9 and 17) and interferon alpha or 
interferon alpha alone did not meet its primary endpoint and failed to show a survival benefit for 
the tested combination (21). In a post-hoc exploratory subgroup analysis, subjects with less than 
the median concentrations of anti-NAP antibodies and IL-6, significantly benefitted from addition 
of NAP. In this subgroup, the median overall survival (OS)/progression-free survival (PFS) was 
63.3/13.7 months versus 31.1/5.8 months for the subjects receiving IFN alone (p=0.02, hazard 
ratio 0.59/p=0.02, hazard ratio 0.62). Most of the adverse events resulting from treatment with 
NAP, related to increased levels of cytokines. Pyrexia (61%), vomiting (37%), nausea (35%), 
chills (27%), and back pain (19.5%) were the more common adverse events reported in the NAP 
treatment arm. Grade 3 hypotension occurred in 2% of subjects. The adverse events were transient, 
often mild and no Grade 4 or 5 toxicities were observed.  
Antibodies binding to NAP (anti-SEA/E-120) may interfere with drug exposure and efficacy. At 
baseline, only low levels of anti-SEA/E-120 antibodies were detected. After the first treatment 
cycle, anti-SEA/E-120 concentrations were increased in the great majority of subjects, they 
increased by more than a 300-fold, in contrast to the phase 1 trials where only low to intermediate 
increases were detected for up to 4 treatment cycles. It was suggested that the combination of NAP 
with interferon alpha might actually have adversely affected the potential therapeutic effect of 
NAP. IFN-α is known to accelerate the formation of antidrug antibodies (ADA) (22), which might 
account for the high ADAs titers seen in the study, resulting in significant reduction in the NAP 
blood levels in cycles 2 and 3.  
 
1.6 
Dose Selection Rationale and Risk 
In the previously conducted phase 1 trials, no DLTs were observed at doses up to 20 µg/kg in the 
initial phase 1 trials. The most frequent adverse reactions consisted of nausea, vomiting, diarrhea, 
hypotension, chills, fever and back pain. Transient liver enzyme elevations were also encountered. 
Dose-limiting toxicities (DLTs) occurred at doses above 20 µg/kg/day x 5 and included fever, 
hypotension, liver toxicity and acute vascular leak syndrome. These DLTs were reversible with no 
significant long-term consequences.  
Antibodies binding to NAP (anti-SEA/E-120) may interfere with the exposure and activity of 
NAP. Low levels of anti-drug antibodies (ADAs) may be present at baseline but these levels are 
expected to increase after initial exposure to NAP, as has been seen in previous clinical trials, 
potentially resulting in significant reduction in NAP blood levels in subsequent treatment cycles. 
Obinutuzumab, a new-generation, glycoengineered, humanized type 2 anti-CD20 monoclonal 
antibody currently approved for the treatment of chronic lymphocytic leukemia and follicular 
lymphoma, depletes B cells and can eliminate the formation of ADAs, presumably without 
adversely impacting on T cell activation nor on dosing, activity or safety of NAP. Hence, when 


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given as a pretreatment, obinutuzumab, is expected to prevent the occurrence of ADAs and may 
result in more prolonged exposure to NAP, therefore potentially enhancing its antitumor activity. 
In this trial, obinutuzumab will be given once, over 2 days, prior to the first cycle of treatment with 
the combination of NAP and docetaxel. Additional administrations of obinutuzumab may be 
considered during the study based on biomarkers collected and B cells level. 
In an ongoing dose escalation and cohort expansion phase 1 trial of a 3-weekly regimen, NAP is 
given daily for 4 consecutive days in combination with durvalumab given on day 2 
(NCT03983954). NAP was tested at 5 dose levels of 2, 5, 10,15 and 20 µg/kg/day (N=19). Two 
of six patients treated at the highest dose level experienced a DLT on day 1, an excessive infusion 
reaction in the first patient and creatinine elevation in a second patient who already had an 
abnormal creatinine level at baseline. The MTD was established at 15 µg/kg/day. The trial then 
incorporated obinutuzumab pre-treatment at two dose levels of NAP, 10 µg/kg/day and 15 
µg/kg/day, with unremarkable safety findings (N=7).  Among these initial 26 patients, 4 achieved 
a RECIST response: 1 CR for 24+ months in pancreatic cancer, 1 CR in a patient with cervical 
cancer, 1 PR for 17+ months in hepatocarcinoma resistant to prior nivolumab and 1 PR for 13 
months in PD-L1 low peritoneal mesothelioma.  The trial went on with expansion cohorts treated 
with NAP 10-15 µg/kg/day in combination with durvalumab and obinutuzumab pretreatment. At 
the higher dose level of NAP, 3 out of 13 subjects experienced grade 3 infusion reactions related 
to NAP (fever, chills, dyspnea and hypotension), which led to treatment discontinuation.  In the 
total of 11 patients who received NAP 10 µg/kg/day in combination with durvalumab and 
obinutuzumab pretreatment, two subjects experienced grade 3 IRRs (chills in one patient and 
worsening of grade 2 dyspnea that predated NAP treatment in the other). No patients had treatment 
discontinuation for safety at that dose level of NAP. All those toxicities were manageable with 
appropriate medical treatment, rapidly reversible and without long-term sequelae. Based on this 
experience, the dose of 10 µg/kg/day for NAP has been selected as the recommended dose for the 
current trial. Dose increase to 15 μg/kg in advanced cycles is not expected to increase NAP toxicity 
profile, as NAP related toxicities predominantly occur on cycles 1-2, and this dose increase may 
overcome ADA formation with time. 
Additional information regarding NAP can be found in the current investigator’s brochure.  
 
1.7 
Obinutuzumab 
Obinutuzumab is a humanized anti-CD20 monoclonal antibody that recognizes a specific epitope 
of CD20 on B cells. Upon binding to CD20, obinutuzumab mediates B-cell lysis through 1) 
engagement of immune effector cells, 2) by directly activating intracellular death signaling 
pathways (direct cell death), and/or 3) activation of the complement cascade. It is currently 
indicated for the treatment of chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL) 
and is marketed in the U.S. as GAZYVA® (Genentech) (14)(15). The drug induces direct cell death 
and antibody-dependent, cell-mediated cytotoxicity (ADCC)/antibody-dependent cell-mediated 
phagocytosis (ADCP), with less complement-dependent cytotoxicity as compared to rituximab 
overall providing for faster and superior direct B cell death as compared to rituximab. In the pivotal 


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clinical study BO21004/CLL11, 91% (40 out of 44) of evaluable patients treated with repeated 4-
week cycles of obinutuzumab, were B-cell depleted (CD19+ B-cell counts < 0.07 x 109/L) at the 
end of treatment period and remained depleted during the first 6 months of follow up. Recovery 
of B-cells was observed within 12-18 months of follow up in 35% (14 out of 40) of patients without 
progressive disease and 13% (5 out of 40) with progressive disease (15). In vitro studies have 
shown that T cells are activated and expand in similar frequencies when cultured with B cells, 
monocytes or both (16). In fact, CD14+ monocytes demonstrated a higher capacity to mediate the 
activation and expansion of TRBV7-9+ T cells as compared to B cells. These observations suggest 
that CD14+ monocytes alone can efficiently mediate NAP activation and expansion of TRBV7-
9+ T cells in human blood. Given these observations, ADA prevention with obinutuzumab is 
expected to deplete B cells, without impacting the NAP mode of action. Hence, when given as a 
pretreatment, obinutuzumab, is expected to prevent the occurrence of ADAs and may result in 
more prolonged exposure to NAP, therefore potentially enhancing its antitumor activity. In this 
trial, obinutuzumab will be given once, over 2 days, prior to the first cycle of treatment with the 
combination of NAP and docetaxel. Additional administrations of obinutuzumab may be 
considered during the study based on biomarkers collected and B cells level. 
 
1.8 
Study Rationale  
Given the ongoing need for novel therapies in the treatment of NSCLC, the previously observed 
preliminary activity of the combination of NAP /docetaxel in NSCLC and the presumptive ability 
of obinutuzumab to suppress the development of ADAs, this study will test the combination of 
NAP /docetaxel following pretreatment with obinutuzumab in a population of subjects with 
NSCLC who have failed checkpoint inhibitor therapy, in an effort to demonstrate an improvement 
in ORR as well as other measures of anti-tumor efficacy.  
 
 


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2 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Study Objectives 
2.1.1 Primary Objective 
To assess the ORR and response duration of NAP and docetaxel, following obinutuzumab 
pretreatment, in subjects with NSCLC previously treated with a checkpoint inhibitor. 
 
2.1.2 Secondary Objectives 
• 
To describe the safety profile of the combination of NAP / docetaxel, following 
obinutuzumab pretreatment in subjects with R/R NSCLC  
• 
To evaluate the overall survival (OS) defined as the time from day 1 of treatment until death 
due to any cause 
• 
To assess the possible impact of prior taxane exposure on the antitumor activity of the 
NAP/docetaxel combination 
• 
To describe the effect of obinutuzumab pretreatment on the development of anti-drug 
antibodies and human anti-mouse antibodies to NAP  
• 
To describe blood levels over time of NAP when administered after B-cell suppression 
 
2.1.3 Exploratory Objectives 
• 
To evaluate and characterize the pharmacodynamic effect of NAP /docetaxel on biomarkers 
in the circulation in subjects pretreated with obinutuzumab  
• 
Clinical activity in relationship to biomarkers including 5T4, NGS results, TMB expression 
and PD-L1 level in the tumor. 
 
 


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2.2 
Study Endpoints 
2.2.1 Primary Endpoints 
• Objective response rate (ORR), per iRECIST, of the combination of NAP /docetaxel following 
obinutuzumab pre-treatment in subjects with NSCLC previously treated with a checkpoint 
inhibitor 
 
2.2.2 Secondary Endpoints 
• Disease control rate (DCR) and duration of response (DOR) of the combination of NAP 
/docetaxel following obinutuzumab pre-treatment in subjects with NSCLC previously treated 
with a checkpoint inhibitor 
• Progression-free survival (PFS) as well as the 6-month and the 12-month PFS rates of NAP 
/docetaxel following obinutuzumab pre-treatment in subjects with NSCLC previously treated 
with a checkpoint inhibitor 
• Overall survival (OS) of NAP /docetaxel following obinutuzumab pre-treatment in subjects 
with NSCLC previously treated with a checkpoint inhibitor 
• Incidence and characteristics of adverse events associated with NAP /docetaxel pretreated with 
obinutuzumab. Safety will be measured by infusion reactions (e.g. fever, chills, hypotension, 
tachycardia etc.), changes from baseline vital signs, physical findings, electrocardiograms 
(ECG), blood and urine safety and thyroid function laboratory tests, graded as per National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 
• The pharmacokinetic profile of NAP  
• The development of anti-drug antibody levels and human anti-murine antibody (HAMA) 
 
2.2.3 Exploratory Endpoints 
• Cytokine production over time (e.g., IL-2, IFNγ, IL-6, TNFα) and B-cell levels in subjects pre-
treated with obinutuzumab. 
• Clinical activity in relationship to biomarkers including 5T4, NGS results, TMB expression 
and PD-L1 level in the tumor. 
 
 
 


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3 
STUDY DESIGN 
This is an open-label, multicenter Phase 2a clinical trial of the combination of NAP/docetaxel 
following pretreatment with obinutuzumab in subjects with NSCLC who have progressive 
neoplastic disease despite having been treated with at most 2 prior systemic therapies, including a 
checkpoint inhibitor; approximately 35 subjects will be entered. 
Subjects will receive obinutuzumab, 1,000 mg, administered by IV infusion on Days -13 and -12 
of the first treatment cycle in order to reduce the titer of anti-drug antibodies to NAP. Additional 
administrations of obinutuzumab may be considered during the study based on biomarkers 
collected and B cell level. If an increase back to the normal level of B cell level is observed, 
additional biomarkers and PK level will be tested in the following visit. NAP will be 
administered in a daily dose of 10 μg/kg by IV bolus on Days 1 - 4 of treatment cycles 1-6, 
followed by docetaxel, 75 mg/m2 on Day 5.  
Treatment cycles will be 21 days in duration and growth factors may be used at the discretion of 
the investigator. The combination of NAP/docetaxel will be given for a maximum of 8 cycles 
(unless, in the opinion of the investigator, the patient may derive benefit from continuing 
docetaxel). Starting Cycle 7, NAP at a higher dose of 15 μg/kg will be administered on Day 1 and 
docetaxel on Day 2, in 21 days treatment cycles. Once NAP is given as monotherapy and not 
earlier than C7, cycles will be of 28 days of duration. In patients whose NAP dose was reduced 
due to toxicities during cycles 1-6, NAP dose will not be further increased in cycle 7. Dose increase 
to 15 μg/kg in advanced cycles is not expected to increase NAP toxicity profile, as NAP related 
toxicities predominantly occur on cycles 1-2, and this dose increase may overcome ADA 
formation with time. NAP as a single agent will be continued until disease progression, untoward 
toxicity or non-compliance for a maximum of up to 24 months from day 1 of therapy.  
Subjects will be screened to assess eligibility within 14 days prior to entry. Subjects must have 
received at least 1 and no more than 2 prior systemic regimens for the treatment of 
advanced/metastatic NSCLC. Patients are required to have progressed following treatment with 
both platinum-based chemotherapy and an anti-PD-(L)1 antibody administered either sequentially 
or concurrently. A prior PD-1/PD-L1 inhibitor is, however, not required if there was prior exposure 
to targeted therapies for driver mutation positive tumors (e.g. EGFR or ALK inhibitors).  Entry 
into this trial is restricted to patients with incurable disease, including those who relapse within 6 
months from chemoradiotherapy for Stage III disease.  Subjects will have available archival or 
fresh tissue collected for the retrospective determination of tumoral 5T4 levels.  
Subjects will be assessed for the primary efficacy endpoint of objective response rate (ORR). ORR 
will be assessed according to the iRECIST criteria. In addition, disease control rate, combining the 
ORR with subjects demonstrating stable disease (SD), progression-free survival (PFS), PFS rate 
at 6 and 12 months and overall survival (OS) will also be determined. If available, NGS results, 
TMB expression and PD-L1 levels will be collected for the expression of exploratory tumor 
biomarkers. 
Ongoing study imaging will be performed at the end of cycle 2 (45 days ± 7 days) and every 6 
weeks for the first 24 weeks and then every 9 weeks (± 7 days) thereafter. Confirmatory scans for 
responses (PR or CR) will be performed after 6 weeks (± 7 days) during the first 24 weeks and 


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every 9 weeks thereafter. As NAP is known to induce an inflammatory reaction in the tumor, 
pseudo-progression may be observed and therefore, in patients who demonstrate objective 
progression but who are clinically stable, 1-2 additional treatment cycle(s) of NAP/docetaxel may 
be administered beyond progression at the discretion of the Investigator, followed by a 
confirmatory imaging after 6 weeks (± 7 days) during the first 24 weeks and every 9 weeks (± 7 
days) thereafter. This schedule should be maintained even if cycles are delayed. 
The safety of the combination of NAP /docetaxel following pretreatment with obinutuzumab in a 
B-cell suppressed setting will be assessed in all treated subjects based on the reporting of adverse 
events, the results of ECGs, results of laboratory determinations, findings on physical exams, vital 
signs and reporting of the ECOG Performance Score. All treatment emergent AEs (TEAEs), drug-
related AEs, SAEs and drug-related SAEs as well as hematology and chemistry lab results will be 
summarized using the worst grade per subject according to the NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 5.0 
The pharmacokinetics of NAP will be based on plasma drug levels obtained at various timepoints 
after administration.  
The pharmacodynamics of the combination of NAP/docetaxel following pretreatment with 
obinutuzumab will be determined by measuring levels of cytokines (e.g., IL-2, IFNγ, IL-6 and 
TNFα) in serum. 
The immunogenicity of NAP will be assessed based on levels of anti-drug antibodies, human anti-
murine antibodies (HAMA) collected at various times after administration of NAP. Neutralizing 
antibodies (Nab) will be also collected for future analysis.  
The primary efficacy endpoint of this trial is the ORR. With 29 evaluable entries, 6 subjects or 
more with a complete or partial response would make this regimen worthy of further investigation. 
Subjects who discontinue from treatment for any reason will continue to be followed for survival 
(even if the subject receives subsequent anti-neoplastic therapy). Subjects will be followed for 
survival until 6 months after the last subject has completed study treatment. Subjects who 
discontinue from treatment for reasons other than progression will continue to be followed for 
progression by CT/MRI scans every 6 weeks (± 7 days) for the first 24 weeks, every 9 weeks (± 7 
days) thereafter; if such a subject receives subsequent anti-neoplastic therapy, further follow-up 
for progression will stop.  
A graphical description of the trial is depicted below: 


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 * Starting Cycle 7, NAP at a higher dose of 15 μg/kg/day will be administered on Day 1 and docetaxel on Day 2, in 21 days 
treatment cycles. Once NAP is given as monotherapy and not earlier than C7, cycles will be of 28 days of duration. In patients 
whose NAP dose was reduced due to toxicities during cycles 1-6, NAP dose will not be further increased in cycle 7. 
 
 
                                                        
                                             
       
      
              
       
                   
                     
                   
         
                          
                   
                              
  
                         
                            
                
                
 
   
                    
 
                
 
                     
 
   
 
                
            
                                                                                                                              
                  
                                                                                                                            
                       
                                                                     
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4 
STUDY POPULATION 
A total of approximately 35 subjects will be enrolled from approximately 10 study sites in the U.S. 
 
4.1 
Inclusion Criteria 
Subjects must meet ALL of the following criteria to be eligible for enrollment into the study: 
1. Subjects must be at least 18 years of age 
2. Subjects must have histologically and/or cytologically confirmed NSCLC  
3. Subjects must have incurable (advanced or metastatic) disease at the time of enrolment 
(Patients who relapse within 6 months from chemoradiotherapy for stage III disease are 
considered incurable) 
4. Subjects must have an Eastern Cooperative Oncology Group (ECOG) Performance Status 
of 0 or 1 
5. Subjects must provide signed informed consent prior to any study specific procedures that 
are not part of standard medical care.  
6. Subjects must have measurable neoplastic disease based on the iRECIST criteria 
7. Subjects must have received at least 1 and no more than 2 prior systemic regimens for the 
treatment of advanced/metastatic NSCLC. Patients are required to have progressed 
following treatment with both platinum-based chemotherapy and an anti-PD-(L)1 antibody 
administered either sequentially or concurrently. A prior PD-1/PD-L1 inhibitor is, 
however, not required if there was prior exposure to targeted therapies for driver mutation 
positive tumors (e.g. EGFR or ALK inhibitors).    
8. Subjects must have adequate hematologic and organ function:  
• WBC ≥3000/µL  
• Absolute neutrophil count ≥1500/µL  
• Platelets ≥100,000/µL 
• Hemoglobin ≥9.0 g/dL  
• Serum creatinine ≤1.5 mg/dL or calculated creatinine clearance (CL) >40 mL/min, as 
determined by Cockcroft-Gault (using actual body weight) 
•  AST < 1.5 X ULN; ALT < 1.5 X ULN; Alk phos < 2.5 X ULN; bilirubin must be 
within normal limits 
• 
International Normalized Ratio (INR) or prothrombin time (PT) and activated partial 
thromboplastin time (aPTT) ≤1.5 X ULN unless subject is receiving anticoagulant 
therapy and the INR, PT or PTT is within therapeutic range of intended use of 
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9. Subjects must be willing and able to comply with scheduled visits, procedures, drug 
administration plan, etc. as outlined in the protocol 
10. Subjects should have an estimated life expectancy of at least 12 weeks 
11. Archival or fresh tumor tissue from a biopsy of a tumor lesion not previously irradiated 
must be provided for 5T4 retrospective analysis, unless discussed with the Medical 
Monitor.  
 
4.2 
Exclusion Criteria 
Subjects with ANY of the following characteristics/conditions will not be included in the study: 
1. Subjects with active infection requiring treatment within 3 days of C1D1. 
2. Subjects with other active neoplastic disease requiring concurrent anti-neoplastic treatment 
3. Subjects with known, suspected or documented parenchymal brain metastases unless 
treated with surgery and/or radiation, with the subject neurologically stable and off 
pharmacologic doses of systemic glucocorticoids; subjects with leptomeningeal metastases 
are not eligible. Patients should have completed brain radiation for at least 14 days and be 
off steroids per exclusion criteria 7. 
4. Active or previously documented autoimmune or inflammatory disorders such as, but not 
limited to rheumatoid arthritis, systemic lupus erythematosus, uveitis, ulcerative colitis, 
Crohn’s syndrome, Wegener’s syndrome, multiple sclerosis, myasthenia gravis, 
scleroderma and sarcoidosis. The following are exceptions to this criterion:  
• Vitiligo or psoriasis not requiring systemic treatment (within the last 2 years)  
• Subjects with endocrinopathies (e.g. following Hashimoto syndrome) stable on 
hormone replacement or do not require any therapy. 
5. History of primary immunodeficiency 
6. Subjects with a history or prior allogeneic organ transplant 
7. The use of immunosuppressive agents within 28 days of enrollment (D-13; obinutuzumab 
pre-treatment) including, but not limited to, cyclosporine, mycophenolate, azathioprine, 
methotrexate, adalimumab, infliximab, vedolizumab, tofacitinib, dupilumab, rituximab, 
etc. Pharmacologic doses of glucocorticoids defined as glucocorticoid equivalents of >10 
mg/day of prednisone (with the exception of systemic steroids given as a premedication 
before each of the study medications, or used prior to administration of radiographic 
contrast material in subjects with allergies) are not acceptable within 14 days prior to 
enrollment. Subjects are permitted to receive topical, intranasal, inhalational and intra-
ocular glucocorticoids. 
8. Subjects who have uncontrolled inter-current illness, including but not limited to, ongoing 
or active infection, symptomatic congestive heart failure, uncontrolled hypertension, 


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unstable angina pectoris, uncontrolled cardiac arrhythmia, active interstitial lung disease, 
serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric 
illness/social situations and substance abuse that would limit compliance with study 
requirement, substantially increase risk of incurring AEs or compromise the ability of the 
subject to follow the dictates of the protocol.  
9. Subjects who have received a live attenuated vaccine within 28 days prior to the first dose 
of obinutuzumab. 
10. Subjects with hepatitis B (positive HBV surface antigen [HBsAg]), hepatitis C (hepatitis 
C antibody) or HIV (HIV antibody). Subjects with a past or resolved HBV infection 
(defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) 
are eligible; subjects positive for hepatitis C (HCV) antibody who have completed a course 
of antiviral therapy are eligible if polymerase chain reaction (PCR) is negative for HCV 
RNA. 
11. Female subjects who are pregnant or breastfeeding.  
12. Male or female subjects of reproductive potential who are not willing to employ effective 
birth control from Screening to 90 days after the last dose of study treatment. Highly 
effective methods of contraception are defined as one that results in a low failure rate (e.g., 
less than 1% per year) when used consistently and correctly.  
13. Prior treatment with chemotherapy or other systemic antineoplastic therapy within 21 days; 
experimental therapy 21 days or 5 half-lives, whichever is shorter. Any unresolved toxicity 
NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, 
vitiligo, and the laboratory values defined in the inclusion criteria. All prior treatments 
should be completed 21 days prior to enrollment (D-13; obinutuzumab pre-treatment). 
14. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the 
exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria. 
15. Subjects who have undergone major surgery or trauma within 4 weeks of study entry (D-
13; obinutuzumab pre-treatment).  
16. Subjects with Grade 2 neuropathy will be evaluated on a case-by-case basis after 
consultation with the Medical Monitor. Subjects with neuropathy grade >2 are not eligible. 
17. Subjects who have been treated with one of the study drugs (NAP and/or docetaxel). 
18. Subjects with NYHA Class III or IV CHF, myocardial infarction or acute coronary 
syndrome within 6 months prior to study enrollment, ongoing angina pectoris, severe 
peripheral vascular disease, CVA within 6 months of study enrollment or any other 
concomitant medical disorder that might interfere with the subject’s participation in the 
trial or interpretation of the study data. 


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19. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms in 
women and ≥450 ms in men, calculated from 3 ECGs (within 15 minutes at 5 minutes 
apart).  
20. Subjects on strong inducers or inhibitors of CYP3A4. 
21. Known allergy or hypersensitivity to any of the study drugs or any of the study drug 
excipients (including kanamycin). 
22. Subjects with a history of progressive multifocal leukoencephalopathy (PML).  
 
 
 


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4.3 
Enrollment 
Subjects will be centrally enrolled; enrollment among the investigational sites will be competitive 
and there is no limitation on enrollment from a particular site.  
Following completion of the Screening phase of the study, each site will submit a signed 
‘Eligibility Request Form’ to The Sponsor or its designee. The form will be reviewed and a 
decision on enrollment made within 24 hours.  
4.4 
Subject Identification 
Each subject who has signed the informed consent will be identified by a unique study ID number 
(combination of a 5-digit unique site identity number and 3-digit subject number). Numbers will 
be allocated to subjects in a sequential order in each site.   
 
4.5 
Screen Failures 
Subjects who fail to meet the entry criteria during the Screening period are defined as screen 
failures. A patient who failed screening may be re-screened. All screen failures will be recorded 
in the screening logs along with the reason for screen failure. The screening log will be kept in the 
Investigators Site File.  
 
4.6 
Subject Discontinuation or Early Withdrawal and Replacement 
Subjects are free to discontinue their participation in the study at any time and without prejudice 
to further treatment. The Investigator must withdraw any subject from the study that requests to 
be withdrawn, or if it is determined that continuing in the study would result in an undue risk to 
the subject.  
Subjects with major protocol enrollment violations, where the risk of remaining in the study 
outweighs any benefit, and those who do not receive a minimum of 1 treatment cycle for reasons 
other than toxicity or progressive neoplastic disease will be replaced, after being approved by The 
Sponsor. 
 
4.6.1 Reasons for Treatment Discontinuation 
Reasons for discontinuation from study treatment include the following: 
• Progressive neoplastic disease (objective or clinical progression) 
• An adverse event or intercurrent medical condition that precludes further administration of 
protocol therapy or continuation with the requirements of the trial 
• A subject withdraws consent for continued treatment 
• A female subject becomes pregnant 
• A subject is unwilling or unable to continue the study or is lost-to-follow-up 


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• A subject is non-compliant to the point where the risk of continued participation in the trial 
outweighs potential benefits 
• The Investigator decides that withdrawal from the study is in the best interest of the subject 
• A subject requires a prohibited medication or treatment 
Subjects who discontinue the trial for reasons other than progressive neoplastic disease should 
continue to be followed until progression by CT/MRI scans every 6 weeks (± 7 days) for the first 
24 weeks, every 9 weeks (± 7 days) thereafter, or until the initiation of new anti-cancer treatment. 
 
4.6.2 Reasons for Study Discontinuation 
Reasons for discontinuation from the trial may include the following: 
• The development of progressive neoplastic disease 
• The death of a subject 
• A subject is lost to follow-up 
• A subject withdraws consent for continued participation in the trial 
• A request by a regulatory authority to discontinue the study 
• Issues with the manufacturing or supply of protocol therapy that precludes continuation of the 
trial 
• Conditions no longer make it reasonable for the Sponsor to continue the study 
 
 


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5 
STUDY DRUGS 
5.1 
Docetaxel 
Docetaxel will be administered IV over 1 hour on Day 5 of cycles 1-6 and starting cycle 7 on Day 
2  of a 21- day treatment cycle in a dose of 75 mg/m2 for a maximum of 8 cycles (unless, in the 
opinion of the investigator, the patient may derive benefit from continuing docetaxel).  
Subjects should be pre-medicated according to institutional standards. Docetaxel should be stored 
according to directions in the Full Prescribing Information. For complete information regarding 
administration of docetaxel, refer to the appropriate Full Prescribing Information, SmPC or local 
product monograph. 
5.1.1 Premedication for Docetaxel 
Subjects should receive pre-medications prior to docetaxel administration as per the standard of 
care at each clinical site. If corticosteroids are administered in multiple days regimen, starting 1 
day prior to docetaxel (on Day 4 of each cycle 1-6, and starting cycle 7 on Day 1) it should be 
administered at least 1 hour after NAP administration. 
5.1.2 Docetaxel Dose Adjustments 
Dose of docetaxel may remain the same throughout the study unless the patient’s weight changes 
≥10% from baseline. 
If docetaxel cannot be administered on schedule because of NAP-induced adverse reactions, 
docetaxel is to be delayed by a maximum of one week and skipped in the absence of adequate 
recovery; the next NAP cycle is then delayed by a maximum of one week as well, as described in 
sections 5.2.6 and 5.2.7.  
If NAP is discontinued, docetaxel may continue as monotherapy, as described in section 5.1. If on 
the day of scheduled treatment with docetaxel, the ANC is <1,500/μL and/or the platelet count is 
<100,000/μL, hold docetaxel and repeat the ANC and platelet counts weekly. Once toxicity due to 
myelosuppression has resolved re-treatment with docetaxel will be at a reduced dose as described 
below. If a second dose delay is required due to myelosuppression despite the dose reduction, 
discontinue docetaxel. Patients who develop ≥grade 3 peripheral neuropathy should have 
docetaxel treatment discontinued entirely. If NAP and docetaxel are to be delayed due to toxicity 
of docetaxel, the whole cycle of NAP and docetaxel may be delayed up to 6 weeks. Patients, for 
whom any treatment cycle is delayed, for any reason, beyond the indicated window, will be 
discussed with the medical monitor to determine whether they should be continued. The schedule 
of the imaging should be maintained, though, even if cycles are delayed.If docetaxel is discontinued 
due to toxicity, Day 5 (Cycles 1-6) or Day 2 (cycle 7 onwards) assessments should not be performed. 
Docetaxel Dose Reduction 
The dose of docetaxel must be reduced to 55 mg/m2 in the event the subject experiences any of the 
following during a treatment cycle: 
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• ANC <500/μL for > 1 week 
• Platelet count <25,000/μL for > 1 week 
• Grade 3 or higher, or cumulative cutaneous toxicities 
• Any other Grade 3 or higher toxicity (except nausea, vomiting or diarrhea brought under 
control with appropriate medical therapy within 72 hours) 
• The need for a dose delay as described above 
 
5.2 
Naptumomab Estafenatox (NAP; ABR-217620) 
Naptumomab estafenatox (NAP; ABR-217620) is a recombinant fusion protein consisting of a 
chimeric staphylococcal enterotoxin A/E (SEA/SEE) superantigen with several additional 
substitutions that is linked to a Fab moiety recognizing a tumor-associated glycoprotein, 5T4.  
 
5.2.1 Naptumomab Estafenatox (NAP) Packaging and Labeling  
 Naptumomab estafenatox (NAP) is provided in two separate packaging: One lyophilized drug 
product stored at 2-8 ⁰C and one dilution kit stored at RT. A dilution kit containing water for 
injection (WFI), Dilution Solution, empty sterile glass vial, syringes and complete instructions for 
the reconstitution and dilution is also supplied. NAP is provided as a lyophilized powder for 
injection. The container-closure system consists of 10 cc colorless glass, type I vials and 
bromobutyl stoppers. The vials are sealed with aluminum caps. Each vial contains 1.25 mg NAP 
and is intended to be reconstituted and diluted prior to use in two steps: Reconstitution with 1.2ml 
of the supplied water for injection (WFI) followed by further dilution with diluent (Dilution 
Solution). The Dilution Solution is a sterile, pyrogen-free, clear and colorless solution supplied in 
10 cc glass bottles containing 10 mL of the diluent. 
For any additional Study Drug related information, refer to the Pharmacy Manual. 
The product may contain residual trace kanamycin from the manufacturing process, which could 
lead to allergic reactions in highly susceptible individuals. 
 
5.2.2 Naptumomab Estafenatox (NAP) Preparation and Administration 
A dilution kit is supplied for dilution of NAP. All handling of NAP should be performed using an 
aseptic technique. Sterile gloves should be used. For safety precautions, see Safety Data Sheet for 
NAP (provided separately).  
NAP will be administered in a dose of 10 μg/kg/day on Days 1 – 4 of cycles 1-6. Starting Cycle 7, 
NAP will be administered on Day 1 only in a dose of 15 µg/kg (unless the dose was previously 
reduced due to toxicity).  The reconstituted NAP will be diluted with the supplied diluent to reach 
the required dose for administration. Fully diluted NAP (5 mL) will be administered as an IV slow 
bolus injection (i.e., administered directly, not via a running IV line). On cycle 1, it could either 
be administered viacentral line (e.g. Port-a-Cath), slowly injected in approximately 3 minutes 


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followed by 10 mL slow (~2 min) saline flush or via a peripheral line (e.g. venflon), by a slow 
injection of approximately 5 minutes, followed by a flush per the site’s standard practice.  
If the subject did not experience any significant infusion related reactions on a full cycle (days 1-
4), further NAP injections in the following cycles may be pushed in less than 5 min in total. 
Any IV fluids given simultaneously with NAP are prohibited. 
Administration of NAP should be performed by an appropriately qualified, Good Clinical Practice 
(GCP)-trained, and experienced member of the study staff (e.g., physician, nurse, physician’s 
assistant, nurse practitioner, pharmacist, or medical assistant), as allowed by local and institutional 
guidance.  
During cycle 1 (days 1-4) and cycle 2 Day 1 (C2D1), all subjects should be observed for 3 hours 
post injection of NAP at the site.  If no G3 or higher infusion related reactions occurred, time of 
observation can be shortened to 1 hour on further treatment days.  Subjects who experience any 
TEAEs during the observation period and/or any other medical condition requiring further 
monitoring at the discretion of the investigator, should be further observed as clinically 
appropriate. Subjects should be advised that in any case of severe and/or persistent fever, chills, or 
shortness of breath beyond 5-7 hours post NAP administration, they should seek a medical 
attention. 
5.2.3 Naptumomab Estafenatox (NAP) Dilution 
Calculation for dilution will be performed by the relevant scheme in the instructions for dilution 
“Flow chart of Dilution Procedure” (found in the pharmacy manual), which must be accurately 
filled in and signed. All dilutions should be performed by strictly following the Instructions 
supplied with the dilution kit. 
The calculation of the dose per subject weight should be done based on subject weight on the day 
of treatment. In sites restricted by pharmacy’s procedures the dose can be calculated based on 
subject weight obtained within 14 days prior to that date. For the purpose of calculating study 
treatment dose, the subject's weight should NOT be rounded off to the closest kg value but rather 
recorded with 1 digit after the decimal point, for example, 70.5 kg, 60.4, 77.0 kg etc. However, 
after multiplying the weight by the relevant dose level (µg/kg), the final dose (in µg) should be 
rounded off, for example, 120.5 µg will be rounded to 121 µg and 150.4 µg will be rounded to 150 
µg. 
5.2.4 Stability of Reconstituted and Diluted Naptumomab Estafenatox (NAP) 
For stability information on reconstituted and diluted NAP please refer to the IFU (Information 
For Use) and the Pharmacy Manual.  
5.2.5 Premedication for Naptumomab Estafenatox (NAP)  
The premedication should be initiated as prophylaxis prior to each NAP administration. 
• Hydration: 
On Cycle 1:  


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o Day 1: 1L saline, IV, beginning 1-3 h before NAP dose.  
o Day 2: 0.5 L saline, IV, beginning 1-3 h prior to NAP dose.  
o Days 3-4: no hydration is needed unless the patient experienced G≥2 hypotension or 
G≥3 infusion related reactions on previous days, and then continue as on Day 2. 
On Cycle 2: 
o Day 1: 0.5 L saline, IV, beginning 1-3 h before NAP dose.  
o Days 2-4: no hydration is needed unless the patient experienced G≥2 hypotension or 
G≥3 infusion related reactions on previous days, and then continue as on Day 1. 
No hydration is needed on further cycles.  
The saline hydration should be completed as close as possible to start of NAP 
administration. 
Excess of IV fluids should be avoided in elderly patients who are prone to develop fluid 
overload (e.g., congestive heart failure, renal failure etc.). In such cases it is recommended 
to consult the medical monitor.  
• 500-650 mg acetaminophen, oral, qid (x 4/day), unless specific contraindications exist 
(allergy or elevated hepatic transaminases), to be administered 30-60 minutes prior to NAP, 
as prophylaxis prior to each NAP injection, , and every 6 hours thereafter up to 24 h after 
last NAP dose of each cycle of NAP treatment. In case of fever > 38.5oC the acetaminophen 
dose can be elevated to 1g to treat the AE.  
• Systemic antihistamine, such as but not limited to promethazine IV, 30 to 60 minutes prior 
to NAP dosing,  
• Anti-emetic agent such as ondansetron 8 mg or metoclopramide 10 mg, 30 to 60 minutes 
prior to NAP dosing. 
5.2.6 Dose Modifications for Naptumomab Estafenatox (NAP)  
The following dose modifications of NAP are required in case of the occurrence of any Grade ≥3 
immune or non-immune AEs that are related to NAP. The dose of NAP will be reduced 
according to the table below; in general, NAP may be reduced by one dose level for G3 AEs, and 
by two dose levels for G4, life-threatening AEs (with the exception of hematologic toxicity and 
laboratory findings). A second dose reduction is permitted for G3 AEs at one level reduced dose, 
with 5 µg/kg/day being the lower dose allowed on this study. NAP treatment will be permanently 
discontinued if same grade 3 or higher adverse event recurs at 5 µg/kg/day reduced dose, (with 
the exception of hematologic toxicity and laboratory findings). 
If, for any reason, the dose was reduced at once for a G3 toxicity, from 10 µg/kg/d to 5 
µg/kg/day, and is tolerated well with no recurrences or further NAP related AEs at the reduced 
dose, then at the PI discretion, the dose may be increased by one dose level, to 7.5 µg/kg/day, in 
the following cycle. 
Please note, NAP is administered in a dose of 10 μg/kg/day on Days 1 – 4 of cycles 1-6. Starting 
Cycle 7, NAP at a higher dose of 15 μg/kg is administered on Day 1. In patients whose NAP 


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dose was reduced due to toxicities during cycles 1-6, NAP dose will not be further increased in 
cycle 7. 
NAP may be administered in one of the following doses: 
Dose Level 
Dose of NAP 
2* 
15 µg/kg/day 
1 
10 µg/kg/day 
-1 
7.5 µg/kg/day 
-2 
5 µg/kg/day 
* NAP at a higher dose of 15 μg/kg will be given starting cycle 7 only in patients whose NAP dose was not reduced 
due to toxicities during cycles 1-6. Otherwise, dose remain the same as in the previous cycle. 
Adverse Event 
Dose Modification 
Within a Treatment Cycle 
Between Cycles 
General disorders and 
Infusion Related Reactions: 
(e.g. Fever, Chills, 
Tachycardia, Fatigue, 
Peripheral Edema, 
Hypotension) 
See also CRS treatment 
guidelines, Section 7.2.3  
Events that do not resolve 
within 6 hours to grade 1 or 
baseline despite appropriate 
medical management, hold 
retreatment until resolution 
of the toxicity to grade 1 or 
baseline (see 5.2.7). The 
next NAP doses may be 
reduced by one dose level 
for G3 events and by two 
dose levels for G4 events, 
per investigator/Medical 
Monitor decision. 
 
Events that do not resolve to at 
least grade 2 within 7 days, 
treat the next cycle (and all 
subsequent cycles) at one dose 
level below for G3 events and 
two levels below for G4 
events. 
 
Gastrointestinal disorders: 
(e.g. Nausea, Vomiting, 
Diarrhea) 
 
Events that do not resolve 
within 6 hours to grade 1 or 
baseline despite appropriate 
medical management, hold 
retreatment until resolution 
of the toxicity to grade 1 or 
baseline (see 5.2.7). The 
next NAP doses may be 
reduced by one dose level 
for G3 events and by two 
dose levels for G4 events, 
Events that do not resolve to at 
least grade 2 within 7 days, 
treat the next cycle (and all 
subsequent cycles) at one dose 
level below for G3 events and 
two levels below for G4 
events. 
 


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per investigator/Medical 
Monitor decision. 
  
Hematologic toxicity: 
Febrile neutropenia, 
Thrombocytopenia, Anemia 
Skip remaining dose(s) of 
the cycle, for G3 or G4 
events. 
Events that do not resolve to at 
least grade 2 within 7 days, 
treat the next cycle at one dose 
level below. 
 
Laboratory findings: 
(e.g. liver enzymes elevation) 
 Skip remaining dose(s) of 
the cycle, for G3 or G4 
events. 
Events that do not resolve to 
grade 2 within 7 days, treat the 
next cycle (and all subsequent 
cycles) at one dose level 
below. 
 
 
 
 


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5.2.7 Dose Delays for Naptumomab Estafenatox (NAP)/Docetaxel Combination 
Dose Delay Prior to Cycle 1 
In case of any obinutuzumab related toxicities of grade ≥2 that exist on the first scheduled day of 
NAP administration (C1D1), Cycle 1 of NAP- docetaxel treatment may be delayed up to 7 days. 
In the absence of resolution after this period, the patient will be discontinued from the study. 
 
Dose Delays During a Treatment Cycle 
Every effort should be made to administer NAP on Days 1 – 4 of  treatment cycles 1-6 and on Day 
1 of each subsequent cycle. Subjects who exhibit Grade 3 or higher toxicity during a treatment 
cycle will have treatment held until resolution of the toxicity to Grade 1 or baseline. The next NAP 
doses may be reduced by one dose level for G3 events and by two dose levels for G4 events, per 
investigator/Medical Monitor decision. If a treatment needs to be delayed or is missed during days 
1-4, that treatment day will be skipped, and treatment will resume the following day. Missed 
treatments will not be made up. Subjects who do not receive at least two NAP doses within a given 
cycle at two consecutive cycles, due to AEs, will discontinue NAP and continue treatment with 
single agent docetaxel. If docetaxel cannot be administered once a treatment cycle has been 
initiated, docetaxel is to be delayed by a maximum of one week and skipped in the absence of 
adequate recovery; the next NAP cycle is then delayed by one week as well. 
 
Dose Delay Between Treatment Cycles 
If on Day 1 of the next scheduled treatment cycle, all toxicities from prior treatment cycles or 
intercurrent medical conditions have not reverted to Grade 1 or baseline, or if the ANC is 
<1,500/μL and/or the platelet count is <100,000/μL, treatment with NAP and docetaxel should be 
held and the subject followed weekly until resolution of any toxicity or intercurrent condition to 
Grade 1 or baseline and the ANC is >1,500/μL and the platelet count is >100,000/μL. If a delay is 
indicated for a cycle of NAP, the entire regimen of NAP + docetaxel is to be delayed. If, in the 
opinion of the investigator, toxicity due to NAP alone has not resolved by 6 weeks after the last 
NAP/docetaxel cycle, discontinue NAP and continue the subject on docetaxel alone.  Once toxicity 
of docetaxel due to myelosuppression has resolved, re-treatment with docetaxel will be at a 
reduced dose as described for docetaxel monotherapy. If a second dose delay is required due to 
myelosuppression despite the dose reduction, discontinue docetaxel and continue NAP alone. 
Delays for any reasons, of up to 7 days in the visit schedule of a full cycle (not within a cycle), are 
allowed. Patients, for whom any treatment cycle is delayed, beyond the indicated window, will be 
discussed with the medical monitor to determine whether they should be continued. The schedule 
of the imaging should be maintained, though, even if cycles are delayed. 
 
5.3 
Obinutuzumab 
Obinutuzumab is a humanized anti-CD20 monoclonal antibody of the IgG1 subclass. It recognizes 
a specific epitope of the CD20 molecule found on B cells. The molecular mass of the antibody is 


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approximately 150 kDa. Obinutuzumab will be administered on Days -13 and -12 of the first 
treatment cycle. Additional administrations of obinutuzumab may be considered during the study 
based on biomarkers collected and B cell level. 
 
5.3.1 Obinutuzumab Packaging 
Obinutuzumab is a sterile, clear, colorless to slightly brown, preservative-free liquid concentrate 
for intravenous use. Obinutuzumab is supplied at a concentration of 25 mg/mL in 1,000 mg single-
dose 40 mL vials. The product is formulated preservative-free in 20 mM L-histidine/L-histidine 
hydrochloride, 240 mM trehalose, 0.02% poloxamer 188. The pH is 6.0. Obinutuzumab must be 
stored at 2°Cto 8°C (36°Fto 46°F). Protect from light. Do not freeze or shake obinutuzumab. 
Obinutuzumab prescription information can be found in the pharmacy manual. 
 
5.3.2 Obinutuzumab Preparation  
Withdraw 40 mL of obinutuzumab solution from the vial. Dilute 40 mL (1,000 mg) into a 250 mL 
0.9% Sodium Chloride Injection, USP infusion bag. Mix diluted solution by gentle inversion. Do 
not shake or freeze. Administer as an intravenous infusion only. Do not administer as an 
intravenous push or bolus. Do not mix obinutuzumab with other drugs. No incompatibilities 
between obinutuzumab and polyvinylchloride (PVC) or non-PVC polyolefin bags and 
administration sets have been observed. The product can be administered at a final concentration 
of 0.4 mg/mL to 4 mg/mL. 
 
5.3.3 Premedication for Obinutuzumab 
Hypotension may occur during obinutuzumab intravenous infusions. Consider withholding 
antihypertensive treatments for 12 hours prior to and throughout each obinutuzumab infusion and 
for the first hour after administration. 
Subjects must receive intravenous corticosteroid (100 mg prednisone/prednisolone or 20 mg 
dexamethasone or 80 mg methylprednisolone) to be completed 1 hour prior to administration of 
obinutuzumab 
followed 
by 
oral 
analgesic/antipyretic 
650 
mg 
– 
1,000 
mg 
acetaminophen/paracetamol p.o. and an anti-histamine (e.g., diphenhydramine 50 mg p.o. or 
promethazine IV) at least 30 minutes prior to administration of obinutuzumab. 
 
5.3.4 Obinutuzumab Administration 
Obinutuzumab should only be administered by a healthcare professional with appropriate medical 
support to manage severe infusion-related reactions that can be fatal if they occur. 
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Administer at 50 mg/hr. The rate of the infusion can be escalated in 50 mg/hr increments every 30 
minutes to a maximum of 400 mg/hr. 
Day (-12) Administration 
CBC and coagulation lab tests are to be collected and results should be available prior to dosing. 
Day -12 treatment will be delayed if platelet count is below 75,000/µL, coagulation abnormalities 
and/or any signs and symptoms of bleeding or thrombosis are present. The second obinutuzumab 
dose can be delayed by Day -7. Any further delay in obinutuzumab dosing is to be discussed with 
the Medical Monitor. 
If no infusion-related reaction or an infusion-related reaction of Grade 1 occurred during the 
previous infusion and the final infusion rate was 100 mg/hr or faster, infusions can be started at a 
rate of 100 mg/hr and increased by 100 mg/hr increments every 30 minutes to a maximum of 400 
mg/hr. If an infusion-related reaction of Grade 2 or higher occurred during the previous infusion, 
administer at 50 mg/hr. The rate of infusion can be escalated in increments of 50 mg/hr every 30 
minutes to a maximum rate of 400 mg/hr. 
See pharmacy manual for more details regarding administration of obinutuzumab. 
Infusion Related Reactions If a subject experience an infusion-related reaction (IRR), adjust the 
infusion as follows  
• Grade 4 (life-threatening): Stop infusion immediately and permanently discontinue 
obinutuzumab. This will have no impact on the subsequent administration of NAP 
/docetaxel, which should occur as scheduled. 
• Grade 3 (severe): Interrupt infusion and manage symptoms. Upon resolution of symptoms, 
consider restarting obinutuzumab infusion at no more than half the previous rate (the rate 
being used at the time that the IRR reaction occurred), and if subject does not experience 
any further IRR symptoms, infusion rate escalation may resume at the increments and 
intervals as appropriate for the treatment cycle dose. Permanently discontinue treatment if 
subjects experience a Grade 3 IRR at rechallenge.  
• Grade 1–2 (mild to moderate): Reduce infusion rate or interrupt infusion and manage 
symptoms. Upon resolution of symptoms, continue or resume obinutuzumab infusion, and 
if subject does not experience any further IRR symptoms, infusion rate escalation may 
resume at the increments and intervals as appropriate for the treatment cycle dose. 
 
5.3.5 Stability of Diluted Obinutuzumab  
For microbiological stability, immediately use diluted obinutuzumab infusion solution. If not used 
immediately, store in a refrigerator at 2°C to 8°C (36°F to 46°F) for up to 24 hours prior to use.  
 


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5.4 
Prohibited Concomitant Medication 
The following medications and treatments are not permitted while a subject is on protocol therapy: 
• Any investigational agent, regardless of the indication 
• Any other anti-neoplastic agents, including cytotoxic agents, monoclonal antibodies, targeted 
agents (e.g., tyrosine kinase inhibitors), checkpoint inhibitors, etc. 
• Systemic glucocorticoids equivalent to more than 10 mg/day of prednisone (with exceptions 
noted below). Topical, intranasal, inhalational and intra-ocular glucocorticoids are permitted. 
Intermittent, brief (less than 1 week) courses of pharmacologic doses of glucocorticoids are 
permitted for use as anti-emetics, premedications, severe AEs, in subjects with radiographic 
contrast allergies prior to radiographic procedures and for exacerbations of concomitant 
conditions such as asthma or COPD.  
• Palliative radiation to a target lesion; prior to administering any palliative radiation, the 
medical monitor should be consulted. 
• Other immunosuppressive agents, including (but not limited to), cyclosporine, mycophenolate, 
azathioprine, methotrexate, adalimumab, infliximab, vedolizumab, tofacitinib, dupilumab, 
rituximab, etc. 
• Live vaccines during protocol treatment and until B-cell recovery occurs; vaccines derived 
from inactive viruses are permitted. 
• Strong inhibitors or inducers of CYP3A4 (a list of these agents may be found in Appendix 
14.5).  In addition, because of the possibility of transient release of cytokines following dosing 
with NAP which can suppress other CYP450 enzymes, subjects receiving substrates of CYP 
enzymes for which small changes in concentration could lead to altered safety or efficacy 
should be monitored closely and have doses adjusted as necessary (Appendix 14.5) 
• The use of herbal and unapproved homeopathic remedies is strongly discouraged, as these 
agents may have subtle but important pharmacologic effects (e.g., effects on the cytochrome 
P450 system) 
Subjects who require any of the above treatments during the study will have protocol therapy 
discontinued and be scheduled for the End of Treatment (EOT) visit. 
All other intercurrent illnesses will be treated at the discretion of the Investigator according to 
community standards of medical practice. Agents commonly used to treat the complications of 
malignancy, such as non-steroidal anti-inflammatory agents, opioid analgesics, anti-depressants, 
anxiolytics, anti-emetics, antibiotics, hematopoietic growth factors and bone agents (such as 
bisphosphonates and denosumab) are permitted, as are transfusions of blood products.  
Hematopoietic growth factors (e.g. G-CSF, erythropoietin) and approved COVID treatments (e.g. 
Paxlovid) are allowed during the study. 
 


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5.5 
Lifestyle Restrictions 
The following restrictions apply while the subject is receiving protocol treatment and for the 
specified times before and after treatment: 
 
5.5.1 Female subject of child-bearing potential 
Female subjects of childbearing potential who are not abstinent and intend to be sexually active 
with a non-sterilized male partner must use at least 1 highly effective method of contraception 
(Appendix 14.6). This should be used from the time of screening throughout the total duration of 
the drug treatment and until 90 days after the last dose of protocol treatment. Female subjects 
should refrain from breastfeeding throughout this period.  
 
5.5.2 Male subjects with a female partner of childbearing potential 
Non-sterilized male subjects who are not abstinent and intend to be sexually active with a female 
partner of childbearing potential must use a male condom plus spermicide from the time of 
screening throughout the total duration of the drug treatment and until 90 days after the last dose 
of protocol treatment. Periodic abstinence, the rhythm method, and the withdrawal method are not 
acceptable methods of contraception. Male subjects should refrain from sperm donation 
throughout this period. 
Please note, females of childbearing potential are defined as those who are not surgically sterile 
(i.e., bilateral salpingectomy, bilateral oophorectomy, or complete hysterectomy) or 
post-menopausal. Women will be considered post-menopausal if they have been amenorrheic for 
12 months without an alternative medical cause. The following age-specific requirements apply:  
• Women <50 years of age would be considered post-menopausal if they have been amenorrheic 
for 12 months or more following cessation of exogenous hormonal treatments and if they have 
luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for 
the institution. 
• Women ≥50 years of age would be considered post-menopausal if they have been amenorrheic 
for 12 months or more following cessation of all exogenous hormonal treatments, had 
radiation-induced menopause with last menses >1 year ago, had chemotherapy-induced 
menopause with last menses >1 year ago. 
• Women who are surgically sterile (i.e., bilateral salpingectomy, bilateral oophorectomy, or 
complete hysterectomy) are eligible.  
 


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5.5.3 Additional Restrictions: All Subjects 
Subjects should not donate blood or blood components while participating in this study and for 
90 days after receipt of the final dose of protocol therapy.  
 
 


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6 
STUDY PROCEDURES 
Subjects will be contacted and invited to participate in the screening process for this study. Upon 
arrival at the clinical site, subjects will be presented with the informed consent form (ICF) and all 
aspects of the study will be explained to them and their questions will be answered. Once subjects 
have provided their consent and signed ICF, they will begin the screening process and eligibility 
will be confirmed. Once permission for enrollment is given the subject will be enrolled via an 
interactive web-based system.  
The study will be comprised of the following periods: 
• 
A Screening period within 1-14 days. Assessments that take place at this visit are described 
in Section 7 and the Schedules of Assessments below. Pregnancy testing must be performed 
within 72 hours prior to first dose of obinutuzumab. 
• 
A Treatment period: as long as the combination of NAP and docetaxel is administered, cycles 
are of 21-day treatment. When NAP is given as monotherapy and not earlier than cycle 7, 
cycles are of 28-day treatment. Treatment will continue until progression or fulfillment of any 
of the reasons for protocol therapy discontinuation as outlined in Section 4.6, for a maximum 
of up to 24 months from day 1 of therapy. If either NAP or docetaxel require discontinuation, 
the other drug will continue as monotherapy. NAP will be administered in a dose of 10 
μg/kg/day on Days 1-4 of cycles 1-6, followed by docetaxel, 75 mg/m2 on Day 5. Starting 
Cycle 7, NAP will be administered on Day 1 only in a dose of 15 µg/kg (unless the dose was 
previously reduced due to toxicity) and docetaxel on Day 2, in 21 days treatment cycles. Once 
NAP is given as monotherapy and not earlier than C7, cycles will be of 28 days of duration. 
In patients whose NAP dose was reduced due to toxicities during cycles 1-6, NAP dose will 
not be further increased in cycle 7 and stays the same as in the previous cycle. During these 
study visits, safety assessments, PK/PD and immunogenicity markers will be collected, and 
response assessments will be performed according to the schedule presented in Table 1. The 
assessments which will be performed are also described in Section 7. 
• An End-of-Treatment (EOT) visit will take place 30 days (±3) following the last dose 
administration to assess for safety parameters and other evaluations and prior to start of a new 
anti-cancer treatment. 
The following Schedules of Assessments describes all required study assessments and the 
timeframes in which these must be performed. All visits must occur within the pre-defined 
windows outlined in this protocol. 
Guidance regarding how to manage subjects exposed to COVID-19 and recommendations for 
the vaccine, can be found in Appendix 14.7. 


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Table 1. Schedule of Assessments: Cycle 1-6 
  
Screening 
Obinutuzumab 
Treatment Cycle 1-6 
Day 15 only 
(+ 2 d) 
Procedure 
Days 
-28-14 
Day - 13 
Day - 12 
Day 1 
Day 2 
Day 3 
Day 4 
Day 522 
Sign consent1 
X 
 
 
 
 
 
 
 
 
Review eligibility criteria 
X 
 
 
 
 
 
 
 
 
Review medical history20 
X 
 
 
 
 
 
 
 
 
Record demographic data 
X 
 
 
 
 
 
 
 
 
Physical Exam 
Complete physical exam 
X 
 
 
X 
 
 
 
 
 
Symptom directed physical exam21 
 
X 
 
X 
 
 
 
X 
X 
Vital signs2 
X 
X14 
X14 
X15 
X15 
X15 
X15 
X 
X 
Weight 
X 
 
 
X 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
ECOG 
X 
 
 
X 
 
 
 
 
 
ECG3 
X 
 
 
 
 
 
 
 
 
Safety Labs 
CBC4 
X 
 
X 
X 
 
 
X 
 
X 
Serum chemistry5 
X 
 
 
X 
 
 
X 
 
X 
Coagulation panel6 
X 
 
X 
X 
 
 
 
 
 
Urinalysis7 
X 
 
 
 
 
 
 
 
 
Pregnancy test8 
X 
 
 
X 
 
 
 
 
 
Thyroid panel9 
X 
 
 
X9 
 
 
 
 
 
HIV, hepatitis serology10 
X 
 
 
 
 
 
 
 
 
Extent of disease (EOD) assessment11 
CT/MRI 
X 
 
 
X 
every 6 weeks (± 7 days) from C1D1 
 
Tumor tissue18 
X 
 
 
 
 
 
 
 
 


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Screening 
Obinutuzumab 
Treatment Cycle 1-6 
Day 15 only 
(+ 2 d) 
Procedure 
Days 
-28-14 
Day - 13 
Day - 12 
Day 1 
Day 2 
Day 3 
Day 4 
Day 522 
PK sampling for NAP 12 
 
 
 
X 
 
 
X 
 
 
Biomarkers 
ADA and Nab 13 
 
X 
 
X 
 
 
 
 
X 
 HAMA 13 
 
X 
 
X 
 
 
 
 
X 
Cytokines16 
 
 
 
X 
 
 
 
 
 
B Cell counts17 
 
X 
 
X 
 
 
 
 
 
Treatment 
Obinutuzumab19 
 
X 
X 
 
 
 
 
 
 
NAP19 
 
 
 
X 
X 
X 
X 
 
 
Docetaxel19 
 
 
 
 
 
 
 
X 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse event reporting 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Notes: 
  1. 
Obtain informed consent prior to performing any study-related procedures 
  2. 
Vital signs to include pulse, systolic and diastolic blood pressure, respiratory rate and temperature. Vital signs will be measured in supine position after at 
least five minutes of rest and prior to any treatment or premedication on treatment days. 
  3. 
ECGs to be performed in triplicate 5 minutes apart; QTc to be calculated via the Fridericia correction. Additional ECGs should be performed during the 
study if clinically indicated. 
  4. 
CBC to include WBC, differential, HGB, HCT, platelet count. Results should be available prior to any treatment and will be collected at screening, Day -
12 prior to obinutuzumab treatment and up to 72 hours prior to study treatment on Day 1 of each cycle. Cycle 1 only: samples will be collected also on 
Day 4, a window is allowed up to 24 hours prior to Day 4, but after NAP administration on Day 3. No further samples will be collected on Day 4 of any 
subsequent cycles, unless it is clinically indicated. Sample will also be collected on cycle 1 day 15. 
  5. 
Serum chemistries to include sodium, potassium, chloride, bicarbonate, glucose, BUN/Urea, creatinine, AST, ALT, GGT, alkaline phosphatase, total 
bilirubin, LDH, calcium, magnesium, phosphorous, uric acid, total protein, albumin. Results should be available prior to any treatment and will be collected 


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at screening and up to 72 hours prior to study treatment on Day 1 of each cycle. Cycle 1 only: samples will be collected also on Day 4, a window is allowed 
up to 24 hours prior to Day 4, but after NAP administration on Day 3. No further samples will be collected on Day 4 of any subsequent cycles, unless it is 
clinically indicated. Sample will also be collected on cycle 1 day 15. 
  6. 
Coagulation panel to include INR and PTT. Results should be available prior to any treatment and will be collected at screening, Day -12 prior to 
obinutuzumab treatment,  up to 72 hours prior to C1D1 and then as clinically indicted during the treatment cycles.  
  7. 
Urinalysis to include pH, specific gravity, dipstick determinations for protein, blood, glucose, ketones and will be collected at screening only and as clinically 
indicted during the treatment cycles. 
  8. 
Urine or serum pregnancy test will be performed at screening and up to 72 hours prior to Day 1 of each treatment cycle. 
  9. 
Thyroid panel to include, TSH, T3, free T4 and will be collected on screening, C3D1, C6D1. Thyroid panel will be collected up to 72 hours prior to any 
study treatment on treatment days.. 
10. 
Serologies to include HbsAg, HIV antibody, HCV antibody. Tests performed as part of routine clinical management are acceptable for use as the screening 
tests if performed up to 30 days prior to screening. 
11. 
EOD assessment to include CT (Chest Abdomen Pelvis), MRI (brain), findings on physical exam and any other appropriate radiographic procedures to 
document sites of neoplastic disease. Scans (Chest Abdomen Pelvis and brain CT/MRI) performed as part of routine clinical management are acceptable 
for use as the screening scan if they are of diagnostic quality and have been performed within three (3) weeks prior to D-13 obinutuzumab pretreatment. 
Ongoing study imaging will be performed at the end of cycle 2 (45 ± 7 days) and every 6 weeks for the first 24 weeks and every 9 weeks (± 7 days) 
thereafter. Confirmatory scans will be performed after 6 weeks (± 7 days) during the first 24 weeks and every 9 weeks thereafter. This schedule should be 
maintained even if cycles are delayed. Scheduled imaging of the brain is not required during the study unless there is involvement at baseline. Additional 
scans of any type may be done for clinical management and can be potentially used for RECIST evaluation upon consultation with the medical monitor.  
12. 
PK samples for NAP will be drawn within 30 minutes prior to NAP administration start time, and then 5 minutes (+ 3 min) and 1 hour (+ 15 min) after 
NAP administration start time. 
13. 
Anti-drug antibodies (ADAs), HAMA and Neutralizing antibodies (Nab) to be obtained within 30 min prior to administration of NAP or obinutuzumab. 
14. 
Vital signs to be obtained prior to premedication administration of obinutuzumab, then every 15 minutes (+ 5 min) for the first hour of infusion, then every 
30 minutes (+ 5 min) for the remainder of the infusion and then every 30 minutes (+ 5 min) for 1 hour after the end of the infusion. 
15. 
Vital signs to be obtained prior to premedication administration of NAP and then 15, 30 (+ 5 min), 60 (+ 5 min), 180 minutes (+ 15 min) after NAP 
administration start time on cycle 1 (days 1-4) and cycle 2 day 1 (C2D1) only. On further treatment days vital signs will be collected before NAP 
premedication and then at 15, 30 (+ 5 min) and 60 (+ 5) minutes post-injection of NAP, unless the subject experienced any G3 or higher infusion related 
reactions previously, and therefore will continue monitoring up to 180 min (+15 min) post NAP administration.  
16. 
Cytokine samples will be collected within 30 min before NAP administration start time, and then 1 h (±15 min) and 3 h (±15 min) after NAP administration 
start time. 


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17. 
B cell count will be collected on Day -13 and C1D1, prior to any study treatment on treatment days. Results are not required to be available prior to 
treatment. If the test was missed in any of the visits, it is important to collect it in the next scheduled visit. This sample should be analyzed at local 
laboratory according to Appendix 14.8. 
18. 
Tumor tissue: Archival or fresh tumor tissue from a biopsy of a tumor lesion not previously irradiated must be provided and sent to central lab during 
screening for retrospective biomarker test of 5T4 expression. If there are multiple archival samples from different time points, the most recent sample 
should be submitted for analysis. Bone samples, fine-needle aspiration, brushing, cell pellets and lavage are not acceptable. 
19. 
Follow pre-medication guidelines in section 5.3.3 for obinutuzumab, section 5.2.5 for NAP and section 5.1.1 for docetaxel. 
20.    Medical history review should also include the collection of NGS results, TMB expression and PD-L1 level, if available.  
21.    Symptom directed physical exam will be performed up to 72 hours prior to study drug administration. It will be performed on Day -13, Days 5 and 15 of 
Cycle 1, Day 1 and Day 5 of each subsequent treatment cycle and as clinically indicated. 
22.    If docetaxel is discontinued due to toxicity, Day 5 assessments should not be performed. 
 
 
 
 


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Table 2. Schedule of Assessments: Subsequent Treatment Cycles for Cycle 7 Onward 
Procedure 
Subsequent Treatment Cycles for Cycle 7 Onward 
EOT 
Long-term F/U  
 
Day 1 
Day 2 
 
 
 
 
 
Physical Exam 
Complete physical exam 
 
 
 
 
 
X 
 
Symptom directed physical 
exam18 
X 
 
 
 
 
 
 
Vital signs1 
X12 
X 
 
 
 
X 
 
Weight 
X 
 
 
 
 
X 
 
ECOG 
X 
 
 
 
 
X 
 
ECG2 
 
 
 
 
 
X 
 
Safety Labs 
CBC3 
X 
 
 
 
 
X 
 
Serum chemistry4 
X 
 
 
 
 
X 
 
Coagulation panel5 
 
 
 
 
 
X 
 
Urinalysis6 
 
 
 
 
 
X 
 
Pregnancy test7 
X 
 
 
 
 
X 
 
Thyroid panel8 
X 
 
 
 
 
X 
 
Extent of disease (EOD) assessment9 
CT/MRI 
X 
 
 
 
 
X 
X13 
Follow-up for survival 
 
 
 
 
 
 
X14 
PK sampling for NAP 10 
X 
 
 
 
 
 
 
Biomark
ers 
ADA and Nab11 
X 
 
 
 
 
X 
 
HAMA11 
X 
 
 
 
 
X 
 
Cytokines16 
X 
 
 
 
 
 
 


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Procedure 
Subsequent Treatment Cycles for Cycle 7 Onward 
EOT 
Long-term F/U  
 
Day 1 
Day 2 
 
 
 
 
 
B Cell counts17 
X 
 
 
 
 
X 
 
Rx 
NAP15 
X 
 
 
 
 
 
 
Docetaxel15 
 
X 
 
 
 
 
 
Concomitant medications 
X 
X 
 
 
 
X 
 
Adverse event reporting 
X 
X 
 
 
 
X 
 
 
Notes 
1. 
Vital signs to include pulse, respiratory rate and systolic and diastolic blood pressure, respiratory rate and temperature. Vital signs will be measured in 
supine position after at least five minutes of rest and prior to any treatment or premedication on treatment days.  
2. 
ECGs to be performed in triplicate 5 minutes apart; QTc to be calculated via the Fridericia correction. Additional triplicate ECGs should be performed 
during the study if clinically indicated and at EOT visit.  
3. 
CBC to include WBC, differential, HGB, HCT, platelet count. Results should be available prior to any treatment and will be collected up to 72 hours prior 
to any study treatment on treatment days and at EOT visit.   
4. 
Serum chemistries to include sodium, potassium, chloride, bicarbonate, glucose, BUN/Urea, creatinine, AST, ALT, GGT, alkaline phosphatase, total 
bilirubin, LDH, calcium, magnesium, phosphorous, potassium, uric acid, total protein, albumin. Results should be available prior to any treatment and to 
be collected up to 72 hours prior to any study treatment on treatment days and at EOT visit.  
5. 
Coagulation panel to include INR and PTT. A coagulation panel should be obtained at EOT visit and as clinically indicted during the treatment cycles. 
6. 
Urinalysis to include pH, specific gravity, dipstick determinations for protein, blood, glucose, ketones and will be collected at EOT visit and as clinically 
indicated. 
7. 
Urine or serum pregnancy test to be obtained up to 72 hours prior to Day 1 of each treatment cycle and at EOT visit. 
8. 
Thyroid panel to include, TSH, T3, free T4 and to be obtained on C9D1 and every third cycle for the duration of the study and at EOT. Thyroid panel will 
be collected up to 72 hours prior to any study treatment on treatment days. In the case of abnormal thyroid function at EOT visit, subject will be followed 
every 3 months up to resolution or starting a new anti-cancer treatment.  


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9. 
EOD assessment to include CT (Chest Abdomen Pelvis ) and MRI (brain – if lesions present at baseline), findings on physical exam and any other 
appropriate radiographic procedures to document sites of neoplastic disease. Ongoing study imaging will be performed at the end of cycle 2 (45 days ± 7 
days) and every 6 weeks for the first 24 weeks and then every 9 weeks (± 7 days) thereafter. Confirmatory scans will be performed after 6 weeks (± 7 days) 
during the first 24 weeks and every 9 weeks thereafter. This schedule should be maintained even if cycles are delayed.   Scheduled imaging of the brain is 
not required during the study unless lesions are present at baseline. Additional scans of any type may be done for clinical management and can be potentially 
used for iRECIST evaluation upon consultation with the medical monitor. 
10. 
PK samples for NAP will be drawn within 30 minutes prior to NAP administration start time, and then 5 minutes (+3 min) and 1 hour (+ 15 min) after NAP 
administration start time. PK samples will be collected on Day 1 of every 2 cycles after cycle 6: cycle 8, cycle 10, cycle 12, cycle 14, cycle 16, cycle 18, 
cycle 20, cycle 22, cycle 24, cycle 26, cycle 28, cycle 30, cycle 32 and cycle 34. If B cell level is increased back to the normal range at any timepoint during 
the study, additional PK samples will be collected in the following visit. 
11. 
Anti-drug antibodies (ADAs), HAMA and Neutralizing Antibodies (Nab) to be obtained within 30 minutes prior to administration of NAP and will be 
collected on Day 1 of every 2nd cycle after cycle 6: cycle 8, cycle 10, cycle 12, cycle 14, cycle 16, cycle 18, cycle 20, cycle 22, cycle 24, cycle 26, cycle 
28, cycle 30, cycle 32 and cycle 34. Samples for ADAs, HAMA and Nab will be collected at EOT visit only if have not been collected on the previous visit. 
If B cell level is increased back to normal range  at any timepoint during the study, additional samples for ADAs, HAMA and Nab will be collected in the 
following visit. 
12. 
Vital signs to be obtained prior to administration of NAP premedication, and then 15, 30 (± 5 min) and 60 (+ 5) minutes after NAP administration start 
time, unless the patient experienced any G3 or higher infusion related reactions in prior cycles which require further monitoring. 
13. 
Subjects who discontinue treatment without progression will be followed for progression every 6 weeks (± 7 days) for the first 24 weeks and every 9 weeks 
thereafter.  
14. 
All subjects will be followed for survival, by monthly (± 7 days) phone calls, for 6 months following treatment completion of the last subject into the trial 
15. 
Follow pre-medication guidelines in section 5.2.5 for NAP and section 5.1.1 for docetaxel. Starting Cycle 7, NAP will be administered on Day 1 only in a 
dose of 15 µg/kg/day (unless the dose was previously reduced due to toxicity and then NAP dose will not be further increased) and docetaxel on Day 2, in 
21 days treatment cycles. The combination of NAP and docetaxel will be given for a maximum of 8 cycles (unless, in the opinion of the investigator, the 
patient may derive benefit from continuing docetaxel), then NAP will be continued as a single agent (Day 2 assessments should not be performed) until 
disease progression, untoward toxicity or non-compliance for a maximum of up to 24 months from day 1 of therapy. Once NAP is given as monotherapy 
and not earlier than C7, cycles will be of 28 days of duration. If NAP is discontinued due to an AE and treatment is continued with single agent docetaxel, 
all assessments of Day 1, with the exception of PK sampling for NAP, cytokines, ADAs, HAMA, 12 Lead ECG and thyroid hormones, B-cells should be 
performed on the day of docetaxel treatment.  
16. 
Cytokine samples will be collected within 30 min before NAP administration start time, and then 1 h (±15 min) and 3 h (±15 min) after NAP administration 
start time. Cytokine samples will be collected on Day 1 of every 2nd cycle after cycle 6: cycle 8, cycle 10, cycle 12, cycle 14, cycle 16, cycle 18, cycle 20, 


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cycle 22, cycle 24, cycle 26, cycle 28, cycle 30, cycle 32, and cycle 34. If B cell level is increased back to normal range at any timepoint during the study, 
additional cytokine samples will be collected in the following visit. 
17. 
B cell count should be obtained on day 1 of each cycle starting from cycle 7 until B cell recovery to at least the lower limit of normal range or End of 
Treatment visit, whichever comes first. Results are not required to be available prior to treatment. This sample should be analyzed at local laboratory 
according to Appendix 14.8. If the test was missed, it is important to collect it in the next scheduled visit. In case of B cell recovery to at least the lower 
limit of normal range at any timepoint during the study, additional samples for PK, ADAs, HAMA and Nab will be collected in the following visit. 
18.    Symptom directed physical exam will be performed up to 72 hours prior to study drug administration. 
     
 
 


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7 
ASSESSMENTS 
All protocol-required assessments are briefly described below. A by-visit presentation of the 
different schedules of assessments is provided in Tables 1 and 2.  
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances, outside of the control of the Investigator that may make it unfeasible to perform 
the test. In these cases, the Investigator will take all steps necessary to ensure the safety and well-
being of the subject. When a protocol-required test cannot be performed, the Investigator will 
document the reason for this and any corrective and preventive actions that have been taken to 
ensure that normal processes are adhered to as soon as possible. The study team will be informed 
of these incidents in a timely fashion. 
Whenever vital signs and blood draws are scheduled for the same nominal time, the assessments 
should occur in the following order: vital signs and then blood draws. The timing of the vital signs 
assessments should be such that it allows the blood draw (e.g., PK blood sample) to occur at the 
time points indicated in the Schedules of Assessments. Whenever electrocardiograms (ECGs) and 
blood draws are scheduled for the same nominal time, the assessments should occur in the 
following order: ECG and then blood draws.  
7.1 
General Assessments 
Demographics 
The age, gender, race, and ethnic origin will be recorded at the Screening visit according to local 
regulations regarding the release of personal subject information.  
Medical History 
A medical history, conducted by interview or based on medical records, will be recorded at the 
Screening visit, and will include all pertinent prior medical conditions, documentation of 
histological or cytological proof of malignancy, NGS results, TMB expression and PD-L1 levels, 
and details of previous anti-cancer treatment or other medical procedures related to the subject's 
current disease, including a complete medications history of anticancer agents, prior surgery, prior 
radiation treatment and COVID-19 (both disease and vaccines).  
Concomitant Medications  
All prescription and over-the-counter or medications, vitamins, vaccinations and/or herbal 
supplements, including medications that are unrelated to cancer management, from 28 days prior 
to Screening throughout the entire study period, will be recorded. These include long-term as well 
as short-term or acute medications ongoing at the time of ICF signature or started at any time after 
ICF signature until 7 days after the last dose of study treatment is administered. Premedication 
prior to protocol therapy administration will also be recorded. Reason for use, start and end dates 
and dosage information (dose, unit, frequency) of all concomitant medications will be recorded.  
Hematopoietic growth factors (e.g. G-CSF, erythropoietin) and approved COVID treatments (e.g. 
Paxlovid) are allowed during the study. 


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Non-permitted treatments are described in Section 5.4. 
7.2 
Safety Assessments 
7.2.1 Physical Examination 
A complete physical examination will be performed at Screening, on Day 1 of Cycle 1, as clinically 
indicated and at the End of Treatment (EOT) visit.  
A symptom-directed physical exam, with focus on any areas of known neoplastic disease or on 
areas referable to any symptoms or AEs, will be performed on Day -13, Days 5 and 15 of Cycle 1, 
Day 1 and Day 5 of each subsequent treatment cycle and as clinically indicated. Symptom directed 
physical exam will be performed up to 72 hours prior to study drug administration. 
The complete physical examination will cover a careful assessment of all body systems, including 
the head, eyes, ears, nose, and throat and the respiratory, cardiovascular, GI, urogenital, 
musculoskeletal, neurological, dermatological, hematologic/lymphatic, and endocrine systems. 
Particular attention should be placed on those areas involved by neoplastic disease. 
 
7.2.2 ECOG Performance Score 
The ECOG PS (Appendix 14.3) will be assessed at the Screening visit, then on day 1 of each cycle 
and at the EOT.  
 
7.2.3 Vital Signs 
Vital signs (temperature, pulse, respiratory rate and resting systolic and diastolic blood pressure) 
will be measured as follows:  
• Time points related to NAP administration start time:  
Vital signs will be obtained before NAP premedication administration, and at 15, 30 (+ 5 
min), 60 (+5 min), and 180 minutes (+ 15 min) post-injection of NAP on cycle 1 (days 1-
4) and cycle 2 day 1 (C2D1) only. On further treatment days vital signs will be collected 
before NAP premedication and then at 15, 30 (+ 5 min) and 60 (+ 5) minutes post-injection 
of NAP, unless the subject experienced any G3 or higher infusion related reactions 
previously, and therefore will continue monitoring up to 180 min (+15 min) post NAP 
administration. Time points related to Docetaxel administration start time:  
Vital signs will be obtained before Docetaxel treatment on day 5 of each cycle. 
• Time points related to obinutuzumab administration start time: 
Vital signs will be obtained before obinutuzumab premedication administration, then every 
15 (+ 5 min) for the first hour of infusion, then every 30 minutes (± 5 min) for the remainder 
of the infusion and then every 30 minutes (± 5 min) for 1 hour after the end of the infusion.  
• Vital signs will be also performed on day 15 of cycle 1, and at EOT visit. 
• Weight will be measured at the start of each treatment cycle and at the EOT visit. The 
calculation of the dose per subject weight should be done on the basis of subject weight on 
the day of treatment. In sites restricted by pharmacy’s procedures the dose can be calculated 
on the basis of subject weight obtained within 14 days prior to that date. For the purpose 
of calculating study treatment dose, the subject's weight should NOT be rounded off to the 


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closest kg value but rather recorded with 1 digit after the decimal point, for example, 70.5 
kg, 60.4, 77.0 kg etc. However, after multiplying the weight by the relevant dose level 
(µg/kg), the final dose (in µg) should be rounded off, for example, 120.5 µg will be rounded 
to 121 µg and 150.4 µg will be rounded to 150 µg.  
• Height will be measured at the screening visit 
 
Vital signs will be measured in supine position after at least five minutes of rest. A special attention 
should be given to cytokine release syndrome (CRS). See instructions below.  
 
Evaluation of cytokine release syndrome (CRS): 
The toxicities related to CRS (23) should be carefully monitored during the entire treatment period 
and specifically on days of NAP dosing.  See Appendix 14.4 for grading of CRS.  
All subjects will receive NAP infusion at a health care facility, followed by on-site monitoring at 
the health care facility for at least 4 h post dosing on the first cycle and 3 hours on each subsequent 
cycle to monitor for signs and symptoms of CRS. 
In addition, subjects and their family members/caregivers should be educated on potential CRS 
symptoms such as fever, dyspnea, confusion, aphasia, dysphasia, somnolence, encephalopathy, 
ataxia, or tremor. Subjects or their family members/caregivers should be instructed to immediately 
contact the treating investigator or seek immediate medical attention if any of these symptoms 
develop anytime during the study. 
 
 


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Guidelines for the treatment of CRS*: 
 
Grade 1 
Monitor fluid status; maintain an open intravenous catheter 
Empiric treatment for febrile neutropenia 
Supportive care with antipyretics, analgesics, antiemetics, etc. 
Grade 2 
Administer bolus of intravenous fluids; consider ICU monitoring 
If hypotension persists following 2 fluid challenges, administer tocilizumab 
If hypotension persists following tocilizumab, begin vasopressor agents; 
consider adding dexamethasone 
Supplemental oxygen as needed 
Supportive care 
Echocardiogram to monitor cardiac function 
Grade 3 
Admit to ICU 
Administer bolus of intravenous fluids 
If hypotension persists following 2 fluid challenges, administer tocilizumab 
If hypotension persists following tocilizumab, begin vasopressor agents; 
consider adding dexamethasone; add high-dose dexamethasone for persistent 
hypotension 
Supplemental oxygen as needed (including high-flow oxygen, CPAP) 
Supportive care 
Echocardiogram to monitor cardiac function 
Grade 4 
Intravenous fluids, tocilizumab, pressors and corticosteroids as for Grade 3 
Mechanical ventilation 
* Adopted from: Riegler LL, Jones GP, Lee DW.  Current approaches in the grading and management of cytokine 
release syndrome after chimeric antigen receptor T-cell therapy.  Therapeutics Clinical Risk Management 15:323-
335, 2019. 
 
 
 


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7.2.4 ECG  
A 12-lead ECG will be taken for each participant at Screening, and at the EOT visit. Additional 
ECG could be done during the study if clinically indicated. At minimum, the following ECG 
parameters will be recorded: heart rate (HR), and PR, QT and QRS and QTcF intervals. In addition, 
a determination of whether the ECG was normal, abnormal but not clinically significant, or 
abnormal AND clinically significant will be recorded in the eCRF.  
 
7.2.5 Laboratory Determinations 
All safety lab evaluations will be performed by a local lab. All laboratory results will be reviewed 
by the Investigator and will be recorded in the eCRF as normal, abnormal but not clinically 
significant, or abnormal AND clinically significant. In the latter case, the laboratory findings 
should be recorded as adverse events. 
Complete blood count 
Blood will be collected for complete blood counts (CBC) at the Screening visit, on Day -12, on 
Days 1, 4 and 15 of Cycle 1 and then on Day 1 only of every cycle thereafter involving combination 
or NAP/docetaxel monotherapy treatment, if applicable (when NAP/docetaxel is discontinued due 
to toxicity or intercurrent medical conditions). A CBC will also be obtained on the 30-day EOT 
visit. A time window for collection of CBC is available of up to 72 hours prior to study treatment 
on Day 1 of each cycle and up to 24 hours prior to Cycle 1 Day 4, but after NAP administration 
on Cycle 1 Day 3. Laboratory results must be known and within acceptable range prior to dosing. 
The CBC assessment will include a determination of hemoglobin, hematocrit, platelet count, white 
blood cells (WBC), and differential (to include percentage of each white blood cell).  
 
B cell counts   
B cell counts samples will be collected on Day -13, C1D1, and day 1 of each further cycle starting 
cycle 7 until B-cell recovery to at least the lower limit of normal range or End of Treatment visit, 
whichever comes first. If the test was missed in any of the visits, it is important to collect it in the 
next scheduled visit (results should be captured in the EDC under an unscheduled visit). If B cell 
level increased back to normal level at any timepoint during the study, additional samples for PK, 
ADAs, HAMA and Nab will be collected in the following visit. Results are not required to be 
available prior to treatment. This sample should be analyzed at local laboratory according to 
Appendix 14.8. 
Serum chemistry  
Blood will be collected for serum chemistry assessments at the Screening visit, on Days 1, 4 and 
15 of Cycle 1, and then on Day 1 of every cycle thereafter. A serum chemistry sample will also be 
obtained on the 30-day EOT. A time window for collection of CBC is available of up to 72 hours 
prior to study treatment on Day 1 of each cycle and up to 24 hours prior to Cycle 1 Day 4, but after 


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NAP administration on Cycle 1 Day 3. Laboratory results must be known and within acceptable 
range prior to dosing.  
Serum chemistries will include assessment of sodium, potassium, chloride, bicarbonate, glucose, 
BUN/Urea, creatinine, alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
gamma-glutamyl transferase (GGT), alkaline phosphatase, total bilirubin, Lactate dehydrogenase 
(LDH), calcium, magnesium, phosphorous, total protein, albumin, and uric acid.  
Coagulation Panel 
A coagulation panel, consisting of an international normalized ratio (INR) and activated partial 
thromboplastin time (aPTT) will be performed at Screening Day -12 prior to obinutuzumab treatment, 
up to 72 hours prior to C1D1,then as clinically indicated during treatment period and at the EOT 
visit.  
Urinalysis 
Urinalyses will be performed by dipstick at  Screening and EOT visit ., then as clinically indicated. 
Urinalysis will include pH, specific gravity, dipstick determinations for blood, nitrites, glucose, 
ketones, protein and bilirubin or urobilinogen. A microscopic examination of the urine will be 
performed if clinically indicated. 
Pregnancy Test – Urine or/ and Blood 
For female subjects of childbearing potential, a urine pregnancy test will be performed at 
Screening, then up to 72 hours prior to any treatment on Day 1 of each treatment cycle and at the 
EOT. If urine pregnancy results cannot be confirmed as negative, a serum β-HCG pregnancy test, 
performed by the local laboratory, is required. A negative pregnancy result is required before the 
subject may receive any protocol therapy. In the case of a positive confirmed pregnancy, the 
subject will be withdrawn from the study and will not proceed to receive the investigational 
product. 
Urine: A urine pregnancy test will be performed in women of child-bearing potential (WOCBP) 
only, up to 7 days prior to dosing of obinutuzumab on Day (-13).  
Blood: A serum pregnancy test will be performed if a confirmation pregnancy test is necessary.  
Thyroid Panel 
A thyroid panel, to include a free T4, T3 and TSH will be performed during Screening, day 1 of 
cycles 3, 6, and every 3rd cycle as long as subject is on study treatment and at EOT. Thyroid panel 
will be collected up to 72 hours prior to any study treatment on treatment days. In the case of 
abnormal thyroid function at EOT visit, subject will be followed every 3 months up to resolution 
or starting a new anti-cancer treatment. 
Viral Serologies 
Viral serologies to include HBsAg, HCV antibody and HCV antibody to be performed at 
Screening. Tests performed as part of routine clinical management are acceptable for use as the 
screening tests if performed up to 30 days prior to screening. 


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7.3 
Efficacy Assessments 
The preferred method for tumor imaging is CT with contrast covering chest, abdomen and pelvis 
and mandatory brain MRI at screening (additional brain MRI will be performed during the study 
only if indicated). CT scan of the brain will also be acceptable if MRI is not available. MRI should 
only be used for subjects with a contraindication to receive contrast agents. In cases where CT 
contrast-agents are unavailable, a non-contrast CT should be used for chest and pelvis and MRI 
with contrast is recommended for abdomen (for better assessment of a specific region by the 
Radiologist e.g. for liver lesions).  
Other specialized imaging or other techniques may also be appropriate for individual case. For 
example, while PET scans are not considered adequate to measure lesions, PET-CT scans may be 
used providing that the measures are obtained from the CT scan and the CT scan is of identical 
diagnostic quality to a diagnostic CT (with IV and oral contrast), and only if a baseline PET-CT is 
available. An initial tumor imaging will be performed within the Screening period (brain and 
CAP). Scans performed as part of routine clinical management will be acceptable for use as the 
screening scan if they are of diagnostic quality and have been performed within three (3) weeks 
prior to D-13 obinutuzumab pretreatment. Ongoing study imaging will be performed at the end of 
cycle 2 (45 days ± 7 days) and every 6 weeks for the first 24 weeks and then every 9 weeks (± 7 
days) thereafter. This schedule should be maintained even if cycles are delayed. Confirmatory 
scans will be performed after 6 weeks (± 7 days) during the first 24 weeks and every 9 weeks 
thereafter. Any imaging performed for subjects without confirmed progression at early 
termination, diagnostic imaging/response assessments should continue every 6 (±1) weeks for the 
first 24 weeks and then every 9 weeks (± 7 days) thereafter, until confirmed progression of disease 
or initiation of alternate therapies. If a subject has a response or stable disease, they can be 
permitted to continue until progression. 
As NAP is known to induce an inflammatory reaction in the tumor, pseudo-progression may be 
observed and therefore, in patients who demonstrate objective progression but who are clinically 
stable, 1-2 additional treatment cycle(s) of NAP/docetaxel may be administered beyond 
progression at the discretion of the Investigator, followed by a confirmatory imaging after 6 weeks 
(± 7 days) during the first 24 weeks and every 9 weeks thereafter. 
The same imaging modality should be used in each subject throughout the trial. Imaging will 
continue at the defined interval until disease progression, pregnancy, the start of a new treatment 
or completion of study participation. Scans will be evaluated by a local radiologist using iRECIST  
(Appendix 14.1).  
 
 
 


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7.4 
Pharmacokinetic Assessments 
Plasma samples for PK analysis will be collected on Day 1 and Day 4 of cycles 1-6, and then on 
D1 of every 2 cycles after cycle 6 , within 30 min prior to NAP administration start time and then 
5 minutes (+3 min) and 1 hour (±15 min) after NAP administration start time.  
 
Details of sample collection and handling will be provided separately in a lab manual.  
Table 3. PK Draws Timepoints 
Cycle/Day 
Timepoint related to NAP administration start time 
D1 and D4 of cycles 1-6 
-30 minutes  
+ 5 minutes (+3 min) 
+ 60 minutes (+ 15 min) 
D1 of every 2nd cycle after cycle 6 
(cycle 8, cycle 10, cycle 12, cycle 14, 
cycle 16, cycle 18, cycle 20, cycle 22, 
cycle 24, cycle 26, cycle 28, cycle 30, 
cycle 32 and cycle 34) 
-30 minutes  
+ 5 minutes (+3 min) 
+ 60 minutes (+ 15 min) 
 
7.5 
Pharmacodynamic Assessments 
 
Serum samples for cytokine levels analysis (such as IL-6, IL-10, IL-2, IFN-γ and TNF-α) will be 
collected within 30 min before NAP administration start time and then 1 h (±15 min) and 3 h (±15 
min) after NAP administration start time on day 1 of cycles 1-6, and Day 1 of every 2 cycles after 
cycle 6: cycle 8, cycle 10, cycle 12, cycle 14, cycle 16, cycle 18, cycle 20, cycle 22, cycle 24, cycle 
26, cycle 28, cycle 30, cycle 32 and cycle 34.  
Serum samples for determining the levels of human anti-murine antibodies (HAMA) will be 
collected within 30 minutes prior to the administration of obinutuzumab or NAP on Day -13 and 
on day 1 of cycles 1-6, cycle 1 Day 15, and Day 1 of every 2 cycles after cycle 6: cycle 8, cycle 
10, cycle 12, cycle 14, cycle 16, cycle 18, cycle 20, cycle 22, cycle 24, cycle 26, cycle 28, cycle 
30, cycle 32and cycle 34.  
Serum samples for determining the levels of anti-drug antibodies (ADAs) and neutralizing 
antibodies (Nab) will be collected within 30 minutes prior to the administration of obinutuzumab  
or NAP on Day -13 and on day 1 of cycles 1-6, cycle 1 Day 15 and Day 1 of every 2 cycles after 
cycle 6: cycle 8, cycle 10, cycle 12, cycle 14, cycle 16, cycle 18, cycle 20, cycle 22, cycle 24, cycle 
26, cycle 28, cycle 30, cycle 32and cycle 34. Nab samples will be collected and kept for future 
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Samples for ADAs, HAMA and Nab will be collected at EOT visit only if have not been collected 
on the previous visit.   
Details of sample collection and handling will be provided separately in a lab manual.  
7.6 
Tumor Biopsy 
Tumor archival or fresh tissue from a biopsy of a tumor lesion not previously irradiated must be 
provided and sent to central lab during screening for retrospective biomarker test of 5T4 
expression. If there are multiple archival samples from different time points, the most recent 
sample should be submitted for analysis. 
The following samples of biopsy are not allowed for 5T4 analysis: 
• 
Bone samples. 
• 
Fine-needle aspiration, brushing, cell pellets and lavage. 
Details of sample collection and handling will be provided separately in a lab manual.  
7.7 
End of Treatment/Early Termination Visit 
Specific assessments and procedures to be performed for the End of Treatment/Early Termination 
visit are listed in Table 2. The End of Treatment visit will occur 30 days (±3) from the last dose of 
protocol therapy and prior to start of a new anti-cancer treatment. 
7.8 
Long Term Follow-Up 
All subjects will be followed for survival, by monthly phone calls, for up to 6 months (± 7 days) 
following treatment completion of the last subject in the trial. 
Subjects without confirmed progression at early termination, diagnostic imaging/response 
assessments should continue every 6 (±1) weeks in the first 24 weeks and every 9 weeks thereafter, 
until confirmed progression of disease or initiation of alternate therapies. Thyroid panel will also 
continue for subjects on study every 3 months for 6 months after study drug discontinuation. 
7.9 
Unscheduled Visits 
Unscheduled visits are those visits that will occur between regularly scheduled visits and will be 
performed in order to assess a previously noted adverse event, abnormal/significant laboratory 
values, and/or clinical findings. In such cases, the patient will be contacted to arrange an 
unscheduled visit to assess the abnormalities. Only focused assessments are foreseen for these 
visits.  
 
8 
ADVERSE EVENTS REPORTING AND MEDICAL MANAGEMENT 
As described in Section 8.13, any AEs attributed to study drug dosing, including laboratory 
abnormalities, should be subsequently followed until the event or its sequelae resolve or stabilize.  
 


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8.1 
Adverse Events 
Safety assessments will include recording TEAEs reported spontaneously by the subject or 
observed by the Investigator. Treatment-emergent AEs will be recorded at each visit on the 
appropriate eCRF. Any AEs occurring between (and including) Screening and D-13 visit will be 
recorded on the Medical History eCRF, as long as treatment has not been initiated. If an AE is 
recorded in Medical History and has worsened, it will be considered a TEAE. 
All observed or volunteered AEs, regardless of study treatment and suspected causal relationship 
to protocol therapy will be reported as described in the following sections.  
For all AEs, the Investigator must pursue and obtain information adequate both to determine the 
outcome of the AE and to assess whether it meets the criteria for classification as a serious adverse 
event (SAE) requiring immediate notification to the Sponsor or its designated representative.  For 
all AEs, sufficient information should be obtained by the Investigator to determine the causality 
of the AE, which must be assessed by the Investigator. Follow up by the Investigator should 
continue until the event or its sequelae resolve, return to a baseline state or stabilize. 
As part of ongoing safety reviews conducted by the Sponsor, any nonserious AE that is determined 
by the Sponsor to be serious will be reported by the Sponsor as an SAE. To assist in the 
determination of case seriousness, further information may be requested from the Investigator to 
provide clarity and understanding of the event in the context of the clinical study. 
 
8.2 
Definition of an Adverse Event 
An AE is any untoward medical occurrence in a subject administered a product or medical device 
after the subject signs the ICF for a clinical study; the event need not necessarily have a causal 
relationship with the treatment or usage. An adverse event can therefore be any unfavorable and/or 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an investigational medicinal product, whether related to the 
investigational medicinal product. TEAEs are defined as events that emerge during treatment 
having been absent pre-treatment or worsen relative to the pre-treatment state. 
All adverse events, including observed or volunteered problems, complaints, or symptoms, are to 
be recorded on the appropriate eCRF, as described in section 8.1. 
 
 
 


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Examples of AEs include but are not limited to:  
• All suspected adverse medication reactions including: 
o Abnormalities in physiological testing or physical examination findings that require 
clinical intervention or further investigation (beyond ordering a repeat [confirmatory] 
test). 
o Laboratory abnormalities that require clinical intervention or further investigation 
(beyond ordering a repeat [confirmatory] test) unless they were associated with an 
already reported clinical event. Laboratory abnormalities associated with a clinical 
event (e.g., elevated liver enzymes in a subject with jaundice) are to be described 
separately unless the underlying pathophysiological cause is known 
o Clinically significant symptoms and signs 
• All reactions from medication overdose, abuse, withdrawal, hypersensitivity, or toxicity. 
• Seemingly unrelated illnesses, including the worsening of a pre-existing illness  
• Injury or accidents Note: if a medical condition is known to have caused the injury or 
accident, the medical condition and the accident should be reported as two separate AEs. 
The outcome of the accident should be recorded under Comments. 
• Progression/worsening of underlying disease (progression of the malignancy under 
evaluation should not be considered as AE).   
 
Pre-existing Conditions 
A pre-existing condition (i.e. a disorder other than cancer present before the AE reporting period 
started and noted on the pre-treatment medical history form) is not to be reported as an AE unless 
the condition worsens or episodes increase in frequency during the AE reporting period. Planned 
or elective surgical procedures for pre-existing conditions that have not worsened are not TEAEs. 
However, any complication that occurs during a planned or elective surgery is a TEAE (Note: If 
the event meets the criteria for a SAE, such as an extended hospitalization, it will be considered 
an SAE). Conditions leading to unplanned surgical procedures may also be TEAEs. 
 
New Cancers 
The development of a new cancer should be regarded as an SAE. New primary cancers are those 
that are not the primary reason for the administration of protocol therapy and have been identified 
after the subject’s inclusion in this study. 
 
 
 


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Concomitant Procedures 
Diagnostic and therapeutic procedures, such as surgery, are not to be reported as AEs. However, 
the medical condition for which the procedure was performed should be reported if it meets the 
definition of an AE. For example, an acute appendicitis that began during the AE reporting period 
is to be reported as the AE and the resulting appendectomy noted as treatment for the AE. 
Events of Special Interest (AOSI) 
Given the expected immunostimulatory effects of the study treatment, special attention should be 
paid to immune-related adverse events. Immune-related AEs (irAEs) will be graded based on 
CTCAE.  
In case the AOSI is classified as an SAE, an SAE report will be completed, signed and sent via 
email to the Sponsor or Sponsor’s designee. 
 
8.3 
Unexpected Adverse Event 
An adverse event is considered "unexpected" if it is not listed in the Investigator Brochure or is 
not listed at the specificity or severity that has been observed; or, if an Investigator Brochure is not 
required or available, is not consistent with the risk information described in the general 
investigational plan or elsewhere in the current application, as amended; or if a marketed product, 
not described as above in the full prescribing information, package insert or summary of product 
characteristics for an approved product. 
 
8.4 
Severity Assessment 
The term “severe” is used to describe the intensity of an AE; the event itself could be of relatively 
minor clinical significance (e.g., ‘severe’ headache). This is not the same as a “serious” AE. 
The severity of the AE will be graded by the Investigator according to the NCI CTCAE Grading 
Scale, v. 5.0 (the NCI CTCAE files can be accessed online at the following URL: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_R
eference_5x7.pdf 
If there is not a specific NCI CTCAE grading scale for an AE, the severity will be characterized 
as mild, moderate, severe, life-threatening or fatal according to the following definitions: 
• Grade 1 (mild) events are usually transient in nature and do not interfere with the 
subject’s daily activities. 
• Grade 2 (moderate) events introduce as low level of inconvenience or concern to the 
subject and may interfere with daily activities. 
• Grade 3 (severe) events interrupt the subject’s usual daily activities. 
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• Grade 5 (fatal) 
 
8.5 
Causality Assessment 
The Investigator’s assessment of causality must be provided for all AEs (serious and non-serious); 
the Investigator must record the causal relationship in the eCRF, as appropriate, and report such 
an assessment in accordance with the SAE reporting requirements, if applicable. An Investigator’s 
causality assessment is the determination of whether there exists a reasonable possibility that the 
investigational product caused or contributed to an AE; generally, the facts (evidence) or 
arguments to suggest a causal relationship should be provided.  
In addition, if the Investigator determines that an AE is associated with a study procedure, the 
Investigator must record this causal relationship in the source documents and eCRF, as appropriate, 
and report such an assessment in accordance with the AE reporting requirements, if applicable. 
The Investigator will make a judgment regarding the relationship of the AE to study treatment, as 
defined below. 
Causality: the relationship of each AE to study treatment will be defined as unrelated or related 
to study treatment using the following definitions: 
o Unrelated: There is little or no possibility that the study treatment caused the reported 
AE; and other factor(s) including concurrent illnesses, progression and expression of the 
disease state, concurrent medications, or a reaction to concurrent medications appear to 
explain the AE. 
o Related: There exists at least a reasonable possibility that the study treatment caused or 
contributed to the AE; an inability to identify an alternate etiology for an AE should not, 
by itself, justify a related attribution. 
 
8.6 
Serious Adverse Events 
Treatment-emergent SAEs will be recorded at each visit throughout the study on the appropriate eCRF. 
Any SAEs occurring between (and including) Screening and Baseline visits will be recorded in the Medical 
History eCRF, as long as treatment has not been initiated. 
A serious adverse event is any untoward medical occurrence at any dose that: 
• Results in death 
• Is life-threatening (immediate risk of death) 
• Requires in-subject hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity (substantial disruption of the ability 
to conduct normal life functions) 
• Results in a congenital anomaly/birth defect 


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• Is an important medical event that doesn’t fulfill any of the above criteria 
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event. An important medical event may not be immediately life-threatening and/or result 
in death or hospitalization. However, if it is determined that the event may jeopardize the subject 
or may require intervention to prevent one of the other SAE outcomes, the important medical event 
should be reported as 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; development 
of drug dependency or drug abuse or a new malignancy. 
Progression/worsening of underlying disease (progression of the malignancy under evaluation 
should not be considered as serious adverse event).   
 
8.7 
Hospitalization 
Hospitalization is defined as any admission or stay in a hospital or equivalent healthcare facility 
lasting more than 24 hours or any prolongation of an existing admission. An emergency room visit 
does not necessarily constitute a hospitalization; however, the event leading to the emergency 
room visit should be assessed for medical importance. 
Hospitalization does not include the following: 
• Admission to a rehabilitation facility 
• Admission to a hospice facility 
• Respite care (e.g., caregiver relief) 
• Admission to a skilled nursing facility 
• Admission to a nursing home 
• Out-subject/same-day/ambulatory procedures 
• Admission for treatment of a preexisting condition not associated with the development of 
a new AE or with a worsening of the preexisting condition (e.g., for workup of persistent 
pretreatment laboratory abnormality) 
• Social admission (e.g., subject has no place to sleep) 
• Administrative admission (e.g., for yearly physical examination) 
• Protocol-specified admission during a study (e.g., for a procedure required by the study 
protocol) 
• Optional admission not associated with a precipitating clinical AE (e.g., for elective 
cosmetic surgery) 
• Hospitalization for observation without a medical AE 


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• Preplanned treatments or surgical procedures. These should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject 
 
8.8 
Suspected Unexpected Serious Adverse Reaction (SUSAR) 
Suspected unexpected serious adverse reactions (SUSARs) are SAEs that are unexpected by the 
Sponsor and that is judged by the Investigator or Sponsor to be related to the study treatment 
administered. All SUSARs will be collected and reported to the regulatory authorities and relevant 
ethics committees in accordance with local pharmacovigilance requirements. 
 
8.9 
Serious Adverse Event Reporting Requirements 
If an SAE occurs, The Sponsor and/or its pharmacovigilance designee(s) are to be notified within 
24 hours of Investigator awareness of the event by sending a written, completed, and signed SAE 
report form to the following group mailbox or Fax: 
Email: clinicalsafety@propharmagroup.com 
Fax: (866) 681-1063 
The Investigator must continue to follow the subject until the SAE has subsided or until the 
condition becomes chronic in nature, stabilizes (in the case of persistent impairment), or the subject 
dies. 
Within 24 hours of receipt of new information, the updated follow-up SAE form, along with any 
supporting documentation (e.g., subject discharge summary or autopsy reports), should be 
transmitted or emailed to The Sponsor or its pharmacovigilance designee(s) at the Fax or email 
address above. 
The Sponsor must report all fatal or life-threatening SAEs to regulatory authorities in an expedited 
manner within 7 calendar days of being made aware of the event; serious adverse event reporting 
to regulatory authorities and all participating investigators will be conducted by NeoTX in 
accordance with 21 Code of Federal Regulations (CFR) 312.32 and international regulations, as 
appropriate. 
 
8.10 Reporting Period 
For all AEs, the active reporting period to The Sponsor or its designated representative begins 
from the time that the subject provides informed consent, which is obtained prior to the subject’s 
participation in the study, i.e., prior to undergoing any study-related procedure and/or receiving 
investigational product, through and including 30 calendar days after the last administration of the 
study treatment or initiation of alternate anticancer therapy. AEs that occur during the Screening 
period prior to first administration of any protocol therapy will be recorded as part of the medical 
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Adverse events (including laboratory abnormalities that constitute AEs) should be described using 
a diagnosis whenever possible, rather than individual underlying signs and symptoms. When a 
clear diagnosis cannot be identified, each sign or symptom should be recorded as a separate AE.  
The Investigator should elicit the reporting of adverse events from subjects in a non-prejudicial 
manner. Adverse events may also be recorded when they are volunteered by the subject, or through 
physical examination, laboratory tests, or other clinical assessments. 
 
8.11 Action Taken Regarding the Study Drugs  
The action taken towards the study drugs must be described as follows: 
- 
Permanently discontinued 
- 
Stopped temporarily/Dose delayed 
- 
Dose modified 
- 
No action taken 
- 
Unknown/Not applicable 
Indicate exactly for which study drug (or combination) the action was taken 
 
8.12 Outcome 
The outcome of each AE must be determined as follows: 
 
Outcome 
Clarification 
Recovered/Resolved 
Subject has fully recovered with no residual effects 
Recovered Resolved with 
sequelae 
Subject has recovered with residual effects  
Not yet recovered/Not Resolved 
Subject status improved but has not yet been recovered 
Ongoing/Not Recovered/Not 
Resolved 
Subject has not recovered and has no improvement 
Fatal 
Resulted in death of the subject 
Unknown 
e.g. lost to follow 
 
8.13 Recording of Adverse Events 
All AEs and SAEs occurring during the clinical investigation as defined above must be 
documented in the subject’s medical records as well as in the eCRF. Whenever possible, diagnoses 


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should be given when signs and symptoms are due to a common etiology (e.g., cough, runny nose, 
sneezing, sore throat, and head congestion should be reported as “upper respiratory infection”). 
Investigators must record their opinion concerning the relationship of the (S)AE to the study drugs 
in the source documents and in the eCRF. All measures required for (S)AE management must be 
recorded in the source documents and reported according to Sponsor’s instructions. 
All AEs occurring at any time during the study (including the follow-up period) will be followed 
by the Investigator until satisfactory resolution, return to a baseline state, stabilization or until final 
database lock. If necessary, in order to obtain additional information to ensure safety to the subject, 
additional tests may be taken at the discretion of the Investigator. Certain long-term AEs related 
to therapy cannot be followed until resolution within the setting of this study. In these cases, 
follow-up will be the responsibility of the treating physician. 
All TEAEs will be reported on the AE page(s) of the eCRF. It should be noted that the form for 
collection and reporting of SAE information is not the same as the AE eCRF. Where the same data 
are collected, the forms must be completed in a consistent manner. For example, the same AE term 
should be used on both forms. AEs should be reported using concise medical terminology on the 
eCRFs as well as on the form for collection and reporting of SAE information. 
 
8.14 Pregnancy 
8.14.1 Maternal Exposure 
Female subjects should refrain from becoming pregnant during the study and for 90 days after the 
last dose of protocol therapy. If a subject becomes pregnant during the course of the study, protocol 
therapy must be discontinued immediately. 
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the 
investigational product under study may have interfered with the effectiveness of a contraceptive 
medication. Congenital abnormalities/birth defects and spontaneous miscarriages should be 
reported and handled as SAEs. Elective abortions without complications should not be handled as 
AEs. The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic 
pregnancy, normal birth or congenital abnormality) should be followed up and documented even 
if the subject was discontinued from the study. 
If a study subject or study subject’s partner becomes or is found to be pregnant during the study 
subject’s treatment with the investigational product, the Investigator must submit this information 
to The Sponsor on a Pregnancy Reporting From, regardless of whether an SAE has occurred as a 
consequence of this exposure.  
The Investigator will follow the pregnancy until completion (or until pregnancy termination) and 
notify The Sponsor of the outcome. In the case of a live birth, the structural integrity of the neonate 
can be assessed at the time of birth. In the event of a termination, the reason(s) for termination 
should be specified and, if clinically possible, the structural integrity of the terminated fetus should 
be assessed by gross visual inspection (unless pre-procedure test findings are conclusive for a 
congenital anomaly and the findings are reported). 


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If the outcome of the pregnancy meets the criteria for an SAE (i.e., ectopic pregnancy, spontaneous 
abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a live-born baby, a 
terminated fetus, an intrauterine fetal demise, or a neonatal death]), the Investigator should follow 
the procedures for reporting SAEs. 
Additional information about pregnancy outcomes that are reported as SAEs are as follows:  
• Spontaneous abortion includes miscarriage and missed abortion 
• Neonatal deaths that occur within 1 month of birth should be reported, without regard to 
causality, as SAEs. In addition, infant deaths after 1 month should be reported as SAEs 
when the Investigator assesses the infant death as related or possibly related to exposure to 
the investigational product.  
In the case of paternal exposure, the Investigator will provide the study subject with the Pregnant 
Partner Release of Information Form to deliver to his partner. The Investigator must document in 
the source documents that the subject was given the Pregnant Partner Release of Information Form 
to provide to his partner. 
 
8.14.2 Paternal Exposure 
Male subjects should refrain from fathering a child or donating sperm during the study and for 
90 days after the last dose of NAP and/or durvalumab therapy. 
Pregnancy of a male subject’s partner is not considered to be an AE. Where a report of pregnancy is 
received, prior to obtaining information about the pregnancy, the Investigator must obtain the consent of 
the subject’s partner. Once consent is obtained, the Investigator will provide the study subject with the 
Pregnant Partner Release of Information Form to deliver to his partner and document in the source 
documents that the subject was given this form. 
The outcome of any pregnancy in the female partner of a male subject (spontaneous miscarriage, 
elective termination, ectopic pregnancy, normal birth, or congenital abnormality) occurring from 
the date of the first dose until 90 days after the last dose will be followed up and documented. 
 
8.15 Withdrawal Due to Adverse Events 
For a subject experiencing a recurrence of the same AE(s) at the same grade or greater, or a subject 
experiencing a recurrence of the same SAE, a consultation between the Sponsor and Investigator 
should be conducted to determine whether the subject should continue on therapy. A determination 
will then be made as to whether the subject should have NAP discontinued, docetaxel 
discontinued, or both agents discontinued based on the nature of the adverse event. 
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, according 
to the definition of AE noted earlier, and recorded on the appropriate AE eCRF page.  
When a subject withdraws because of an SAE, the SAE must be reported in accordance with the 
reporting requirements defined above.  


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For subjects without confirmed progression at early termination, diagnostic imaging/response 
assessments should continue every 6 (±1), in the first 24 weeks and every 9 weeks thereafter, until 
confirmed progression of disease or initiation of alternate therapies. If a subject has a response or 
stable disease, they can be permitted to continue until progression.  
 
9 
STATISTICAL METHODS 
Detailed methodology for summary and statistical analyses of the data collected in this study will 
be documented in a statistical analysis plan (SAP). 
 
9.1 
Analysis Populations 
Safety Population: includes all subjects who received at least one day of any study treatment 
(including pre-treatment, obinutuzumab).  
Evaluable subject population: subjects completing at least one treatment cycle and having had an 
evaluable pre-treatment and one post-treatment tumor assessment (according to the iRECIST  
criteria) in the absence of eligibility and compliance issues. 
 
9.2 
Sample Size Determination 
The primary endpoint is ORR. A subject is considered evaluable if there is at least one pre-
treatment and one post-treatment tumor assessment (according to the iRECIST criteria) in the 
absence of eligibility and compliance issues. 
Sample size is derived testing the null hypothesis H0: true ORR ≤ 0.10 versus the alternative H1: 
true ORR ≥ 0.30. With one-sided alpha = 0.05 and power = 0.80, 6 or more responses in a total of 
29 subjects may be of further clinical interest. The trial may be stopped if there is a single responder 
or no responder in the first 10 evaluable subjects. 
Patients who are found to be clearly ineligible on medical review or left the study before 
completion of one cycle for reasons other than disease progression or study drug toxicity, will be 
replaced.  
 
9.3 
Efficacy Analyses 
All efficacy analyses will be performed on the evaluable subject population.  
Descriptive statistics will be used to describe the results of the trial. Continuous variables will be 
summarized by reporting the number of observations, mean, standard deviation, median, minimum 
and maximum. Categorical/discrete variables will be summarized using frequency tables showing 
the number and percentage of subjects within a particular category. 


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Response to treatment will be assessed using iRECIST criteria into the following categories: 
(iCR, iPR, iSD) complete response (iCR), partial response (iPR), stable disease (iSD), 
unconfirmed progressive disease (iUPD) and confirmed progressive disease (iCPD). Any 
subject with no evaluable response assessment at a scheduled time-point will be assigned a 
response of not evaluable (NE) at that time-point. Best overall response is the highest overall 
response achieved by the subject on study. Subjects with no evaluable response assessment on 
study will be scored as not evaluable (NE). Objective response rate (ORR) is defined as the 
proportion of subjects who achieve either an iCR or an iPR. Immunotherapy may result in 
infiltration of immune cells leading to transient increase in the size in malignant lesions, or 
undetectable lesions becoming detectable. The criteria are identical to those of RECIST 1.1 in 
many respects but have been adapted to account for instances where an increase in tumor 
burden, or the appearance of new lesions, does not reflect true tumor progression. iRECIST 
requires the confirmation of progression, which should be done after 6 weeks (± 7 days) during 
the first 24 weeks and every 9 weeks thereafter. 
 
The ORR, with corresponding 95% confidence intervals, will be computed.  
Disease control rate is the proportion of subjects demonstrating CR, PR, or SD. The analysis of 
disease control rate will be similar to ORR.  
Duration of response (DOR), in subjects with CR or PR, is the time from the first observation of 
aCR or PR to the first documented PD. Duration of response of subjects with no PD will be 
censored at the date of last evaluable response assessment.  
Distributions of DOR will be estimated using the Kaplan-Meier method. The median DOR will be 
estimated as well.  
Progression-free survival (PFS) is the time from first day of study drug treatment (obinutuzumab) 
to the first time of documented PD or death for any cause. PFS of living subjects with no PD will 
be censored at the date last evaluable response assessment.  
Distributions of PFS times will be estimated using the Kaplan-Meier product-limit method. The 
median PFS times with 2-sided 95% confidence intervals, as well of PFS rates at 6 and 12 months, 
will be estimated.  
Overall survival (OS) is the time from first day of study drug treatment (obinutuzumab) to death 
for any cause. OS of living subjects will be censored at the date last known to be alive and will be 
assessed up to 6 months following treatment completion of the last subject in the trial. Analysis of 
OS will be similar to that of PFS. 
 
9.4 
Safety Analyses 
Safety analyses will be performed on the safety population.  
Adverse events (AEs) will be graded by the Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0 and coded using Medical Dictionary for Regulatory Activities (MedDRA).  


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Treatment emergent adverse events (TEAEs) are those AEs that occur or worsen on or after first 
study treatment up through 30 days post last study treatment, and/or any treatment-related adverse 
event, regardless of the onset date. TEAEs are summarized by the MedDRA System Organ Class, 
Preferred Term, and worst CTCAE grade per subject, by treatment group.  
Serious adverse events (SAEs) are those events that result in death, are life-threatening, require or 
prolong inpatient hospitalization, result in persistent or significant disability/incapacity, or cause 
congenital anomaly/birth defect.  
SAEs and AEs leading to dose reduction, dosing delay, discontinuation of study therapy or any 
other premature interruption will be tabulated and summarized by treatment group. 
The incidence of CRS will be analyzed separately by the nature, onset, frequency and severity of 
CRS, dose modifications caused by CRS and tolerance of the modified dose or recurrence of CRS 
with dose reduction or drug withdrawal.  Narratives will be prepared for subjects with fatal and/or 
severe CRS and will include the dose, the time to onset, duration, information about dose 
modification and any evidence of recurrence of CRS with dose reduction or drug withdrawal. 
Clinical laboratory results will be collected pretreatment through 30 days after the last 
administration of any study treatment and prior to start of a new anti-cancer treatment. Clinically 
significant laboratory abnormalities, namely tests that result in treatment modification and/or 
require intervention, will be recorded as AEs. Where applicable, laboratory results will be 
classified according to the NCI CTCAE and will be summarized by worst grade per subject.  
 
9.5 
Pharmacokinetic Analysis 
A detailed description of pharmacokinetic parameters to be analyzed will be part of a separate PK 
analysis plan.  
PK analysis will be performed on the PK population (i.e. enrolled subjects, with analyzable PK 
data and without relevant deviation interfering with the PK evaluations). 
 
9.6 
Pharmacodynamic Analyses  
The following parameters and the corresponding change from baseline will be measured and 
summarized by descriptive statistics and data listings for the NAP /docetaxel treatment:  
• Cytokine levels  
• B-cell levels 
• Anti-drug antibodies and human anti-murine antibodies (ADA and HAMA) 
 
 


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10 ETHICS 
10.1 Institutional Review Board/Ethics Committee 
It is the responsibility of the Investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, e.g., 
recruitment advertisements, if applicable, from the IRB/EC. All correspondence with the IRB/EC 
must be retained in the Investigator file. Copies of IRB/EC approvals should be forwarded to The 
Sponsor or its designee. 
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is when 
the change is necessary to eliminate an apparent immediate hazard to the subjects. In that event, 
the Investigator must notify the IRB/EC and The Sponsor in writing immediately after the 
implementation. 
Before the start of the study, the Investigator (or Sponsor where required) will provide the IRB/EC 
with current and complete copies of the following documents: 
- 
final protocol and, if applicable, amendments 
- 
Sponsor-approved ICF (and any updates or any other written materials to be provided to the 
subjects) 
- 
Sponsor-approved subject recruiting materials 
- 
Investigator Brochure (or equivalent information) and addenda 
- 
additional available safety information as required 
- 
information on compensation for study-related injuries or payment to subjects for participation 
in the study, if applicable 
- 
Investigator’s current curriculum vitae or other documentation evidencing qualifications 
(unless not required, as documented by the IRB/EC) 
- 
information regarding funding, name of the Sponsor, institutional affiliations, other potential 
conflicts of interest, and incentives for subjects 
- 
any other documents that the IRB/EC may require to fulfill its obligation 
 
This study will be undertaken only after the IRB/EC has given full written approval of the final 
protocol and amendments (if any), the ICF(s) and updates (if any), applicable recruiting materials, 
and any other written information to be provided to the subjects, and the Sponsor has received a 
copy of this approval. This approval letter must be dated and must clearly identify the IEC/IRB 
and the documents being approved. 
During the study, the Investigator (or Sponsor where required) will send the following documents 
and updates to the IRB/EC for its review and approval, where appropriate:  
- 
protocol amendments 


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- 
revision(s) to the ICF and any other written materials to be provided to the subjects 
- 
new or revised subject recruiting materials approved by the Sponsor 
- 
revisions to compensation for study-related injuries or payment to subjects for participation 
in the study 
- 
Investigator’s Brochure addenda or new edition(s) 
- 
summaries of the status of the study at intervals stipulated in guidelines of the IRB/EC (at 
least annually) 
- 
reports of AEs that are serious, unlisted, and associated with study drugs 
- 
new information that may adversely affect the safety of the subjects or the conduct of the study 
- 
deviations from or changes to the protocol to eliminate immediate hazards to the subjects 
- 
notification if a new Investigator is responsible for the study  
- 
Development Safety Update Report, Short-Term Study Specific Safety Summary and Line 
Listings, where applicable 
- 
any other requirements of the IRB/EC 
 
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the amendment and applicable ICF revisions 
must be submitted promptly to the IRB/EC for review and approval before implementation of the 
change(s), except when necessary to eliminate immediate hazard to the study subjects. If a 
deviation from or a change to the protocol was implemented to eliminate an immediate hazard to 
study subjects, then the implemented deviation or change, the reasons for it, and, if appropriate, 
the protocol amendment should be submitted to the IRB/EC as soon as possible. 
The Investigator (or Sponsor where required) will notify the IRB/EC about the study completion.  
 
10.2 Ethical Conduct of the Study 
The study will be conducted in accordance with the protocol, legal and regulatory requirements, 
as well as the general principles set forth in the International Ethical Guidelines for Biomedical 
Research Involving Human Subjects (Council for International Organizations of Medical Sciences 
2002), Guidelines for GCP (ICH 1996 and revisions), U.S. laws and regulations regarding conduct 
of clinical trials: National Health Regulations - Clinical Trials in Humans, 1980 (including all 
amendments until 1999)and the Declaration of Helsinki (World Medical Association).  
The Investigator(s) should be qualified by education, training, and experience to assume 
responsibility for the proper conduct of the study, should meet all the qualifications specified by 
the applicable regulatory requirement(s), and should provide evidence of such qualifications 
through up-to-date curriculum vitae or other relevant documentation requested by the Sponsor, the 
IRB, or the regulatory authority(ies). 


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10.3 Subject Information and Consent 
All parties will ensure protection of subject personal data and will not include subject names or 
other identifiable data in any reports, publications, or other disclosures, except where required by 
law. The use of Subject initials should be avoided. 
When study data are compiled for transfer to The Sponsor and other authorized parties, subject 
names, addresses, and other identifiable data will be replaced by a numerical code based on a 
numbering system provided by the Sponsor or its designee. in order to de-identify study subjects. 
The study site will maintain a confidential list of subjects who participated in the study, linking 
each subject’s numerical code to his or her actual identity. In case of data transfer, the Sponsor 
and/or its designee will maintain confidentiality and protection of subjects’ personal data to the 
extent possible and within applicable privacy laws. 
The informed consent documents must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements, including applicable privacy laws. 
The informed consent documents used during the informed consent process must be reviewed and 
approved by the sponsor, approved by the IRB before use, and available for inspection.  
Potential subjects will be fully informed of the nature of the study and of the risks and requirements 
of the study before any study-related assessment will be carried out. During the study, subjects 
will be given any new information that may affect their decision to continue participation. They 
will be informed that their participation in the study is voluntary and that they may withdraw from 
the study at any time with no reason given and without penalty or loss of benefits to which they 
would otherwise be entitled. Only subjects or their legal representatives who are fully able to 
understand the risks, benefits, and potential AEs of the study, and who provide their consent 
voluntarily will be enrolled in the study. 
Each subject must give written consent according to local requirements after the nature of the study 
has been fully explained. The consent form must be signed before performance of any study-
related activity. The consent form that is used must be approved by both the Sponsor and the 
reviewing IRB.  
Subjects will be told that the Investigator will maintain a subject identification register for the 
purposes of long-term follow-up if needed and that their records may be accessed by health 
authorities and the Sponsor and/or its designee without violating the confidentiality of the subject, 
to the extent permitted by the applicable law(s) or regulations. By signing the ICF the subject is 
authorizing such access and agrees to allow his or her study physician to recontact the subject for 
the purpose of obtaining consent for additional safety evaluations, if needed. 
The language about the study used in the oral and written information, including the ICF, should 
be non-technical and practical and should be understandable to the subject (or the subject’s legally 
acceptable representative). The subject will be given sufficient time to read the ICF and the 
opportunity to ask questions. After this explanation and before entry into the study, consent should 


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be appropriately recorded by means of the subject's personally dated signature. After having 
obtained consent, a copy of the ICF must be given to the subject. 
The collection and processing of personal data from subjects enrolled in the study will be limited 
to those data that are necessary to investigate the safety, quality, and utility of the study drug used 
in the study. 
These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized disclosures 
or access, accidental or unlawful destruction, or accidental loss or alteration must be put in place. 
Sponsor personnel whose responsibilities require access to personal data need to agree to keep the 
identity of the study subjects confidential. 
The informed consent obtained from the subjects includes explicit consent for the processing of 
personal data and for the Investigator to allow direct access to subjects’ original medical records 
for study-related monitoring, audit, IRB review, and regulatory inspection. This consent also 
addresses the transfer of the data to other entities and to other countries. 
 
10.4 Subject Recruitment 
Advertisements approved by IRBs and Investigator databases may be used as recruitment 
procedures. 
The Sponsor will have an opportunity to review and approve the content of any study recruitment 
materials directed to potential study subjects before such materials are submitted to IRB for 
approval before use.  
 
10.5 Reporting of Safety Issues and Serious Breaches of the Protocol or 
ICH GCP 
In the event of any prohibition or restriction imposed (i.e., clinical hold) by an applicable 
competent authority in any area of the world, or if the Investigator is aware of any new information 
that might influence the evaluation of the benefits and risks of the investigational product, The 
Sponsor must be informed immediately.  
In addition, the Investigator will inform The Sponsor immediately of any urgent safety measures 
taken by the Investigator to protect the study subjects against any immediate hazard, and of any 
serious breaches of this protocol or of ICH GCP that the Investigator becomes aware of. 
 


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10.6 Protocol Deviations 
A protocol deviation is any change, divergence or departure from the IRB-approved protocol by 
the study staff (intentional or unintentional).  All deviations are to be documented at the site and 
reported to the IRB according to the IRB’s guidelines. 
In the event of an emergency, the Investigator shall implement any medical procedures deemed 
appropriate for subject safety.  All such procedures must have written documentation and be 
promptly reported to the Sponsor.  
 
10.7 Protocol Amendments 
Neither the Investigator nor the Sponsor will modify this protocol without a formal written 
amendment. All protocol amendments must be issued by the Sponsor and signed and dated by the 
Investigator. Protocol amendments must not be implemented without prior IRB approval nor when 
the relevant competent authority has raised any grounds for non-acceptance, except when 
necessary to eliminate immediate hazard to the subjects, in which case an amendment must be 
promptly submitted to the IRB and relevant competent authority. Documentation of amendment 
approval by the Investigator and IRB must be provided to the Sponsor or his designee. When the 
change(s) involves only logistic or administrative aspects of the study, the IRB only needs to be 
notified. 
 
10.8 Subject Identification, Enrollment, and Screening Logs 
The Investigator agrees to complete a subject identification log to permit easy identification of 
each subject during and after the study. This document will be reviewed by the Sponsor site contact 
for completeness. 
The subject identification log will be treated as confidential and will be filed by the Investigator 
in the study file. To ensure subject confidentiality, no copies will be made. All reports and 
communications related to the study will identify subjects by assigned study number only. 
The Investigator must also complete a subject screening and enrollment log which reports on all 
subjects who were seen to determine eligibility for inclusion in the study. 
 
10.9 Publication Policy 
All data are the property of the Sponsor. Any formal presentation or publication of data from this 
study will be considered for joint publication by both the Sponsor and the Investigator(s). Prior to 
any such publication or presentation, the Sponsor reserves the right to review and comment on any 
articles, manuscripts, abstracts, posters, or other modes of presentation at least 30 days prior to 
submission. The Sponsor strongly discourages the publication of incomplete trial data. 
Authorship of any publications will be based on the criteria of the International Committee of 
Medical Journal Editors (www.icmje.org). 
 


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11 QUALITY CONTROL AND QUALITY ASSURANCE 
The Sponsor or its designee will conduct periodic monitoring visits during study conduct to ensure 
that the protocol and study requirements as well as Good Clinical Practices (GCPs) are being 
followed. The monitor will review source documents to confirm that the data recorded on eCRF 
are accurate. The Investigator and institution will allow the Sponsor monitor/auditors or its 
designee and appropriate regulatory authorities direct access to source documents.  
During study conduct and/or after study completion, the study site may be subject to review by the 
IRB/EC and to quality assurance audits performed by the Sponsor or designee and to inspection 
by relevant regulatory authorities. 
The Investigator or designee will notify the Sponsor, and/or its designee, immediately of any 
regulatory inspection notification in relation to the study. Furthermore, the Investigator will 
cooperate with the Sponsor and/or its designee to prepare the study site for the inspection and will 
allow the Sponsor and/or its designee, whenever feasible, to be present during the inspection. The 
Investigator will promptly provide copies of the inspection findings to the Sponsor and/or its 
designee. Before submitting a response to the regulatory authorities, the Investigator will provide 
the Sponsor or its agents with an opportunity to review and comment on responses to any such 
findings. 
It is important that the Investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process. 
 
 
 


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12 DATA HANDLING AND RECORD RETENTION 
12.1 Electronic Case Report Forms 
An eCRF should be completed for each included subject. The completed eCRFs are the sole 
property of the Sponsor and should not be made available in any form to third parties, except for 
authorized representatives of the Sponsor or appropriate regulatory authorities, without written 
permission from the Sponsor. 
The Investigator has ultimate responsibility for the collection and reporting of all clinical, safety 
and laboratory data entered into the eCRFs as well as any other data collection forms (source 
documents) and ensuring that these are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required. The eCRF 
must be (electronically) signed by the Investigator to attest that the data contained on the eCRF 
are accurate. Any corrections to entries made in the eCRF or source documents must be dated, 
initialed, and explained (if necessary) and must be auditable.  
 
12.2 Records Retention 
To enable evaluations and/or audits from regulatory authorities or the Sponsor, the Investigator 
agrees to keep records, including the identity of all participating subjects (sufficient information 
to link records, e.g., eCRF, study source documentation and hospital records), all originally signed 
informed consent forms, safety reporting forms, source documents, detailed records of treatment 
disposition, and adequate documentation of relevant correspondence (e.g., letters, meeting 
minutes, and telephone call reports). The records should be retained by the Investigator according 
to the ICH guidelines, according to local regulations, or as specified in the Clinical Study 
Agreement (CSA), whichever is longer. 
If the Investigator becomes unable for any reason to continue to retain study records for the 
required period (e.g., retirement, relocation), the Sponsor should be prospectively notified. The 
study records must be transferred to a designee acceptable to the Sponsor, such as another 
Investigator, another institution, or an independent third party arranged by the Sponsor. Study 
records must be kept for 15 years after completion or discontinuation of the study or for as required 
by applicable local regulations.  
The Investigator must obtain the Sponsor's written permission before disposing of any records, 
even if retention requirements have been met. Requirements to prolong the retention time of 
records will be subject to an agreement with the clinical center. 
 
 
 
 


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13 REFERENCES 
1. 
Shepherd FA, Dancey J, Ramlau R, et al:  Prospective randomized trial of docetaxel versus 
best supportive care in subjects with non-small cell lung cancer previously treated with 
platinum-based chemotherapy. J Clin Oncol 18:2095 – 103, 2000   
 
2. 
Borghaei H, Paz-Ares L, Horn L, et al:  Nivolumab versus docetaxel in advanced 
nonsquamous non-small cell lung cancer.  N Engl J Med 373:1627 – 1639, 2015 
 
3. 
Rittmeyer A, Barlesi F, Waterkamp D, et al:  atezolizumab versus docetaxel in subjects with 
previously treated non-small cell lung cancer (OAK): a phase 3, open-label, multicenter, 
randomised controlled trial.  Lancet 373:255 – 265, 2017 
 
4. 
Herbst RS, Baas P, Kim D-W, et al:  Pembrolizumab versus docetaxel for previously treated, 
PD-L1-positive, advanced non-small cell lung cancer (JEYNOTE-010): a randomised 
controlled trial.  Lancet 387:1540-1550, 2016 
 
5. 
Barlesi F, Vansteenkiste J, Spigel D, et al:  Avelumab versus docetaxel in subjects with 
platinum-treated advanced non-small cell lung cancer (JAVELIN Lung 200): an open-label, 
randomised, phase 3 study.  Lancet Oncology 19:1468-1479, 2018  
 
6. 
Hedlund G, Forsberg G, Nederman T et al: Tumor Targeted Superantigens, in Schmidt SR 
(ed): Fusion Protein Technologies for Biopharmaceuticals: Applications and Challenges 
First Edition.  Hoboken, NJ, John Wiley and Sons, 2013, pp 365-381 
 
7. 
Stern PL, Harrop R: 5T4 oncofoetal antigen: an attractive target for immune intervention in 
cancer. Cancer Immunol Immunother 66:415–426, 2017 
 
8. 
Harper J, Lloyd C, Dimasi N et al: Preclinical evaluation of MEDI0641, a 
pyrrolobenzodiazepine-conjugated antibody–drug conjugate targeting 5T4. Mol Cancer 
Ther 16:1576-1587, 2017 
 
9. 
Azulay M, Lifshits S, Fridman A, et al: NAP   induces T cell recognition, turning anti-PD-1 
unresponsive “cold” tumors into “hot” responsive tumors. Presented at the American 
Association of Cancer Research, Chicago, IL, April 14-18, 2018.  
 


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10. Sundstedt A, Celander M, Wallen Ohman M, et al: Immunotherapy with tumor-targeted 
superantigens (TTS) in combination with docetaxel results in synergistic anti-tumor effects. 
International Immunopharm 9: 1063-1070, 2009 
 
11. Azulay M, Lifshits S, Shany E, et al. Selective T cell Redirection Proteins (STR) Enhance 
the Anti-Tumor Activity of Checkpoint Inhibitors (CPIs) and can Lead to Long-Lasting 
Immunity Against the Tumor.  Presented at the SITC Annual Meeting November 2019. 
 
12. Sundstedt A, Celander M, Eriksson H, et al. Monotherapeutically nonactive CTLA-4 
blockade results in greatly enhanced antitumor effects when combined with tumor-targeted 
superantigens in a B16 melanoma model. J Immunother. 2012; 35 (4): 344-53. 
 
13. Borghaei H, Alpaugh K, Hedlund G, et al:  Phase I dose escalation, pharmacokinetics and 
pharmacodynamics study of naptumomab estafenatox alone in subjects with advanced 
cancer and with docetaxel in subjects with advanced non-small-cell lung cancer.  J Clin 
Oncol 27:4116-4123, 2009 
 
14. Tobinai K, Klein C, Oya N and Fingerle-Rowson G. A Review of Obinutuzumab (GA101), 
a Novel Type II Anti-CD20 Monoclonal Antibody, for the Treatment of Patients with B-Cell 
Malignancies. Adv Ther 34:324-356, 2017 
 
15. Gazyva (obinutuzumab) prescribing information 
https://www.accessdata.fda.gov/spl/data/a4db57aa-aaf4-4714-97d5-
b2daa6c67a73/a4db57aa-aaf4-4714-97d5-b2daa6c67a73.xml  
 
16. NeoTX Data on File, in vitro experiment # 00082. 
 
17. American Cancer Society, Cancer Facts and Figures 2020, 
https://www.cancer.org/research/cancer-facts-statistics.html. 
 
18. Globocan 2018, https://gco.iarc.fr/today/data/factsheets/populations/900-world-fact-
sheets.pdf. 
 
19. TAGRISSO® (osimertinib) Full Prescribing Information, 
https://www.azpicentral.com/tagrisso/tagrisso.pdf#page=1 
 


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20. Proto C, Ferrara R, Signorelli D, et al:  Choosing wisely first line immunotherapy in non-
small cell lung cancer (NSCLC): what to add and what to leave out.  Can Treat Rev 75:39 – 
51, 2019 
 
21. Hawkins RE, Gore M, Shparyk Y, et al: A randomized phase II/III study of NAP   + IFN 
alpha versus IFN alpha in renal cell carcinoma: Final analysis with baseline biomarker 
subgroup and trend analysis. Clin Cancer Res 22:3172-3182, 2016 
 
22. Hervas-Stubbs S, Perez-Gracia JL, Rouzaut A, et al. Direct effects of type I interferons on 
cells of the immune system. Clin Cancer Res 2011;17:2619-2627. doi: 10.1158/1078-
0432.CCR-10-1114. Epub 2011 Mar 3. 
 
23. Lee DW, Santomasso BD, Locke FL, et al. ASTCT Consensus Grading for Cytokine Release 
Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Biol Blood 
Marrow Transplant. 2019;25(4):625-638. Doi:10.1016/j.bbmt. 2018.12.758. Epub 2018 Dec 
25. 
24. Marabelle A, Fakih M, Lopez J, et al.  Association of tumour mutational burden with 
outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective 
biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study.  Lancet 
Oncol 2020; 21: 13531365 
25. Galsky MD, Saci A, Szabo PM, et al. Nivolumab in patients with advanced platinum-
resistant urothelial carcinoma: efficacy, safety, and biomarker analyses with extended 
follow-up from CheckMate 275. Clin Cancer Res 2020; 26: 5120-5128 
 
 


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14 APPENDICES 
14.1 
iRECIST Guidelines for Disease Evaluation  
A detailed description of the iRECIST criteria may be found at the following: 
Seymour L, Bogaerts J, Perrone A, et al. iRECIST: guidelines for response criteria for use in 
trials testing immunotherapeutics. Lancet Oncol. 2017;18 (3): e143-e152. 
 
14.2 
CTCAE v5 
The Common Terminology Criteria for Adverse Events (CTCAE) v5 may be found at 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_R
eference_5x7.pdf 
 
14.3 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
 
Activity Status 
Description 
0 
Fully active, able to carry on all pre-disease 
performance without restriction. 
 
1 
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 
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 
Capable of only limited self-care, confined to bed or 
chair more than 50% of waking hours. 
 
4 
Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair. 
 
5 
Dead. 
 
Reference 
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol 1982; 5(6):649-655. 
 
 


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14.4 
Infusion Related Reactions and Cytokine Release Syndrome Grading (CTCAE v5) 
 
 
Condition 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Infusion-
Related 
reaction 
Mild transient 
reaction; 
infusion 
interruption 
not indicated; 
intervention 
not indicated 
Therapy or 
infusion 
interruption 
indicated but 
responds 
promptly to 
symptomatic 
treatment 
(e.g., 
antihistamines, 
NSAIDs, 
narcotics, IV 
fluids); 
prophylactic 
medications 
indicated for < 
24 hrs 
Prolonged 
(e.g., not 
rapidly 
responsive to 
symptomatic 
medication 
and/or brief 
interruption of 
infusion); 
recurrence of 
symptoms 
following 
initial 
improvement; 
hospitalization 
indicated for 
clinical 
sequelae 
Life-
threatening 
consequences; 
urgent 
intervention 
needed 
Fatal 
 
 
 


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ASTCT Consensus Grading of CRS (23) 
CRS 
Parameter 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Fever1 
Temp > 38°C 
Temp > 38°C 
Temp > 38°C 
Temp > 38°C 
 
With 
Hypotension 
None 
Not requiring 
vasopressors 
Requiring 
vasopressors with 
or without 
vasopressin 
Requiring multiple 
vasopressors 
(excluding 
vasopressin) 
 
And/or2 
Hypoxia 
None 
Requiring low-
flow nasal 
cannula or blow-
by 
Requiring high-
flow nasal 
cannula3, 
facemask, 
nonrebreather 
mask or Venturi 
mask 
Requiring positive 
pressure (e.g., 
CPAP, BiPAP, 
intubation and 
mechanical 
ventilation 
1 
Fever is defined as a temperature > 38°C not attributable to any other cause.  In subjects who have CRS then 
receive antipyretic or anticytokine therapy such as tocilizumab or steroids, fever is no longer required to 
grade subsequent CRS severity.  In this case, CRS grading is driven by hypotension and or hypoxia. 
2 
CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other 
cause.  For example, a patient with a temperature of 39.5°C, hypotension requiring 1 vasopressor, and 
hypoxia requiring low-flow nasal cannula is classified as grade 3 CRS. 
3 
Low-flow nasal cannula is defined as oxygen delivered at < 6 L/minute.  Low flow also includes blow-by 
oxygen delivery, sometimes used in pediatrics.  High-flow nasal cannula is defined as oxygen delivered at > 
6 L/minute. 
 
 
 


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14.5 
Inhibitors and Inducers of CYP3A4 
 
Strong Inhibitors 
Inducers 
Clarithromycin 
Barbiturates 
Indinavir 
Brigatinib 
Itraconazole 
Carbamazepine 
Ketoconazole 
Efavirenz 
Nefazodone 
Enzalutamide 
Nelfinavir 
Modafinil 
Saquinavir 
Nevirapine 
Ritonavir 
Oxcarbazepine 
Idelalisib 
Phenobarbital 
Ribociclib 
Phenytoin 
Telithromycin 
Pioglitazone 
 
Rifabutin 
 
Rifampin 
 
St. John’s Wort 
 
Troglitazone 
 
Source: Flockhart Table, https://drug-interactions.medicine.iu.edu/MainTable.aspx 
 
 
 


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CYP450 Sensitive Substrates 
 
 
 
Source: https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-
interactions-table-substrates-inhibitors-and-inducers 


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14.6 
Highly effective methods of contraception (<1% failure rate) 
 
Barrier/intrauterine methods 
Hormonal methods 
• Copper T intrauterine device 
• Levonorgestrel-releasing intrauterine 
system (eg, Mirena®) 
 
• Implants: Etonogestrel-releasing 
implants (eg, Implanon® or 
Norplant®) 
• Intravaginal Devices: 
Ethinylestradiol/etonogestrel-releasing 
intravaginal devices (eg, NuvaRing®)  
• Injection: Medroxyprogesterone 
injection (eg, Depo-Provera®) 
• Combined Pill: Normal and low dose 
combined oral contraceptive pill 
• Patch: 
Norelgestromin/ethinylestradiol-
releasing transdermal system (eg, 
Ortho Evra®) 
• Minipill: Progesterone based oral 
contraceptive pill using desogestrel: 
Cerazette® is currently the only 
highly effective progesterone-based 
pill  
 
 
 


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14.7 
COVID-19 Related Guidance 
 
14.7.1 Guidance for Subjects on Study with COVID-19 
Subjects who test positive for COVID-19, study treatment can be delayed for up to 2 weeks and 
may be resumed at the discretion of the investigator. This should be listed as COVID-19, in the 
adverse event listings. 
Quarantined subjects due to possible exposure to COVID-19, should follow local policy for study 
visits and treatments. Every effort should be made to comply with the study protocol schedule.  
Prior COVID disease details should be captured in the Medical History form. Vaccination 
information should be captured in Concomitant Medications form with standard terminology. 
Therefore, the patient should be asked by the treating physician if they just received or are planning 
to receive the Covid vaccine. 
 
14.7.2 Recommendations for the study patients regarding COVID-19 Vaccines 
These recommendations are based on Interim Clinical Considerations for Use of mRNA 
COVID-19 Vaccines Currently Authorized in the United States. The recommendations are as 
follows: 
Considerations for timing of COVID-19 vaccination in relation to immunosuppressive therapies:  
For timing of COVID-19 vaccination for immunocompromised patients, please refer to the CDC 
guidelines.  
Reference: Interim Clinical Considerations for Use of mRNA COVID-19 Vaccines Currently 
Authorized in the United States; https://www.cdc.gov/vaccines/covid-19/info-by-
product/clinical-considerations.html  
 
14.8 
Example for B cells quantitation Procedure 
Collection:  
Collect 5 ml blood in Cyto-Chex BCT tube. Samples will be stained and analyzed the same day 
received (most preferred) but can be performed up to 7 days from sample collection.  
 
Reagents 
Manufacturer 
Catalog No. 
Volume to use 
CD45-Krome Orange 
Beckman Coulter 
BC-B36294 
5μL 
CD19-RPE 
Beckman Coulter 
BC-A07769 
5μL 
VersaLyse 
Beckman Coulter 
BC-A09777 
1 mL 
Staining samples: 
Set up the following tubes for each sample.  
Tube 1: CD45-KO + CD19-RPE  


NeoTX 
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Staining Procedure: 
• 
Adequately mix the sample before starting. Mix gently by inverting tube at least 8-10 
times until all cells are thoroughly suspended 
• 
Add 5 μL CD45, and 5 μL CD19 into a 15mL tube  
• 
Pipet 100 μL of blood  
• 
Incubate tube at RT in the dark for 30 minutes  
• 
Add 1 mL Versalyse  
• 
Vortex  
• 
Incubate tube at RT for 10 minutes  
• 
Centrifuge for 5 minutes 400g  
• 
Decant supernatant 
• 
Add 3 mL PBS and centrifuge for 5 minutes 400g  
• 
Decant supernatant 
• 
Add 600 μL PBS and vortex for 2-3 seconds 
• 
Move the cells suspension into a proper 12X75 tube  
• 
Samples are now ready for analysis on FACS Navius 
• 
The FACS Navius is calibrated by the flow check protocol of the instrument  
• 
The analysis will give the percentage of B cells out of Lympho absolute number  
• 
In order to get the lympho absolute number perform a CBC count from the EDTA tube  
 
Results values: 
The results of the B-cells should be presented in percentages and absolute numbers. Please 
include in the report the result units (% and cells/microL) and the normal range.