Clinical trial NCT02587962
Conditions: Solid Tumors
Sponsor: Medivir
Start date: 2017-08-04; Completion date: 2020-02-17
Enrollment: 34 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
An ascending dose study in patients with solid tumors to evaluate the safety, tolerability, pharmacodynamics and efficacy of birinapant when given in combination with pembrolizumab. A dose expansion phase of 4 cohorts will also be included.

Detailed description:
This study will be conducted in two phases. The Phase 1 portion of the study will employ a sequential group dose-escalation design to determine the dose-limiting toxicity (DLT) and recommended Phase 2 dose (RP2D) of birinapant administered in combination with 200 mg pembrolizumab, both administered as a 30-minute intravenous (IV) infusion. The following proposed doses of birinapant are to be evaluated: 5.6, 11, 17, and 22 mg/m2.

The Phase 2 portion, the dose expansion phase, will compromise 4 cohorts of 26-30 patients.

The 4 cohorts will include the following:

* Colorectal cancer
* Ovarian Cancer
* Cervical cancer
* Various solid tumors (30 patients, including 5 patients with each of the following 6 tumor types: Head and Neck Squamous Cell Carcinoma (HNSCC)-checkpoint-inhibitor naïve; and HNSCC checkpoint-inhibitor experienced; Gastroesophageal carcinoma; Mesothelioma; Small cell lung cancer (SCLC); Cholangiocarcinoma

A Simon's 2-stage design will be used for each of the cohorts in colorectal cancer, ovarian cancer and cervical cancer. A predefined interim analysis allowing stopping each of these cohorts for futility and safety will be conducted in the first stage to limit undue exposure before further inclusion into a given cohort. The design of the various solid tumors cohort will limit undue exposure in any of the selected tumor types by limiting the number of enrolled patient to five in each tumor type.

Arms: arm 1: Birinapant in combination with pembrolizumab
Interventions: intervention 1: Birinapant intervention 2: Pembrolizumab
Intervention descriptions: intervention 1: Birinapant intravenous (IV) on Days 1 and 8 of each 21-Day Cycle. The following escalating doses of birinapant to be studied: 5.6, 11, 17, and 22 mg/m2. In the expansion phase the assigned recommended phase two dose will be administered in all cohorts intervention 2: 200 mg pembrolizumab IV on Day 1 of each 21-Day Cycle

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol 
Title: A Phase 1/2, Multicenter, Single-Arm, Open-Label, 
Dose-Escalation Study of Birinapant in Combination with 
Pembrolizumab (KEYTRUDA™) in Patients with Relapsed or 
Refractory Solid Tumors 
Date: 16 August 2018 
NCT number: NCT02587962 
 


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TITLE PAGE 
 
Clinical Study Protocol 
 
Protocol Number: 
BPT-201 v5.0/incl amendment 04  
Study Title: 
A Phase 1/2, Multicenter, Single-Arm, Open-Label, 
Dose-Escalation Study of Birinapant in Combination with 
Pembrolizumab (KEYTRUDA™) in Patients with Relapsed or 
Refractory Solid Tumors 
Sponsor: 
Medivir AB 
Box 1086  
141 22 Stockholm 
Phone: + (46) 08 546 831 00 
Investigational 
Product: 
Birinapant Injection and Pembrolizumab (KEYTRUDA™) 
Indication: 
Relapsed or refractory solid malignant tumors 
Phase: 
Phase 1/2 
Protocol Version: 
V 5.0 incl. amendment 04 
Protocol Date: 
16 Aug 2018 
Statement of Compliance 
This clinical study will be conducted in compliance with the protocol, the Guidelines of 
the World Medical Association Declaration of Helsinki (2013), International Conference 
on Harmonization (ICH) Good Clinical Practice (GCP), and applicable regulatory 
requirements. 
Confidentiality Statement 
The confidential information in the following document is provided to you as an 
Investigator, potential Investigator, or consultant for review by you, your staff and 
applicable ethical review committee or institutional review board. By accepting this 
document, you agree the information contained herein will not be disclosed to others, 
without written authorization from Medivir AB, except to the extent necessary to obtain 
informed consent from those persons to whom the study drug is administered. 
 


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STUDY CONTACTS 
SPONSOR: 
Name:  
Stefan Norin MD, PhD 
Title:  
Associate Director 
, Medivir AB  
Address:  
Medivir AB 
 
Box 1086 
 
 141 22 Huddinge, Sweden  
Telephone:  +46 8 546 831 00 
Email: 
stefan.norin@medivir.com 
 
 
Name:  
Cecilia Wadell, Ph.D. 
Title:  
Director, Clinical R&D, Medivir AB  
Address: 
Medivir AB 
 
Box 1086 
 
 141 22 Huddinge, Sweden  
Telephone:  +46 8 546 831 00 
Email: 
Cecilia.Wadell@medivir.com 
 
 




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SYNOPSIS 
Sponsor: Medivir AB 
Study drug: Birinapant Injection (hereafter referred to as birinapant) and pembrolizumab 
Title of Study: A Phase 1/2, Multicenter, Single-Arm, Open-Label, Dose-Escalation Study of Birinapant in 
Combination with Pembrolizumab (KEYTRUDA™) in Patients with Relapsed or Refractory Solid Tumor 
Protocol Number: BPT-201 v 4.0 incl. amendment 03  
Number of Centers Planned: Approximately 10 sites 
Phase of development: Phase 1/2 
Study Objectives: 
Dose Escalation Phase 
Primary Objective: 
To determine the safety and tolerability of the recommended phase 2 dose (RP2D) of birinapant when given in 
combination with pembrolizumab IV   
Secondary Objective: 
To assess preliminary efficacy of the combination of pembrolizumab and birinapant in patients with relapsed or 
refractory cancer by effects on tumor size as measured by imaging (CT or MRI) assessed by RECIST 1.1 
Exploratory Objectives: 
1. 
To assess preliminary efficacy of the combination of pembrolizumab and birinapant in patients with relapsed or 
refractory cancer by effects on tumor size as measured by imaging (CT or MRI) assessed by iRECIST 
2. 
To determine the pharmacodynamic markers of birinapant and of pembrolizumab when given in combination at the 
schedule and dose as defined by the protocol, to include but not be limited to mechanism of action (inhibition of 
cIAP1), and of immune surveillance and activation. 
3. 
To assess biomarkers that might predict for responders to the combination treatment and allow comparison to know 
potential predictive biomarkers of pembrolizumab response 
4. 
To evaluate birinapant pharmacokinetics in plasma when administered in combination with pembrolizumab. 
Dose Expansion Phase 
Primary Objective 
The primary objective in each of the cohorts is as follows: 
1. To determine whether the combination of pembrolizumab and birinapant has sufficient antitumor activity, as 
assessed by ORR, against colorectal cancer to warrant more extensive development.  
2. To determine whether the combination of pembrolizumab and birinapant has sufficient antitumor activity, as 
assessed by ORR against ovarian cancer to warrant more extensive development.  
3. To determine whether the combination of pembrolizumab and birinapant has sufficient antitumor activity, as 
assessed by ORR against cervical cancer to warrant more extensive development. 
4. To determine the safety and tolerability of the RP2D of birinapant when given in combination with 
pembrolizumab to patients in the various solid tumors cohort  
Secondary Objectives 


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1. To assess the safety and tolerability of the combination of pembrolizumab and birinapant; overall and in 
the defined tumor types, colorectal cancer, ovarian cancer and cervical cancer. 
2. To assess efficacy of the combination of pembrolizumab and birinapant in the defined tumor types by 
effects on tumor response, including CBR, time to response and duration of response, assessed by 
RECIST v1.1  
3. To assess efficacy of the combination of pembrolizumab and birinapant in the defined tumor types by 
effect on overall survival 
4. To assess efficacy of the combination of pembrolizumab and birinapant in the defined tumor types by 
effect on progression free survival. 
Exploratory Objectives 
1. To assess efficacy of the combination of pembrolizumab and birinapant in the defined tumor types by 
effects on tumor response, including; CBR, time to response, duration of response, iBOR, duration of 
iBOR and time to iCPD, assessed by iRECIST  
2. To assess the pharmacodynamic markers of birinapant and of pembrolizumab when given in 
combination at the schedule and dose as defined by the protocol, to include but not to be limited to 
mechanism of action (inhibition of cIAP1), and of immune surveillance and activation. 
3. To determine biomarkers that might predict for response and/or indicate response to the combination 
treatment and allow comparison to known potential predictive biomarkers of pembrolizumab 
response.  
4. To evaluate birinapant pharmacokinetics in plasma when administered in combination with 
pembrolizumab 
 
Number of Patients Planned: Up to 24 patients in the dose-escalation phase. The dose expansion phase will comprise 
of four patient cohorts totaling up to 111 patients defined as follows:  
• 
Colorectal cancer (28 patients) 
• 
Ovarian cancer (27 patients) 
• 
Cervical cancer (26 patients) 
• 
Various solid tumors (30 patients, including 5 patients with each of the following 6 tumor types: 
[Small cell lung cancer; Cholangiocarcinoma; Gastroesophageal carcinoma; Mesothelioma; Head and 
Neck Squamous Cell Carcinoma (HNSCC)-checkpoint inhibitor-naïve; and HNSCC checkpoint 
inhibitor-experienced] 
Predefined interim analyses for futility and safety will be conducted in each of the cohorts in colorectal cancer, ovarian 
cancer and cervical cancer to limit undue exposure before further inclusion into a given cohort. The design of the 
various solid tumors cohort will limit undue exposure in any of the selected tumor types by limiting the number of 
enrolled patient to five in each tumor type.  
Selection of Study Population: 
Inclusion Criteria: All inclusion criteria for the study are listed below. Unless otherwise stated, inclusion criteria 
apply to all phases and cohorts in the study. Patients will be eligible for study participation if they meet ALL of the 
following inclusion criteria, applicable for the cohort/tumor type, after patient has provided written informed consent. 
1. The patient is male or female ≥ 18 years of age on the day of signing informed consent. 
2. The patient is able to understand and voluntarily sign a written informed consent, and is willing and able 
to comply with the protocol requirements. 
3. The patient must have a histologically confirmed solid malignancy that is metastatic or unresectable and 
for which standard curative or palliative measures do not exist or are no longer effective.  Patients with 


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tumors with mutations for which there are FDA-approved therapies must have progressed following these 
therapies in order to be eligible for this study.  Patients with metastatic colorectal cancer should have 
progressed on prior fluoropyrimidine-based therapies, and have no curative therapies available to them, in 
order to be eligible for this study. Colorectal cancer patients should be assessed for microsatellite 
instability (MSI) status as per the local site routines. (Dose Escalation Phase only) 
4. Patients must have measurable disease based on RECIST 1.1 as determined by the site study team.  Tumor 
lesions situated in a previously irradiated area are considered measurable if progression has been 
demonstrated in such lesions. 
5. Patients must have an Eastern Cooperative Oncology Group (ECOG) score of 0 or 1 at screening.   
6. Patients must have a life expectancy of greater than 12 weeks. 
7. Patients must have amylase and lipase values < ULN 
8. Patients must demonstrate adequate organ function as defined in Table 1.. All screening labs should be 
performed within 10 days of treatment initiation. 
Table 1 
Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L  
Renal 
Creatinine OR 
Measured 
or 
calculateda 
creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤1.5xULN OR 
≥60 mL/min for patient with  
creatinine levels >1.5x institutional ULN 
Hepatic 
Total bilirubin 
≤1.5xULN OR 
Direct bilirubin ≤ULN for patients with total 
bilirubin levels >1.5xULN), unless known Gilbert’s 
Syndrome has been diagnosed 
AST (SGOT) and ALT (SGPT) 
≤2.5xULN OR 
≤5.0xULN for patients with liver metastases 
Coagulation 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
 
Activated Partial Thromboplastin Time 
(aPTT) 
≤1.5xULN unless patient is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic 
range of intended use of anticoagulants 
≤1.5xULN unless patient is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic 
range of intended use of anticoagulants 
a Creatinine clearance should be calculated per institutional standard. 
 
9. Female patients of childbearing potential must have a negative urine or serum pregnancy test within 72 
hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be 
confirmed as negative, a serum pregnancy test will be required.   
10. Female patients of childbearing potential must be willing to use an adequate method of contraception for 
the course of the study through 120 days after the last dose of study medication. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the patient. 
11. Male patients with female partners of childbearing potential must agree to use an adequate method of 


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contraception starting with the first dose of study therapy through 120 days after the last dose of study 
therapy. (Not applicable for ovarian cancer cohort or cervical cancer cohort) 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the patient. 
12. An tumor tissue sample for PD-L1 biomarker analysis from archival material, a newly obtained core or 
excisional biopsy is available for submission.  Repeat samples may be required if adequate tissue is not 
provided.     
13. Have resolution of toxic effect(s) of the most recent prior chemotherapy to Grade 1 or less (except 
neuropathy or alopecia; see Exclusion criteria below). If patients received major surgery or radiation 
therapy of > 30 Gy, they must have recovered from the toxicity and/or complications from the 
intervention. 
Dose expansion phase cohort-specific inclusion criteria 
14. Patients with metastatic colorectal cancer with no available therapy options that are known to provide 
clinical benefit per institutional standard of care.  Patients with tumors with mutations for which there are 
available therapies that are known to provide clinical benefit, as defined by national authority and/or 
ratified by national guidelines or equivalent, must have progressed following these therapies in order to be 
eligible for this study. (colorectal cancer cohort only) 
15. Patients with histological or cytologically confirmed metastatic colorectal cancer which is Microsatellite 
Stable (MSI-Stable) accordingly to local laboratory testing.  (colorectal cancer cohort only) 
16. Patients must have a histologically confirmed epithelial ovarian cancer, primary peritoneal cancer or 
fallopian tube solid tumor cancer that is locally advanced or metastatic with no available therapy options 
that are known to provide clinical benefit per institutional standard of care.  Patients with tumors with 
mutations for which there are available therapies that are known to provide clinical benefit, as defined by 
national authority and/or ratified by national guidelines or equivalent, must have progressed following 
these therapies in order to be eligible for this study. (ovarian cancer cohort only) 
17. Patients must have histologically or cytologically confirmed cervical squamous cell carcinoma that is 
locally advanced or metastatic with no available therapy options that are known to provide clinical benefit 
per institutional standard of care. Patients with tumors with mutations for which there are available 
therapies that are known to provide clinical benefit, as defined by national authority and/or ratified by 
national guidelines or equivalent, must have progressed following these therapies in order to be eligible 
for this study (cervical cancer cohort only) 
18. Patients must have histologically or cytologically confirmed head and neck squamous cell carcinoma that 
is locally advanced or metastatic with no available therapy options that are known to provide clinical 
benefit per institutional standard of care. Patients with tumors with mutations for which there are available 
therapies that are known to provide clinical benefit, as defined by national authority and/or ratified by 
national guidelines or equivalent, must have progressed following these therapies in order to be eligible 
for this study (various solid tumors cohort: head and neck squamous cell carcinoma groups only). 
19. Patients with head and neck squamous cell carcinoma who are to participate in the group of checkpoint 
inhibitor experienced patients must have received prior therapy with an anti-PD-1 or anti-PD-L1 antibody, 
administered either as monotherapy, or in combination with other therapies. Patients must have received at 
least two doses of an approved anti-PD-1/anti-PD-L1 antibody and have experienced documented 
radiographic progression of disease by RECIST v1.1. The initial evidence of disease progression is to be 
confirmed by a second assessment no less than four weeks from the date of the first documented disease 
progression in the absence of rapid clinical progression. The date for documentation of initial progression 
will be considered the date for disease progression. Progressive disease must have been documented 
during or within 12 weeks after last dose of such treatment. (various solid tumors cohort head and neck 
squamous cell carcinoma, checkpoint inhibitor experienced group only). 
20. Patients must have histologically or cytologically confirmed small cell lung carcinoma that is locally 


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advanced or metastatic with no available therapy options that are known to provide clinical benefit per 
institutional standard of care. Patients with tumors with mutations for which there are available therapies 
that are known to provide clinical benefit, as defined by national authority and/or ratified by national 
guidelines or equivalent, must have progressed following these therapies in order to be eligible for this 
study (various solid tumors cohort, SCLC group only) 
21. Patients must have histologically or cytologically confirmed cholangiocarcinoma that is locally advanced 
or metastatic with no available therapy options that are known to provide clinical benefit per institutional 
standard of care. Patients with tumors with mutations for which there are available therapies that are 
known to provide clinical benefit, as defined by national authority and/or ratified by national guidelines or 
equivalent, must have progressed following these therapies in order to be eligible for this study (various 
solid tumors cohort, cholangiocarcinoma group only) 
22. Patients must have histologically or cytologically confirmed pleural mesothelioma that is locally advanced 
or metastatic with no available therapy options that are known to provide clinical benefit per institutional 
standard of care. Patients with tumors with mutations for which there are available therapies that are 
known to provide clinical benefit, as defined by national authority and/or ratified by national guidelines or 
equivalent, must have progressed following these therapies in order to be eligible for this study (various 
solid tumors cohort, mesothelioma group only) 
23. Patients must have histologically or cytologically confirmed carcinoma of the esophagus including the 
gastroesophageal junction that is locally advanced or metastatic with no available therapy options that are 
known to provide clinical benefit per institutional standard of care.  Patients with tumors with mutations 
for which there are available therapies that are known to provide clinical benefit, as defined by national 
authority and/or ratified by national guidelines or equivalent, must have progressed following these 
therapies in order to be eligible for this study (various solid tumors cohort, gastroesophageal carcinoma 
group only) 
  
Exclusion Criteria: All exclusion criteria for the study are listed below. Unless otherwise stated, exclusion criteria 
apply to all phases and cohorts in the study. Patients are excluded from participating in this study if one or more of 
the following criteria, applicable for the specific cohort/tumor type, are met: 
1. Patients who have had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 
1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered 
more than 4 weeks earlier prior to study Day 1. 
2. Patients who have had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 
weeks prior to study Day 1 or who have not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events 
due to a previously administered agent. 
Note:  Patients with ≤ Grade 2 neuropathy or ≤ Grade 2 alopecia are an exception to this criterion and may 
qualify for the study. 
Note:  If patients have received major surgery, they must have recovered adequately from the toxicity 
and/or complications from the intervention prior to starting therapy.   
3. Patients who are currently participating and receiving study therapy or who have participated in a study of 
an investigational agent and received study therapy or who have used an investigational device within 4 
weeks of the first dose of treatment. 
 
4. Patients who have received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-
Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other 
antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways) or if the patient has 
previously participated in Merck MK-3475 clinical trials. (Not applicable for various solid tumors cohort, 
head and neck squamous cell carcinoma, checkpoint inhibitor experienced group) 


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5. Patients with known active central nervous system (CNS) metastases and/or carcinomatous meningitis.  
Note: Patients with previously treated brain metastases may participate provided they are stable (without 
evidence of progression by imaging (using the identical imaging modality for each assessment, either MRI 
or CT scan) for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms 
have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using 
systemic steroids for at least 7 days prior to trial treatment.  This exception does not include 
carcinomatous meningitis which is excluded regardless of clinical stability. 
6. Patients with a known additional malignancy that is progressing or requires active treatment.  Exceptions 
include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone 
potentially curative therapy or in situ cervical cancer. 
7. Patients who have a history of allergic reactions attributed to compounds of similar chemical or biologic 
composition to birinapant or pembrolizumab or their constituents. 
8. Patients requiring the use of anti-tumor necrosis factor (anti-TNF) therapies, such as infliximab, or 
patients who have received treatment with anti-TNF therapies within 5 half-lives of the drug. 
9. Patients with a diagnosis of immunodeficiency or who are receiving systemic steroid therapy (in dosing 
exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 
7 days before the first dose of study drug. The use of physiologic doses of corticosteroids may be 
approved after consultation with the Sponsor.  
10. Patients with an uncontrolled intercurrent illness including, but not limited to, symptomatic congestive 
heart failure, hypertension, unstable angina pectoris, cardiac arrhythmia, autoimmune or inflammatory 
diseases, or psychiatric illness that would limit compliance with study requirements. 
11. Patients with an active autoimmune disease that has required systemic treatment in the past 2 years (i.e., 
with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy 
(e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary 
insufficiency) is not considered a form of systemic treatment.  
  
12. Patients who have evidence of active, non-infectious pneumonitis. Patients with a history of (non-
infectious) pneumonitis that required steroids or current pneumonitis.  
 
13. Patients with a history of interstitial lung disease. 
 
 
14. Patients who are pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial 
treatment. Pregnant women and men who expect to conceive a child are excluded from this study because 
birinapant and pembrolizumab are agents with unknown potential for teratogenic or abortifacient effects in 
humans. Because there is an unknown risk for AEs in nursing infants secondary to treatment of the mother 
with birinapant and pembrolizumab, breastfeeding should be discontinued if the mother is treated on this 
study.  
15. Patients who have a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies), or 
active Hepatitis B (e.g., HBsAg reactive). Patients with active Hepatitis C (e.g., HCV RNA [qualitative] is 
detected).  
16. Patients who have received a live-virus vaccination within 30 days of planned treatment start. Seasonal flu 
vaccines that do not contain live virus are permitted. 
17. Patients who have disease that is suitable for local therapy administered with curative intent. 
18. Patients who have received transfusion of blood products (including platelets or red blood cells) or 
administration of colony stimulating factors (including G-CSF, GM-CSF or recombinant erythropoietin) 


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within 4 weeks prior to study Day 1.  
19. Patients who have a history or current evidence of any condition, therapy, or laboratory abnormality that 
might confound the results of the trial, interfere with the patient’s participation for the full duration of the 
trial, or is not in the best interest of the patient to participate, in the opinion of the treating investigator.  
20. Patients who have known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial. 
21. Patients who have severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients. 
22. Patient who have received anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte-associated antigen-4 
(CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-
stimulation or checkpoint pathways) (various solid tumors cohort, head and neck squamous cell 
carcinoma checkpoint inhibitor experienced group only) 
23. Patient who have previously received birinapant treatment 
 
Study Drug Dose, Mode of Administration, and Administration Rate: 
During a 21-day treatment cycle, patients will receive 200 mg pembrolizumab intravenously (IV) on Day 1 and IV 
birinapant on Days 1 and 8. A week without treatment (i.e., Days 15-21) will follow the second week of treatment, 
immediately after which the next 21-day treatment cycle will start. All doses will be administered via a 30-minute (+10 
min) IV infusion.  Pembrolizumab will be administered first on Day 1.  The birinapant infusion will begin 30 minutes 
(+ 10 minutes) following the completion of the pembrolizumab infusion on Day 1.  Patients will be eligible to receive 
study medication for 35 treatment cycles or until documentation of disease progression or unacceptable toxicity.   
Study drug will be administered in the arm opposite to the site of blood-sample collection or via other venous access as 
appropriate. 
Dose-escalation phase 
Inter-patient dose escalation of birinapant will proceed at the birinapant dose indicated in the dose-escalation table, 
below. A minimum of 3 and up to 6 evaluable patients will be enrolled per dose level. 
Dose-Escalation Schedule 
Dose Level 
Pembrolizumab + Birinapant (per 21-day cycle) 
Level -1 
200 mg pembrolizumab on Day 1 + birinapant 2.8 mg/m2/week on Days 1 and 8 
Level 1 
200 mg pembrolizumab on Day 1 + birinapant 5.6 mg/m2/week on Days 1 and 8 
Level 2 
200 mg pembrolizumab on Day 1 + birinapant 11 mg/m2/week on Days 1 and 8 
Level 3 
200 mg pembrolizumab on Day 1 + birinapant 17 mg/m2/week on Days 1 and 8 
Level 4 
200 mg pembrolizumab on Day 1 + birinapant 22 mg/m2/week on Days 1 and 8 
The inter-patient dose escalation of birinapant will be based on the number of patients that experience a protocol-
defined dose-limiting toxicity (DLT). A DLT is a clinically significant event attributed to birinapant, pembrolizumab, 
or the combination of the 2 study drugs, during the first cycle of drug therapy and is defined as follows: 
Non-hematological toxicity: 
• 
Common Toxicity Criteria for Adverse Event (CTCAE; v4.03) Grade 3 nausea, vomiting, or diarrhea despite 
maximal anti-emetic or anti-diarrheal treatment and lasting > 48 hours; or Grade 4 vomiting or diarrhea; 


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• 
≥ Grade 3 other non-hematological toxicity, excluding isolated laboratory abnormalities without clinical 
sequelae, except for the following: 
o 
Prolonged (> 7 days) serum amylase or lipase elevation; 
o 
Prolonged (> 7 days) aspartate aminotransferase (AST) elevation; 
o 
Prolonged (> 7 days) alanine aminotransferase (ALT) elevation; 
All of which will be considered dose limiting. 
Hematological toxicity: 
• 
Grade 4 neutropenia; 
• 
Grade ≥ 3 neutropenia with fever > 38.3°C or > 38°C (> 100.9°F or > 100.4°F) for more than one hour; 
• 
Grade ≥ 3 thrombocytopenia with bleeding. 
If Day 8 of treatment is held due to toxicity, then the event will be considered a DLT.  A prolonged delay (> 2 weeks) 
in initiating Cycle 2 secondary to drug-related toxicity may be considered a DLT. Events related to disease progression, 
intercurrent illness, or concomitant medication will not constitute a DLT.  If a patient experiences a DLT that is deemed 
related to birinapant, the dose of birinapant may be reduced and the patient may remain on study.   
The decisions on when to dose escalate birinapant for each Dose Level are indicated in the table below. 
Number of Patients with DLT at a 
Given Dose Level 
Escalation-decision Rule 
Zero of 3 to 6 
Enter 3 to 6 patients at the next dose level. 
1 out of 3 to 6 
Enter up to a total of 6 patients at this dose level. 
• If 1 of these 3 to 6 patients experiences a DLT, proceed to the next dose 
level, if the next highest dose has not already been declared intolerable*. 
• If 1 of these 3 to 6 patients experiences a DLT and the next highest dose 
has already been declared intolerable, enroll a minimum of 6 patients at 
this dose level.  
≥ 2 
Dose escalation will be stopped. This dose level may be declared the 
maximally administered dose (highest dose administered) and may be 
declared intolerable. Three additional patients may be entered at the next 
lowest dose level if only 3 patients were treated previously at that dose. 
*Defined as ≥2 patients from 3-6 experiencing a DLT 
Safety data at each dose-escalation level will be reviewed by a Safety Review Committee (SRC), which will consist of 
representatives from the Sponsor and the study sites before each dose escalation. A separate safety review will be 
performed by the SRC to determine the recommended phase 2 dose (RP2D) of the combination of birinapant and 
pembrolizumab and to begin the dose-expansion phase of the study. 
Dose-expansion phase 
Once the RP2D of birinapant combined with pembrolizumab is defined, additional patients with relapsed or refractory 
carcinoma will be enrolled in the dose-expansion phase of the study.   
 
Dose Level 
Pembrolizumab + Birinapant (per 21-day cycle) 
Expansion 
200 mg pembrolizumab on Day 1+ birinapant at the RP2D mg/m2/week on Days 1 and 8 
 


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The dose expansion phase will comprise 4 cohorts of 26-30 patients.  
The 4 cohorts will include the following: 
• 
Colorectal cancer  
• 
Ovarian Cancer  
• 
Cervical cancer  
• 
Various solid tumors (30 patients, including 5 patients with each of the following 6 tumor types: Head and 
Neck Squamous Cell Carcinoma (HNSCC)-checkpoint-inhibitor naïve; and HNSCC checkpoint-inhibitor 
experienced; Gastroesophageal carcinoma; Mesothelioma; Small cell lung cancer (SCLC); 
Cholangiocarcinoma 
Predefined interim analyses for futility and safety will be conducted in each of the cohorts in colorectal cancer, ovarian 
cancer and cervical cancer to limit undue exposure before further inclusion into a given cohort. The design of the 
various solid tumors cohort will limit undue exposure in any of the selected tumor types by limiting the number of 
enrolled patient to five in each tumor type. During the dose-expansion phase of the study the SRC will be replaced by 
an independent Data Monitoring Committee (DMC). The DMC will meet approximately biannually to review the 
complete analysis of combined observed toxicities including emerging safety reports and reported SAEs. Specifically, 
they will monitor AEs and SAEs related to the treatments received in accordance with the recommendations of 
performing a clinical study of an IMP. 
 
Duration of Patient Participation: 
Patients are to receive study treatment for up to 35 treatment cycles or until documented progressive disease (PD) or 
unacceptable toxicity (See Section 6.1).   
 
General Design and Methodology: 
This is a Phase 1/2, multicenter, single-arm, open-label, dose-escalation study in patients with relapsed or refractory 
solid tumors. 
The study will determine the recommended Phase 2 birinapant dose in combination with pembrolizumab and will 
assess the tolerability, safety, pharmacokinetics, and pharmacodynamics of this birinapant dose in combination with 
pembrolizumab in male and female patients with relapsed or refractory solid tumors. Study visits to investigate the 
objectives of the study will be conducted as follows: 
• 
Screening is conducted ≤ 28 days before dosing. 
• 
Patients will be required to attend the investigative unit for screening to confirm eligibility. Eligible patients will be 
required to return to the investigative unit to receive, via IV infusion, 200 mg pembrolizumab on Day 1 and the 
assigned dose of birinapant on Days 1 and 8 of every 21-day cycle. 
• 
The active treatment phase commences on Day 1 and patients will be treated on a 21-day cycle for a maximum of 


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35 cycles, until disease progression or unacceptable toxicity.  While on active treatment study assessments to 
monitor safety and pharmacodynamics will be conducted. 
• 
Patients will also be required to return to the clinic for radiological tumor assessment (according to RECIST v 1.1 
and iRECIST) at the end of the third week (± 3 days) of every notional third 21-day cycle (every 9 weeks). 
• 
A follow-up visit to monitor safety, including ECOG performance status, will be conducted 30 days after 
study-drug discontinuation. 
• 
For patients that discontinue therapy for reasons other than progressive disease, a follow-up visit to 
confirm/document disease progression or initiation of a new therapy for patients’ disease must be performed every 
30 days after study-drug discontinuation. 
• 
A survival follow-up telephone contact visit must also be completed every 3 months to confirm survival status and 
the date of the next cancer therapy and type of therapy. 
Study Parameters: 
Dose escalation phase: 
Primary Endpoint 
Safety and tolerability, will be assessed by monitoring: 
• 
Incidence and severity of adverse events (AEs) experienced by patients receiving birinapant in combination with 
pembrolizumab. 
• 
Incidence and magnitude of clinically significant changes in clinical laboratory parameters experienced by patients 
receiving birinapant and pembrolizumab, or overall pattern of shifts by treatment group in individual laboratory 
values suggestive of possible trends, but not necessarily establishing, clinical abnormality.  
• 
Incidence and severity of clinically significant adverse findings in vital signs, electrocardiogram (ECGs), and other 
physical examination parameters identified among patients receiving birinapant and pembrolizumab. 
Secondary Endpoints 
Efficacy: 
Tumor response and progression evaluated using RECIST v 1.1 
Measures defined by the ORR, will be assessed through RECIST v 1.1 until response or progression and will be 
subsequently analyzed through iRECIST as an exploratory endpoint. 
Exploratory Endpoints 
Efficacy: 
Tumor response and progression evaluated using iRECIST. 
a) 
iBOR 
b) 
Duration of iBOR  
c) 
Time to iCPD 
Efficacy, as defined by the ORR, will be assessed through RECIST v 1.1 until response or progression and will be 
subsequently analyzed through iRECIST (iCR, or iPR or iSD or after iUPD iCR, iPR or iSD or iCPD). iBOR will also 
be assessed.  
Overall survival will also be assessed. 
Pharmacokinetics: 
The pharmacokinetics of birinapant in plasma when administered in combination with pembrolizumab will be 
evaluated. 
Pharmacodynamics: 
Translational biomarker assessments obtained from blood will be evaluated at a central laboratory:  
 


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• 
Pre- and post-treatment levels in the expression of cIAP1 
• 
Cytokines levels such as GM-CSF, IFNγ, IL10, IL2, IL3, IL4, IL5, IL6, IL7, IL8, MIP-1α, MIP-1β, MCP-1, 
TNFα, and TNFβ  
• 
Gene expression analysis by Nanostring 
 
Blood samples looking at CD3+, CD4+, CD8+, and CD19+ cell counts as well as absolute neutrophil count and absolute 
lymphocyte count will be analyzed by each investigational site’s local laboratory.   
 
Translational biomarker assessments such as listed below, will be evaluated from archival or fresh pre-treatment biopsy 
samples, and optional post-treatment tumor biopsy samples, which will be analyzed at central laboratory:  
• 
Pre-treatment PD-L1 levels by immunohistochemistry  
• 
Gene expression analysis by Nanostring 
• 
cIAP1 expression by immunohistochemistry 
• 
Inhibition of apoptosis protein (IAP) gene copy number  
• 
Tumor infiltrating lymphocytes (TILs) CD3, CD4, CD8, CD20 and FOXP3   
Note that the exploratory biomarker analyses listed are planned but may not be conducted if deemed as obsolete during 
later stages of the study; other exploratory analyses may be added based on emerging new findings. 
Dose expansion phase: 
Primary Endpoint 
The primary endpoint in each of the cohorts is as follows: 
1. The overall response assessed through RECIST v.1.1 until response or progression in colorectal cancer  
2. The overall response assessed through RECIST v1.1 until response or progression in ovarian cancer 
3. The overall response assessed through RECIST v1.1 until response or progression in cervical cancer 
4. Safety and tolerability in cohort with various solid tumor types will be assessed by monitoring: 
• 
Incidence and severity of adverse events (AEs) experienced by patients receiving birinapant in combination 
with pembrolizumab. 
• 
Incidence and magnitude of clinically significant changes in clinical laboratory parameters experienced by 
patients receiving birinapant and pembrolizumab, or overall pattern of shifts by treatment group in individual 
laboratory values suggestive of possible trends, but not necessarily establishing, clinical abnormality. 
• 
Incidence and severity of clinically significant adverse findings in vital signs, electrocardiogram (ECGs), and 
other physical examination parameters among patients receiving birinapant and pembrolizumab. 
Secondary Endpoints 
Safety and tolerability will be assessed in colorectal cancer, ovarian cancer and cervical cancer by monitoring: 
• 
Incidence and severity of adverse events (AEs) experienced by patients receiving birinapant in combination 
with pembrolizumab. 
• 
Incidence and magnitude of clinically significant changes in clinical laboratory parameters experienced by 
patients receiving birinapant and pembrolizumab, or overall pattern of shifts by treatment group in individual 
laboratory values suggestive of possible trends, but not necessarily establishing, clinical abnormality.  
• 
Incidence and severity of clinically significant adverse findings in vital signs, electrocardiogram (ECGs), and 
other physical examination parameters among patients receiving birinapant and pembrolizumab. 
Clinical Activity: Tumor response will be assessed in all four cohorts by monitoring: 
• 
Progression Free Survival (PFS) 
• 
Clinical Benefit Rate (CBR) defined as CR+PR+SD 
• 
Time to response 
• 
Duration of response 
• 
Overall Survival (OS) 
Measures of tumor response will be evaluated using RECIST v1.1 until response or progression and will be 
subsequently analyzed through iRECIST. 


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Exploratory endpoints 
Clinical Activity 
Tumor response and progression evaluated in all four cohorts using iRECIST. 
• 
Overall Response 
• 
iBOR 
• 
Duration of iBOR  
• 
Time to iCPD 
• 
Clinical Benefit Rate (CBR) defined as iCR+iPR+iSD  
• 
Time to response 
• 
Duration of response 
Pharmacokinetics 
The pharmacokinetics of birinapant in plasma when administered in combination with pembrolizumab will be 
evaluated. 
Pharmacodynamics 
Translational biomarker assessments obtained from blood will be evaluated at a central laboratory.  
• 
Pre- and post-treatment levels of cIAP1 expression 
• 
Cytokine levels such as GM-CSF, IFNγ, IL10, IL2, IL3, IL4, IL5, IL6, IL7, IL8, MIP-1α, MIP-1β, MCP-1, 
TNFα, and TNFβ  
• 
Gene expression analysis by Nanostring may be performed 
Blood samples looking at CA-125 (for ovarian cancer patients), CEA (for CRC patients), CD3+, CD4+, CD8+, and 
CD19+ cell counts as well as absolute neutrophil count and absolute lymphocyte count will be analyzed by each 
investigational site’s local laboratory. 
Translational biomarker assessments such as listed below, will be evaluated from archival or fresh pre-treatment biopsy 
samples, and optional post-treatment tumor biopsy samples, which will be analyzed at central laboratory: 
• 
Pre-treatment PD-L1 levels by immunohistochemistry       
• 
Gene expression analysis by Nanostring 
• 
cIAP1 expression by immunohistochemistry 
• 
Inhibition of apoptosis protein (IAP) gene copy number  
• 
Tumor infiltrating lymphocytes (TILs) CD3, CD4, CD8, CD20, FoxP3 
The exploratory biomarker analyses listed are planned but may not be conducted if deemed as obsolete during later 
stages of the study; other exploratory analyses may be added based on emerging new findings. Details regarding the 
processing and shipping of all pharmacodynamic samples will be outlined in the study specific laboratory manual.   
 
 


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Statistical Considerations: 
The analysis of all the clinical activity, safety, pharmacokinetic and pharmacodynamic parameters will be performed by 
Medivir AB or its designee. 
Demographics and Baseline Characteristics 
Descriptive statistics will be provided to summarize demographics and baseline characteristics. 
Dose Escalation phase: 
Primary Endpoint: Safety 
The safety and tolerability of pembrolizumab and birinapant will be based on results of DLT incidence, reported SAEs, 
AEs, vital sign measurements, physical examinations, clinical laboratory information, ECOG performance status, and 
concomitant medications. Exposure to study drug and reasons for discontinuation will be tabulated. These data will be 
summarized descriptively for the ITT population overall.   
Adverse events will be coded using the current Medical Dictionary for Regulated Activities (MedDRA) classification 
system, and will be summarized by system organ class and preferred term. 
Additional safety analyses may be determined in order to most clearly describe toxicity rates and to further define the 
safety profile of pembrolizumab and birinapant. 
Secondary Endpoints: Efficacy 
Efficacy, as defined by ORR, will be assessed through RECIST v 1.1 until response or progression.  Overall survival 
will also be assessed. 
Results will be summarized descriptively.  For parameters measured over time, data and changes from baseline will be 
summarized for each time point. Exploratory Endpoints: Efficacy, Pharmacodynamics and Pharmacokinetics 
Efficacy, as defined by the ORR, will be assessed through RECIST v 1.1 until response or progression and will be 
subsequently analyzed through iRECIST (iCR, or iPR or iSD or after iUPD iCR, iPR or iSD or iCPD). iBOR will also 
be assessed. Results will be summarized descriptively. 
Pharmacodynamic results will be summarized descriptively. 
Pharmacokinetics results will be summarized descriptively. Population PK modeling may also be applied. 
 
Dose Expansion phase: 
Primary Endpoints: 
Cohorts in colorectal cancer, ovarian cancer and cervical cancer: Clinical Activity 
The primary objective will be evaluated using Simon’s two-stage design. The null hypothesis that the true ORR is (5%, 
7% and 10% for colorectal cancer, ovarian cancer and cervical cancer, respectively) will be tested against a one-sided 
alternative. The design yields a type I error rate of 5% and power of 80% for each of the three indications individually. 
No correction for multiplicity will be done. In addition to tabulate the result of the statistical tests, results will be 
summarized descriptively. 
 
Various solid tumors cohort: Safety 
The safety and tolerability of pembrolizumab and birinapant will be based on results of reported SAEs, AEs, vital sign 
measurements, physical examinations, clinical laboratory information, ECOG performance status, and concomitant 
medications. Safety data will be summarized descriptively. Exposure to study drug and reasons for discontinuation will 
be tabulated.  
Adverse events will be coded using the current Medical Dictionary for Regulated Activities (MedDRA) classification 
system, and will be summarized by system organ class and preferred term. 
Additional safety analyses may be determined in order to most clearly describe toxicity rates and to further define the 


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safety profile of pembrolizumab and birinapant. 
Secondary Endpoints: 
Cohorts in colorectal cancer, ovarian cancer and cervical cancer: Safety 
The safety and tolerability of pembrolizumab and birinapant will be based on results of reported SAEs, AEs, vital sign 
measurements, physical examinations, clinical laboratory information, ECOG performance status, and concomitant 
medications. Safety data will be summarized descriptively by cohort and also summarized descriptively over cohorts 
within each of the two phases of the protocol. Exposure to study drug and reasons for discontinuation will be tabulated.  
Adverse events will be coded using the current Medical Dictionary for Regulated Activities (MedDRA) classification 
system, and will be summarized by system organ class and preferred term. 
Additional safety analyses may be determined in order to most clearly describe toxicity rates and to further define the 
safety profile of pembrolizumab and birinapant. 
 
All Cohorts: Clinical Activity 
Efficacy, as defined by PFS, CBR, Time to response and Duration of response, will be assessed through RECIST v 1.1 
and until response or progression.  Overall survival will also be assessed. 
Results will be summarized descriptively.  For parameters measured over time, data and changes from baseline will be 
summarized for each time point. 
Exploratory Endpoints: Clinical Activity, Pharmacodynamics and Pharmacokinetics 
All Cohorts: 
Clinical Activity, as defined by PFS, CBR, Time to response and duration of response, iBOR, Duration of iBOR and 
Time to iCPD, will be assessed through iRECIST. Results will be summarized descriptively. 
Pharmacodynamic results will be summarized descriptively. 
Pharmacokinetics results will be summarized descriptively. Population PK modeling may also be applied. 
 
 
 
 
 


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TABLE OF CONTENTS 
TITLE PAGE .....................................................................................................................1 
STUDY CONTACTS .........................................................................................................2 
PROTOCOL APPROVAL ...............................................................................................3 
SYNOPSIS ..........................................................................................................................4 
Primary Objective ..............................................................................................................4 
Secondary Objectives.........................................................................................................4 
Exploratory Objectives ......................................................................................................5 
Efficacy 
.................................................................. Error! Bookmark not defined. 
Pharmacokinetics .............................................................................................................15 
Pharmacodynamics ..........................................................................................................15 
TABLE OF CONTENTS ................................................................................................18 
LIST OF ABBREVIATIONS .........................................................................................24 
INVESTIGATOR STATEMENT ..................................................................................28 
 
INTRODUCTION ....................................................................................................29 
1.1 
Inhibitors of Apoptosis Proteins and Cancer ....................................................29 
1.2 
Birinapant Background .......................................................................................31 
 
Pre-Clinical Studies .......................................................................................31 
 
Birinapant and Clinical Trials ......................................................................32 
1.3 
Checkpoint Inhibition and Cancer .....................................................................32 
1.4 
Pembrolizumab Background ..............................................................................33 
 
Pre-Clinical Studies .......................................................................................33 
 
Pembrolizumab and Clinical use ..................................................................33 
1.5 
Rationale for Patient Population ........................................................................34 
 
Colorectal cancer ...........................................................................................34 
 
Ovarian cancer ...............................................................................................36 
 
Cervical cancer ...............................................................................................38 
 
Various solid tumors cohort ..........................................................................39 
1.5.4.1 
Head and Neck Squamous Cell Carcinoma...........................................39 
1.5.4.2 
Gastroesophageal carcinoma ..................................................................40 
1.5.4.3 
Mesothelioma............................................................................................42 
1.5.4.4 
Small Cell Lung Cancer ..........................................................................43 
1.5.4.5 
Cholangiocarcinoma ................................................................................44 
1.6 
Rationale for Dose Selection ...............................................................................45 
 
Rationale for Birinapant Starting Dose .......................................................45 
 
Rationale for Pembrolizumab Dose Selection .............................................45 
 
STUDY OBJECTIVES ............................................................................................46 
2.1 
Study Objectives Dose Escalation Phase ...........................................................46 
 
Primary Objective ..........................................................................................46 
 
Secondary Objective ......................................................................................47 
 
Exploratory Objectives ..................................................................................47 
2.2 
Study Objectives Dose Expansion Phase ...........................................................47 
 
Primary Objective ..........................................................................................47 
 
Secondary Objectives.....................................................................................47 
 
Exploratory Objectives ..................................................................................48 
 
Investigational Plan ..................................................................................................48 


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3.1 
Description of Study Design ................................................................................48 
 
Description of Study Design Dose Escalation Phase ...................................48 
 
Description of Study Design Dose Expansion Phase ...................................49 
 
Safety Review Committee Dose Escalation Phase .......................................50 
 
Data Monitoring Committee Dose Expansion Phase ..................................51 
3.2 
Discussion of Study Design ..................................................................................51 
 
Design Rationale including Dose Rationale Dose Escalation Phase ..........51 
 
Design Rationale Dose Expansion Phase Study Design ..............................52 
3.3 
Expected Duration of Study ................................................................................52 
3.4 
Study Endpoints ...................................................................................................53 
 
Study Endpoints: Dose Escalation Phase .....................................................53 
3.4.1.1 
Primary Endpoint ....................................................................................53 
3.4.1.2 
Secondary Endpoints ...............................................................................53 
3.4.1.3 
Exploratory endpoints .............................................................................54 
3.4.1.3.1 
Efficacy................................................................................................54 
3.4.1.3.2 
Pharmacokinetics ...............................................................................54 
3.4.1.3.3 
Pharmacodynamics ............................................................................54 
 
Study Endpoints; Dose Expansion Phase ....................................................55 
3.4.2.1 
Primary Endpoint ....................................................................................55 
3.4.2.2 
Secondary Endpoints ...............................................................................55 
3.4.2.3 
Exploratory endpoints .............................................................................56 
3.4.2.3.1 
Efficacy.................................................... Error! Bookmark not defined. 
3.4.2.3.2 
Pharmacokinetics ................................... Error! Bookmark not defined. 
3.4.2.3.3 
Pharmacodynamics ............................................................................56 
 
STUDY POPULATION ...........................................................................................57 
4.1 
Inclusion Criteria .................................................................................................57 
4.2 
Exclusion Criteria ................................................................................................61 
4.3 
Withdrawal Criteria and Procedures ................................................................63 
 
INVESTIGATIONAL PRODUCT AND COMCOMITANT 
MEDICATIONS .......................................................................................................64 
5.1 
Formulation, Packaging and Labeling ...............................................................64 
5.2 
Storage, Preparation, Stability and Accounting ...............................................65 
 
Investigational Product Storage, Preparation and Stability ......................65 
 
Investigational Product Accountability .......................................................65 
 
Retention of Samples .....................................................................................65 
 
Investigational Product Waste Handling .....................................................65 
5.3 
Dose Administration ............................................................................................66 
5.4 
Dose-Limiting Toxicity and Recommended Phase 2 Dose ...............................67 
5.5 
Dosing Delays/Dose Modifications .....................................................................68 
 
Dose Modifications Schema and Supportive Care Guidelines for 
Birinapant .......................................................................................................69 
 
Dose Modification Schema for Pembrolizumab..........................................70 
 
Supportive Care Guidelines for Pembrolizumab........................................70 
5.5.3.1 
Dose Modification and Toxicity Management Guidelines for 
Pembrolizumab ........................................................................................70 
5.6 
Concomitant Medications ...................................................................................75 


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Restricted and prohibited medications ........................................................76 
5.7 
Diet/Activity/Other considerations .....................................................................77 
 
Diet ..................................................................................................................77 
 
Contraception .................................................................................................77 
 
Use in Nursing Women ..................................................................................78 
 
Phototoxicity ...................................................................................................78 
5.8 
Patient Compliance ..............................................................................................78 
 
STUDY PROCEDURES ..........................................................................................79 
6.1 
Duration of Patient Participation .......................................................................84 
6.2 
Timing of Study Procedures ...............................................................................84 
 
Screening .........................................................................................................84 
 
During Active Protocol Treatment ...............................................................86 
6.3 
Procedures After Active Protocol Treatment Phase.........................................87 
 
Safety Follow up Visit ....................................................................................88 
 
Disease Progression Follow up Visit .............................................................88 
 
Overall Survival Follow up Visit ..................................................................88 
 
STUDY ASSESSMENTS .........................................................................................89 
7.1 
Safety Measurements ...........................................................................................89 
 
Medical History and Disease Characteristics ..............................................89 
 
Concomitant Therapy or Medication...........................................................89 
 
Eastern Cooperative Oncology Group Performance Status ......................89 
 
Physical Examination ....................................................................................89 
 
Vital Signs .......................................................................................................89 
 
Electrocardiograms........................................................................................90 
 
Clinical Laboratory Tests..............................................................................90 
7.1.7.1 
Hematology, Serum Chemistry, Immunology and Urinalysis, 
Serology .....................................................................................................90 
7.1.7.2 
Pregnancy Testing ....................................................................................90 
7.1.7.3 
Histology ...................................................................................................90 
 
ADVERSE EVENTS ................................................................................................91 
8.1 
Definition of Adverse Events...............................................................................91 
 
Recording and Reporting of Adverse Events ..............................................91 
 
Severity of an Adverse Event ........................................................................92 
 
Relationship of an Adverse Event ................................................................92 
8.2 
Serious Adverse Events .......................................................................................94 
 
Definition of a Serious Adverse Event .........................................................94 
 
Expectedness ...................................................................................................94 
8.3 
Notification/Reporting of a Serious Adverse Event ..........................................94 
8.4 
Notification of Events of Clinical Interest .........................................................96 
8.5 
Withdrawal Due to an Adverse Event ...............................................................96 
8.6 
Pregnancy .............................................................................................................97 
 
Reporting of Pregnancy and Lactation to the Sponsor ..............................97 
 
EFFICACY ................................................................................................................98 
9.1 
Antitumor Effect ..................................................................................................98 
 
Tumor Imaging ..............................................................................................98 
 
RECIST 1.1 Response Criteria .....................................................................99 


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9.1.2.1 
Lesions that become too small to measure ...........................................100 
9.1.2.2 
Lesions that split or grow together .......................................................100 
 
On-Study Tumor Imaging ...........................................................................100 
 
Immune RECIST (iRECIST) .....................................................................101 
 
In Study iRECIST Assessment of Disease .................................................105 
 PHARMACODYNAMIC SAMPLING ................................................................107 
 PHARMACOKINETIC SAMPLING ..................................................................110 
 STATISTICAL CONSIDERATIONS ..................................................................110 
12.1 
General Considerations .....................................................................................110 
12.2 
Determination of Sample Size ...........................................................................111 
12.3 
Randomization and Stratification ....................................................................112 
12.4 
Analysis Population ...........................................................................................112 
12.5 
Demographics and Baseline Characteristics ...................................................112 
12.6 
Analysis of Safety Data ......................................................................................112 
12.7 
Efficacy Analysis ................................................................................................113 
12.8 
Analysis of Pharmacodynamic Parameters .....................................................114 
12.9 
Analysis of Pharmacokinetic data ....................................................................114 
 DATA COLLECTION, STUDY MONITORING AND DATA 
DISCLOSURE ........................................................................................................114 
 DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ..................................115 
 QUALITY CONTROL AND QUALITY ASSURANCE ....................................115 
 ETHICS AND GOOD CLINICAL PRACTICE COMPLIANCE .....................116 
16.1 
Patient Information and Consent .....................................................................117 
 STUDY SITE CLOSURE ......................................................................................118 
 Record retention .....................................................................................................119 
 Provision of study results and information to Investigators ...............................119 
 Financing and insurance ........................................................................................120 
 Study administrative information .........................................................................120 
21.1 
Protocol Amendments .......................................................................................120 
21.2 
Biological Specimens ..........................................................................................121 
 REFERENCES .......................................................................................................122 
 APPENDICES .........................................................................................................135 
Appendix 1 Blood Volume .................................................. Error! Bookmark not defined. 
Appendix 2 
Inclusion/Exclusion criteria for individual cohorts ............................136 
Appendix 2.1 
Inclusion/Exclusion criteria Dose Escalation Phase .....................136 
Appendix 2.2 
Inclusion/Exclusion criteria Dose Expansion Phase Colorectal 
cancer cohort ................................................................................................141 
Appendix 2.3 
Inclusion/Exclusion criteria Dose Expansion Phase Ovarian 
cancer cohort ................................................................................................146 
Appendix 2.4 
Inclusion/Exclusion criteria Dose Expansion Phase Cervical 
cancer cohort ................................................................................................151 
Appendix 2.5 
Inclusion/Exclusion criteria Dose Expansion Phase Various 
Solid tumor cohort .......................................................................................156 
Appendix 2.5.1  
Inclusion/Exclusion criteria Dose Expansion Phase Diverse 
Solid tumor cohort, Head and Neck Squamous Cell Carcinoma 
(HNSCC)-check-point-inhibitor naïve group ............................................156 


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Appendix 2.5.2  
Inclusion/Exclusion criteria Dose Expansion Phase Diverse 
Solid tumor cohort, HNSCC check-point -inhibitor experienced 
group 
161 
Appendix 2.5.3  
Inclusion/Exclusion criteria Dose Expansion Phase Various 
Solid tumor cohort, Gastroesophageal carcinoma group ........................166 
Appendix 2.5.4  
Inclusion/Exclusion criteria Dose Expansion Phase Diverse 
Solid tumor cohort, Mesothelioma group ..................................................171 
Appendix 2.5.5  
Inclusion/Exclusion criteria Dose Expansion Phase Diverse 
Solid tumor cohort, Small cell lung cancer group ....................................176 
Appendix 2.5.6  
Inclusion/Exclusion criteria Dose Expansion Phase Diverse 
Solid tumor cohort, Cholangiocarcinoma group ......................................181 
 
 
 


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TABLE OF TABLES 
Table 1 
Adequate Organ Function Laboratory Values .......................................6 
Table 2 
Dose Escalation Schedule ........................................................................49 
Table 3 
Expected enrollment duration for individual cohorts of Study BPT-201 
53 
Table 4 
Adequate Organ Function Laboratory Values .....................................58 
Table 5 
Escalation Decision Rules ........................................................................68 
Table 6  
Dose modification and toxicity management guidelines for immune-related AEs 
associated with pembrolizumab .............................................................71 
Table 7 
Pembrolizumab Infusion Reaction Dose modification and Treatment Guidelines
....................................................................................................................74 
Table 8 
Schedule of Study Procedures and Assessments ...................................79 
Table 9 
Disease Response Criteria for Target and Non-Target Lesions ..........99 
Table 10 
Time Point Response:  Patients with Target (+/- Non-Target) Disease100 
Table 11 
Comparison of RECIST 1.1, iRECIST and irRECIST ......................103 
Table 12 
Trajectory of progression in iRECIST ................................................104 
Table 13 
Imaging and treatment after first radiologic evidence of PD (iRECIST 
designation iUPD) ..................................................................................106 
Table 14 
Timing of Pharmacodynamic Sampling ..............................................108 
Table 15 
Summary of Pharmacodynamic Assessments .....................................108 
Table 16 
Timing of Pharmacokinetic Sampling .................................................110 
Table 17 
 Simon’s two-stage design settings in each of the three main cohorts113 
 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ADL 
Activities of daily living 
AE 
Adverse Event 
ALC 
Absolute lymphocyte count 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase  
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase  
BCG 
Bacillus Calmette–Guérin 
BSA 
Body surface area 
BUN 
Blood urea nitrogen 
CBC 
CCA 
CEA 
Complete blood count 
Cholangiocarcinoma  
Carcinoembryonic antigen 
CDMS 
Clinical Data Management System 
CI 
CLcr 
Confidence interval 
Creatinine Clearance 
CR 
Complete Response 
CRS 
Cytokine release syndrome 
CRC 
Colorectal carcinoma 
CRO 
Clinical Research Organization 
CSR 
Clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
Cytotoxic T-lymphocyte-associated antigen-4 
CYP 
Cytochrome P450 
DLT 
Dose limiting toxicity 
dMMR 
Deficient in mismatch repair 
ECG 
Electrocardiogram 
ECI 
Event of clinical interest 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 


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FDA 
Food and Drug Administration 
GCP 
GEJ 
GFR 
Good Clinical Practice 
Gastroesophageal Junction 
Glomerular Filtration Rate 
GM-CSF 
Granulocyte-macrophage colony-stimulating factor 
HNSCC 
HPV 
Head and neck squamous cell carcinoma 
Human papillomavirus 
HSV 
Herpes Simplex Virus 
IAP 
Inhibitor of Apoptosis Protein 
IB 
Investigator’s Brochure 
iBOR 
Immune response for immuno-therapeutics (i) Best 
Overall Response 
ICH 
International Conference on Harmonization 
iCPD 
Immune response for immune-therapeutics (i) 
Confirmed Progressive Disease 
IRB 
Institutional Review Board 
iRECIST 
Immune Response Evaluation Criteria in Solid 
Tumors (Lancet Oncology 18, 143 – 152. 2017) 
irRECIST 
 
iUPD 
Immune-related Response Evaluation Criteria in 
Solid Tumors 
Immune response for immuno-therapeutics (i) 
Unconfirmed Progressive Disease 
ITS 
Investigator initiated study 
ITT 
Intent-to-treat 
IV 
Intravenous 
LDH 
Lactate dehydrogenase 
MedDRA 
MM 
MPM 
Medical Dictionary for Regulatory Activities 
Malignant Mesothelioma 
Malignant Pleural Mesothelioma 
MSI 
Microsatellite instability 
MSS 
Microsatellite stable 
MTD 
Maximum tolerated dose 
NCI 
National Cancer Institute 
NF-kB 
Nuclear factor kappa-light-chain-enhancer of 
activated B cells 


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NCCN 
National Comprehensive Cancer Network 
NSAID 
Non-steroidal anti-inflammatory drug 
NSCLC 
Non small cell lung cancer 
ORR 
Overall Response Rate 
OS 
pCCA 
Overall survival 
Perihilar Cholangiocarcinoma  
PD 
PD-1 
PD-L1 
PFS 
P-gp 
Progressive disease  
Programmed cell death protein 1 
Programmed death-ligand 1  
Progression-free survival 
P-glycoprotein 
PK 
PR 
PS 
Q2W 
Pharmacokinetic 
Partial Response 
Performance Status 
Every 2 weeks 
Q3W 
Every 3 weeks 
RBC 
Red Blood Cell 
RIPK1 
Receptor interacting protein kinase-1 
RP2D 
Recommended phase 2 dose  
SAE 
Serious adverse event 
SC 
Subcutaneous 
SCLC 
Small cell lung cancer 
SMAC 
Second mitochondria-derived activator of caspase 
SOP 
Standard Operating Procedure 
SRC 
Safety Review Committee 
T1DM 
Type I diabetes mellitus 
TIL 
Tumor Infiltrating Lymphocytes 
TNF 
Tumor necrosis factor 
TRAF-2 
TNF receptor-associated factor 2 
ULN 
Upper limit of normal 
US 
United States 
USP 
US Pharmacopeia 
VZV 
Varicella Zoster Virus 


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WBC 
White blood cell count 
WHO 
World Health Organization 
XIAP 
X-linked inhibitors of apoptosis protein  
 
 
 


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INVESTIGATOR STATEMENT 
I have read and understood the protocol and agree to conduct this study as detailed herein, in 
compliance with current Good Clinical Practice1 (GCP) and the applicable regulatory requirements, 
and will make every reasonable effort to complete the study within the time designated. 
I will provide adequate protocol training to my associates, colleagues, and employees assisting in the 
conduct of the study. The protocol and all relevant information on the study drug relating to pre-
clinical and prior clinical experience, which was furnished by the Sponsor, will be made available to 
all physicians, nurses and other personnel who participate in the conduct of this study. I will discuss 
this material with them to assure that they are fully informed regarding the drug(s) and the conduct of 
the study. 
I will obtain approval from, the institutional review board (IRB) for the protocol and Informed 
Consent Form (ICF) before enrollment of patients in the study. I understand that any modifications to 
the protocol made during the course of the study must first be approved by the IRB except when such 
modification is made to remove an immediate hazard to the patient. 
I will ensure that a fully executed ICF is obtained from each patient before initiation of any study 
procedures. 
I will report any Serious Adverse Event (SAE), adverse events of clinical interest, overdose, and new 
cancer that occur during the course of the study in accordance with the procedures described in 
Section 8.3  and Section 8.4 of the protocol. 
I will allow the Sponsor, Medivir AB and its agents, as well as the United States Food and Drug 
Administration (US FDA) and other regulatory agencies, to inspect study facilities and pertinent 
records at reasonable times and in a reasonable manner, ensuring patient confidentiality. If I am 
notified that this study is to be inspected by a regulatory agency, I will notify Medivir AB as soon as 
possible thereafter. 
This document contains information that is privileged or confidential. As such, it may not be 
disclosed unless specific prior permission is granted in writing by Medivir AB or such disclosure is 
required by federal or other laws or regulations. Persons to whom any of this information is to be 
disclosed must first be informed that the information is confidential. These restrictions on disclosure 
will apply equally to all future information supplied, which is indicated as privileged or confidential. 
Medivir AB will have access to any source documents from which Case Report Form (CRF) 
information may have been generated. The CRF and other data pertinent to this study are the sole 
property of Medivir AB, which may utilize the data in various ways, such as for submission to 
government regulatory authorities, or in publication of the results of the study. 
 
 
 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
 
 
 
Print Name 
 
Site Number 
 
 
 


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 INTRODUCTION 
1.1 
Inhibitors of Apoptosis Proteins and Cancer 
The dysregulation of apoptosis is recognized as a fundamental contributor to  the 
pathogenesis of cancer. Apoptosis is a highly-regulated process that enables cells in non-
tumor tissues to respond to either external death receptor signals or intracellular stress 
signals (such as deoxyribonucleic acid (DNA) damage) in order to rapidly eliminate 
damaged cells through the activation of intracellular caspases. In many tumors however, the 
ability to undergo apoptosis is impaired and the transformed cell can remain in a viable, pro-
survival state, even in the presence of strong pro-apoptotic signals. Therefore, dysregulation 
of apoptosis in tumors contributes to the malignant phenotype and is associated with 
resistance to certain chemotherapeutics and biological therapies (Hanahan et al. 2000). 
A family of proteins known as the Inhibitors of Apoptosis (IAPs) plays a critical role in 
blocking the apoptotic signals at multiple points in the apoptotic pathway. The IAP gene 
family encodes a group of structurally-related proteins (including X-linked inhibitor of 
apoptosis protein [XIAP], cellular IAP1 [cIAP1], cIAP2, and Melanoma-IAP [ML-IAP]) that 
can suppress apoptotic cell death (Hunter et al. 2007, LaCasse et al. 2008). Many of the IAP 
proteins are known to be over-expressed in cancer cells, and can contribute to resistance to 
apoptosis in response to certain biological and conventional cytotoxic drug therapies (Fesik 
2005, Bertrand et al. 2008). Members of the IAP family of proteins including cIAP1, cIAP2, 
and XIAP can block caspase activation at the cell death receptor pathway level (cIAP1 and 
cIAP2) and at the last step in the pathway by directly binding to and suppressing caspase-3/7 
activity. In addition, cIAP1 and cIAP2 critically regulate nuclear factor-kappa B (NF-κB), 
leading to the activation of pro-survival canonical NF-κB signaling pathways (Gyrd-Hansen 
et al. 2010, Fulda 2012).  
Dysregulation of IAPs may be critical for the development and progression of certain 
malignancies.  Over-expression of IAPs has been linked to resistance to chemotherapy and 
radiation in multiple tumor types (Tamm et al. 2000, Janzen et al. 2015), (Eytan et al. 
2016))(Eytan et al. 2016). Similarly, there is data demonstrating IAP gene amplification in 
the majority of tumor types including pancreatic, non-small cell lung cancer (NSCLC), small 
cell lung cancer (SCLC), glioblastoma multiforme, head and neck, cervical, bladder, gastric, 
ovarian, breast and esophageal tumors, as noted below. The evidence of widespread IAP 
gene amplification across multiple human tumors underlines the importance of this pathway 
in mechanisms of oncogenesis and drug-resistance. 
The activity of IAPs is regulated by a protein known as a second mitochondria-derived 
activator of caspases (SMAC) (Du et al. 2000, Verhagen et al. 2000, Condon 2011). SMAC 
is a natural IAP antagonist that, once released from mitochondria following cellular stress, 
rapidly antagonizes the IAPs, resulting in caspase activation and apoptosis (Du et al. 2000, 
Vince et al. 2007). Small molecule SMAC mimetics mimic endogenous SMAC, resulting in 
the rapid and irreversible initiation of apoptotic cell death. Bivalent SMAC mimetics also 
potently suppress pro-survival NF-κB pathways (Li et al. 2004, Fesik 2005, Hunter et al. 
2007, Petersen et al. 2007, Varfolomeev et al. 2007, Vince et al. 2007, Bertrand et al. 2008, 
LaCasse et al. 2008, Chen et al. 2009, Ndubaku et al. 2009) . cIAP1 and cIAP2 are critical 


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components of the Tumor Necrosis Factor (TNF) receptor I complex. This complex initiates 
canonical NF-κB signaling in response to receptor ligation by TNF. cIAP1 and cIAP2, 
through their intrinsic E3 ubiquitin ligase activity, catalyze the ubiquitination of several 
proteins (including cIAP1 itself, cIAP2, and receptor interacting protein kinase-1 [RIPK1]), a 
necessary modification for the activation of pro-survival NF-κB signaling. Antagonism of 
TNF receptor-associated factor 2 (TRAF-2)-bound cIAP1 and cIAP2 by SMAC mimetics 
such as birinapant results in their auto-ubiquitination and subsequent proteasomal 
degradation (Varfolomeev et al. 2007) (Vince et al. 2007).  In the absence of cIAP proteins, 
ubiquitination does not occur and the non-ubiquitinated RIPK1 promotes the formation of a 
cytosolic complex (complex II), which includes the adaptor protein FADD, caspase 8, and 
RIPK1. Complex II mediates the activation of caspase 8, ultimately leading to apoptosis. 
Thus, SMAC mimetics can switch the function of TNFα from a proinflammatory, pro-
survival role to an inducer of cell death. 
cIAP1 and cIAP2 proteins are also negative regulators of the non-canonical NF-κB pathway, 
acting as ubiquitin ligases for the NF-κB Inducing Kinase (NIK) and directing it for 
proteasomal degradation (Demchenko et al. 2010). On stimulation of the non-canonical NF-
κB pathway by the binding of ligands such as CD40L or BAFF, cIAP proteins are recruited 
to the cell membrane and can no longer ubiquitinate NIK, which is thus allowed to 
accumulate and then catalyzes NFKB2 p100 to p52 processing and activation of non-
canonical signaling (Demchenko et al. 2010). Degradation of cIAP1 by SMAC mimetics 
such as birinapant also prevents ubiquitination and degradation of NIK and leads to 
activation of alternative NF-κB signaling, and increased expression of target genes including 
TNFα and other cytokines. Enhanced production of TNFα can then further catalyze TNF-
dependent apoptosis as described above.  
Activation of non-canonical NF-κB signaling by SMAC mimetics induces co-stimulatory 
activity in T cells and induces dendritic cell maturation leading to enhanced immune 
activation (Dougan et al. 2010, Muller-Sienerth et al. 2011, Knights et al. 2013). 
Proinflammatory cell death induction by SMAC mimetic also elicits the adaptive immune 
response, leading to increased Tumor Infiltrating Lymphocytes (TILs), interferon gamma 
production and activation of CD8 positive cytotoxic lymphocytes (Emeagi et al. 2012). The 
enhanced production of inflammatory cytokines in the local tumor microenvironment can be 
further enhanced by the combination of SMAC mimetics and anti-PD1 checkpoint inhibitors 
(Beug et al. 2017) which will then be expected to attract further immune cell infiltration to 
enhance the anti-tumor effect. These multiple mechanisms of enhanced immune activation 
lead to potent anti-tumor activity and synergistic combinations with multiple immunotherapy 
strategies (Dougan et al. 2010, Knights et al. 2013, Beug et al. 2015, Beug et al. 2017).  
 In particular, the combination of SMAC mimetics, including birinapant, with anti-PD1 
checkpoint inhibitors leads to synergistic anti-tumor activity in preclinical models of 
glioblastoma, mammary tumors and multiple myeloma (Chesi et al. 2016, Beug et al. 2017).  
Birinapant was shown to enhance the TNF-dependent cytotoxic lymphocyte killing of tumor 
cells which was further enhanced by combination with anti-PD-1 antibodies (Kearney et al. 
2017 Cell Death and Differentiation). These and other data provide a strong rationale for a 
potential benefit of combining birinapant with pembrolizumab due to two complementary 


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mechanisms:  
(1) Increased efficiency of activation of immune cells by activation of non-canonical NF-
κB signaling, 
(2) Increased local delivery of TNFα by activated T cells is converted to an induction of 
apoptosis as described above  
These arguments support investigation of the combination of birinapant and pembrolizumab 
in various cancer indications and underpin the rationale for the selection of indications in the 
expansion phase of this study, which is further described in section 1.5. 
1.2 
Birinapant Background 
Birinapant is a potent, bivalent SMAC-mimetic (molecular weight 806.9 g/mol) that binds 
with differential affinity to multiple members of the IAP family including cIAP1, cIAP2, 
XIAP, and ML-IAP (Condon et al. 2014). Birinapant is differentiated from related bivalent 
SMAC-mimetics in that birinapant results in the loss of cIAP1 and selective degradation of 
cIAP2 bound to TRAF-2 in the TNF receptor complex, but sparing non-TRAF-2 bound 
cIAP2 (Benetatos et al. 2014). This unique IAP antagonism profile of birinapant is thought to 
result in the improved tolerability and therapeutic index observed with this agent compared 
to other bivalent SMAC-mimetics (Condon et al. 2014). Birinapant is differentiated from 
monovalent SMAC mimetics by the ability of birinapant to access TRAF 2-bound cIAP1 and 
target it for degradation (Mitsuuchi et al. 2017). In contrast, monovalent SMAC mimetic 
treatment leaves a residual inaccessible cIAP1-TRAF2 complex undegraded, which results in 
an incomplete shutdown compared to birinapant (Mitsuuchi et al. 2017).  
 
Pre-Clinical Studies 
Birinapant shows marked anti-tumor activity and a high therapeutic index in human tumor 
xenografts in mice following intraperitoneal or IV administration.  The minimal efficacious 
dose when administered every 3 days to mice bearing an orthotopic MDA-MB-231 
(birinapant-sensitive sub-clone) breast tumor was 1.25 mg/kg (3.75 mg/m2) with no toxicity 
at doses up to 60 mg/kg (180 mg/m2), the highest dose evaluated in this model.  Single agent 
efficacy of birinapant was also observed in the SKOV-3 ovarian cancer xenograft model 
where the tumor was implanted subcutaneously in the axillary region. Birinapant also 
displays single agent efficacy in cell line and primary patient-derived tumors, transplanted 
into mice including ovarian, melanoma, ALL, AML, Diffuse Large B Cell Lymphoma and 
pancreatic tumor models (Benetatos et al. 2014, Carter et al. 2014, Condon et al. 2014, Yang 
et al. 2016). However, while some tumor models are sensitive to birinapant administration as 
a monotherapy, much greater efficacy in a wider variety of tumor models is observed in 
combination treatments. This is consistent with the concept of birinapant blocking the anti-
apoptotic effect of IAP proteins, while a simultaneously applied inducer of apoptosis is 
required for a combined optimal anti-tumor effect. Potent anti-tumor activity in combination 
studies has been observed in preclinical models of e.g. ovarian cancer (Janzen et al. 2015) 
and head and neck cancer (Eytan et al. 2016), particularly in those tumors with a high 
expression of cIAP1. Taken together these findings indicate that birinapant therapy will elicit 
the maximal benefit when used in combination treatments (Fulda 2015). 


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Birinapant and Clinical Trials 
Clinical trials with birinapant include 9 studies that are complete targeting oncology and 
HBV indications.  As of 21 October 2017, 470 patients have been enrolled in these studies, 
of which 411 have received birinapant. 
The oncology program includes 8 studies conducted under multiple sponsor-initiated and 
investigator-initiated clinical applications.  As of 21 October 2017, 463 patients with solid 
tumors or hematological malignancies have been enrolled in studies designed to evaluate 
birinapant in the oncology setting, either as a single agent or in combination with other 
chemotherapeutics at doses up to 63 mg/m2/dose.  To date, 5 oncology studies sponsored by 
TetraLogic Pharmaceuticals (the previous owner of birinapant) and 3 investigator-sponsored 
studies have been completed. 
Birinapant has demonstrated single-agent efficacy in combination when given with standard 
agent and investigational agent chemotherapy in patients with advanced cancers including 
but not limited to colorectal carcinoma (CRC), ovarian cancer and myelodysplastic 
syndrome (MDS). 
For further information, please see the birinapant Investigator’s Brochure. 
1.3 
Checkpoint Inhibition and Cancer 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades (Disis 2010).  Accumulating evidence shows a 
correlation between tumor-infiltrating lymphocytes (TILs) in cancer tissue and prognosis in 
various malignancies (Dunn et al. 2007, Uppaluri et al. 2008, Bellati et al. 2009, Oble et al. 
2009, Nosho et al. 2010, Shirabe et al. 2010, Bremnes et al. 2011, Gooden et al. 2011, 
Schreiber et al. 2011, Talmadge 2011, Mei et al. 2014, Schatton 2014, Salgado et al. 2015). 
In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector T-cells/FoxP3+ 
regulatory T-cells seem to correlate with improved prognosis and long-term survival in many 
solid tumors (Kirk 2010, Nosho et al. 2010, Liu et al. 2011, Mathai et al. 2012, Yoon et al. 
2012, Kim et al. 2013, Preston et al. 2013, Chang et al. 2014). 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control (Pedoeem et al. 2014).  The normal function of PD-1, expressed on the cell 
surface of activated T-cells under healthy conditions, is to down-modulate unwanted or 
excessive immune responses, including autoimmune reactions.  PD-1 (encoded by the gene 
Pdcd1) is an Ig superfamily member related to CD28, which has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2).  
The structures of murine PD-1 alone (Zhang et al. 2004) and in complex with its ligands 
were first resolved (Lazar-Molnar et al. 2008, Lin et al. 2008) and more recently the NMR-
based structure of the human PD-1 extracellular region and analyses of its interactions with 
its ligands were also reported (Cheng et al. 2013).  PD-1 and family members are type I 
transmembrane glycoproteins containing an Ig Variable-type (V-type) domain responsible 
for ligand binding and a cytoplasmic tail which is responsible for the binding of signaling 
molecules.  The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an 
immunoreceptor tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-


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based switch motif (ITSM).  Following T-cell stimulation, PD-1 recruits the tyrosine 
phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules, such as CD3ζ, PKCθ and ZAP70, which are 
involved in the CD3 T-cell signaling cascade (Sheppard et al. 2004).  PD-1 was shown to be 
expressed on activated lymphocytes, including peripheral CD4+ and CD8+ T-cells, B-cells, 
T regs and Natural Killer cells (Yao et al. 2014). Expression has also been shown during 
thymic development on CD4-CD8- (double negative) T cells (Nishimura et al. 1996), as well 
as subsets of macrophages (Huang et al. 2009) and dendritic cells (Pena-Cruz et al. 2010). 
The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in a 
variety of cell types (Keir et al. 2008). PD-L1 is expressed at low levels on various non-
hematopoietic tissues, most notably on vascular endothelium, whereas PD-L2 protein is only 
detectably expressed on antigen-presenting cells found in lymphoid tissue or chronic 
inflammatory environments (Keir et al. 2008). Both ligands are type I transmembrane 
receptors containing both IgV- and IgC-like domains in the extracellular region and short 
cytoplasmic regions with no known signaling motifs.  Binding of either PD-1 ligand to PD-1 
inhibits T cell activation triggered through the T cell receptor. PD-L2 is thought to control 
immune T-cell activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted 
T cell function in peripheral tissues.  Although healthy organs express little (if any) PD-L1, a 
variety of cancers were demonstrated to express abundant levels of this T cell inhibitor 
(Karim et al. 2009, Taube et al. 2012), which, via its interaction with the PD-1 receptor on 
tumor-specific T cells, plays a critical role in immune evasion by tumors (Sanmamed et al. 
2014).  As a consequence, the PD-1/PD-L1 pathway is an attractive target for therapeutic 
intervention in cancer (Topalian et al. 2012a). 
1.4 
Pembrolizumab Background  
 
Pre-Clinical Studies 
Therapeutic studies in mouse models have shown that administration of antibodies blocking 
PD-1/PD-L1 interaction enhances infiltration of tumor-specific CD8+ T cells and ultimately 
leads to tumor rejection, either as a monotherapy or in combination with other treatment 
modalities (Strome et al. 2003, Blank et al. 2004, Hirano et al. 2005, Curran et al. 2010, 
Pilon-Thomas et al. 2010, Weber 2010, Spranger et al. 2014).  Anti-mouse PD-1 or anti-
mouse PD-L1 antibodies have demonstrated antitumor responses in models of squamous cell 
carcinoma, pancreatic carcinoma, melanoma, acute myeloid leukemia and colorectal 
carcinoma (Strome et al. 2003, Nomi et al. 2007, Zhang et al. 2009, Pilon-Thomas et al. 
2010).  In such studies, tumor infiltration by CD8+ T cells and increased IFN-γ, granzyme B 
and perforin expression were observed, indicating that the mechanism underlying the anti-
tumor activity of PD-1 checkpoint inhibition involved local infiltration and activation of 
effector T cell function in vivo (Curran et al. 2010). Experiments have confirmed the in vivo 
efficacy of anti-mouse PD-1 antibody as a monotherapy, as well as in combination with 
chemotherapy, in syngeneic mouse tumor models (see the Investigator’s Brochure [IB]). 
 
Pembrolizumab and Clinical use 
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody 
(mAb) with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus 


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inhibiting its interaction with programmed cell death ligand 1 (PD-L1) and programmed cell 
death ligand 2 (PD-L2).  Based on preclinical ad data, pembrolizumab has high affinity and 
potent receptor blocking activity for PD-1.  Pembrolizumab has an acceptable preclinical 
safety profile and is in clinical development as an intravenous (IV) immunotherapy for 
advanced malignancies.  KEYTRUDA™ (pembrolizumab) is indicated for the treatment of 
patients across a number of indications.  For more details on specific indications refer to the 
Investigator brochure. 
1.5 
Rationale for Patient Population 
 
Colorectal cancer 
Colorectal cancer is the second most common in cancer in women and the third most 
common in men.  The American Cancer Society estimates that 95,520 new cases of colon 
cancer will be diagnosed in the United States in 2017. Estimates for mortality from colon and 
rectal cancer (the two are combined because of classification difficulties) are for 50,260 
deaths in 2017 (Siegel et al. 2017). The approximate 5-year survival rate for colorectal 
cancer patients in the United States (all stages included) is 65%. Survival is inversely related 
to stage: approximate 5-year survival rates are 95% for patients with stage I disease, 60% for 
those with stage III disease, and 10% for those with stage IV (metastatic) disease (NCI 
2017a). 
Surgery is the only curative modality for localized colon cancer (stage I-III). Surgical 
resection potentially provides the only curative option for patients with limited metastatic 
disease in liver and/or lung (stage IV disease). Adjuvant chemotherapy is standard for 
patients with stage III disease and has been shown to reduce death rate by 33% (Moertel et al. 
1990).  At present, the role of radiation therapy is limited to palliative therapy for selected 
metastatic sites such as bone or brain metastases. Chemotherapy rather than surgery has been 
the standard management for patients with metastatic colorectal cancer. Biologic agents have 
assumed a major role in the treatment of metastatic cases, with selection increasingly guided 
by genetic analysis of the tumor.  Biologic agents used in the treatment of colon cancer 
include monoclonal antibodies against vascular endothelial growth factor (VEGF) and 
epidermal growth factor receptor (EGFR), as well as a kinase inhibitor and a decoy receptor 
for VEGF.  
Combination regimens provide improved efficacy and prolonged progression-free survival 
(PFS) in patients with metastatic colon cancer, and the advent of new classes of active drugs 
and biologics for colorectal cancer has improved the expected survival (Kim et al. 2009).  
However, despite the improvements in the past decades, the long-term outcome is still 
dismal with a median overall survival of 11-15 months in published trials after start of 
second-line therapy with only a modest improvement in Overall Survival (OS) and PFS with 
regimens containing new compounds (Giantonio et al. 2007) , (Van Cutsem et al. 2012) 
(Tabernero et al. 2015). Therefore, an unmet medical need still exists in order to improve 
outcomes for patients progressing after initial therapy. 
Microsatellite Instability (MSI) is a hypermutable phenotype of certain cancers caused by 
defects in the DNA mismatch repair system, most frequently due to hypermethylation of the 


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MLH1 gene or loss of MSH2 expression (Boland et al. 2010). Microsatellites are small 
regions of repeated sequences in DNA, and these can present challenges to the DNA 
replication machinery which can result in mismatches between the DNA strands which must 
be repaired by the DNA mismatch repair system. If these mismatches are unrepaired, they 
lead to a very high mutation rate and the consequent generation of thousands of neoantigens 
which are readily recognized as foreign by the immune system. This leads to a high degree 
of tumor infiltration by lymphocytes and a priming of the immune system for reactivation.  
MSI occurs in approximately 15% of colorectal cancers, with ~ 3% arising from the 
hereditary Lynch syndrome and ~12% arising spontaneously (Boland et al. 2010).  MSI 
status has been further categorized as MSI-High, in which >30% of the microsatellite marker 
panel is mutated, or MSI-Low where at least 1 but <30% are mutated, as defined in the 
Bethesda guidelines (Boland et al. 1998). Mismatch repair status can also be determined 
using immunohistochemistry, and termed as deficient mismatch repair (dMMR), which is 
equivalent phenotypically to MSI. Cancers with intact mismatch repair systems are termed 
microsatellite stable (MSS). MSI-High tumors are characterized with a high degree of Tumor 
Infiltrating Lymphocytes (TILs) whereas MSI-Low tumors have clinical features of 
microsatellite-stable tumors. 
Rationale for birinipant in colorectal cancer 
In microsatellite-stable CRC, birinapant was active in multiple CRC PDX models that were 
both KRAS wild-type (WT) and KRAS mutant (Benetatos et al. 2014).  These data suggest 
that KRAS status is not decisive for SMAC-mimetic treatment.  In addition, increased IAP 
gene copy number has been detected in 45% of 573 CRC tumors analyzed 
(http://cancergenome.nih.gov). IAP genes have been suggested as prognostic markers of 
colorectal cancer (Miura et al. 2011). Consistent with the preclinical data, birinapant showed 
evidence of clinical activity in patient studies. In the phase 1 monotherapy trial of birinapant, 
Amaravadi et al. (Amaravadi et al. 2015) reported evidence of clinical activity in CRC (1 
patient prolonged SD, 2 patients radiographical shrinkage) and demonstration of target 
modulation (reduction in cIAP expression in PBMC and tumors) correlating with PK 
assessment. Furthermore, 6 PR seen in CRC in combination with irinotecan were seen in 
another of the studies (TL32711-POC-078-PTL) (For more details on specific indications 
refer to the Investigator’s brochure). 
Pembrolizumab in colorectal cancer 
Pembrolizumab gained accelerated approval from the FDA in May 2017 due to its specific 
efficacy in unresectable or metastatic colon cancer that has tested positive for MSI-High or 
dMMR, and has progressed following treatment with a fluoropyrimidine, oxaliplatin, and 
irinotecan. The approval for pembrolizumab was based on data from 149 patients with MSI-
High or dMMR cancers enrolled across 5 single-arm clinical trials (KEYNOTE-012, -016, -
028, -154 and -164), that included ninety patients with colorectal cancer (CRC). The ORR 
with pembrolizumab was 39.6%, including 11 (7.4%) complete responses (CRs). Among 
patients who responded to pembrolizumab, 78% had responses that lasted for at least 6 
months (Keytruda 2017). 


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However, despite these good response rates of immune checkpoint antibodies for MSI-High / 
dMMR colorectal cancer, there is little evidence of activity in microsatellite stable (MSS) 
colorectal cancers. In a phase II study by Le et al. investigating pembrolizumab, with an 
objective response rate of 40% in MSI CRC, no responses were recorded in the mismatch 
repair-proficient cohort (Le et al. 2015). Only 1/14 CRC patients responded to anti-PD1 
antibody (MDX-1106, nivolumab), and the one responding patient was diagnosed as MSI-
High (Brahmer et al. 2010). Subsequently, no objective responses were observed in 19 CRC 
patients with anti-PD1 antibody nivolumab not assessed for MSI status (aka BMS-936558; 
(Topalian et al. 2012b)). No objective responses are described with nivolumab or the 
combination of nivolumab and ipilumimab in MSS CRC (Overman 2016). No objective 
responses were observed in 18 CRC patients with anti-PD-L1 antibody BMS-936559 
(Brahmer et al. 2012). 
Thus, there is a substantial unmet medical need and opportunity to unlock immune responses 
in the MSS population of colorectal cancer patients. 
 
Ovarian cancer 
Ovarian cancer is the most common cause of cancer death from gynecologic tumors in the 
United States. Around the world, more than 200,000 women are estimated to develop 
ovarian cancer every year and about 100,000 die from the disease. (NCI 2017b) The 
American Cancer Society estimates that 22,440 new cases of ovarian cancer will be 
diagnosed in 2017 and 14,080 women will die from the disease (NCS 2017).  Although the 
5-year survival rate for ovarian cancer has improved significantly in the past 30 years, the 
prognosis for ovarian cancer remains poor overall, with a 46% 5-year survival rate. The 
prognosis of ovarian cancer is closely related to the stage at diagnosis (Chan et al. 2008);. 
Standard treatment for ovarian cancer involves cytoreductive debulking surgery and 
neoadjuvant chemotherapy which offers some improvement in morbidity and possibly 
survival. Postoperative chemotherapy is indicated in all patients with ovarian cancer except 
those with surgical-pathologic stage I disease with low-risk characteristics. The standard is a 
platinum compound and taxanes combination therapy (e.g., carboplatin and paclitaxel).   The 
National Comprehensive Cancer Network (NCCN) recommends three to six cycles of 
intravenous taxane/carboplatin adjuvant chemotherapy for high-risk stage IA, IB, or IC 
epithelial ovarian cancer (NCCN 2016a).  For stage II-IV disease, the recommended options 
include intraperitoneal chemotherapy, in patients with <1 cm optimally debulked stage II and 
III disease; or intravenous taxane/carboplatin for six cycles. In addition, completion surgery, 
as indicated by tumor response and potential resectability, may be used in selected patients 
(NCCN 2016a). Additional agents may be used for recurrent disease including targeted 
therapy with bevacizumab and olaparib. 
Recurrent ovarian cancer is classified into two categories, depending on the length of time 
the patient remained disease-free after completing chemotherapy: (1) relapse that occurs 
more than 6 months after initial chemotherapy is considered platinum-sensitive; (2) earlier 
relapse is considered platinum-resistant. Patients with platinum-sensitive disease may exhibit 
a good response if rechallenged with a platinum-based regimen (Parmar et al. 2003), 


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(Pfisterer et al. 2006). The probability of response increases with the duration of the disease-
free interval. 
Results from clinical trials suggest that combination chemotherapy offers an improvement in 
response rate, progression-free survival, and overall survival. Several chemotherapy agents 
elicit a response in patients whose disease is resistant to platinum-based therapies. These 
include liposomal doxorubicin, topotecan, oral etoposide, gemcitabine, docetaxel, and 
vinorelbine. Bevacizumab has approval for both platinum-resistant as well as platinum-
sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in 
combination therapy (Aghajanian et al. 2015) (Coleman et al. 2017), In patients receiving 
third- line therapy, response rates are generally low with a short time to progression (Hanker 
et al. 2012). There is a clear need for more effective treatments.  
Rationale for birinapant in ovarian cancer 
Ovarian carcinomas often have an increased copy number of IAP genes.  Published data 
suggests that ovarian carcinomas may be sensitive to birinapant / IAP antagonist treatment 
(Brunckhorst et al. 2012, Benetatos et al. 2014, Janzen et al. 2015).  Birinapant has 
demonstrated activity against ~70% (8/11) ovarian cancer cell lines as a single-agent or in 
combination with TNF.  Furthermore, birinapant treatment delayed growth in patient derived 
xenograft and cell line models (Benetatos et al. 2014, Gatti et al. 2014).High TNFα 
expression is common in ovarian cancers, and they are resistant to TNFα-dependent killing, 
suggesting that birinapant may be able to convert this TNFα towards a pro-apoptotic function 
by antagonizing cIAP1. 
Birinapant was shown to significantly reduce cIAP1 expression levels in PBMCs and tumor 
biopsies in a clinical study in ovarian carcinoma (Noonan et al. 2016), demonstrating target 
engagement in this population. In combination with carboplatin/paclitaxel one out of two 
patients showed PR (for more details on specific indications refer to the Investigator 
brochure). 
Pembrolizumab in ovarian cancer 
The introduction of immune checkpoint inhibitors has revolutionized treatment of multiple 
cancers and has bolstered interest in this treatment approach. So far, emerging clinical data 
show limited clinical efficacy of these agents in ovarian cancer with objective response rates 
of 10–15% with some durable responses (Gaillard et al. 2016). 
Overexpression of the PD-1 ligand PD-L1 has been demonstrated in ovarian cancer and may 
hinder an effective antitumor immune response. A preliminary analysis of the ovarian cancer 
cohort of the KEYNOTE-028 study (NCT02054806) showed pembrolizumab had only 
modest antitumor activity in patients with PD-L1+ advanced ovarian cancer. ORR was 
11.5% (95% CI, 2.4%-30.2%). Tumor reduction was observed in 6/26 (23.1%); all 3 patients 
who responded completed 2 years of treatment. Median duration of response was not reached 
(range, 24.9+ to 26.5+ months). Median (95% CI) PFS and OS were 1.9 months (1.8 to 3.2 
months) and 13.1 months (6.7 to 17.5 months) respectively (Varga 2017). 


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Other PD-1 antibodies have been evaluated in ovarian cancer. Nivolumab demonstrated a 
best overall response rate of 15% (Hamanishi et al. 2015). High PD-L1 expression was 
observed in 80% of ovarian cancers in this study, and although this did not correlate with 
response to nivolumab, it may indicate the possibility to reactivate immune-dependent 
responses in combination with drugs that can facilitate this. 
 
Cervical cancer 
Cervical cancer is the third most common malignancy in women worldwide and the fourth 
most common cause of cancer-related deaths in women worldwide (Torre et al. 2015).  
Human papillomavirus (HPV) infection must be present for cervical cancer to occur. Most 
cervical cancers are associated with oncogenic HPV subtypes, high-risk type HPV-16 and 
HPV-18 being the most frequently involved in cervical cancer development. (zur Hausen 
2002). HPV plays an etiologic role in cervical cancer and is included in the screening 
regimen for young women. (Torre et al. 2015); (Sant et al. 2015). A significant number of 
women present with or develop advanced disease despite advances in screening (Pap test and 
HPV screening) and HPV vaccination. The prognosis is poor and depends on the disease 
stage. In general, the 5-year survival rates are as follows: Stage I - Greater than 90%; Stage 
II - 60-80%; Stage III - Approximately 50%, and Stage IV - Less than 30%. 
The treatment of cervical cancer varies with the stage of the disease.  Early-stage cervical 
cancer can be cured with surgery, while concurrent chemoradiation is the treatment of choice 
for locally advanced stages. Patients with recurrent or metastatic cancers have, however, 
limited treatment options. (NCCN 2016b). 
For platinum-sensitive recurrent or metastatic tumors, the standard of care is chemotherapy 
with paclitaxel and cisplatin (Moore 2008) (Monk et al. 2009). Bevazicumab was approved 
by FDA in 2014 in combination with paclitaxel and cisplatin or paclitaxel and topotecan 
based on a phase III study that showed an improvement of overall survival by 3.5 months to 
16.8 months compared to standard chemotherapy. No validated treatment options exist 
beyond this first-line treatment regimen. Chemotherapy regimens in this situation are 
associated with substantial toxicity and poor efficacy with a median overall survival of 
7 months (Tewari et al. 2017). There is still a significant unmet medical need. 
Rationale for birinapant in cervical cancer 
Squamous carcinomas of the head and neck, the cervix and the esophagus have similar 
etiologies and high rate of amplification of IAP genes, and cervical carcinomas have a high 
frequency of amplification of cIAP1 and cIAP2 genes (Derakhshan et al. 2017). cIAP1 gene 
expression in cervical cancers has been linked to resistance to radiotherapy (Imoto et al. 
2002). Squamous carcinomas of the head and neck with high expression and amplification of 
cIAP1/2 have recently been shown to be sensitive to birinapant (Eytan et al. 2016) and by 
analogy, these related cancers with high expression of cIAP1/2 are also expected to be 
sensitive to birinapant (Imoto et al. 2002) (Liu et al. 2001). HPV E6 and E7 proteins have 
been shown to activate NF-κB, induce cIAP2 expression and protect against TNFα-induced 
apoptosis (James et al. 2006). HPV 16 E6 protein has also been shown to directly bind to 
TNFR1 and to block TNFα-induced apoptosis (Filippova et al. 2002). Birinapant may be 


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able to resensitize HPV-infected cervical cancer cells to apoptosis through degradation of 
cIAP1 and cIAP2. 
Pembrolizumab in cervical cancer 
The central role of HPV infection in cervical cancer oncogenesis provides a strong rationale 
for the utility of immunotherapy. The presence of viral antigens may allow the development 
of an HPV-specific response that may facilitate tumor clearance. Pembrolizumab and 
multiple other checkpoint antibodies are being evaluated in cervical cancer and early 
evidence suggests a relatively modest response to date (Borcoman et al. 2017).  In the 
cervical cancer cohort of the KEYNOTE-028 trial, 24 PD-L1 positive patients were treated 
with pembrolizumab. ORR was 17% (all PR) and the median duration of response was 
5.4 (4.1-7.5) months. A phase II trial (KEYNOTE-158) in advanced cervical cancer is 
ongoing (Frenel et al. 2017). There remains a substantial fraction of patients who could 
derive benefit from a combination therapy that can enhance the effect of checkpoint 
antibodies. 
 
Various solid tumors cohort 
1.5.4.1 
Head and Neck Squamous Cell Carcinoma 
In the United States, 63,030 new cases of Head and neck squamous cell carcinoma (HNSCC) 
are expected in 2017, with nearly 13,360 deaths related to HNSCC. Tobacco smoking, 
alcohol consumption and HPV infection are risk factors for the development of HNSCC 
(Blot et al. 1988) (Chaturvedi 2012). HPV-related HNSCC is a distinct subgroup with a 
better prognosis (Schwartz et al. 2001). 
Early-stage HNSCC disease is treated with relative success using single-modality therapy 
(either surgery or radiation alone). However, nearly 66% of patients present with advanced 
disease (stage III and IV), and fewer than 30% of these patients are cured, which underlines 
the present medical need in this indication. 
The management of advanced HNSCC consists of multiple-modality therapy with surgery, 
radiation, and chemotherapy. Despite significant improvements in these modalities, long-
term survival rates in patients with advanced-stage HNSCC have not increased significantly 
in the past 30 years.  
Cetuximab is the only targeted molecule approved by the FDA for the treatment of HNSCC. 
In a phase III trial that included patients with locoregionally advanced HNSCC, radiotherapy 
and cetuximab was shown to be superior to radiotherapy alone. The median OS was 49.0 and 
29.3 months in the two arms of the study (Bonner et al. 2006). In another phase III study, 
patients with recurrent or metastatic disease were randomized between cisplatin/carboplatin, 
5-FU and cetuximab or cisplatin/carboplatin and 5-FU only. Patients treated with cetuximab 
survived a median of 10.1 months, compared with 7.4 months for those patients who 
received chemotherapy alone (Vermorken et al. 2008).  
Rationale for Birinapant in HNSCC 


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HNSCC has been reported to have genomic amplification and gene expression increases in 
cIAP1, cIAP2 and XIAP genes as well as other components of the NF-κB and apoptosis 
pathways (Derakhshan et al. 2017). HNSCC cell lines containing these amplifications are 
sensitive to birinapant alone and in combination with radiation or chemotherapy (Eytan et al. 
2016). Other IAP antagonists have also shown preclinical activity in HNSCC (Yang et al. 
2011, Matzinger et al. 2015, Kadletz et al. 2017). Multiple studies have shown high TNFα 
expression is common and a negative prognostic factor in HNSCC. Birinapant may be able 
to convert this TNFα towards a pro-apoptotic function by antagonizing cIAP1. As described 
for cervical cancer, HPV infected cells may also be sensitive to birinapant treatment. 
Pembrolizumab in HNSCC 
Pembrolizumab has demonstrated clinical activity in HNSCC (Chow et al. 2016), and the 
FDA granted accelerated approval to pembrolizumab in August 2016 for patients with 
recurrent or metastatic HNSCC with disease progression on or after platinum-containing 
chemotherapy based on results from the open-label phase Ib KEYNOTE-012 trial.  
The accelerated approval was specifically based on an efficacy analysis of 174 patients 
treated with a prior platinum-based agent. In this assessment, the ORR with pembrolizumab 
was 16% (95% CI, 11-22), which included a complete response (CR) rate of 5%. Responses 
lasted for ≥6 months for 82% of patients. Median PFS was 2.0 months with pembrolizumab 
(95% CI, 1.9-2.1). The 6-month PFS rate was 25% and the 12-month rate was 17%. Median 
OS across evaluable patients was 8.0 months (95% CI, 6-10). The 6-month OS rate was 
58%. At 12 months, 38% of patients remained alive (Larkins et al. 2017).   
There are no approved treatments for recurrent/metastatic head and neck squamous cell 
carcinoma refractory to platinum and cetuximab. The single-arm, phase II KEYNOTE-055 
study evaluated pembrolizumab, in this platinum- and cetuximab-pre-treated (concurrent or 
sequential) population with poor prognosis. 
Among 171 patients treated, 75% received two or more prior lines of therapy for metastatic 
disease, 82% were PD-L1 positive, and 22% were HPV positive. Overall response rate was 
16% (95% CI, 11% to 23%), with a median duration of response of 8 months (range, 2+ to 
12+ months); 75% of responses were ongoing at the time of analysis. Response rates were 
similar in all HPV and PD-L1 subgroups. Median progression-free survival was 2.1 months, 
and median overall survival was 8 months (Bauml et al. 2017).  Even though these data are 
encouraging, the duration of clinical benefit is still modest which leaves a substantial need 
for additional treatments.  
1.5.4.2 
Gastroesophageal carcinoma 
Gastroesophageal cancer (which comprises cancer of the stomach, esophagus, and 
gastroesophageal junction (GEJ) has one of the highest incidences of all cancers and is 
responsible for over one million annual deaths worldwide. Cancers of the upper 
gastrointestinal tract are a group of highly aggressive malignancies. In the USA alone, 
16,910 new cases of esophageal cancer and 26,370 cases of stomach cancer are estimated to 


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be diagnosed in 2016, and approximately 15,690 and 10,730 deaths will be attributed to 
these diseases, respectively (Siegel et al. 2016).  
Options for treatments in the first line settings are limited to the platinum/5-fluoropyrimidine 
(5FU) backbone which results in modest survival benefits in patients with good performance 
status (Wagner et al. 2006).  This benefit was further enhanced by 2.7 months survival 
difference when adding trastuzumab to chemotherapy in the specific population of Her2/neu 
overexpression which accounts for 20%–30% of esophagogastric adenocarcinomas (Bang et 
al. 2010) (Kim et al. 2011) (Park et al. 2012). 
In the second line treatment setting, vascular endothelial growth factor receptor (VEGF) 
inhibition with ramucirumab  as monotherapy(Fuchs et al. 2014), or in combination with 
paclitaxel, resulted in a median OS of 9.6 months (Wilke et al. 2014). This target was also 
studied in the first line setting in a with bevacizumab in combination with cisplatin and 
capecitabine with a reported median PFS (6.7 vs. 5.3 months) and ORR 46.0% vs. 37.4%, 
with significant improvement for the bevacizumab arm versus placebo (Ohtsu et al. 2011). 
These survival numbers remain poor, urging the development of more effective treatment 
approaches for esophageal and gastric adenocarcinomas. 
Rationale for birinapant in Gastroesophageal Cancer 
Gastroesophageal cancer has frequent amplification of cIAP1 and cIAP2 genes (Derakhshan 
et al. 2017). SMAC was significantly downregulated in 63% of esophageal squamous cell 
carcinoma samples and SMAC expression by immunohistochemistry was significantly lower 
in chemoresistant patient tumors (Xu et al. 2011). SMAC mimetics showed activity in the 
SMAC-deficient tumor cells suggesting a rationale for increased response to birinapant. 
Pembrolizumab in Gastroesophageal Cancer 
Programmed death ligand 1 (PD-L1) overexpression, a possible biomarker predicting 
response to immune checkpoint inhibitors, approaches forty percent in esophageal and 
gastric cancers (Shaib et al. 2016). Translational and molecular studies have shown that 
esophageal cancers are possible candidate malignancies for immune checkpoint inhibition 
(Shaib et al. 2016). Muro et al. investigated the safety and activity of pembrolizumab in 
advanced gastric and GEJ cancer patients in a phase Ib KEYNOTE-012 trial. PD-L1 
expression was demonstrated in 40% of the patients, 39 of whom were treated with 
pembrolizumab. The ORR was 22%  (Muro et al. 2016).  
In September 2017, the FDA granted accelerated approval for pembrolizumab for patients 
with recurrent locally advanced or metastatic gastric or GEJ adenocarcinoma who have 
received two or more lines of systemic therapy and whose tumors express PD-L1. This 
approval was based on promising ORR (11%) from one cohort of the Phase II  KEYNOTE-
059 study in heavily pre-treated patients (Fuchs 2017). Keytruda has also shown promise in 
an early-Phase esophageal cancer trial (KEYNOTE-028). ORR was 30%, and the stable 
disease rate was 9%; 6-months and 12-months PFS rates were 30% and 22%.  The median 
duration of response was 15 months (Doi et al. 2017). Additional pembrolizumab studies 


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have been completed or are ongoing in various settings to further develop the treatment for 
gastroesophageal carcinoma. 
1.5.4.3 
Mesothelioma 
Malignant mesothelioma (MM) is an aggressive tumor that arises from the mesothelial cells 
that line the pleural, pericardial, and peritoneal cavities. The incidence is predicted to rise in 
the coming years – as individuals with prior exposure to asbestos live longer: In the United 
States, an estimated 2500 people are diagnosed with MM each year.  
Malignant pleural mesothelioma (MPM) has a median survival of 9–12 months even with 
trimodality therapy (chemotherapy, surgical resection, and thoracic radiation). The only 
currently recommended systemic therapy for MPM, based on the phase III EMPHACIS trial, 
is platinum/antifolate regimen that has extended the median OS of MPM patients to 
approximately 1 year with a median PFS of less than 6 months, and a 5-year survival rate of 
less than 5%. (Vogelzang et al. 2003) (Haas et al. 2013).  Most patients are treated upfront 
by chemotherapy containing pemetrexed and a platinum agent; however, nearly all patients 
progress during or after first-line therapy, and no standard second-line and further-line 
therapies are available.  
Recently, immunotherapy by targeting of immune checkpoints such as CTLA-4 and PD-1 
has changed the treatment framework of several tumors including melanoma, lung cancer, 
renal cancer, and urothelial neoplasms. However, malignant pleural mesothelioma does not 
rank high in terms of mutational load which is an important determinant of the response to 
checkpoint blockade inhibitors (Bueno et al. 2016).  Indeed, mesothelioma pathogenesis 
seems to be essentially driven by inflammation (Yamagishi et al. 2015). Tumor-associated 
macrophages, which are key inflammatory cells with potent immunosuppressive activity, are 
abundantly expressed in the stroma of malignant pleural mesothelioma; moreover, in 
malignant pleural mesothelioma, a low lymphocyte to monocyte ratio in peripheral blood 
and tissue is reported to have negative prognostic significance (Yamagishi et al. 2015).  
Rationale for birinapant in mesothelioma 
Despite high levels of TNF-α, mesothelioma cells are relatively resistant to apoptosis due to 
overexpression of IAP , that can be further upregulated by TNF-α by autocrine secretion 
(Gordon et al. 2002). TNF-α mediates resistance to cisplatin in vitro that can be reversed by 
NF-κB inhibition (Gordon et al. 2007b).(Gordon et al. 2007a)  Birinapant can cause 
inhibition of TNFα-induced NF-κB signaling and promote TNFα-induced apoptosis 
suggesting a rationale for clinical benefit. 
Pembrolizumab in Mesothelioma  
Alley and colleagues reported the results of pembrolizumab, an anti-PD-1 antibody, in 25 
patients with pre-treated malignant pleural mesothelioma expressing PD-L1 (KEYNOTE-
028 trial). The ORR was 20%, PFS 5.4 months and OS 18 months – well beyond the survival 
observed with second line therapies in this setting (Alley et al. 2017). 


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1.5.4.4 
Small Cell Lung Cancer 
Lung cancer overall is the second most common malignancy in both sexes in the United 
States (ACS 2017).  While the incidence of small cell lung cancer (SCLC) has declined over 
the last few years in the United States, as smoking rates have fallen, it still comprises about 
15% of all lung cancers. (PDQ 2017). SCLC is a distinct type of lung cancer. It is a 
neuroendocrine tumor characterized by aggressive behavior, rapid growth, early 
dissemination, exquisite sensitivity to chemotherapy and radiation, and frequent association 
with distinct paraneoplastic syndromes. (Boffetta 2008) (Pietanza 2015) (Cascone 2016).  
Approximately 60-70% of patients with SCLC have clinically disseminated or extensive 
disease at presentation. Extensive-stage SCLC (i.e. SCLC that has spread beyond the 
supraclavicular areas, or with distant metastases) is incurable. For individuals with limited-
stage disease that is treated with combination chemotherapy plus chest radiation, a complete 
response rate of 80% and survival of 17 months have been reported; 12-15% of patients are 
alive at 5 years (Janne et al. 2002).  Extensive-stage disease remains incurable with current 
management options median survival is only 7-9 months and only 2% are alive at 5 years 
(Jackman et al. 2005).   
Several chemotherapy combinations are active in SCLC, but usually a platinum-containing 
regimen is chosen. However, despite strides in the management of SCLC, there has been 
little change in survival over the past 2 decades for limited- or extensive-stage disease. 
Indeed, very few new agents with activity in SCLC have been identified (compared to 
NSCLC) (Hanna et al. 2002, Lally et al. 2007).  Unlike NSCLC, SCLC has not been shown 
to respond well to targeted therapies. Studies of vascular endothelial growth factor (VEGF) 
and VEGF receptor (VEGFR) inhibitors have yielded disappointing results: bevacizumab, 
aflibercept, and vandetanib have failed to demonstrate significant improvements in 
survival. (Spigel et al. 2011) (Hanna et al. 2002) (Lally et al. 2007). However, a phase II trial 
of sunitinib maintenance therapy in patients with untreated extensive-stage SCLC reported a 
modest but significant improvement in median progression-free survival, from 2.1 months 
with placebo to 3.7 months with sunitinib (Leighl 2015).  The modest progress in 
improvements in life expectancy for patients diagnosed with this aggressive disease highlight 
the clear unmet medical need to develop more effective treatments. 
 
 
Rationale for birinapant in lung cancer 
cIAP1 expression has been shown to contribute to resistance to chemotherapy and apoptosis 
in SCLC (Pardo et al. 2003). TNFα can induce NF-κB signaling and differentiation in SCLC, 
but does not cause cell death (Haley et al. 1998), suggesting that birinapant may allow 
switching this to an apoptotic response.  
Pembrolizumab in SCLC 


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SCLC has a very high mutational burden due to the carcinogenic effects of smoking (George 
et al. 2015), which is the most common cause of SCLC, suggesting a potential susceptibility 
to checkpoint inhibition, and pembrolizumab and a number of other checkpoint inhibitors are 
currently in clinical investigation. 
The safety and efficacy of pembrolizumab, were assessed in patients with programmed death 
ligand 1 (PD-L1)–expressing extensive-stage SCLC in the multicohort, phase Ib open-label 
KEYNOTE-028 study (NCT02054806) (Ott et al. 2017). 
Twenty-four patients with PD-L1–expressing SCLC were enrolled and received at least one 
pembrolizumab dose. At the data cutoff date (June 20, 2016), the median follow-up duration 
was 9.8 months (range, 0.5 to 24 months). One patient had a complete response, and seven 
patients had partial responses, resulting in an ORR of 33% (95% CI, 16% to 55%). 
Pembrolizumab demonstrated promising antitumor activity in patients with pre-treated, PD-
L1–expressing SCLC.  
1.5.4.5 
Cholangiocarcinoma 
Cholangiocarcinoma (CCA) is comprised of malignancy arising from the intrahepatic 
(iCCA), perihilar (pCCA) and distal biliary tree (dCCA) with features of cholangiocyte 
differentiation. Intrahepatic CCA (iCCA) is the second most common primary hepatic 
malignancy, after hepatocellular carcinoma, and accounts for 10-20% of primary liver 
cancers. In the past decade, iCCA has risen in incidence and mortality rate whereas those of 
extrahepatic CCA (eCCA) are either stable or decreasing.  
Only 10-15% of the patients with CCA are amenable to potentially curative surgery due to 
late presentation at an advanced stage because no effective screening strategies exist. Despite 
resection, high recurrence rates of 50-60% persist, conferring a five-year OS of only 30% 
(Nathan et al. 2007) (Mavros et al. 2014). The prognosis of patients with unresectable or 
metastatic CCA is universally poor, with a median OS of less than one year (Valle et al. 
2010).  
Marginal advances with chemotherapy has shifted emphasis to molecularly targeted 
therapies, either as a single agent or in combination with chemotherapy. The poor 
understanding of the biology of CCA and the lack of known oncogenic addiction loops has 
hindered the development of effective targeted therapies and a high unmet medical need is 
still present 
Rationale for birinapant in cholangiocarcinoma 
Cholangiocarcinoma is a form of cancer that displays prominent inflammatory traits with 
high TNFα expression. Macrophage infiltration has been shown to lead to local TNFα 
release leading to epithelial-mesenchymal transition and increased invasiveness. Kupffer 
cell-derived TNFα can enhance tumorigenesis and cancer cell proliferation, and >50% of 
CCA stained positive for TNFα (Yuan et al. 2017).  Birinapant may allow these local TNFα 
concentrations to induce an apoptotic response in cancer cells. 


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Pembrolizumab in Cholangiocarcinoma 
PD-L1 expression, PD-1 expression and TNM stage are significantly associated with the 
survival time of patients. Furthermore, multivariate analysis revealed the PD-L1 expression 
as an independent prognostic factor of patients with eCCA. These preliminary results 
suggested that PD-L1 or PD-1 immunodetection may be a valuable prognostic marker for 
eCCA patients (Ma et al. 2017). Increased levels of tumor-infiltrating CD8+ cytotoxic T 
cells and/or CD4+ T cells have been shown to be associated with improved prognosis in 
biliary tract cancers (Oshikiri et al. 2003). Given the success of checkpoint inhibitors in the 
treatment of metastatic melanoma, there has been growing interest of the benefit of 
immunomodulation in biliary tract cancers. In a preclinical study of iCCA it has been shown 
that both gemcitabine and interferon -γ led to an upregulation of PD-L1, which suggests that 
treatment with PD-L1 blockade may be beneficial (Koido et al. 2014).  KEYNOTE-028 
included a group of biliary tract cancers of which 42% were positive for PD-L1., with a 17% 
overall response rate in PD-L1 positive patients (Bang 2015).  
1.6 
Rationale for Dose Selection 
 
Rationale for Birinapant Starting Dose 
The starting dose for the first in human study of birinapant (birinapant Investigator’s 
Brochure) was 0.18 mg/m2 and doses were escalated to 63 mg/m2. Two patients out of three 
(67%) who received birinapant at 63 mg/m2 developed Grade 2 AEs of Bell’s palsy. Based 
upon these events the dose of 63 mg/m2 of birinapant was considered to be above the 
maximum tolerated dose (MTD).  The MTD of birinapant was defined at a dose of 47 mg/m2 
administered once weekly.  Further clinical studies have utilized total weekly doses of 
birinapant up to and including 22 mg/m2 weekly in combination with chemotherapy.  The 
starting dose escalation cohort of 5.6 mg/m2 weekly is consistent with these data, and is 
below the combination MTD seen previously in the birinapant program when used in 
combination with other cancer drugs. 
 
Rationale for Pembrolizumab Dose Selection 
The dose of pembrolizumab planned to be studied in this trial is 200 mg Q3W.  The dose 
approved in the United States and several other countries is 2 mg/kg every 3 weeks (Q3W).  
Information on the rationale for selecting 200 mg Q3W is summarized below. 
In KEYNOTE-001, an open-label Phase 1 study conducted to evaluate the safety, tolerability, 
pharmacokinetics (PK) and pharmacodynamics, and anti-tumor activity of pembrolizumab 
when administered as monotherapy.  The dose escalation portion of this trial evaluated three 
dose levels, 1 mg/kg, 3 mg/kg and 10 mg/kg, administered every 2 weeks (Q2W) and dose 
expansion cohorts evaluated 2 mg/kg Q3W and 10 mg/kg Q3W in subjects with advanced 
solid tumors.  All dose levels were well tolerated and no dose-limiting toxicities were 
observed.  This first-in-human study of pembrolizumab showed evidence of target 
engagement and objective evidence of tumor size reduction at all dose levels.  No MTD has 
been identified.  In addition, two randomized cohort evaluations of melanoma subjects 
receiving pembrolizumab at a dose of 2 mg/kg versus 10 mg/kg Q3W have been completed, 


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and one randomized cohort evaluating 10 mg/kg Q3W versus 10 mg/kg Q2W has also been 
completed.  The clinical efficacy and safety data demonstrate a lack of important differences 
in efficacy or safety profile across doses. 
An integrated body of evidence suggests that 200 mg Q3W is expected to provide similar 
response to 2 mg/kg Q3W, 10 mg/kg Q3W and 10 mg/kg Q2W.  Previously, a flat 
pembrolizumab exposure-response relationship for efficacy and safety has been found in 
subjects with melanoma in the range of doses between 2 mg/kg and 10 mg/kg.  Exposures 
for 200 mg Q3W are expected to lie within this range and will be close to those obtained 
with 2 mg/kg Q3W dose. 
A population pharmacokinetic (PK) model, which characterized the influence of body weight 
and other patient covariates on exposure, has been developed.  The PK profile of 
pembrolizumab is consistent with that of other humanized monoclonal antibodies, which 
typically have a low clearance and a limited volume of distribution.  The distribution of 
exposures from the 200 mg fixed dose is predicted to considerably overlap those obtained 
with the 2 mg/kg dose and importantly will maintain individual patient exposures within the 
exposure range established in melanoma as associated with maximal clinical response.  
Pharmacokinetic properties of pembrolizumab, and specifically the weight-dependency in 
clearance and volume of distribution are consistent with no meaningful advantage to weight-
based dosing relative to fixed dosing.  
In translating to other tumor indications, similarly flat exposure-response relationships for 
efficacy and safety as observed in subjects with melanoma can be expected, as the anti-tumor 
effect of pembrolizumab is driven through immune system activation rather than through a 
direct interaction with tumor cells, rendering it independent of the specific tumor type.  In 
addition, available PK results in subjects with melanoma, NSCLC, and other tumor types 
support a lack of meaningful difference in pharmacokinetic exposures obtained at tested 
doses among tumor types.  Thus the 200 mg Q3W fixed-dose regimen is considered an 
appropriate fixed dose for other tumor indications as well. 
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians 
and to reduce potential for dosing errors.  A fixed dosing scheme will also reduce complexity 
in the logistical chain at treatment facilities and reduce wastage.  The existing data suggest 
200 mg Q3W as the appropriate dose for pembrolizumab. 
 STUDY OBJECTIVES 
2.1 
Study Objectives Dose Escalation Phase  
 
Primary Objective 
To determine the safety and tolerability of the recommended phase 2 dose (RP2D) of 
birinapant when given in combination with pembrolizumab IV 


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Secondary Objective 
To assess preliminary efficacy of the combination of pembrolizumab and birinapant in 
patients with relapsed or refractory cancer by effects on tumor size as measured by 
imaging (CT or MRI) assessed by RECIST 1.1. 
 
Exploratory Objectives 
1. To assess preliminary efficacy of the combination of pembrolizumab and 
birinapant in patients with relapsed or refractory cancer by effects on tumor size 
as measured by imaging (CT or MRI) assessed by iRECIST. 
2. To determine the pharmacodynamic markers of birinapant and of pembrolizumab 
when given in combination at the schedule and dose as defined by the protocol, to 
include but not to be limited to mechanism of action (inhibition of cIAP1), and of 
immune surveillance and activation. 
3. To assess biomarkers that might predict for responders to the combination 
treatment and allow comparison to known potential predictive biomarkers of 
pembrolizumab response. 
4. To evaluate birinapant pharmacokinetics in plasma when administered in 
combination with pembrolizumab. 
2.2 
Study Objectives Dose Expansion Phase 
 
Primary Objective 
The primary objective in each of the cohorts is as follows: 
1. To determine whether the combination of pembrolizumab and birinapant has 
sufficient antitumor activity, as assessed by ORR, against colorectal cancer to 
warrant more extensive development.  
2. To determine whether the combination of pembrolizumab and birinapant has 
sufficient antitumor activity, as assessed by ORR, against ovarian cancer to warrant 
more extensive development.  
3. To determine whether the combination of pembrolizumab and birinapant has 
sufficient antitumor activity, as assessed by ORR, against cervical cancer to warrant 
more extensive development. 
4. To determine the safety and tolerability of the RP2D of birinapant when given in 
combination with pembrolizumab to patients in the various solid tumors cohort  
 
Secondary Objectives 
1. To assess the safety and tolerability of the combination of pembrolizumab and 
birinapant; Overall and in the defined tumor types, colorectal cancer, ovarian 
cancer and cervical cancer. 


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2. To assess clinical activity of the combination of pembrolizumab and birinapant in 
the defined tumor types by effects on tumor response, including CBR, time to 
response and duration of response, assessed by RECIST 1.1  
3. To assess clinical activity of the combination of pembrolizumab and birinapant in 
the defined tumor types by effect on overall survival 
4. To assess clinical activity of the combination of pembrolizumab and birinapant in 
the defined tumor types by effect on progression free survival. 
 
Exploratory Objectives 
1. To assess clinical activity of the combination of pembrolizumab and birinapant 
in the defined tumor types by effects on tumor response, including: CBR, time to 
response, duration of response, iBOR, duration of iBOR and time to iCPD, 
assessed by iRECIST  
2. To assess the pharmacodynamic markers of birinapant and of pembrolizumab 
when given in combination at the schedule and dose as defined by the protocol, 
to include but not to be limited to mechanism of action (inhibition of cIAP1), and 
of immune surveillance and activation. 
3. To determine biomarkers that might predict for response and/or indicate response 
to the combination treatment and allow comparison to known potential predictive 
biomarkers of pembrolizumab response.  
4. To evaluate birinapant pharmacokinetics in plasma when administered in 
combination with pembrolizumab 
 INVESTIGATIONAL PLAN 
3.1 
Description of Study Design 
This is a phase 1/2, multicenter, single-arm, open-label, dose-escalation, safety, tolerability, 
pharmacokinetic and pharmacodynamic study of birinapant and pembrolizumab, conducted 
in male and female patients, ≥18 years of age, who have relapsed or refractory solid tumors. 
Patients must qualify for study participation within 28 days before initiation of study-drug 
treatment; must have a histologically confirmed solid malignancy that is metastatic or 
unresectable and for which standard curative or palliative measures do not exist or are no 
longer effective; must have measurable disease according to RECIST v 1.1 and must have an 
Eastern Cooperative Oncology Group (ECOG) score of 0 or 1. 
 
Description of Study Design Dose Escalation Phase 
The dose escalation phase of this study will employ a sequential group dose-escalation 
design to determine the dose-limiting toxicity (DLT) and RP2D of birinapant administered in 
combination with pembrolizumab, both administered as a 30-minute intravenous (IV) 
infusion. Pembrolizumab will be administered first on Day 1.  The birinapant infusion will 
begin 30 minutes (+10 minutes) following the completion of the pembrolizumab infusion on 


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Day 1.  An additional dose of birinapant only will be administered on Day 8.  The dose 
levels of birinapant and pembrolizumab are outlined in Table 2. 
Table 2 
Dose Escalation Schedule 
Dose-Escalation Schedule 
Dose Level 
Pembrolizumab + Birinapant (per 21-day cycle)* 
Level -1 
200 mg pembrolizumab on Day 1 + birinapant 2.8 mg/m2/week on Days 1 
and 8 
Level 1 
200 mg pembrolizumab on Day 1 + birinapant 5.6 mg/m2/week on Days 1 
and 8 
Level 2 
200 mg pembrolizumab on Day 1 + birinapant 11 mg/m2/week on Days 1 
and 8 
Level 3 
200 mg pembrolizumab on Day 1 + birinapant 17 mg/m2/week on Days 1 
and 8 
Level 4 
200 mg pembrolizumab on Day 1 + birinapant 22 mg/m2/week on Days 1 
and 8 
*Note: A week without treatment (i.e., Days 15-21) will follow the second week of treatment, immediately 
after which the next 21-day cycle commences. 
A minimum of 3 and up to 6 evaluable patients will be enrolled per dose level. For patients 
enrolled in Dose Level 1, the birinapant starting dose will be 5.6 mg/m2/week. Dose 
escalation of birinapant will occur in up to three steps.  The Safety Review Committee (SRC) 
will review all the cumulative safety data up to and including completion of Day 21 for the 
last patient in a cohort from that treatment group prior to dose escalation.  Upon review of 
the safety data the SRC will determine whether or not the safety data supports dose 
escalation to the next sequential dose level.  If the first dose level (5.6 mg/m2) is deemed 
intolerable, defined as ≥2 patients from 3-6 experiencing a DLT, the SRC may decrease the 
starting dose of the next dosing cohort to 2.8 mg/m2 (dose level -1).  
If 1 of the 3 to 6 patients enrolled at a given dose level experiences a DLT, enrollment at the 
next dose level will proceed, if the next highest dose has not already been declared 
intolerable. However, if 1 of these 3 to 6 patients experiences a DLT at the given dose level 
and the next highest dose has already been declared intolerable, a minimum of 6 patients are 
to be enrolled at the given level and the dose at the given level may be the RP2D. A separate 
safety review will be performed by the SRC to determine the RP2D of the combination of 
birinapant and pembrolizumab and to begin the dose-expansion phase of the study. 
 
Description of Study Design Dose Expansion Phase 
Once the RP2D of birinapant combined with pembrolizumab is defined, additional patients 
with relapsed or refractory carcinoma will be enrolled in the dose-expansion phase of the 
study.  
Dose Level 
Pembrolizumab + Birinapant (per 21-day cycle) 
Expansion 
200 mg pembrolizumab on Day 1+ birinapant at the RP2D mg/m2/week on Days 1 
and 8 
 


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The dose expansion phase will comprise of four patient cohorts defined as follows;: The 4 
cohorts will include the following 
a. 
Colorectal cancer (28 patients) 
b. 
Ovarian cancer (27 patients) 
c. 
Cervical cancer (26 patients) 
d. 
Various solid tumors (30 patients, including 5 patients with each of the 
following 6 tumor types: [Small cell lung cancer; Cholangiocarcinoma; 
Gastroesophageal carcinoma; Mesothelioma; Head and Neck Squamous Cell 
Carcinoma (HNSCC)-checkpoint inhibitor-naïve; and HNSCC checkpoint 
inhibitor-experienced]) 
Predefined interim analyses for futility and safety will be conducted in each of the cohorts in 
colorectal cancer, ovarian cancer and cervical cancer to limit undue exposure before further 
inclusion into a given cohort. The design of the various solid tumors cohort will limit undue 
exposure in any of the selected tumor types by virtue of the fact that it limits the number of 
enrolled patient to five in each tumor type.  
 
Safety Review Committee Dose Escalation Phase 
A SRC will be involved in the conduct of the dose escalation phase of this study.  The SRC 
will be comprised of representatives from the Sponsor and the study sites, and the SRC may 
recommend that the study be interrupted or terminated at any time if, in their judgment, 
serious or unexpected AEs of sufficient concern warrant such action.  See reporting 
requirements (Section 8.3) for Serious AEs (SAEs). The SRC has the responsibility for 
monitoring the clinical study’s progress and the safety of the participating patients  
Following completion of a dosing level, an evaluation of the safety of that dose will be 
performed by the SRC (based on cumulative data to the time of SRC assessment). The SRC 
will review the safety, efficacy and pharmacodynamic data (when available) from all patients 
enrolled at each dose level to confirm any DLTs that were experienced and to make a 
recommendation regarding enrollment in the next dose level.  Each of the 3 to 6 patients at a 
dose level must have completed Cycle 1 (21-day cycle) to be eligible for SRC review. On the 
basis of the findings, the committee will have several options: 
1. Recommend escalation to the next dose level, 
2. In case of unexpected or unacceptable toxicity during the dose escalation phase 
recommend early discontinuation of the study, or  
Alter the subsequent dose as per the dose escalation criteria presented in Section 5.4. 
The SRC will make the decision on RP2D based on an MTD of the combination being the 
occurrence of greater than 2 defined grade 3 or above SAEs (for definition of DLTs see 
section 5.4) in the final cohort of 3 plus 3 subjects. In the absence of an MTD, the SRC will 
consider pharmacodynamic and PK of birinapant as applicable considering that birinapant 
monotherapy has been studied previously at 10 to 63 mg/m2. Doses > 47 mg/m2 will not be 
considered. 
Further details on the SRC procedures are presented in the SRC-charter 


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Data Monitoring Committee Dose Expansion Phase 
During the dose-expansion phase of the study the SRC will be replaced by an independent 
Data Monitoring Committee (DMC). The independent DMC will include an independent 
chair having specialist oncology expertise and experience of studies in this area, an 
independent statistician and one other member will also be appointed. The DMC will meet 
approximately biannually to review the complete analysis of combined observed toxicities 
including emerging safety reports and reported SAEs. Specifically, they will monitor AEs 
and serious SAEs related to the treatments received in accordance with the recommendations 
of performing a clinical study of an IMP. On the basis of the findings, the committee will 
have several options: 
1. Recommend reappraisal of the MTD 
2. Reconsider RP2D, including dose de-escalation, based on safety, tolerability, PK, 
pharmacodynamic data and preliminary clinical activity, 
3. In case of unexpected or unacceptable toxicity during the dose expansion phase 
recommend early discontinuation of the study 
 
It is also the main responsibility for the DMC to conduct the interim analyses in the cohorts 
applying the Simon’s two-stage design; the independent DMC will make recommendations 
on continuation of each of the cohorts based on the predefined futility rules outlined in 
section 12.8, in addition to assessing the safety and tolerability overall and for the defined 
tumor types. 
Considering the potential delayed clinical activity known for immune related cancer 
treatments, the DMC may delay the interim analysis by up to 4 months if indicated as 
beneficial for the involved patients as judged by the relevant investigators. The time 
extension would in such case increase the treatment time for all patients that are judged to 
still be benefitting from treatment up to the new set date of the interim. 
 
Further details on the DMC procedures are presented in the DMC-charter. 
3.2 
Discussion of Study Design 
 
Design Rationale including Dose Rationale Dose Escalation Phase 
The study design is appropriate to evaluate safety, tolerability, pharmacokinetics, and 
pharmacodynamics in male and female patients, who have relapsed or refractory solid 
tumors. A low starting dose is initially used to evaluate safety with minimal risk and is 
selected based on previous safety data obtained in oncology studies. 
See Section 1.5  for discussion of the patient population and Section 1.6 for discussion of the 
dose-selection rationale. 


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Design Rationale Dose Expansion Phase Study Design 
The phase 2a part of this study is constituted by a number of individual single-arm treatment 
cohorts in order to obtain an estimate of the degree of the anti-tumor effect. Simon’s two-
stage design is used for the dose expansion component of this study. The intent is to expose 
as few patients as possible to an ineffective drug. It is ethically imperative that the study is 
terminated if the drug is shown to have little or no anti-tumor activity. Simon’s two-stage 
design gives the option to stop development of the drug in a given indication after the first or 
second stage if insufficient activity is demonstrated. The design also enables an early readout 
of sufficiently promising activity to warrant further investigation in a phase 3 study. The 
design of the various solid tumors cohort will limit undue exposure in any of the selected 
tumor types by virtue of the fact that it limits the number of enrolled patients to five in each 
tumor type.  Following any positive results, it is the sponsor may consider the initiation of an 
expansion cohort in any of the tumor types included in the various solid tumor cohort, 
following submission of a protocol amendment. For further information of the patient 
population and the specific rationale for including these groups with high unmet medical 
need in this trial, refer to section 1.5. 
The dose of birinapant is the RP2D chosen from the dose escalation part of the study. All 
patients in this part of study will therefore receive birinapant at a dose within the expected 
therapeutic range with the possibility to halt dosing as described in section 5.5 in the case of 
adverse event and may reinitiate at a lower dose according to the schema in section 5.5.1. 
The dose of pembrolizumab is the manufacturer’s standard recommended dose used in 
approved indications. Available preclinical data for birinapant discussed in section 1.1 
indicates the potential for an added clinical benefit with the combination of birinapant and 
pembrolizumab. Birinapant has a favorable safety profile based on data from previous trials, 
which indicates that the combination has a low risk of generating unacceptable toxicity.  
In all the phase 1 approach employing a stepwise definition of the recommended birinapant 
dose in combination with pembrolizumab together with the balanced evaluation allowed by 
Simons’s two-stage design and taking the beneficial preclinical basis into consideration, it is 
judged that the proposed phase 2 design has a favorable benefit-risk ratio.  
3.3 
Expected Duration of Study 
It is expected to take approximately 6 months to enroll patients to the dose-escalation phase 
of the study. In the dose expansion phase is it expected to take approximately 4 months to 
enroll patients into the colorectal cancer cohort participating in the interim analysis. 
Following the interim analysis, it is expected to take additional 4 months to enroll all 
remaining patients. It is expected that to take approximately 8 months to enroll patients into 
the cohorts in ovarian cancer and cervical cancer participating in the interim analysis. 
Following the interim analysis is it expected to take approximately 5 months to enroll to the 
additional patients to complete the cohorts. For the various solid tumors cohort it is expected 
to take approximately 15 months to enroll all patients. 


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Table 3 
Expected enrollment duration for individual cohorts  
 
Dose escalation phase 
Enrollment duration 
6 months 
 
Enrollment duration 
to interim analysis 
Enrollment duration 
from interim analysis 
to full cohort size 
Dose expansion 
phase 
Colorectal cancer cohort 
4 months 
4 months 
 
Ovarian cancer cohort 
8 months 
5 months 
 
Cervical cancer cohort 
8 months 
5 months 
 
Various solid tumor cohort 
15 months 
Patients will be allowed to remain on active treatment for 35 treatment cycles or until 
documented progressive disease (PD) or unacceptable toxicity.  All patients will be followed 
for survival.  
3.4 
Study Endpoints 
 
Study Endpoints: Dose Escalation Phase 
3.4.1.1 
Primary Endpoint 
Safety and tolerability will be assessed by monitoring: 
• Incidence and severity of adverse events (AEs) experienced by patients receiving 
birinapant in combination with pembrolizumab. 
• Incidence and magnitude of clinically significant changes in clinical laboratory 
parameters experienced by patients receiving birinapant and pembrolizumab, or overall 
pattern of shifts by treatment group in individual laboratory values suggestive of possible 
trends, but not necessarily establishing, clinical abnormality.  
• Incidence and severity of clinically significant adverse findings in vital signs, 
electrocardiogram (ECGs), and other physical examination parameters among patients 
receiving birinapant and pembrolizumab. 
3.4.1.2 
Secondary Endpoints 
Efficacy: 
• Tumor response and progression evaluated using RECIST v 1.1 
Measures defined by the ORR, will be assessed through RECIST v 1.1 until response or 
progression and will be subsequently analyzed through iRECIST as an exploratory endpoint 
(see below). 


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3.4.1.3 
Exploratory endpoints 
3.4.1.3.1 
Efficacy 
Tumor response and progression evaluated using iRECIST. 
a) iBOR 
b) Duration of iBOR  
c) Time to iCPD 
Efficacy, as defined by the ORR, will be assessed through RECIST v 1.1 until response or 
progression and will be subsequently analyzed through iRECIST (iCR, or iPR or iSD or after 
iUPD iCR, iPR or iSD or iCPD). iBOR will also be assessed.  
Overall survival will also be assessed. 
3.4.1.3.2 
Pharmacokinetics 
The pharmacokinetics of birinapant in plasma when administered in combination with 
pembrolizumab will be evaluated. 
3.4.1.3.3 
Pharmacodynamics 
Translational biomarker assessments obtained from blood will be evaluated at a central 
laboratory.  
• 
Pre- and post-treatment levels in the expression of cIAP1 
• Cytokine levels such as GM-CSF, IFNγ, IL10, IL2, IL3, IL4, IL5, IL6, IL7, IL8, 
MIP-1α, MIP-1β, MCP-1, TNFα, and TNFβ  
• Gene expression analysis by Nanostring may also be performed 
Blood samples looking at CD3+, CD4+, CD8+, and CD19+ cell counts as well as absolute 
neutrophil count and absolute lymphocyte count will be analyzed by each investigational 
site’s local laboratory. 
Translational biomarker assessments such as listed below, will be evaluated from archival or 
fresh pre-treatment biopsy samples, and optional post-treatment tumor biopsy samples, 
which will be analyzed at central laboratory: 
• Pre-treatment PD-L1 levels by immunohistochemistry       
• Gene expression analysis by Nanostring 
• cIAP1 expression by immunohistochemistry 
• Inhibition of apoptosis protein (IAP) gene copy number  
• Tumor infiltrating lymphocytes (TILs) CD3, CD4, CD8, CD20 and FOXP3  
The exploratory biomarker analyses listed are planned but may not be conducted if deemed 
as obsolete during later stages of the study; other exploratory analyses may be added based 


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on emerging new findings. Details regarding the processing and shipping of all 
pharmacodynamic samples will be outlined in the study specific laboratory manual.   
 
Study Endpoints; Dose Expansion Phase 
3.4.2.1 
Primary Endpoint 
The primary endpoint in each of the cohorts is as follows: 
1. The overall response assessed through RECIST v.1.1 until response or progression in 
colorectal cancer 
2. The overall response assessed through RECIST v1.1 until response or progression in 
ovarian cancer 
3. The overall response assessed through RECIST v1.1 until response or progression in 
cervical cancer 
4. Safety and tolerability in the cohort with various solid tumor types will be assessed 
by monitoring: 
• 
Incidence and severity of adverse events (AEs) experienced by patients 
receiving birinapant in combination with pembrolizumab. 
• 
Incidence and magnitude of clinically significant changes in clinical 
laboratory parameters experienced by patients receiving birinapant and 
pembrolizumab, or overall pattern of shifts by treatment group in 
individual laboratory values suggestive of possible trends, but not 
necessarily establishing, clinical abnormality. 
• 
Incidence and severity of clinically significant adverse findings in vital 
signs, electrocardiogram (ECGs), and other physical examination 
parameters among patients receiving birinapant and pembrolizumab. 
Measures of tumor response will be evaluated using RECIST v1.1 until response or 
progression and will be subsequently analyzed through iRECIST as an exploratory endpoint 
(see below). 
 
3.4.2.2 
Secondary Endpoints 
Safety and tolerability will be assessed in colorectal cancer, ovarian cancer and cervical 
cancer by monitoring: 
• 
Incidence and severity of adverse events (AEs) experienced by patients 
receiving birinapant in combination with pembrolizumab. 
• 
Incidence and magnitude of clinically significant changes in clinical 
laboratory parameters experienced by patients receiving birinapant and 
pembrolizumab, or overall pattern of shifts by treatment group in 
individual laboratory values suggestive of possible trends, but not 
necessarily establishing, clinical abnormality.  
• 
Incidence and severity of clinically significant adverse findings in vital 
signs, electrocardiogram (ECGs), and other physical examination 
parameters among patients receiving birinapant and pembrolizumab. 


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Clinical Activity: Tumor response will be assessed in all four cohorts by monitoring: 
• 
Progression Free Survival (PFS) 
• 
Clinical Benefit Rate (CBR) defined as CR+PR+SD 
• 
Time to response 
• 
Duration of response 
• 
Overall Survival (OS) 
Measures of tumor response will be evaluated using RECIST v1.1 until response or 
progression and will be subsequently analyzed through iRECIST as an exploratory endpoint 
(see below). 
3.4.2.3 
 Exploratory endpoints 
 
3.4.2.3.1 
Clinical Activity 
Tumor response and progression evaluated in all four cohorts using iRECIST: 
• 
Overall response 
• 
iBOR 
• 
Duration of iBOR  
• 
Time to iCPD 
• 
Clinical Benefit Rate (CBR) defined as iCR+iPR+iSD  
• 
Time to response 
• 
Duration of response 
 
3.4.2.3.2 
Pharmacokinetics 
The pharmacokinetics of birinapant in plasma when administered in combination with 
pembrolizumab will be evaluated. 
3.4.2.3.3 
Pharmacodynamics 
Translational biomarker assessments obtained from blood will be evaluated at a central 
laboratory.  
• 
Pre- and post-treatment levels of cIAP1 expression 
• Cytokine levels such as GM-CSF, IFNγ, IL10, IL2, IL3, IL4, IL5, IL6, IL7, IL8, 
MIP-1α, MIP-1β, MCP-1, TNFα, and TNFβ  
• Gene expression analysis by Nanostring may also be performed 
Blood samples looking at CA-125 (for ovarian cancer patients), CEA (for CRC patients), 
CD3+, CD4+, CD8+, and CD19+ cell counts as well as absolute neutrophil count and absolute 
lymphocyte count will be analyzed by each investigational site’s local laboratory. 


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Translational biomarker assessments such as listed below, will be evaluated from archival or 
fresh pre-treatment biopsy samples, and optional post-treatment tumor biopsy samples, 
which will be analyzed at central laboratory: 
• Pre-treatment PD-L1 levels by immunohistochemistry       
• Gene expression analysis by Nanostring 
• cIAP1 expression by immunohistochemistry 
• Inhibition of apoptosis protein (IAP) gene copy number  
• Tumor infiltrating lymphocytes (TILs) CD3, CD4, CD8, CD20 and FOXP3 
The exploratory biomarker analyses listed are planned but may not be conducted if deemed 
as obsolete during later stages of the study; other exploratory analyses may be added based 
on emerging new findings. Details regarding the processing and shipping of all 
pharmacodynamic samples will be outlined in the study specific laboratory manual.   
 STUDY POPULATION 
In the dose-escalation phase the study population will consist of approximately 24 male and 
female patients, ≥ 18 years of age, with relapsed or refractory solid tumors, who meet all of 
the inclusion criteria and none of the exclusion criteria.  
Additional patients with relapsed or refractory carcinoma will be enrolled in the dose-
expansion phase of the study.   The dose expansion phase will comprise 4 cohorts of 26-30 
patients. Three cohorts will enroll distinct cancer subtypes (colorectal cancer, ovarian cancer 
and cervical cancer) while the 4th cohort will include patients with one of 6 candidate tumors: 
small cell lung cancer; cholangiocarcinoma; gastroesophageal, mesothelioma; head and neck 
squamous cell carcinoma (HNSCC)-checkpoint naïve; and HNSCC check-point 
experienced).   
4.1 
Inclusion Criteria 
All inclusion criteria for the study are listed below. Unless otherwise stated, inclusion 
criteria apply to all phases and cohorts in the study. Individual lists of inclusion and 
exclusion criteria applicable for the dose escalation phase and for each tumor type of the 
dose expansion phase can be found in Appendices 2.1 to 2.5.6.  
Patients will be eligible for study participation if they meet ALL of the following inclusion 
criteria, after patient has provided written informed consent.  
1. The patient is male or female ≥ 18 years of age on the day of signing informed consent. 
2. The patient is able to understand and voluntarily sign a written informed consent, and is 
willing and able to comply with the protocol requirements. 
3. The patient must have a histologically confirmed solid malignancy that is metastatic or 
unresectable and for which standard curative or palliative measures do not exist or are no 
longer effective.  Patients with tumors with mutations for which there are FDA-approved 
therapies must have progressed following these therapies in order to be eligible for this 
study.  Patients with metastatic colorectal cancer should have progressed on prior 
fluoropyrimidine-based therapies, and have no curative therapies available to them, in 


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order to be eligible for this study. Colorectal cancer patients should be assessed for 
microsatellite instability (MSI) status as per the local site routines. (Dose Escalation 
Phase only) 
4. Patients must have measurable disease based on RECIST 1.1 as determined by the site 
study team.  Tumor lesions situated in a previously irradiated area are considered 
measurable if progression has been demonstrated in such lesions.  
5. Patients must have an Eastern Cooperative Oncology Group (ECOG) score of 0 or 1 at 
screening.   
6. Patients must have a life expectancy of greater than 12 weeks. 
7. Patients must have amylase and lipase values < ULN. 
8. Patients must demonstrate adequate organ function as defined in Table 4.  All screening 
labs should be performed within 10 days of treatment initiation. 
 
Table 4 
Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L  
Renal 
Creatinine OR 
Measured 
or 
calculateda 
creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤1.5xULN OR 
≥60 mL/min for patient with  
creatinine levels >1.5x institutional ULN 
Hepatic 
Total bilirubin 
≤1.5xULN OR 
Direct bilirubin ≤ULN for patients with total 
bilirubin levels >1.5xULN), unless known Gilbert’s 
Syndrome has been diagnosed 
AST (SGOT) and ALT (SGPT) 
≤2.5xULN OR 
≤5.0xULN for patients with liver metastases 
Coagulation 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
 
Activated Partial Thromboplastin Time 
(aPTT) 
≤1.5xULN unless patient is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic 
range of intended use of anticoagulants 
≤1.5xULN unless patient is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic 
range of intended use of anticoagulants 
a Creatinine clearance should be calculated per institutional standard. 
9. Female patients of childbearing potential must have a negative urine or serum 
pregnancy test within 72 hours prior to receiving the first dose of study medication. 
If the urine test is positive or cannot be confirmed as negative, a serum pregnancy 
test will be required.   


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10. Female patients of childbearing potential must be willing to use an adequate 
method of contraception for the course of the study through 120 days after the last 
dose of study medication. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred 
contraception for the patient. 
11. Male patients with female partners of childbearing potential must agree to use an 
adequate method of contraception, starting with the first dose of study therapy 
through 120 days after the last dose of study therapy. (Not applicable for ovarian 
cancer cohort or cervical cancer cohort) 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred 
contraception for the patient. 
12. A tumor tissue sample for PD-L1 biomarker analysis from archival material, a 
newly obtained core or excisional biopsy is available for submission.  Repeat 
samples may be required if adequate tissue is not provided.   
13. Have resolution of toxic effect(s) of the most recent prior chemotherapy to Grade 1 
or less (except neuropathy or alopecia). If patients have received major surgery or 
radiation therapy of > 30 Gy, they must have recovered from the toxicity and/or 
complications from the intervention.  
Dose expansion phase cohort-specific inclusion criteria 
14. Patients with metastatic colorectal cancer with no available therapy options that are 
known to provide clinical benefit per institutional standard of care.  Patients with 
tumors with mutations for which there are available therapies that are known to 
provide clinical benefit, as defined by national authority and/or ratified by national 
guidelines or equivalent, have progressed following these therapies in order to be 
eligible for this study. (colorectal cancer cohort only) 
15. Patients with histological or cytologically confirmed metastatic colorectal cancer 
which is Microsatellite Stable (MSI-Stable) accordingly to local laboratory testing.  
(colorectal cancer cohort only) 
16. Patients must have a histologically confirmed epithelial ovarian cancer, primary 
peritoneal cancer or fallopian tube solid tumor cancer that is locally advanced or 
metastatic with no available therapy options that are known to provide clinical 
benefit per institutional standard of care.  Patients with tumors with mutations for 
which there are available therapies that are known to provide clinical benefit, as 
defined by national authority and/or ratified by national guidelines or equivalent, 
must have progressed following these therapies in order to be eligible for this study. 
(ovarian cancer cohort only) 
17. Patients must have histologically or cytologically confirmed cervical squamous cell 
carcinoma that is locally advanced or metastatic with no available therapy options 
that are known to provide clinical benefit per institutional standard of care. Patients 
with tumors with mutations for which there are available therapies that are known 


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to provide clinical benefit, as defined by national authority and/or ratified by 
national guidelines or equivalent, must have progressed following these therapies 
in order to be eligible for this study (cervical cancer cohort only) 
18. Patients must have histologically or cytologically confirmed head and neck 
squamous cell carcinoma that is locally advanced or metastatic with no available 
therapy options that are known to provide clinical benefit per institutional standard 
of care. Patients with tumors with mutations for which there are available therapies 
that are known to provide clinical benefit, as defined by national authority and/or 
ratified by national guidelines or equivalent, must have progressed following these 
therapies in order to be eligible for this study (various solid tumors cohort: head 
and neck squamous cell carcinoma groups only). 
19. Patients with head and neck squamous cell carcinoma who are to participate in the 
group of Checkpoint inhibitor experienced patients must have received prior 
therapy with an anti-PD-1 or anti-PD-L1 antibody, administered either as 
monotherapy, or in combination with other therapies. Patients must have received 
at least two doses of an approved anti-PD-1/anti-PD-L1 antibody and have 
experienced documented radiographic progression of disease by RECIST v1.1. The 
initial evidence of disease progression is to be confirmed by a second assessment 
no less than four weeks from the date of the first documented disease progression 
in the absence of rapid clinical progression. The date for documentation of initial 
progression will be considered the date for disease progression. Progressive disease 
must have been documented during or within 12 weeks after last dose of such 
treatment. (various solid tumors cohort head and neck squamous cell carcinoma, 
Checkpoint inhibitor experienced group only). 
20. Patients must have histologically or cytologically confirmed small cell lung 
carcinoma that is locally advanced or metastatic with no available therapy options 
that are known to provide clinical benefit per institutional standard of care. Patients 
with tumors with mutations for which there are available therapies that are known 
to provide clinical benefit, as defined by national authority and/or ratified by 
national guidelines or equivalent, must have progressed following these therapies 
in order to be eligible for this study (various solid tumors cohort, SCLC group only) 
21. Patients must have histologically or cytologically confirmed cholangiocarcinoma 
that is locally advanced or metastatic with no available therapy options that are 
known to provide clinical benefit per institutional standard of care. Patients with 
tumors with mutations for which there are available therapies that are known to 
provide clinical benefit, as defined by national authority and/or ratified by national 
guidelines or equivalent, must have progressed following these therapies in order to 
be eligible for this study (various solid tumors cohort, cholangiocarcinoma group 
only) 
22. Patients must have histologically or cytologically confirmed pleural mesothelioma 
that is locally advanced or metastatic with no available therapy options that are 
known to provide clinical benefit per institutional standard of care. Patients with 


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tumors with mutations for which there are available therapies that are known to 
provide clinical benefit, as defined by national authority and/or ratified by national 
guidelines or equivalent, must have progressed following these therapies in order to 
be eligible for this study (various solid tumors cohort, mesothelioma group only) 
23. Patients must have histologically or cytologically confirmed carcinoma of the 
esophagus including the gastroesophageal junction that is locally advanced or 
metastatic with no available therapy options that are known to provide clinical 
benefit per institutional standard of care.  Patients with tumors with mutations for 
which there are available therapies that are known to provide clinical, as defined by 
national authority and/or ratified by national guidelines or equivalent, must have 
progressed following these therapies in order to be eligible for this study (various 
solid tumors cohort, gastroesophageal carcinoma group only) 
4.2 
Exclusion Criteria 
All exclusion criteria for the study are listed below. Unless otherwise stated, exclusion 
criteria apply to all phases and cohorts in the study. Individual lists of inclusion and 
exclusion criteria applicable for the dose escalation phase and for each tumor type of the 
dose expansion phase can be found in Appendices 2.1 to 2.5.6.  
 A patient will be excluded from the study for any one or more of the following reasons: 
1. Patients who have had a prior anti-cancer monoclonal antibody (mAb) within 4 
weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) 
from adverse events due to agents administered more than 4 weeks earlier prior to 
study Day 1. 
2. Patients who have had prior chemotherapy, targeted small molecule therapy, or 
radiation therapy within 2 weeks prior to study Day 1 or who have not recovered (i.e., 
≤ Grade 1 or at baseline) from adverse events due to a previously administered agent. 
Note:  Patients with ≤ Grade 2 neuropathy or ≤ Grade 2 alopecia are an exception 
to this criterion and may qualify for the study. 
Note:  If patients have received major surgery, they must have recovered 
adequately from the toxicity and/or complications from the intervention prior to 
starting therapy.   
3. Patients who are currently participating and receiving study therapy or who have 
participated in a study of an investigational agent and received study therapy or who 
have used an investigational device within 4 weeks of the first dose of treatment. 
4. Patients who have received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, 
anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) 
antibody (including ipilimumab or any other antibody or drug specifically targeting 
T-cell co-stimulation or checkpoint pathways) or if the patient has previously 
participated in Merck MK-3475 clinical trials. (Not applicable for various solid 
tumors cohort, head and neck squamous cell carcinoma check-point inhibitor 
experienced group)  


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5. Patients with known active central nervous system (CNS) metastases and/or 
carcinomatous meningitis.   
Note:  Patients with previously treated brain metastases may participate provided 
they are stable (without evidence of progression by imaging (using the identical 
imaging modality for each assessment, either MRI or CT scan) for at least four 
weeks prior to the first dose of trial treatment and any neurologic symptoms have 
returned to baseline), have no evidence of new or enlarging brain metastases, and 
are not using systemic steroids for at least 7 days prior to trial treatment.  This 
exception does not include carcinomatous meningitis which is excluded 
regardless of clinical stability. 
6. Patients with a known additional malignancy that is progressing or requires active 
treatment.  Exceptions include basal cell carcinoma of the skin, squamous cell 
carcinoma of the skin that has undergone potentially curative therapy or in situ 
cervical cancer. 
7. Patients who have a history of allergic reactions attributed to compounds of similar 
chemical or biologic composition to birinapant or pembrolizumab or their 
constituents. 
8. Patients requiring the use of anti-tumor necrosis factor (anti-TNF) therapies, such as 
infliximab, or patients who have received treatment with anti-TNF therapies within 5 
half-lives of the drug. 
9. Patients with a diagnosis of immunodeficiency or who are receiving systemic steroid 
therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form 
of immunosuppressive therapy within 7 days before the first dose of study drug. The 
use of physiologic doses of corticosteroids may be approved after consultation with 
the Sponsor.  
10. Patients with an uncontrolled intercurrent illness including, but not limited to, 
symptomatic congestive heart failure, hypertension, unstable angina pectoris, cardiac 
arrhythmia, autoimmune or inflammatory diseases, or psychiatric illness that would 
limit compliance with study requirements. 
11. Patients with an active autoimmune disease that has required systemic treatment in 
the past 2 years (i.e., with use of disease modifying agents, corticosteroids or 
immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) 
is not considered a form of systemic treatment. 
 
12. Patients who have evidence of active, non-infectious pneumonitis. Patients with a 
history of (non-infectious) pneumonitis that required steroids or current pneumonitis.  
 
13. Patients with a history of interstitial lung disease 
 
14. Patients who are pregnant or breastfeeding, or expecting to conceive or father 
children within the projected duration of the trial, starting with the screening visit 


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through 120 days after the last dose of trial treatment. Pregnant women and men who 
want to conceive a child are excluded from this study because birinapant and 
pembrolizumab are agents with unknown potential for teratogenic or abortifacient 
effects in humans. Because there is an unknown risk for AEs in nursing infants 
secondary to treatment of the mother with birinapant and pembrolizumab, 
breastfeeding should be discontinued if the mother is treated on this study.  
15. Patients who have a known history of Human Immunodeficiency Virus (HIV) (HIV 
1/2 antibodies), or active Hepatitis B (e.g., HBsAg reactive). Patients with active 
Hepatitis C (e.g., HCV RNA [qualitative] is detected).  
16. Patients who have received a live-virus vaccination within 30 days of planned 
treatment start. Seasonal flu vaccines that do not contain live virus are permitted. 
17. Patients who have disease that is suitable for local therapy administered with curative 
intent. 
18. Patients who have received transfusion of blood products (including platelets or red 
blood cells) or administration of colony stimulating factors (including G-CSF, GM-
CSF or recombinant erythropoietin) within 4 weeks prior to study Day 1.  
19. Patients who have a history or current evidence of any condition, therapy, or 
laboratory abnormality that might confound the results of the trial, interfere with the 
patient’s participation for the full duration of the trial, or it is not in the best interest 
of the patient to participate, in the opinion of the treating investigator.  
20. Patients who have known psychiatric or substance abuse disorders that would 
interfere with cooperation with the requirements of the trial. 
21. Patients who have severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any 
of its excipients.  
22. Patients who have received anti-PD-L2, anti-CD137, or anti-Cytotoxic T-
lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any 
other antibody or drug specifically targeting T-cell co-stimulation or checkpoint 
pathways) (Various solid tumor cohort, head and neck squamous cell carcinoma 
check point inhibitor experienced group only) 
23. Patients who have previously received birinapant treatment.  
4.3 
Withdrawal Criteria and Procedures 
In accordance with the Declaration of Helsinki (and consistent with the applicable country’s 
acceptance), each patient is free to withdraw from the study at any time. Medivir AB 
reserves the right to terminate the study at any time for any reason. 
The Investigator also has the right to withdraw a patient from the study in the event of any of 
the following: 
• 
Confirmed disease progression (refer to Section 9.1.5) 


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• 
Pregnancy or intent to become pregnant 
• 
Occurrence of AEs or drug toxicities requiring permanent discontinuation of birinapant 
or pembrolizumab 
• 
Intercurrent illness that prevents further administration of study drug 
• 
Patient decides to withdraw consent for study participation 
• 
General or specific changes in the patient’s condition that, in the judgment of the 
Investigator, render the patient unacceptable for further treatment 
• 
Protocol Violation: Study-related findings or conduct fail to meet the protocol entry 
criteria or the patient fails to adhere to the protocol requirements. 
A patient discontinued from study participation will continue the follow-up procedures 
specified in Section 6. All AEs will be monitored until resolution or stabilization, or if not 
study related, until transfer of medical responsibility to non-study medical personnel. 
Patients discontinuing from treatment will be assessed for possible AEs and SAEs up to 
30 days after the last dose of study drug. If an AE is identified or suspected, the patient will 
be required to return to the clinical site, if possible, for full evaluation, regardless of causal 
relationship to study-drug administration. 
The reason for and date of discontinuation of study-drug treatment and the reason for and 
date of withdrawal from the study must be recorded on the source documentation and 
transcribed into the case report form (CRF). If a patient withdraws consent, every attempt 
will be made to determine the reason. If the reason for withdrawal is an AE or a clinically 
significant abnormal laboratory test result, monitoring will be continued by the Investigator 
until the event has resolved or stabilized, until the patient is referred to the care of a health 
care professional, or until a determination of a cause unrelated to the study drug or study 
procedure is made. The specific AE or test result(s) must be recorded on the source 
documentation and transcribed into the CRF. 
 INVESTIGATIONAL PRODUCT AND CONCOMINANT 
MEDICATIONS 
Investigational product (IP) refers to birinapant and pembrolizumab. Other medications 
consumed either before dosing or concomitantly with study drug, may be permitted or result 
in the patient’s exclusion or discontinuation, respectively as described below (see Section 5.5 
and Section 5.6). 
5.1 
Formulation, Packaging and Labeling 
Birinapant is supplied as a sterile-filled, clear, colorless-to-pale yellow, liquid solution. 
Birinapant will be supplied by the Sponsor in single use 10 mL amber glass vials, formulated 
in 50 mM citrate buffer (pH 5.0) at a concentration of 1 mg/mL containing a total fill volume 
of approximately 10.5 mL.  Each vial is packaged in secondary packaging (carton) to further 
prevent the product from potential degradation on exposure to light. 
Pembrolizumab is provided by the Sponsor as a solution for injection (100 mg/4 mL). 


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5.2 
Storage, Preparation, Stability and Accounting 
 
Investigational Product Storage, Preparation and Stability 
Birinapant must be stored frozen in secondary packaging (below -10ºC) in a secured area 
until ready to use. When ready to prepare the birinapant solution, the desired dose is to be 
removed from the vial, under aseptic conditions, and the contents injected into an IV bag 
containing 250 mL of 0.9% sodium chloride for injection USP. The prepared solution of 
birinapant is stable under typical in-use conditions (i.e., ambient light and temperature) for 
4 hours (time of preparation through to the end of infusion). Birinapant is stable through at 
least 5 freeze/thaw cycles. 
Pembrolizumab must be stored under refrigerated conditions at 2°C to 8°C (36°F to 46°F).  
Details regarding preparation of pembrolizumab can be found in the pharmacy manual. 
 
Investigational Product Accountability 
The Investigator must maintain an accurate inventory log of all investigational product 
received, used, returned, and destroyed.  Investigational product dispensed for all patients 
must be recorded on the drug accountability log. Information to be documented for each 
dispensed vial includes: 
• 
Patient number and initials 
• 
Treatment cohort number 
• 
Dose level 
• 
Date that investigational product was dispensed 
• 
Amount dispensed (volumes and number of vials) per patient 
The investigational product accountability log and remaining investigational product 
inventory will be reviewed at each monitoring visit by the Sponsor’s clinical monitor. 
The investigational products supplied for this study are for use only in patients properly 
consented and enrolled into this protocol. 
 
Retention of Samples 
It will be the responsibility of the Sponsor to ensure that adequate samples of all 
investigational products are retained in accordance with the relevant regulatory guidelines. 
 
Investigational Product Waste Handling 
It is recommended that healthcare workers follow the institution’s standard procedures for 
handling cytotoxic drugs during preparation and administration of study drugs. The waste 
generated during the preparation and administration of study drug, including materials that 
come into direct contact with study drug (e.g., needles, gauze, and sponges), should be 
disposed in accordance with applicable governmental, and institutional policies regarding the 
disposal of hazardous biological materials and medical waste. Although birinapant did not 


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exhibit any evidence of mutagenicity in the Ames assay at 10 µM and does not demonstrate 
significant activity in the in vitro micronucleus assay at concentrations up to 130 µM in 
either the presence or absence of S9 metabolic activation. 
Handling of pembrolizumab study drug waste is detailed in the study-specific pharmacy 
manual. 
5.3 
Dose Administration 
All doses of investigational product will be administered via a 30-minute (± 10 minutes) 
peripheral or central IV infusion.  During each 21-day treatment cycle, pembrolizumab will 
be administered first on Day 1 as a 30-minute (± 10 minutes) infusion.  Sites should make 
every effort to target infusion timing to be as close to 30 minutes as possible.  However, 
given the variability of infusion pumps from site to site, a window between -5 minutes and 
+10 minutes is permitted (i.e., infusion time is 30 minutes -5 min/+10 min). Birinapant will 
be administered 30 minutes (+10 minutes) following the completion of the pembrolizumab 
infusion.  Birinapant will be administered alone on Day 8.  A week without treatment (i.e., 
Days 15-21) will conclude each 21-day cycle, immediately after which the treatment cycle 
will be repeated (i.e., with pembrolizumab on Day 1 and birinapant on Days 1 and 8).  Study 
drugs will be administered in the arm opposite to the site of blood-sample collection. 
The birinapant dose will be administered according to the dose-escalation schedule and in 
the dose-expansion phase of the study, according to the RP2D that will be determined in the 
dose escalation phase of the study.  
Dose Level 
Pembrolizumab + Birinapant (per 21-day cycle) 
Expansion 
200 mg pembrolizumab on Day 1+ birinapant at the RP2D 
mg/m2/week on Days 1 and 8 
The dose will be prepared by the site’s Pharmacy and administered using materials known to 
be compatible with birinapant formulation. A filter should not be used during the birinapant 
infusion. 
The birinapant dose calculation will be based on the patient’s body surface area (BSA) using 
the Mosteller or institutional standard formula (to be calculated to the first decimal place) 
determined by height and weight at Screening (see the Pharmacy Manual). If a patient’s BSA 
is > 2.5, then 2.5 will be used to calculate the patient’s study-drug dose. If the patient’s body 
weight has changed > 10% from that used to calculate the prior BSA, the BSA will be 
recalculated and the dose adjusted. 
Pembrolizumab will be administered as a dose of 200 mg using a 30-minute IV infusion.   
The pharmacy manual contains specific instructions for the preparation of the 
pembrolizumab infusion and administration of infusion solution. The dosing arm will be 
noted and all study blood samples for collection of safety and pharmacodynamic samples 
must be drawn from the contralateral arm.  


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5.4 
Dose-Limiting Toxicity and Recommended Phase 2 Dose 
The inter-patient dose escalation of birinapant will be based on the number of patients that 
experience a DLT. A DLT is a clinically significant event attributed to birinapant, 
pembrolizumab, or the combination of the 2 study drugs, during the first cycle of drug 
therapy and is defined as follows: 
Non-hematological toxicity: 
• Common Toxicity Criteria for Adverse Event (CTCAE; 4.03) Grade 3 nausea, 
vomiting, or diarrhea despite maximal (according to treating investigator) anti-emetic 
or anti-diarrheal treatment and lasting > 48 hours; or Grade 4 vomiting or diarrhea;  
• ≥ Grade 3 other non-hematological toxicity, excluding isolated laboratory 
abnormalities without clinical sequelae, except for the following: 
o Prolonged (> 7 days) serum amylase or lipase elevation; 
o Prolonged (> 7 days) aspartate aminotransferase (AST) elevation; 
o Prolonged (> 7 days) alanine aminotransferase (ALT) elevation; 
All of which will be considered dose limiting. 
Hematological toxicity: 
• Grade 4 neutropenia; 
• Grade ≥ 3 neutropenia with fever > 38.3°C or > 38°C (> 100.9°F or > 100.4°F) for 
more than one hour; 
• Grade ≥ 3 thrombocytopenia with bleeding 
Specific toxicity: 
• Cytokine release syndrome (CRS); Grade 3 or 4. Furthermore, if a Grade >2 CRS 
occurs during the DLT period (Cycle 1), this also triggers the permanent 
discontinuation of all study dosing (birinapant AND pembrolizumab) with 
subsequent adequate care to treat the condition (see also sections 5.5.1 and 5.5.3). 
If Day 8 of treatment is held due to toxicity then the event will be considered a DLT.  A 
prolonged delay (> 2 weeks) in initiating Cycle 2 secondary to drug-related toxicity may be 
considered a DLT as judged by the SRC. Events related to disease progression, intercurrent 
illness, or concomitant medication will not constitute a DLT.  Since patients are assessed for 
DLTs during the first cycle, dose modifications may not be performed. If a patient 
experiences a DLT that is deemed related to birinapant, the dose of birinapant may be 
restarted at a reduced level for Cycle 2 according to dose levels indicated in Table 2/section 
3 and the rules stated in section 5.5, and the patient may remain on study. 
The decisions to dose-escalate birinapant for each Dose Level are indicated in Table 5 
below. 


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Table 5 
Escalation Decision Rules 
Number of Patients with DLT 
at a Given Dose Level 
Escalation-decision Rule 
Zero of 3 to 6 
Enter 3 to 6 patients at the next dose level. 
1 out of 3 to 6 
Enter up to a total of 6 patients at this dose level. 
• If 1 of these 3 to 6 patients experiences a DLT, 
proceed to the next dose level, if the next highest 
dose has not already been declared intolerable*. 
• If 1 of these 3 to 6 patients experiences a DLT and 
the next highest dose has already been declared 
intolerable, enroll a minimum of 6 patients at this 
dose level.  
≥ 2 out of 3 to 6 
Dose escalation will be stopped. This dose level may 
be declared the maximally administered dose (highest 
dose administered) and may be declared intolerable. 
Three additional patients may be entered at the next 
lowest dose level if only 3 patients were treated 
previously at that dose. 
*Defined as ≥2 patients from 3-6 experiencing a DLT 
Once the RP2D of birinapant combined with pembrolizumab is defined, additional patients 
with relapsed or refractory carcinoma will be enrolled in the dose-expansion phase of the 
study.   
 
During the dose-expansion phase, an independent DMC will meet at least biannually to 
review the complete analysis of combined observed toxicities including emerging safety 
issues and reported SAEs. Such meetings may result in a reappraisal of the MTD and /or 
RP2D. In the event that dose de-escalation is to occur the same dose levels as indicated in 
Table 2 / section 3.1.1 should be applied.  
5.5 
Dosing Delays/Dose Modifications 
During the dose escalation phase dose modifications of birinapant will only be permitted in 
Cycle 2 and beyond (section 5.5.1). During the first cycle, patients are assessed for DLTs 
and dose modifications may not be performed.   
Following the completion of the first cycle of therapy and in the dose expansion phase, if an 
AE is assessed as related to study drug the dosing may be modified according to the starting 
cohort dose by reducing the dose of birinapant according to the schema in Section 5.5.1 .  In 
the case where causality cannot be assigned to only one of the agents, the Investigator should 
first dose de-escalate birinapant, followed by withholding pembrolizumab if required. There 
will be no pembrolizumab dose reductions permitted in this study (for pembrolizumab 
dosing rules, see Table 6) 


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Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology. These AEs may occur shortly after the first dose or 
several months after the last dose of treatment.  Pembrolizumab must be withheld for drug-
related toxicities and severe or life-threatening AEs as per Section 5.5.2 and Section 5.5.3 for 
supportive care guidelines, including use of corticosteroids. Dosing interruptions are 
permitted in the case of medical or surgical events or logistical reasons not related to study 
therapy (e.g., elective surgery, unrelated medical events, patient vacation, and/or holidays). 
Patients should be placed back on study therapy within 3 weeks of the scheduled interruption, 
unless otherwise discussed with the Sponsor. The reason for interruption should be 
documented in the patient's study record. 
If a patient experiences an AE in cycle 2 or beyond in the dose escalation phase or in the 
dose expansion phase of the study, the Investigator may hold birinapant for up to 14 days.  
On resolution of the AE (or return to baseline) birinapant may be restarted at their prior dose, 
or de-escalated, depending on the type and severity of the event.  After a delay of > 14 days, 
the Investigator should consider removing the patient from the study. 
 
Dose Modifications Schema and Supportive Care Guidelines for 
Birinapant 
The following dose modification schemas for birinapant are required for selected AEs 
below. 
Cranial Nerve Palsy 
Birinapant 
≤ Grade 1 
No change; initiate corticosteroids1,2 
≥ Grade 2 
Interrupt up to 14 days; may restart at same or one dose below initial dose received2 
1Corticosteroids should be considered at the onset of any Grade cranial nerve palsy; the recommended dose is 
1-2 mg/kg day of prednisone or prednisone-equivalent, until resolution or return to baseline. 
2 All patients that develop a cranial nerve palsy should have a blood sample taken to assess for HSV and VZV.  
Sites may also consider sending the patient for a MRI.   
In the event of facial pain, ear pain, retro-orbital pain, or atypical or new-onset headache, it is 
recommended that birinapant be held, and that a course of nonsteroidal anti-inflammatory 
agents (NSAIDs), such as ibuprofen, be initiated, at an appropriate anti-inflammatory dose. 
If within 24 hours symptoms do not resolve, or worsen, or the patient develops a cranial 
neuropathy, a course of steroids (prednisone) should be initiated.  Birinapant may be re-
introduced at the resolution of the event, at the same dose or at a reduced dose (by 1 dose 
level) depending on the severity of the event, if the Investigator and the patient are in 
agreement. 
Cytokine Release 
Syndrome 
Birinapant 
≤ Grade 1 
Interrupt up to 14 days; initiate diphenhydramine, acetaminophen*. Restart at 
same dose. 
Grade 2 
Interrupt up to 14 days; initiate diphenhydramine, corticosteroids. Restart 
treatment at one dose level down 
> Grade 2 
Interrupt permanently; initiate diphenhydramine, corticosteroids. 
*Diphenhydramine, acetaminophen or intravenous fluids should be considered at the onset of cytokine 
release syndrome, until resolution. 


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Management of Cytokine Release Syndrome (CRS): Cytokine release syndrome is defined in 
CTCAE v4.03 as a disorder characterized by nausea, headache, tachycardia, hypotension, 
rash, and shortness of breath. CRS occurs when lymphocytes (B cells, T cells, and/or natural 
killer cells) and/or myeloid cells (macrophages, dendritic cells, and monocytes) become 
activated and release inflammatory cytokines. In addition to the symptomatology defined 
under CTCAE, CRS may present with fever, chills, myalgias, and malaise.   
Amylase or lipase 
Elevation 
Birinapant 
≤ Grade 1 
No change 
≥Grade 2 
Interrupt up to 14 days; restart at same dose*. 
*On second occurrence, after resolution or return to baseline, a dose reduction to one dose level down 
should be considered. 
 
Dose Modification Schema for Pembrolizumab 
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology.  These AEs may occur shortly after the first dose or 
several months after the last dose of treatment. Pembrolizumab must be withheld for drug-
related toxicities and severe or life-threatening AEs.  See Section 5.5.3 for supportive care 
guidelines, including use of corticosteroids. 
Dosing interruptions are permitted in the case of medical / surgical events or logistical 
reasons not related to study therapy (e.g., elective surgery, unrelated medical events, patient 
vacation, and/or holidays). Subjects should be placed back on study therapy within 3 weeks 
of the scheduled interruption, unless otherwise discussed with the Sponsor. The reason for 
interruption should be documented in the patient's study record. 
 
Supportive Care Guidelines for Pembrolizumab 
5.5.3.1 
Dose Modification and Toxicity Management Guidelines for 
Pembrolizumab 
Dose modification and toxicity management for immune-related AEs associated with 
pembrolizumab 
AEs associated with pembrolizumab exposure may represent an immunologic etiology. 
These immune-related AEs (irAEs) may occur shortly after the first dose or several months 
after the last dose of pembrolizumab treatment and may affect more than one body system 
simultaneously. Therefore, early recognition and initiation of treatment is critical to reduce 
complications.  Based on existing clinical trial data, most irAEs were reversible and could be 
managed with interruptions of pembrolizumab, administration of corticosteroids and/or other 
supportive care. For suspected irAEs, ensure adequate evaluation to confirm etiology or 
exclude other causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin 
biopsy may be included as part of the evaluation. Based on the severity of irAEs, withhold or 
permanently discontinue pembrolizumab and administer corticosteroids. Dose modification 
and toxicity management guidelines for irAEs associated with pembrolizumab are provided 
in Table 6.  
 


 
 
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Table 6  
Dose modification and toxicity management guidelines for immune-related AEs associated with 
pembrolizumab  
General instructions: 
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks. 
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and corticosteroid has 
been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot be 
reduced to ≤10 mg prednisone or equivalent per day within 12 weeks.  
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment should be 
initiated if irAEs cannot be controlled by corticosteroids. 
 
Immune-related 
AEs 
Toxicity grade or 
conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management with corticosteroid 
and/or other therapies  
Monitor and follow-up  
Pneumonitis  
Grade 2 
Withhold  
Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
 
Monitor participants for signs and symptoms of 
pneumonitis 
Evaluate participants with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment 
Add prophylactic antibiotics for opportunistic 
infections 
Grade 3 or 4, or 
recurrent Grade 2 
Permanently 
discontinue 
Diarrhea / Colitis  Grade 2 or 3 
Withhold 
Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
 
Monitor participants for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, blood 
or mucus in stool with or without fever) and of 
bowel perforation (ie, peritoneal signs and ileus). 
Participants with ≥ Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis.  
Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear fluids.  
If sufficient oral fluid intake is not feasible, fluid 
and electrolytes should be substituted via IV 
infusion. 
Grade 4 
Permanently 
discontinue 


 
 
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AST / ALT 
elevation or 
Increased 
bilirubin 
Grade 2 
Withhold 
Administer corticosteroids (initial 
dose of 0.5- 1 mg/kg prednisone or 
equivalent) followed by taper 
Monitor with liver function tests (consider 
weekly or more frequently until liver enzyme 
value returned to baseline or is stable 
Grade 3 or 4  
Permanently 
discontinue 
Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia 
 
Newly onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-cell 
failure 
Withhold 
Initiate insulin replacement therapy 
for participants with T1DM  
Administer anti-hyperglycemic in 
participants with hyperglycemia  
 
Monitor participants for hyperglycemia or other 
signs and symptoms of diabetes. 
Hypophysitis 
Grade 2 
Withhold 
Administer corticosteroids and initiate 
hormonal replacements as clinically 
indicated.   
 
Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal 
insufficiency)  
Grade 3 or 4  
Withhold or 
permanently 
discontinue1  
Hyperthyroidism  
Grade 2 
Continue  
Treat with non-selective beta-blockers 
(e.g., propranolol) or thionamides as 
appropriate  
Monitor for signs and symptoms of thyroid 
disorders.  
 
Grade 3 or 4  
Withhold or  
permanently 
discontinue1 
Hypothyroidism 
Grade 2-4 
Continue  
Initiate thyroid replacement hormones 
(eg, levothyroxine or liothyroinine) 
per standard of care 
Monitor for signs and symptoms of thyroid 
disorders.  
 
Nephritis and 
Renal 
dysfunction 
Grade 2 
Withhold  
Administer corticosteroids 
(prednisone 1-2 mg/kg or equivalent) 
followed by taper. 
Monitor changes of renal function 
 
Grade 3 or 4  
Permanently 
discontinue 
Myocarditis 
Grade 1 or 2 
Withhold 
Based on severity of AE administer 
corticosteroids 
Ensure adequate evaluation to confirm etiology 
and/or exclude other causes 


 
 
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Grade 3 or 4 
Permanently 
discontinue 
 
All other 
immune-related 
AEs 
Intolerable/ 
persistent Grade 2 
Withhold 
Based on type and severity of AE 
administer corticosteroids  
Ensure adequate evaluation to confirm etiology 
and/or exclude other causes 
 
Grade 3 
Withhold or 
discontinue based 
on the type of 
event.  Events that 
require 
discontinuation 
include and not 
limited to:  
Gullain-Barre 
Syndrome, 
encephalitis 
Grade 4 or 
recurrent Grade 3  
Permanently 
discontinue 
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.   
NOTE:  
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed when 
AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).   
 
 


 
 
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Dose modification and toxicity management of infusion-reactions related to 
pembrolizumab 
Pembrolizumab may cause severe or life threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly 
after drug infusion and generally resolve completely within 24 hours of completion of 
infusion. Dose modification and toxicity management guidelines on pembrolizumab 
associated infusion reaction are provided in Table 7.  
Table 7 
Pembrolizumab Infusion Reaction Dose modification and Treatment 
Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at Subsequent 
Dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital 
signs as medically indicated 
until the subject is deemed 
medically stable in the opinion 
of the investigator. 
None 
Grade 2 
Requires therapy or infusion 
interruption but responds 
promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDs, narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 hrs. 
Stop Infusion. 
Additional appropriate medical 
therapy may include but is not 
limited to: 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Increase monitoring of vital 
signs as medically indicated 
until the subject is deemed 
medically stable in the opinion 
of the investigator. 
If symptoms resolve within 1 
hour of stopping drug infusion, 
the infusion may be restarted at 
50% of the original infusion rate 
(e.g. from 100 mL/hr to 50 
mL/hr).  Otherwise dosing will 
be held until symptoms resolve 
and the subject should be 
premedicated for the next 
scheduled dose. 
Subjects who develop Grade 2 
toxicity despite adequate 
premedication should be 
permanently discontinued from 
further study drug treatment 
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of pembrolizumab with: 
Diphenhydramine 50 mg po (or 
equivalent dose of 
antihistamine). 
Acetaminophen 500-1000 mg po 
(or equivalent dose of analgesic). 


 
 
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Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae (e.g., 
renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
Stop Infusion. 
Additional appropriate medical 
therapy may include but is not 
limited to: 
Epinephrine** 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Increase monitoring of vital 
signs as medically indicated 
until the subject is deemed 
medically stable in the opinion 
of the investigator. 
Hospitalization may be 
indicated. 
**In cases of anaphylaxis, 
epinephrine should be used 
immediately. 
Subject is permanently 
discontinued from further 
study drug treatment. 
No subsequent dosing 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available 
during the period of drug administration. 
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.03 
(CTCAE) at http://ctep.cancer.gov 
 
Other allowed dose interruption for pembrolizumab  
Pembrolizumab may be interrupted for situations other than treatment-related AEs such 
as medical / surgical events or logistical reasons not related to study therapy. Subjects 
should be placed back on study therapy within 3 weeks of the scheduled interruption, 
unless otherwise discussed with the Sponsor. The reason for interruption should be 
documented in the patient's study record. 
5.6 
Concomitant Medications 
All patients will be required to be administered 800 mg of ibuprofen (or equipotent and 
equivalent alternative NSAID) prior to administration of birinapant on Day 1 and Day 8 
as prophylaxis for possible events of cranial nerve palsy associated with the 
administration of birinapant.  Patients with a history of peptic ulcer disease or gastritis 
will receive proton pump inhibitor for prophylaxis. 
 


 
 
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Restricted and prohibited medications 
Patients are prohibited from receiving the following therapies during screening and the 
treatment phase (dose-escalation and dose-expansion) of this study: 
• Antineoplastic systemic chemotherapy or biological, immune- or chemotherapy 
not specified in this protocol; 
• Granulocyte-macrophage colony-stimulating factor (GM-CSF) 
• Investigational agents other than pembrolizumab and birinapant; 
• Radiation therapy 
• Radiation therapy to a symptomatic solitary lesion or to the brain may be 
considered on an exceptional case by case basis after consultation with 
Sponsor’s Medical Monitor.  The patient must have clear measurable 
disease outside the radiated field.  Administration of palliative radiation 
therapy will be considered clinical progression for the purposes of 
determining progression. 
• Live vaccines within 30 days before the first dose of trial treatment and while 
participating in the study. Examples of live vaccines include, but are not limited 
to, the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, 
BCG, and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are 
generally killed virus vaccines and are allowed. However, intranasal influenza 
vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed. 
• Systemic glucocorticoids for any purpose other than to modulate symptoms from 
adverse event of suspected immunologic etiology. The use of physiologic doses of 
corticosteroids may be approved after consultation with the Sponsor’s Medical 
Monitor. 
• Inhaled steroids are allowed for management of asthma. 
• Anti-TNF agents are excluded while on study treatment and must be discontinued 
prior to Cycle 1 Day 1 for a period of 5 half-lives.  Examples include: 
• Infliximab (Remicade®) 
• Entanercept (Enbrel®) 
• Adalimumab (Humira®) 
• Certolizumab (Cimzia®) 
• Golimumab (Simponi®) 
Patients who, in the assessment by the Investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the study. 
Patients may receive other medications that the Investigator deems to be medically 
necessary. 


 
 
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Based on in vitro studies, birinapant is a weak-to-moderate inhibitor of CYP3A4. Co-
administration of medications that are substrates for CYP3A4 may result in an increase in 
their systemic exposures. Therefore, drugs with a narrow therapeutic index (e.g. 
alfentanil, cyclosporine, sirolimus, tacrolimus, cisapride, pimozide, fentanyl, quinidine, 
ergotamine, dihydroergotamine, astemizole, terfenadine) should be avoided. Birinapant is 
also an inhibitor of P-glycoprotein (P-gp), therefore digoxin should be used with caution. 
Birinapant is a substrate for the hepatic uptake transporter OATP1B3 and medications 
that are OATP1B3 inhibitors (e.g. cyclosporine, rifampicin, lopinavir, ritonavir) should 
be avoided.  
Because there is a potential for interaction of birinapant with other concomitantly 
administered drugs through the cytochrome P450 system and transporters such as P-gp 
and OATP1B3, the case report form must capture the concurrent use of all other drugs, 
over-the-counter medications, or alternative therapies. The Investigator should be alerted 
if the patient is taking any agent known to affect or has the potential to affect selected 
CYP450 isoenzymes, P-gp or OATP1B3.   
Medications or vaccinations specifically prohibited in the exclusion criteria are not 
allowed during the ongoing study. If there is a clinical indication for any medication or 
vaccination specifically prohibited during the study, discontinuation from study treatment 
or vaccination may be required. The Investigator should discuss any questions regarding 
this with the Sponsor’s Medical Monitor. The final decision on any supportive therapy or 
vaccination rests with the Investigator and/or the patient's primary physician. However, 
the decision to continue the patient on study treatment or vaccination schedule requires 
the mutual agreement of the Investigator, the Sponsor and the patient. 
All treatments that the Investigator considers necessary for a patient’s welfare may be 
administered at the discretion of the Investigator in keeping with the community 
standards of medical care. 
All concomitant medication will be recorded on the CRF including all prescription, over-
the-counter (OTC) medication, herbal supplements, and IV medications and fluids. 
Details regarding the generic name, reason for use, dose, route, and frequency of all 
prescription medications, OTC medications, or alternative therapies taken within 14 days 
before administration of first study dose and through 7 days after the last study-drug dose 
will be recorded. 
5.7 
Diet/Activity/Other considerations 
 
Diet 
Subjects should maintain a normal diet unless modifications are required to manage an 
AE such as diarrhea, nausea or vomiting. 
 
Contraception 
Pembrolizumab or birinapant may have adverse effects on a fetus in utero.  Furthermore, 


 
 
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it is not known if either have adverse effects on sperm.   
Subjects should be informed that taking the study medication may involve unknown risks 
to the fetus (unborn baby) if pregnancy were to occur during the study.  In order to 
participate in the study subjects of childbearing potential must adhere to the contraception 
requirement (two forms of highly effective contraception (e.g. oral contraceptive and 
condom, or intra uterine device and condom, abstinence is acceptable if this is the usual 
lifestyle and preferred contraception for the patient) from the day of study medication 
initiation (or 14 days prior to the initiation of study medication for oral contraception) 
throughout the study period up to 120 days after the last dose of study treatment.  If there 
is any question that a subject of childbearing potential will not reliably comply with the 
requirements for contraception, that subject should not be entered into the study. 
 
Use in Nursing Women 
It is unknown whether birinapant and/or pembrolizumab are excreted in human milk.  
Since many drugs are excreted in human milk, and because of the potential for serious 
adverse reactions in the nursing infant, subjects who are breast-feeding are not eligible 
for enrollment. 
 
Phototoxicity 
The initial assessment of phototoxicity (UV/visible light absorption and the MEC value) 
indicates for possible phototoxic reactions by birinapant. Therefore. as a precaution, it is 
advised that patients avoid prolonged exposure to natural or artificial sunlight (UVA/B, 
such as a tanning bed) while taking the study drug by wearing sun-protective clothes, 
applying effective sunblock to your skin, and by wearing UV protective sunglasses. 
5.8 
Patient Compliance 
Investigational product will be administered as an IV infusion by study staff and 
administration information will be recorded in the appropriate CRF. There will be no 
self-administration of investigational product by the study patients. 


 
 
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 STUDY PROCEDURES 
Study procedures and assessments to be performed for all subjects are summarized in Table 8. 
Table 8 
Schedule of Study Procedures and Assessments  
Study Procedures 
Screening 
(Within 
28 Days of 
Cycle 1 
Day 1) 
Cycle 1 
Subsequent 
Cycles 
 
 
 
Follow up  
Day 1 Day 2 
Day 8 
Day 1 
Day 8  
End of 
the Third 
Week of 
Every 
Third 21-
Day 
Cycle 
Every 
six 
weeks 
Every 
12 
weeks 
Safety Follow up Visit 
(30 Days After Study 
Drug Discontinuation) 
Progressive 
Disease/ 
Study Drug 
Discontinuation20 
Overall 
Survival 
Follow-up21 
Visit Window 
 
 
 
± 2 Days 
 
± 2 Days 
± 3 Days 
 
 
+7 Days 
± 3 Days 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ 
Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
and Disease 
Characteristics1 
X 
 
 
 
 
 
 
 
 
 
 
 
ECOG 
Performance Status 
X 
X 
 
 
X 
 
 
 
 
X 
X 
 
Serology2 (HSV, 
VZV) 
X 
 
 
 
 
 
 
 
 
 
 
 
Review Prior/ 
Concomitant 
Medications 
X 
X 
 
X 
X 
X 
 
 
 
X 
 
 
Measurement of 
Vital Signs3 
X 
X 
 
X 
X 
X 
 
 
 
X 
 
 


 
 
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Study Procedures 
Screening 
(Within 
28 Days of 
Cycle 1 
Day 1) 
Cycle 1 
Subsequent 
Cycles 
 
 
 
Follow up  
Day 1 Day 2 
Day 8 
Day 1 
Day 8  
End of 
the Third 
Week of 
Every 
Third 21-
Day 
Cycle 
Every 
six 
weeks 
Every 
12 
weeks 
Safety Follow up Visit 
(30 Days After Study 
Drug Discontinuation) 
Progressive 
Disease/ 
Study Drug 
Discontinuation20 
Overall 
Survival 
Follow-up21 
Visit Window 
 
 
 
± 2 Days 
 
± 2 Days 
± 3 Days 
 
 
+7 Days 
± 3 Days 
 
Physical 
Examination 
X 
X 
 
 
X 
 
 
 
 
X 
 
 
Weight and Height4 
X 
X 
 
 
X 
 
 
 
 
 
 
 
BSA Calculation5 
 
X 
 
 
X 
 
 
 
 
 
 
 
Serum Chemistry6 
X 
X 
 
X 
X 
X 
 
 
 
X 
X 
 
Hematology7 
X 
X 
 
X 
X 
X 
 
 
 
X 
X 
 
Urinalysis8 
X 
X 
 
 
X 
 
 
 
 
X 
 
 
Hepatitis C 
antibody 
X 
 
 
 
 
 
 
 
 
 
 
 
CA-125 (Ovarian 
Cancer patients 
only) 
X 
X 
 
 
X 
 
 
 
 
X 
 
 
CEA (CRC patients 
only) 
X 
 
 
 
 
 
 
 
X 
X 
 
 
MSI for CRC 
patients16 
X 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test 9 
X 
X 
 
 
X 
 
 
 
 
X 
 
 
12-Lead 
Electrocardiogram 
X 
X 
 
X 
X 
X 
 
 
 
X 
 
 
Adverse Events10 
 
X 
X 
X 
X 
X 
 
 
 
X 
 
 


 
 
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Study Procedures 
Screening 
(Within 
28 Days of 
Cycle 1 
Day 1) 
Cycle 1 
Subsequent 
Cycles 
 
 
 
Follow up  
Day 1 Day 2 
Day 8 
Day 1 
Day 8  
End of 
the Third 
Week of 
Every 
Third 21-
Day 
Cycle 
Every 
six 
weeks 
Every 
12 
weeks 
Safety Follow up Visit 
(30 Days After Study 
Drug Discontinuation) 
Progressive 
Disease/ 
Study Drug 
Discontinuation20 
Overall 
Survival 
Follow-up21 
Visit Window 
 
 
 
± 2 Days 
 
± 2 Days 
± 3 Days 
 
 
+7 Days 
± 3 Days 
 
Administration of 
pembrolizumab11 
 
X 
 
 
X 
 
 
 
 
 
 
 
Administration of 
NSAIDs12 
 
X 
 
X 
X 
X 
 
 
 
 
 
 
Administration of 
birinapant13 
 
X 
 
X 
X 
X 
 
 
 
 
 
 
Pharmacodynamic 
Blood Sampling14 
 
X 
X 
X 
 
 
 
 
 
 
 
 
CD3+, CD4+, 
CD8+, CD19+, 
ANC, ALC Blood 
Sampling 
 
X15 
 
X17 
 
 
 
 
 
 
 
 
Archival Tumor 
Tissue Sample for 
Pharmacodynamic 
Analysis18 
X 
 
 
 
 
 
 
 
 
 
 
 
Optional Tumor 
Biopsy Sample for 
Pharmacodynamic 
Analysis 
X18 
 
 
 
X18 
 
 
 
 
 
 
 
Radiological 
Tumor Assessment 
19 
X 
 
 
 
 
 
X 
 
 
 
X 
 


 
 
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Study Procedures 
Screening 
(Within 
28 Days of 
Cycle 1 
Day 1) 
Cycle 1 
Subsequent 
Cycles 
 
 
 
Follow up  
Day 1 Day 2 
Day 8 
Day 1 
Day 8  
End of 
the Third 
Week of 
Every 
Third 21-
Day 
Cycle 
Every 
six 
weeks 
Every 
12 
weeks 
Safety Follow up Visit 
(30 Days After Study 
Drug Discontinuation) 
Progressive 
Disease/ 
Study Drug 
Discontinuation20 
Overall 
Survival 
Follow-up21 
Visit Window 
 
 
 
± 2 Days 
 
± 2 Days 
± 3 Days 
 
 
+7 Days 
± 3 Days 
 
ANC and ALC 
 
 
X 
 
 
 
 
 
 
 
 
 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
X 
Pharmacokinetic 
Blood Sampling22 
 
X 
X 
X 
 
 
 
 
 
 
 
 
Thyroid testing6 
X 
 
 
 
 
 
 
X 
 
 
 
 
1 
Medical history and disease characteristics should include the date of the initial cancer diagnosis, a listing of relevant past and current diseases, and the details of active 
disease. 
2 
For those patients that may develop cranial nerve palsy, a second sample will be collected at the time of the event to assess for HSV (herpes simplex virus) and VZV 
(varicella zoster virus) viral titers.   
3 
Vital signs will be collected at Screening and on Days 1, and 8 of every 21-day cycle and will include blood pressure, respiration rate, heart rate, and body temperature. Vital 
signs should be collected pre- and post-administration of pembrolizumab, and; pre- and post-administration of birinapant). 
4 
Height and weight is to be measured at screening. Weight should be measured for each BSA calculation. 
5 
If a patient’s BSA is > 2.5, then 2.5 will be used to calculate the patient’s study-drug dose. If the patient’s body weight has changed > 10% from that used to calculate the 
prior BSA, the BSA will be recalculated and the dose adjusted. 
6 
Serum chemistry will be performed at screening (within 10 days of Cycle 1 Day 1) and on Days 1 and 8 of every cycle beginning with Cycle 1 Day 1.  Chemistry panel is to 
include the following parameters:  lipase, amylase, albumin, total protein, blood glucose (non-fasting), sodium, potassium, chloride, bicarbonate, magnesium, calcium, blood 
urea nitrogen (BUN), creatinine, AST, ALT, alkaline phosphatase (ALP), total bilirubin, direct bilirubin, lactate dehydrogenase (LDH), gamma glutamyltransferase (GGT), 
and phosphate.  If screening chemistry is performed within 72 hours of Cycle 1 Day 1, the sample does not need to be repeated.  Thyroid function testing includes 
triiodothyronine (T3) or free triiodothyronine (FT3), Thyroxine (T4) or free thyroxine (FT4), and TSH 
7  
Hematology will include CBC and differentials. Hematology will be performed at screening (within 10 days of Cycle 1 Day1) and on Days 1 and 8 of every cycle beginning 
with Cycle 1 Day 1. If screening hematology is performed within 72 hours of Cycle 1 Day 1, the sample does not need to be repeated  
8  
Urinalysis will be performed at screening and on Day 1 of every 21-day cycle. If screening urinalysis is performed within 72 hours of Cycle 1 Day 1, the sample does not 
need to be repeated 
9 
For women of child bearing potential, a serum pregnancy test must be performed at screening only. Urine or serum pregnancy tests must be done within 72 hours before the 
first dose of study drug.  A urine pregnancy test can be performed at all other study visits.  Monthly pregnancy testing should be conducted as per local regulations where 
applicable. 


 
 
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10 
The adverse event reporting period is from the time the patient signs consent until 30 days after study-drug discontinuation. 
Adverse events that lead to study-drug discontinuation should be followed until resolution or stabilization.  
11 
Pembrolizumab 200 mg will be administered first on Day 1 of each 21-day cycle.  
12 
All patients will be required to be administered All patients will be required to be administered 800 mg of ibuprofen (or equipotent and equivalent alternative NSAID) prior 
to administration of birinapant on Day 1 and Day 8 as prophylaxis for possible events of cranial nerve palsy associated with the administration of birinapant. 
13 
Birinapant will be administered 30 minutes (+10 minutes) after pembrolizumab on Day 1 and by itself on Day 8 of each 21-day cycle.   
14 
Pharmacodynamic blood samples will be collected from all patients in Cycle 1.  These samples will be sent to a central laboratory for analysis. 
• 
Day 1: prior to pembrolizumab (sample 1) and 4 hours post-birinapant dose (sample 2) 
• 
Day 2: 24 hours post-birinapant dose (from Day 1) (sample 3) 
• 
Day 8: prior to birinapant (sample 4) and 4 hours post-birinapant dose (sample 5) 
15 
A peripheral blood sample will be collected to assess for CD3+, CD4+, CD8+, CD19+, ANC and ALC on cycle 1 day 1 prior to the pembrolizumab infusion A CBC is 
required prior to dosing.  This sample will be analyzed locally.  
16 
MSI testing for CRC patients done at local laboratory. Results from an historical sample can be used if done within 24 months of C1D1 
17 
A peripheral blood sample will be collected to assess for CD3+, CD4+, CD8+, CD19+, ANC and ALC on cycle 1 day 8 4 hours after the completion of the birinapant infusion. 
A CBC is required prior to dosing. This sample will be analyzed locally. 
18 
Archival tumor tissue sample for biomarkers should be obtained during screening (pre-dose; paraffin embedded archival); if no archival sample is available, a fresh biopsy, 
though not required, may be obtained. A subsequent second optional fresh tumor biopsy may be requested at any time during Cycle 2 (time of sampling post-dose will be 
recorded) or after to assess the pharmacodynamics of birinapant and pembrolizumab in this patient population. For further information, consult the laboratory manual. 
19 
All patients will be required to have a CT scan of their chest, abdomen and pelvis during screening.  MRIs will be allowed but the same radiological modality must be used at 
each repeat assessment.  Repeat radiological assessments will be performed every 9 weeks (last week of every 3rd cycle).  In the event of a response, a confirmatory scan 
must be performed 4 weeks following initial assessment of response.  All radiological assessments will be reviewed according to both RECIST v 1.1 and iRECIST criteria.   
20 
Patients who discontinue from study treatment due to reasons other than disease progression will need to be followed every 30 days until documentation of disease 
progression or initiation of a new therapy for their disease. Once disease progression is documented or new therapy is initiated the patient will move into the survival follow 
up stage of the protocol.  
21 
Patients will be contacted by telephone every 3 months after last study-drug treatment for survival information and subsequent therapy information 
22  
Pharmacokinetic blood samples will be collected from all patients in Cycle 1.  These samples will be sent to a bioanalytical laboratory for analysis. 
• 
Day 1: 4 hours after completion of birinapant infusion (sample 2) 
• 
Day 2: 24 hours after completion of birinapant infusion (from Day 1) (sample 3) 
• 
Day 8: prior to birinapant (sample 4) and 4 hours after completion of birinapant infusion (sample 5) 


 
 
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6.1 
Duration of Patient Participation 
The anticipated duration of participation for the screening and treatment periods, for each 
patient, is determined by the following: 
Screening may not exceed 28 days before the first dose of study drug. In the absence of 
treatment delays due to AE(s), treatment may continue until one of the following criteria 
applies: 
1. 
Confirmed disease progression (refer to Section 9.1.2 and Section 9.1.5), 
2. 
Intercurrent illness or unacceptable AE(s) that prevents further administration of 
treatment, 
3. 
Patient decides to withdraw from the study, or 
4. 
General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the Investigator. 
 
Patients will be allowed to remain on active treatment for 35 treatment cycles or until 
documented progressive disease (PD) or unacceptable toxicity.  All patients will be 
followed for survival.   
Patients will be followed for survival until death, withdrawal of consent, or study closure, 
whichever occurs first. Patients removed from study treatment for unacceptable AE(s) 
should be followed until resolution or stabilization of the AE, and should be followed for 
disease progression and or initiation of a new therapy and survival where feasible.  
In addition, the study may be terminated by the study Sponsor; in this case all efforts will 
be made to continue to provide study drug to patients who are continuing to benefit 
clinically from them. However, this cannot be guaranteed. 
6.2 
Timing of Study Procedures 
 
Screening 
Potential patients will be contacted to determine their interest in participating in this 
study and, after providing written informed consent, will be evaluated for eligibility by 
screening tests and conformity to study inclusion and exclusion criteria. 
Once a patient is determined to be eligible for Screening and satisfy all initial inclusion 
and exclusion criteria (Section 4.1 and Section 4.2 respectively), screening procedures 
will be performed as listed below.  If at any point during Screening, a finding disqualifies 
the patient from study participation, no further screening tests will be performed. 
The Screening visit will occur within 28 days before dosing with study drug unless 
otherwise specified. 
The following assessments will be performed at the Screening visit: 
• Demographics 


 
 
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• Medical history and disease characteristics, including the following: 
o Date of initial cancer diagnosis 
o Listing of relevant past and current diseases 
o Details of active disease 
• Serology (Hepatitis C Antibody, HSV and VZV) 
• Review prior/concomitant medications 
• Vital signs (blood pressure, respiratory rate, heart rate, and body temperature) 
• CT Scan (chest, abdomen, pelvis) 
• RECIST 1.1 entry measurements. 
• Physical examination 
• Height and weight 
• ECOG performance status 
• 12-lead electrocardiogram (ECG) 
• Safety laboratory studies (chemistry, urinalysis, and other studies including serum 
pregnancy test in females of childbearing potential), complete blood count (CBC) 
and differential within 10 days of Cycle 1 Day 1 
• CA-125 sampling for ovarian cancer patients 
• MSI testing for CRC patients done at local laboratory. Results from an historical 
sample can be used if done within 24 months of C1D1  
• CEA sampling for CRC patients 
• Thyroid function testing: 
o Triiodothyronine (T3) or free triiodothyronine (FT3) 
o Thyroxine (T4) of free thyroxine (FT4) 
o TSH 
• Mandatory archival sample for pharmacodynamic analysis (pre-dose; paraffin 
embedded archival); if no archival sample is available, a fresh pre-dose biopsy, 
though not required, may be obtained. 
The patient may be enrolled upon confirmation by the Sponsor/Designee CRO that the 
patient meets the enrollment criteria. 
The Investigator will review each patient’s screening data and document the patient’s 
acceptability for study participation. If results are acceptable, the patient will be asked to 
return to the study site for the treatment phase of the study. 
For patients who fail screening, the Investigator will record demographics and reason for 
screen fail in the appropriate sections of the CRF and note the reason for exclusion.  
These documents and the patient’s signed informed consent will be retained in the study 
files. 


 
 
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During Active Protocol Treatment 
The following procedures will be performed during active protocol treatment at the times 
specified in the Study Procedures table. (Refer to Table 8) 
Day 1 of Each Cycle 
• ECOG performance status 
• Concomitant medications 
o Any medication other than the investigational products are considered 
concomitant medication and will be documented in the eCRF. This 
includes natural supplements. 
• Physical examination and vital signs 
o Vital signs including temperature, respiratory rate, blood pressure, and 
heart rate before administration of investigational product, and 
immediately following administration of investigational product. (Pre- and 
post-administration of pembrolizumab, and; pre- and post-administration 
of birinapant) Temperatures for individual patients must be measured 
using the same method at all visits. 
• Weight and BSA 
o If the patient’s BSA is greater than 2.5, 2.5 will be used to calculate the 
dose. If the patient’s body weight has changed >10% from that used to 
calculate the prior BSA, the BSA will be recalculated and the dose 
adjusted. 
• Hematology, chemistries, urinalysis and pregnancy (if applicable) 
• CA-125 sampling for ovarian cancer patients 
• 12-lead ECG 
• CD3+, CD4+, CD8+, CD19+, ANC and ALC peripheral blood sample [Cycle 1 
only (pre pembrolizumab infusion)] 
• Pharmacodynamic blood sample collection (Cycle 1 only) 
• Pharmacokinetic blood sample collection (Cycle 1 only) 
• Pharmacodynamic optional fresh tumor biopsy (Cycle 2 onwards) 
• Adverse events 
• Administration of pembrolizumab  
• Administration of NSAIDs prior to birinapant 
• Administration of birinapant followed by observation for 4 hours after completed 
infusion  
Day 2 of Cycle 1 Only 
• Pharmacodynamic blood sample collection 
• Pharmacokinetic blood sample collection 
• Absolute neutrophil count (ANC) and lymphocyte (ALC) 
• Adverse events 
 


 
 
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Day 8 of Each Cycle 
• Concomitant medications 
• Vital signs (pre- and post-administration of birinapant) 
• Adverse events 
• Pharmacodynamic blood sample collection (Cycle 1 only) 
• Pharmacokinetic blood sample collection (Cycle 1 only) 
• CD3+, CD4+, CD8+, CD19+, ANC and ALC peripheral blood sample [Cycle 1 
only (4 hours post birinapant infusion)] 
• Hematology, serum chemistry 
• 12-lead ECG 
• Administration of NSAIDs prior to birinapant 
Administration of birinapant followed by observation for 4 hours after completed 
infusion  
 End of the Third Week of Every Third Cycle 
• Radiological tumor assessment (RECIST v1.1 and iRECIST) at the end of 
Weeks 9, 18, 27, 36, etc. 
 
Every Six weeks 
• Thyroid function testing: 
o Triiodothyronine (T3) or free triiodothyronine (FT3) 
o Thyroxine (T4) or free thyroxine (FT4) 
o TSH 
Every Twelve weeks 
• CEA sampling for CRC patients 
 
6.3 
Procedures After Active Protocol Treatment Phase 
Patients will be treated until unacceptable toxicity, confirmed disease progression (refer 
to Section 9.1.5), or another criterion for treatment discontinuation is encountered.  
Patients who discontinue treatment because of adverse events will be followed until 
resolution to baseline or stabilization of the adverse event. All patients will return for a 
safety evaluation 30 days (+ 7 days) following the last dose of study drug.  
Those patients that are discontinued from study treatment due to reasons other than 
disease progression, but have not withdrawn consent to be followed for survival will need 
to be followed every 30 days until documentation of disease progression or initiation of a 
new therapy for their disease.  Once there is documentation of disease progression or 
initiation of a new therapy for their disease, the patient will move into the long-term 
survival follow up phase of the study.   
All patients will be followed every 3 months for survival. 


 
 
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Patients will be considered lost-to-follow-up only if no contact has been established by 
the time the study is completed such that there is insufficient information to determine the 
patient’s status at the end of the study. Investigators should document attempts to re-
establish contact with missing patients throughout the study period. If contact with a 
missing patient is re-established, follow-up should resume according to the protocol. 
 
Safety Follow up Visit 
The following procedures will be performed at the safety follow-up visit: 
• Physical examination 
• Vital signs 
• ECOG performance status 
• Clinical laboratory evaluations including hematology, serum chemistry, urinalysis 
and pregnancy test 
• Concomitant medication inquiry 
• Adverse events 
• 12-lead Electrocardiogram 
• CA-125 sampling for ovarian cancer patients 
• CEA sampling for CRC patients 
 
Disease Progression Follow up Visit 
Those patients that are discontinued from study treatment due to reasons other than 
disease progression, but have not withdrawn consent to be followed for survival; will 
need to be followed every 30 days until documentation of disease progression or 
initiation of a new therapy for their disease. Once there is documentation of disease 
progression or initiation of a new therapy for their disease, the patient will move into the 
long-term survival follow up phase of the study. 
The following procedures will be performed at this follow up visit: 
• Hematology, serum chemistry 
• ECOG PS 
• Radiological tumor assessment (RECIST v1.1 and iRECIST) until documentation 
of disease progression as defined by RECIST or iRECIST 
• Initiation of any new cancer therapy and type of therapy 
 
Overall Survival Follow up Visit 
Patients will be monitored by telephone every 3 months for the following: 
• Survival status 
• Date of next cancer therapy and type of therapy. Participation in any other 
interventional clinical study during follow-up is permitted. 


 
 
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 STUDY ASSESSMENTS 
7.1 
Safety Measurements 
The primary objective of the dose escalation phase and the secondary objective of the 
dose expansion phase is to assess the safety and tolerability of birinapant in combination 
with pembrolizumab, which in addition to adverse events assessments will be evaluated 
using the assessments described below. For timing of each of the safety assessments for 
all enrolled subjects refer to Section 6 and Table 8.   
 
Medical History and Disease Characteristics 
A complete medical history will include evaluation for past or present cardiovascular, 
respiratory, gastrointestinal, renal, hepatic, neurological, endocrine, metabolic, lymphatic, 
hematologic, immunologic, dermatologic, psychiatric, and genitourinary disorders, 
medication and surgical history, and review of any other diseases or disorders. 
 
Concomitant Therapy or Medication 
Concomitant therapy or medication usage will be monitored throughout the study. Details 
of restricted medications and potential drug interactions are found in Section 5.6.   
 
Eastern Cooperative Oncology Group Performance Status 
Eastern Cooperative Oncology Group (ECOG) performance status will be will be 
assessed throughout the study. 
 
Physical Examination 
The physical examination will include examination of the following: general appearance, 
head, ears, eyes, nose, throat, neck (including thyroid), skin, cardiovascular system, 
respiratory system, gastrointestinal system, musculoskeletal system, lymph nodes and 
nervous system. Any findings made during the physical examination must be noted 
regardless of if they are part of the patient’s medical history. 
 
Vital Signs 
Vital signs include sitting blood pressure, heart rate, respiratory rate, and temperature. 
Temperature for individual patients must be measured using the same methodology on 
each occasion. Respiratory rate and sitting heart rate will be counted for at least 30 
seconds. Serial measurements of heart rate and blood pressure will be obtained using the 
same arm, after two minutes’ rest, preferably using a mercury sphygmomanometer. 
Blood pressure will be recorded to the nearest mm. 


 
 
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Electrocardiograms 
12-lead ECGs will be taken in the supine position, after the patient has been lying down 
for at least three minutes. 
The following parameters will be assessed: heart rate; PR, QRS, QT, QTcF (Fridericia’s 
correction) intervals. The Investigator (or a qualified observer at the investigational site) 
will interpret the ECG using one of the following categories: within normal limits, 
abnormal but not clinically significant, or abnormal and clinically significant. 
 
Clinical Laboratory Tests 
7.1.7.1 
Hematology, Serum Chemistry, Immunology and Urinalysis, 
Serology 
The following samples will be analyzed by the local laboratory.   
Hematology with Differential: to include; hemoglobin, hematocrit, red blood cells 
(RBCs), white blood cells (WBCs), platelet count, WBC subset count (neutrophils, 
eosinophils, basophils, lymphocytes, and monocytes), mean corpuscular volume (MCV), 
mean corpuscular hemoglobin (MCH), mean cell hemoglobin concentration (MCHC). 
Clinical Chemistry - to include; lipase, amylase, albumin, total protein, blood glucose 
(non-fasting), sodium, potassium, chloride, bicarbonate, magnesium, calcium, blood urea 
nitrogen (BUN), creatinine, AST, ALT, alkaline phosphatase (ALP), total bilirubin, direct 
bilirubin, lactate dehydrogenase (LDH), gamma glutamyltransferase (GGT), and 
phosphate, thyroid function testing (triiodothyronine (T3) or free triiodothyronine (FT3), 
Thyroxine (T4) or free thyroxine (FT4), TSH). 
Immunology:  to include CD3, CD4, CD8 and CD19 
Urinalysis – Urine collected to determine pH, blood, protein, ketones, leukocyte elastase, 
nitrite, glucose, specific gravity, urobilinogen, and bilirubin.  If blood, leukocytes or 
nitrites are detected, microscopy will be completed. 
Serology: to include Hepatitis C Antibody 
7.1.7.2 
Pregnancy Testing 
The following samples will be analyzed at local laboratory.   
For women of childbearing potential, a negative serum β-HCG pregnancy test is required 
at screening to confirm eligibility.  A stat negative urine pregnancy test is required before 
dosing on Days 1 of each cycle.  
7.1.7.3 
Histology 
Submission of formalin-fixed paraffin embedded tumor tissue sample blocks are 
preferred; if submitting unstained slides, the slides should be freshly cut and submitted to 


 
 
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the testing laboratory within 7 days from site slide sectioning date otherwise a new 
specimen will be requested. See laboratory manual.         
Note:  Subjects for whom an archived sample cannot be obtained may submit a newly 
obtained specimen only upon agreement from the Sponsor.  
 ADVERSE EVENTS 
8.1 
Definition of Adverse Events 
As defined by the ICH/GCP (CPMP/ICH/135/95), an AE is: 
• Any untoward medical occurrence in a study patient administered a 
pharmaceutical product and which does not necessarily have a causal relationship 
with this treatment.  
• An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal product, whether or not considered related to the medicinal 
product. 
An AE includes but is not limited to: 
• Any clinically significant worsening of a patient’s pre-existent condition 
• An overdose, whether accidental or deliberate, defined as a dose higher than that 
prescribed by a healthcare professional for clinical reasons, or a dose higher than 
that described in the approved labelling for a marketed product, or in available 
clinical data for a study drug 
• Abuse (i.e., use for nonmedical reasons) of an investigational or marketed product 
Note: Progression of the cancer under study is not considered an adverse event. 
A protocol-related AE is any AE that bears a direct relationship to a study procedure or 
the alteration of ongoing pre-study drug regimens, medical procedures, or treatments 
discontinued as required by the protocol.  
 
Recording and Reporting of Adverse Events 
All adverse events that occur after the consent form is signed but before treatment start 
must be reported by the investigator if they cause the subject to be excluded from the 
study, or are the result of a protocol-specified intervention, including but not limited to 
washout or discontinuation of usual therapy, diet, placebo treatment or a procedure. 
From the time of treatment start through 30 days following cessation of treatment, all 
adverse events must be reported by the investigator. Such events will be recorded at each 
examination on the Adverse Event case report forms/worksheets.  The reporting 
timeframe for adverse events meeting any serious criteria is described in section 
Immediate Reporting of Adverse Events to the Sponsor. The investigator will make every 
attempt to follow all subjects with non-serious adverse events for outcome. 


 
 
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AEs will be reported in accordance with the NCI CTCAE v4.03, using a recognized 
medical term or diagnosis that accurately reflects the event. AEs will be assessed by the 
Investigator 
for 
severity 
and 
relationship 
to 
investigational 
product 
(birinapant/pembrolizumab), for other possible etiologies, and whether the event meets 
criteria as an SAE and therefore requires immediate notification to the Sponsor. If an AE 
has not resolved at the end of the study reporting period, it will be documented as 
ongoing. If an AE evolves into a condition that becomes “serious,” it will be reported as 
an SAE. 
For hematological toxicity fluctuations, record the highest grade during the cycle on the 
patient’s eCRF. 
 
Severity of an Adverse Event 
Severity of AEs will be graded according to NCI CTCAE version 4.03. 
AEs that are not included in the NCI CTCAE lists will be graded according to the NCI 
CTCAE general guideline for grades as follows: 
Grade 1 
Mild, asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
Grade 2 
Moderate, minimal, local intervention, or noninvasive intervention indicated; 
limiting age-appropriate instrumental activities of daily living (ADL), e.g., 
preparing meals, shopping for groceries or clothes, using the telephone, 
managing money. 
Grade 3 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL, e.g., bathing, dressing and undressing, feeding self, 
using the toilet, taking medications, and not bedridden. 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to adverse event  
 
Relationship of an Adverse Event 
Causal relationship to study drug will be rated as follows: 
• Not Related – 
o A medical condition that is present before the administration of study drug 
unless the condition worsens or episodes increase in frequency after 
administration of investigational product; 
o Symptoms that are reasonably determined to be the normal course of the 
disease state (NOTE: life-threatening complications from cancer are 
considered SAEs); 
o An event for which sufficient information exists to indicate the etiology is 
related to a concomitant medication; 


 
 
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o Medical events (e.g., unrelated illness, accident, or trauma) that occur 
during the clinical study for which sufficient information exists to indicate 
that the etiology is not related to the investigational product; 
o Symptoms from procedures such as surgery or radiation which are not a 
direct result of receiving investigational product. 
• Possibly Related – 
o An event that follows a reasonable temporal sequence from administration 
of the investigational product; 
o An event that follows a known or expected response pattern to the 
suspected investigational product but could readily have been produced by 
a number of other factors. 
• Probably Related - 
o An event that follows a reasonable temporal sequence from investigational 
product administration; 
o An event that follows a known or expected response pattern to the 
suspected investigational product; 
o Is confirmed by stopping or reducing the dosage of the investigational 
product; 
o Cannot be reasonably explained by the known characteristics of the 
patient’s clinical state or by other factors. 
• Definitely Related - 
o An event that follows a reasonable temporal sequence from investigational 
product administration; 
o Follows a known or expected response pattern to the suspected 
investigational product; 
o Is confirmed by improvement on stopping or reducing the dosage of the 
investigational product and reappearance of the reaction on repeated 
exposure unless the latter is considered to be medically unethical. 
Certain drug-mediated AEs and laboratory abnormalities may not resolve promptly upon 
dechallenge.  While dechallenge-rechallenge may afford the Investigator greater 
confidence regarding causality of an AE, the welfare and consent of the patient must be 
primary in any decision to rechallenge with discontinued investigational product.  In the 
absence of rechallenge, the Investigator will use his/her best judgment and consider all 
available information when determining the most likely relationship between the AE and 
investigational product treatment. 
The designee CRO pharmacovigilance physician will review AE attribution 
independently.  This is not a conclusive determination of causal association between the 
investigational product and the event.  Whenever the Investigator’s assessment is 


 
 
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unknown or unclear, the AE will be treated as investigational product-related for the 
purposes of reporting to regulatory authorities. 
8.2 
Serious Adverse Events 
 
Definition of a Serious Adverse Event 
A SAE is an AE that results in any of the following outcomes: 
• Results in death 
• Is life threatening (i.e. the patient is at immediate risk of death at the time the 
event occurred; it does not refer to an event which might hypothetically have 
caused death had it been more severe) 
• Requires in-patient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Other (medically important) events that may not result in death, be life-
threatening, or require hospitalization may be considered serious when, based 
upon appropriate medical judgment, they may jeopardize the patient and may 
require medical or surgical intervention to prevent one of the outcomes listed in 
this definition.  Examples include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that 
do not result in in-patient hospitalization, or the development of drug dependency 
or drug abuse. 
If there is any doubt whether the AE constitutes an SAE, it should be treated as serious 
and reported as such, until confirmation can be obtained. 
 
Expectedness 
An AE is considered unexpected if it has not been described previously in either 
published descriptions of the investigational product (e.g., package inserts), in the 
medical literature, or in reports of previous clinical trials of the investigational product, 
including the IB. 
8.3 
Notification/Reporting of a Serious Adverse Event 
In addition to the criteria listed in Section 8.2.1, adverse events meeting either of the 
below criteria, although not serious per ICH definition, are reportable to the Sponsor in 
the same timeframe as SAEs to meet certain local requirements. 
Therefore, these events are considered serious by the Sponsor for collection purposes, if 
they are. 
● 
A new cancer (that is not a part of the cancer being studied); or 
● 
Associated with an overdose. 


 
 
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For the time period beginning when the consent form is signed until treatment start, any 
serious adverse event, or follow up to a serious adverse event, including death due to any 
cause other than progression of the cancer under study (refer to Section 9.1 for additional 
details), that occurs to any subject must be reported within 24 hours to the Sponsor if it 
causes the subject to be excluded from the study, or is the result of a protocol-specified 
intervention, including but not limited to washout or discontinuation of usual therapy, 
diet, placebo treatment or a procedure. 
For the time period beginning at treatment start through 90 days following cessation of 
treatment, or 30 days following cessation of treatment if the subject initiates new 
anticancer therapy, whichever is earlier, any serious adverse event, or follow up to a 
serious adverse event, including death due to any cause other than progression of the 
cancer under study (refer to Section 9.1 for additional details), whether or not related to 
the Sponsor's product, must be reported within 24 hours to the Sponsor by paper.. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent) 
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
investigator at any time following consent through the end of the specified safety follow-
up period specified in the paragraph above, or at any time outside of the time period 
specified in the previous paragraph also must be reported immediately to the Sponsor. 
After submitting an initial SAE report for a patient, the Investigator is required to follow 
the patient proactively and provide further information on the patient’s condition to 
Diamond PV Services Ltd. 
 
 
All subjects with SAEs should be followed to resolution or stabilization by the 
Investigator or until 30 days after the last dose of any investigational product.  All related 
SAEs should continue to be followed, even if this extends beyond the study reporting 
period. Resolution of an SAE is defined as the return to baseline status or stabilization of 
the condition with the expectation that it will remain chronic.  
To the Institutional Review Board 
In addition to reporting the SAE to the Sponsor or representative, the Investigator must 
also notify the IRB which approved the study according to their requirements. 
Copies of all correspondence relating to reporting of any SAEs should be maintained in 
the site’s study files and will be checked routinely by the Study Monitor. 
 
Diamond PV Services Ltd 
 
 
Central Email 
pvservices@diamondpharmaservices.com  
Fax number 
+44 (0) 1279 418 964 


 
 
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8.4 
Notification of Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical 
Interest (ECI) and must be reported to the Sponsor. 
Events of clinical interest for this study include: 
1. An overdose of Sponsor's product, as defined for pembrolizumab as ≥1000 mg (5 
times the dose) and for birinapant as any dose ≥15% greater than the protocol 
assigned cohort dose that may or may not be associated with clinical symptoms or 
abnormal laboratory results. No specific information is available on the treatment of 
overdose of pembrolizumab or birinapant. In the event of overdose, the subject should 
be observed closely for signs of toxicity.  Appropriate supportive treatment should be 
provided if clinically indicated. 
2. An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit 
of normal and an elevated total bilirubin lab value that is greater than or equal to 2X 
the upper limit of normal and, at the same time, an alkaline phosphatase lab value that 
is less than 2X the upper limit of normal, as determined by way of protocol-specified 
laboratory testing or unscheduled laboratory testing.  Corresponding redacted local 
laboratory report must be sent in with the SAE reporting form. 
The purpose of the criteria is to specify a threshold of abnormal hepatic tests that may 
require an additional evaluation for an underlying etiology.  The trial site guidance for 
assessment and follow up of these criteria can be found in the Investigator Trial File 
Binder (or equivalent). 
3. A cranial nerve palsy 
For the time period beginning when the consent form is signed until treatment start, any 
ECI, or follow up to an ECI, that occurs to any subject must be reported within 24 hours 
to the Sponsor if it causes the subject to be excluded from the study, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure. 
For the time period beginning at treatment start through 30 days following cessation of 
treatment, any ECI, or follow up to an ECI, whether or not related to the Sponsor’s 
product, must be reported within 24 hours to the Sponsor, by paper.    Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent). 
8.5 
Withdrawal Due to an Adverse Event 
Any patient who experiences an AE may be withdrawn from investigational product 
treatment and/or the study at any time, at the discretion of the Investigator.  If a patient is 
withdrawn wholly or in part because of an AE, both the AE page and termination page 
(end of treatment termination and/or study termination) of the CRF will be completed at 
that time, especially if the patient may not be able to return to the investigative site for the 
regularly scheduled follow-up visit. 


 
 
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The patient’s condition will be monitored until the event has resolved or stabilized, until 
the patient is referred to the care of a health care professional, or until a determination of 
a cause unrelated to the study drug or study procedure is made. 
8.6 
Pregnancy 
Based on information solicited by the Investigator at scheduled study follow-up or 
provided spontaneously by patients at any time, if a patient becomes pregnant or the 
partner of a male patient participating in the study becomes pregnant during the study or 
within 3 months of discontinuing the investigational product (birinapant/pembrolizumab), 
the Investigator will report the pregnancy to Diamond PV Services Ltd within 24 hours. 
If treatment with investigational product is ongoing at the time, the investigational 
product will be immediately discontinued for any female patient who becomes pregnant.  
The female patient or the partner of a male patient should be followed at least monthly by 
the Investigator and the subject’s status documented until the pregnancy has been 
completed or terminated.  The outcome of the pregnancy will be reported to the Sponsor 
without delay and within 24 hours if the outcome is a serious adverse experience (e.g., 
death, abortion, congenital anomaly, or other disabling or life-threatening complication to 
the mother or newborn).  The study investigator will make every effort to obtain 
permission to follow the outcome of the pregnancy and report the condition of the fetus 
or newborn to the Sponsor.  If the pregnancy ends for any reason before the anticipated 
date, the Investigator will attempt to determine the cause and will notify the Sponsor.  At 
the completion of the pregnancy, the Investigator will document the outcome of the 
pregnancy.  If the outcome of the pregnancy meets the criteria for immediate 
classification as an SAE (i.e. postpartum complication, spontaneous abortion, stillbirth, 
neonatal death, or congenital anomaly) the Investigator will pregnancy will be reported to 
the Sponsor without delay and within 24 hours if the outcome is a serious adverse 
experience (e.g., death, abortion, congenital anomaly, or other disabling or life-
threatening complication to the mother or newborn). The study investigator will make 
every effort to obtain permission to follow the outcome of the pregnancy and report the 
condition of the fetus or newborn to the Sponsor.   
 
Reporting of Pregnancy and Lactation to the Sponsor 
Although pregnancy and lactation are not considered adverse events, it is the 
responsibility of investigators or their designees to report any pregnancy or lactation in a 
subject (spontaneously reported to them) that occurs during the study.  
Pregnancies and lactations that occur after the consent form is signed but before 
treatment start must be reported by the investigator if they cause the subject to be 
excluded from the study, or are the result of a protocol-specified intervention, including 
but not limited to washout or discontinuation of usual therapy, diet, placebo treatment or 
a procedure.   


 
 
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Pregnancies and lactations that occur from the time of treatment start through 120 days 
following cessation of Sponsor’s product, or 30 days following cessation of treatment if 
the subject initiates new anticancer therapy, whichever is earlier, must be reported by the 
investigator.  All reported pregnancies must be followed to the completion/termination of 
the pregnancy. Pregnancy outcomes of spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage and 
stillbirth must be reported as serious events (Important Medical Events). If the pregnancy 
continues to term, the outcome (health of infant) must also be reported. 
Such events must be reported within 24 hours to the Sponsor by paper. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent). 
 EFFICACY 
Although the clinical benefit of the combination of these drug(s) has not yet been 
established, the intent of offering this treatment is to provide a possible therapeutic 
benefit, and thus the patient will be carefully monitored for tumor response and symptom 
relief in addition to safety and tolerability.  Patients with measurable disease will be 
assessed using RECIST v 1.1 and iRECIST (Seymour et al. 2017). For the purposes of 
this study, all patients will be required to have a CT scan of their chest, abdomen, and 
pelvis within 28 days of Cycle 1 Day 1 and then will be re-evaluated every 9 weeks (end 
of every 3rd treatment cycle).  The same radiological imagining modality used at 
screening must be used throughout the patient’s course of treatment (CT or MRI; X-ray is 
not adequate to assess measurable disease).  In the event of a response, a confirmatory 
scan must be performed 4 weeks following initial assessment of response. 
9.1 
Antitumor Effect 
Response and progression will be evaluated in this study using Response Evaluation 
Criteria in Solid Tumors (RECIST) guideline version 1.1. and iRECIST.    
 
Tumor Imaging  
Tumor imaging should be performed by computed tomography (CT) (preferred). MRI 
should only be used when CT is contraindicated or for imaging in the brain, but the same 
imaging technique should be used in a patient throughout the study.  An MRI can be 
utilized if clinically appropriate.  X-ray may not be used to assess disease. 
All patients are required to have a CT of the chest, abdomen, and pelvis within 28 days of 
Cycle 1 Day 1.  Local site study team reading (Investigator assessment with site 
radiology reading) based on RECIST 1.1 and iRECIST will be used to determine patient 
eligibility and response.   
Scans performed as part of routine clinical management are acceptable for use as initial 
tumor imaging if they are of diagnostic quality and performed within 28 days before 
Cycle 1 Day 1.   


 
 
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RECIST 1.1 Response Criteria 
Table 9 
Disease Response Criteria for Target and Non-Target Lesions 
Category 
Response Criteria 
Target Lesions 
Non-Target Lesions 
Complete 
Response (CR) 
Disappearance of all target lesions.  Any 
pathological lymph nodes (target or non-
target) must have reduction in short axis 
to < 10mm.   
Disappearance of all non-target 
lesions.  All lymph nodes must 
be non-pathological in size (< 
10mm short axis).   
Partial Response 
(PR) 
A ≥ 30% decrease in the sum of the 
longest diameter of target lesions, taking 
as reference the baseline sum longest 
diameter 
N/A 
Non-CR/Non PD 
N/A 
Persistence of one or more non-
target lesion(s). 
Not Evaluable 
When no imagining/measurement is done 
at a particular time-point or if only a 
subset of lesions is made at an assessment. 
When no 
imagining/measurement is 
done at a particular time-point 
or if only a subset of lesions is 
made at an assessment.   
Stable Disease 
(SD) 
Neither sufficient shrinkage to qualify for 
PR nor sufficient increase to qualify for 
PD, taking as reference the smallest sum 
longest diameter since treatment started.   
N/A 
Progressive 
Disease (PD) 
A ≥ 20% increase in the sum of the 
longest diameter of target lesions, taking 
as reference the smallest sum longest 
diameter recorded since the treatment 
started, or the appearance of one or more 
new lesions.   
Appearance of one or more 
new lesions, and/or 
unequivocal progression of 
existing non-target lesions.   
Source: (Eisenhauer et al. 2009). 
 


 
 
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Table 10 
Time Point Response:  Patients with Target (+/- Non-Target) Disease 
Target Lesions 
Non-Target Lesions 
 New Lesions 
 Overall Response  
CR 
CR 
No  
CR 
CR 
Non CR/Non-PD 
No 
PR 
CR 
Not Evaluated 
No 
PR 
PR 
Non-PD or Not all 
Evaluated 
No 
PR 
SD 
Non-PD or Not all 
Evaluated 
No 
SD 
Not All Evaluated 
Non-PD 
NO 
NE 
PD 
Any 
Yes or NO 
PD 
Any 
PD 
Yes or NO 
PD 
Any 
Any 
Yes 
PD 
CR=complete response, PR=partial response, SD=stable disease, PD=progressive disease, and NE=not 
evaluated 
Source:  (Eisenhauer et al. 2009). 
9.1.2.1 
Lesions that become too small to measure 
As patients respond to treatment, target lesions may be too small to measure.  The 
radiologist performing the tumor evaluation must provide clear documentation that the 
lesion is either ‘present, but too small to measure’ or must document that the lesion has in 
fact disappeared.  In the case where the lesion has disappeared then the measurement 
would be recorded as 0 mm.  However, in all cases the radiologist must make an attempt 
to provide an actual measurement of all target lesions, even if the lesion measures less 
than 5mm.  In cases where the lesion is too small to measure and the radiologist cannot 
provide a measurement, a measurement of 5 mm will be documented.   
9.1.2.2 
Lesions that split or grow together 
If a target lesion splits into two separate lesions, the lesion diameters need to be added 
together to calculate the sum of the lesions.  If two target lesions grow together, the 
vector of the longest diameter of the now merged lesions will be recorded as the lesion 
measurement.   
 
On-Study Tumor Imaging 
Following the screening CT scans, patients are to have repeat radiological assessments at 
the end of Cycle 3 [9 weeks (63 days ±3 days) from Cycle 1 Day 1].  Subsequent 
radiological assessments are to be performed every 9 weeks (at the end of every 3rd 
treatment cycle) until documentation of disease progression.  If cycles become delayed, 
for whatever reason, the imaging schedule will as a default follow a nine-week pattern 
regardless of where in terms of cycles the subject is.  If there is a large mismatch the PI 
can discuss frequency with the medical monitor   
Per RECIST 1.1, if a patient has a documented partial or complete response, a 


 
 
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confirmatory tumor radiological assessment is to be performed not less than 4 weeks 
from the date the response was first documented.   
Patients are to continue to have tumor assessments performed until whichever of the 
following occurs first:  
• Site-assessed disease progression is documented 
• The start of new anti-cancer treatment 
• Withdrawal of consent 
• Death  
• The end of the study 
 
Immune RECIST (iRECIST) 
RECIST 1.1 will be adapted to account for the unique tumor response characteristics seen 
with treatment of pembrolizumab.  Immunotherapeutic agents such as pembrolizumab 
may produce antitumor effects by potentiating endogenous cancer-specific immune 
responses.  The response patterns seen with such an approach may extend beyond the 
typical time course of responses seen with cytotoxic agents, and can manifest a clinical 
response after an initial increase in tumor burden or even the appearance of new lesions.  
Standard 
RECIST 
may 
not 
provide 
an 
accurate 
response 
assessment 
of 
immunotherapeutic agents such as pembrolizumab. Therefore, RECIST 1.1 will be used 
with the following adaptations: 
• If radiologic imaging verifies initial progressive disease (PD), tumor assessment 
should be repeated ≥4 (iRECIST 4-8) weeks later in order to confirm PD with the 
option of continuing treatment per below while awaiting radiologic confirmation 
of progression. 
At initial progressive disease based on RECIST 1.1 criteria, iRECIST: can have iUPD 
(Unconfirmed Progressive Disease).  Imaging must then be repeated 4-8 weeks later.  
Progression is defined as the time of the first iUPD followed by the next confirmatory 
scan showing progression.  Thus, iPFS is defined as the time to iUPD if the next scan (4-
8 weeks later) confirms PD (state change from iUPD to iCPD, time to progression 
defined in this instance as iUPD).  Note: following iUPD, if the next assessment is not a 
CPD, treatment can continue until iCPD is documented. 
• iRECIST criteria: 
o For iUPD; if repeat imaging shows < 20% tumor burden increase 
compared to nadir, stable or improved previous new lesion (if identified as 
cause for initial PD), and stable/improved non-target disease (if identified 
as cause for initial PD), treatment may be continued/resumed.   
o NOTE; if repeat imaging confirms PD due to any of the scenarios listed 
below, patients will be discontinued from study therapy.  
 


 
 
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In determining whether or not the tumor burden has increased or decreased, site study 
team should consider all target lesions as well as non-target lesions. 
 
Scenarios where PD is confirmed at repeat imaging (iCPD): 
• Tumor burden remains ≥ 20% and at least 5 mm absolute increase compared to nadir 
• Non-target disease resulting in initial PD is worse (qualitative) 
• New lesion resulting in initial PD is worse (qualitative) 
• Additional new lesion(s) since last evaluation 
In patients who have initial evidence of radiological PD, it is at the discretion of the 
treating physician whether to continue a patient on study treatment until repeat imaging is 
obtained.  This clinical judgment decision should be based on the patient’s overall 
clinical condition, including performance status, clinical symptoms, and laboratory data. 
iRECIST criteria include the above RECIST 1.1 derived criteria (see Table 11 and Table 
12 below) with the proviso that the increase in tumor burden must be shown to increase, 
but in the case of iUSD, iUPR or iCR, the assessment time bar is reset. 
For target lesions, iCR, iPR and iSD can all be assigned after iUPD has been documented 
as long as iCPD has not been confirmed.  Progression is confirmed in the target lesion 
category if the next imaging assessment after iUPD (4-8 weeks later) confirms an 
increase in the sum of target lesions dimensions of greater than 5 mm.  However, iCPD is 
not met if the imaging assessment after iUPD is followed by CR, PR or SD (compared to 
baseline as defined in RECIST 1.1).  The status is reset and assessment continues.  Please 
note this is different from RECIST 1.1 
Thus iUPD can be assigned on multiple occasions, as long as iCPD is not declared. 


 
 
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Table 11 
Comparison of RECIST 1.1, iRECIST and irRECIST 
 
RECIST 1.1 
iRECIST 
irRECIST 
Definitions of disease: 
numbers, sites and 
target or non 
Measurable are 
diameters greater 
than 10 mm (15 for 
nodes maximum of 5 
(2 per organ) 
No change from 
RECIST 1.1 
No change from 
RECIST 1.1 
CR, PR or SD 
Cannot have met 
criteria for 
progression 
Can have had iUPD 
(more than once) but 
not iCPD before iCR, 
iPR or iSD 
Use of terminology 
based around 
RECIST 1.1 
Confirmation of CR or 
PR 
Only in non-
randomized studies 
As per RECIST 1.1 
As per RECIST 1.1 
Confirmation of SD 
Not required 
As per RECIST 1.1 
As per RECIST 1.1 
New lesions 
Progression: recorded 
but not measured 
iUPD but only 
becomes iCPD if on 
the next scan there 
are new lesions or the 
size increases by 
greater than 5 mm 
Unclear 
Confirmation of 
progression 
Not required 
Required 
Required 
Consideration of clinical 
status 
Not required 
Clinical stability 
considered at iUPD 
to decide treatment 
continuation 
As iRECIST without 
terminology 
considering 
unconfirmed findings 
 


 
 
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Table 12 
Trajectory of progression in iRECIST 
 
Time point response with 
no previous iUPD in any 
category 
Time point response with 
previous iUPD in any 
category* 
Target Lesions: iCR, Non-
target: iCR, no new lesions 
iCR 
iCR 
Target lesions: iCR, Non-
target: non iCR/non iUPD, 
no new lesions 
iPR 
iPR 
Target Lesions: iPR, Non-
target: non iCR/non iUPD, 
no new lesions 
iPR 
iPR 
Target lesions: iSD, Non-
target: non iCR/non iUPD, 
no new lesions 
iSD 
iSD 
Target lesions: iUPD with no 
change or with a decrease 
from the last time point, 
Non-target: iUPD with no 
change or decrease from last 
time point, new lesions 
NA 
New lesions confirm iCPD if 
new lesions previously 
identified and increased in size 
(≥ 5 mm in sum of measures 
for new lesions or any increase 
for new lesion non-target) or 
increase in number.  If no 
change is seen in new lesions 
assignment remains iUPD  
Target lesions: iSD, iPR, 
iCR, non-target: iUPD, no 
new lesions 
iUPD 
Remains iUPD unless iCPD is 
confirmed by increase in the 
size of non-targets (does not 
need to meet RECIST 1.1 
criteria) 
Target lesions: iUPD, non-
target: non iCR/non iUPD, 
no new lesions 
iUPD 
Remains iUPD unless iCPD 
confirmed on the basis of 
further increase ≥ 5 mm; 
otherwise stays as iUPD 
Target lesions: iUPD, non-
target: iUPD, no new lesions 
iUPD 
Remains iUPD unless iCPD 
confirmed on previously 
identified targets iUPD ≥ 5 
mm or non-target iUPD 


 
 
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Target lesions: iUPD, non-
targets: iUPD, new lesions 
iUPD 
Remains iUPD unless iCPD 
confirmed by increase of ≥ 5 
mm previously identified 
target, or non-target or an 
increase in size or number of 
new lesions 
Target lesions non iUPD or 
progression, non-targets: 
non iUPD or progression, 
new lesions 
iUPD 
Remains iUPD unless iCPD 
confirmed by increase in size 
or number of new lesions 
previously identified.  
Target lesions, non-target lesions and new lesions are defined according to RECIST 1.1 criteria: if no 
pseudoprogression occurs, RECIST 1.1 and iRECIST categories for CR, PR and SD are the same.  * 
Previously identified in the assessment prior to this time point.  ‘I’ indicates immune responses assigned 
using iRECIST 
Patients may receive study drugs treatment while waiting for confirmation of PD if they 
are clinically stable as defined by the following criteria: 
• Absence of signs and symptoms indicating disease progression 
• No decline in ECOG performance status 
• Absence of rapid progression of disease 
• Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention 
• No requirement for intensified management of disease related symptoms exists, 
including analgesia, radiotherapy and palliative care 
 
When feasible, patients should not be discontinued until progression is confirmed.  This 
allowance to continue treatment despite initial radiologic progression takes into account 
the observation that some patients can have a transient tumor flare in the first few months 
after the start of immunotherapy, but with subsequent disease response.  Patients that are 
deemed clinically unstable are not required to have repeat imaging for confirmation of 
progressive disease. 
 
In Study iRECIST Assessment of Disease 
As noted above, if tumor imaging shows initial disease progression, the study site may 
elect to continue treatment, repeat imaging 4-8 weeks later and assess tumor response or 
confirmed progression per iRECIST. 
iRECIST is the adaptation of RECIST 1.1 as described below to account for the unique 
tumor response seen with immunotherapeutic drugs. iRECIST will be used by site 
investigator/local radiology review to assess tumor response and progression, and make 
treatment decisions. This data will be collected in the clinical database. Treatment 
efficacy based on iRECIST as assessed by central imaging vendor review will be 


 
 
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evaluated retrospectively.  
Table 13 
Imaging and treatment after first radiologic evidence of PD (iRECIST 
designation iUPD)  
 
Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
1st radiologic 
evidence of PD by 
RECIST 1.1  
Repeat imaging at > 
4 weeks at site to 
confirm PD 
May continue study 
treatment at the 
local site 
Investigator’s 
discretion while 
awaiting 
confirmatory tumor 
imaging by site by 
iRECIST. 
Repeat imaging at > 
4 weeks to confirm 
PD per physician 
discretion only 
Discontinue 
treatment 
Repeat tumor 
imaging confirms 
PD by iRECIST at 
the local site 
No additional 
imaging required 
Discontinue 
treatment (exception 
is possible upon 
consultation with 
sponsor) 
No additional 
imaging required 
N/A 
Repeat tumor 
imaging shows SD, 
PR or CR by 
iRECIST by the 
local site 
 
Continue regularly 
scheduled imaging 
assessments  
Continue study 
treatment at the 
local site 
Investigator’s 
discretion 
Continue regularly 
scheduled imaging 
assessments  
May restart study 
treatment if 
condition has 
improved and/or 
clinically stable per 
Investigator’s 
discretion. Next 
tumor image should 
occur according to 
the every 9 week 
(63  ± 7 days) 
imaging schedule  
 
• 
In determining whether or not the tumor burden has increased or decreased, local 
study site investigators should consider all target lesions as well as non-target 
lesions.  Subjects that are deemed clinically unstable are not required to have 
repeat tumor imaging for confirmation. 
• For a clinically stable subject with first radiologic evidence of progressive 
disease by RECIST 1.1 (i.e., unconfirmed progression of disease or iUPD), it 
is at the discretion of the site investigator to continue treating the subject with 
the assigned treatment per protocol until progression of disease (iCPD) is 
confirmed at least 28 days from the date of the scan first suggesting PD. If 
radiologic progression is confirmed by subsequent scan then the subject will be 
discontinued from trial treatment. If radiologic progression is not confirmed by 
iRECIST per the site, then the patient should resume or continue trial treatment 
and have their next tumor imaging according to the protocol schedule of every 9 
weeks (end of every 3rd treatment cycle) until progression is confirmed at a later 
timepoint by the site. In applying iRECIST, the appropriate documentation at 


 
 
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each time point must be made (i.e. iSD, iUPR, iUCR). For a more comprehensive 
and detailed account of the application of RECIST 1.1 and iRECIST for in-study 
imaging assessments please refer to the imaging guide document Note that 
RECIST 1.1 must always serve as the primary imaging assessment guide up to the 
first indication of disease progression after which iRECIST may be used as 
described. 
• Any subject deemed clinically unstable should be discontinued from trial 
treatment at 1st radiologic evidence of PD and is not required to have repeat 
imaging for PD confirmation. 
• In subjects who discontinue study therapy without documented disease 
progression, every effort should be made to continue monitoring their disease 
status by tumor imaging using the same imaging schedule used while on treatment 
(every 9 weeks), until (1) the start of new anti-cancer treatment, (2) disease 
progression (3) death, or (4) the end of the study, whichever occurs first. 
If a subject has confirmed radiographic progression (i.e. 2 scans at least 4 weeks apart 
demonstrating progressive disease) per iRECIST, but the subject is achieving a clinically 
meaningful benefit, and there is no further increase in the tumor burden at the 
confirmatory tumor imaging, an exception to continue treatment may be considered 
following consultation with the Sponsor’s Medical Monitor. In this case, if treatment is 
continued, tumor imaging should continue to be performed following the intervals as 
outlined in sections 6.0 Study Flowchart and be submitted to the central imaging vendor. 
iRECIST: for the sequences of imaging assessments following iUPD please see Table 11 
and Table 12. 
  PHARMACODYNAMIC SAMPLING 
Pharmacodynamic blood samples will be collected on Cycle 1 Day 1 before the dose of 
pembrolizumab and 4 hours post-birinapant dose and on Cycle 1 Day 2 at 24 hours post-
birinapant dose.  On Cycle 1 Day 8, pharmacodynamics blood samples will be collected 
before the dose of birinapant, and 4 hours post-birinapant dose.  Refer to Table 14.   


 
 
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Table 14 
Timing of Pharmacodynamic Sampling 
Birinapant Infusion (Cycle 1 Day 1) 
Sample 1 
Prior to pembrolizumab infusion 
Sample 2 
4 hours after the end of the birinapant infusion 
Birinapant Infusion (Cycle 1 Day 2) 
Sample 3 
24 hours after completion of birinapant infusion 
Birinapant Infusion (Cycle 1 Day 8) 
Sample 4 
Prior to birinapant infusion 
Sample 5 
4 hours after the end of the birinapant infusion 
Blood samples will be collected to evaluate changes in cIAP1 expression in pre- and 
post-treatment samples as a pharmacodynamic marker of birinapant activity. Blood 
samples (PBMCs) may also be evaluated for gene expression studies to understand the 
mechanism of action of the combination of birinapant and pembrolizumab. 
Serum samples will be evaluated for cytokines such as GM-CSF, IFNγ, IL10, IL2, IL3, 
IL4, IL5, IL6, IL7, IL8, MIP-1α, MIP-1β, MCP-1, TNFα, and TNFβ. 
Paraffin embedded archival tumor tissue will be obtained if available from all patients for 
gene expression studies, immunohistochemistry for PD-L1 and cIAP1 expression and for 
assessment of Tumor Infiltrating Lymphocytes (TILs). In patients for whom a paraffin 
embedded archival tissue sample is not available, a pre-dose fresh tumor biopsy may be 
performed however this is not required for participation on the study, and patients 
without a paraffin embedded archival sample or a fresh biopsy may still be enrolled. 
Patients may also consent to have an optional post-dose tumor biopsy at a single time-
point any time during or after Cycle 2. 
Translational biomarker assessments of blood, archival tumor samples and optional 
tumor biopsy samples will be evaluated (see Table 15). Pre- and post-treatment changes 
in the expression of cIAP1 in peripheral blood samples will be assessed. Pre-treatment 
PD-L1, cIAP1 and Tumor Infiltrating Lymphocytes (TILs) will also be evaluated in 
archival tumor samples and / or pre- and post-treatment optional tumor biopsy. Inhibitor 
of apoptosis protein (IAP) gene copy number studies in archival tumor samples or pre-
treatment optional tumor biopsy samples will be conducted. Blood or serum samples may 
also be evaluated for cytokines such as GM-CSF, IFNγ, IL10, IL2, IL3, IL4, IL5, IL6, 
IL7, IL8, MIP-1α, MIP-1β, MCP-1, TNFα, and TNFβ.  CD3, CD4, CD8, and CD19 and 
FOXP3 as well as absolute neutrophil count and absolute lymphocyte count will be 
assessed through peripheral blood pre- and post-dosing of birinapant and pembrolizumab. 
Table 15 
Summary of Pharmacodynamic Assessments 
Marker 
Tissue 
Purpose of analysis 


 
 
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Pre- and post-treatment levels 
of cIAP1 expression 
Blood (PBMC) 
Evidence of target engagement 
of birinapant 
Gene expression analysis 
Blood (PBMC) 
Evidence of immune system 
modulation 
Serum Cytokines such as 
GM-CSF, IFNγ, IL10, IL2, 
IL3, IL4, IL5, IL6, IL7, IL8, 
MIP-1α, MIP-1β, MCP-1, 
TNFα, and TNFβ  
Blood (serum) 
Evidence of immune system 
modulation 
Blood samples looking at 
CD3, CD4, CD8, and CD19 
as well as absolute neutrophil 
count and absolute 
lymphocyte count 
Blood 
Peripheral changes in WBC 
populations 
Pre-treatment PD-L1 
expression 
Archival tumor 
May predict pembrolizumab 
sensitivity 
Gene expression analysis by 
Nanostring     
Archival tumor or pre-
treatment optional biopsy 
May predict pembrolizumab 
sensitivity. May allow 
derivation of predictive 
response signature of 
combination 
  
Post-treatment optional 
biopsy 
Evidence of treatment-induced 
changes 
cIAP1 expression 
Archival tumor 
May predict birinapant or 
combination sensitivity 
  
Post-treatment optional 
biopsy 
Evidence of target expression 
and modulation in tumor 
Inhibition of apoptosis protein 
(IAP) gene copy number  
Archival tumor 
May predict birinapant or 
combination sensitivity 
Tumor infiltrating 
lymphocytes (TILs) CD3, 
CD4, CD8 and CD20 and 
FOXP3  
Archival tumor 
May predict birinapant or 
combination sensitivity 
  
Post-treatment optional 
biopsy 
May provide evidence of 
increased anti-tumor immune 
activity 
MSI mismatch repair 
assessment (CRC only) 
Archival tumor 
May predict pembrolizumab 
sensitivity 
 


 
 
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 PHARMACOKINETIC SAMPLING 
Pharmacokinetic blood samples will be collected on Cycle 1 Day 1 4 hours after 
completion of birinapant infusion and on Cycle 1 Day 2 at 24 hours after completion of 
birinapant infusion.  On Cycle 1 Day 8, pharmacokinetic blood samples will be collected 
before the dose of birinapant, and 4 hours after completion of birinapant infusion (Table 
16).   
Table 16 
Timing of Pharmacokinetic Sampling 
Birinapant Infusion (Cycle 1 Day 1) 
Sample 2 
4 hours after completion of birinapant infusion 
Birinapant Infusion (Cycle 1 Day 2) 
Sample 3 
24 hours after completion of birinapant infusion 
Birinapant Infusion (Cycle 1 Day 8) 
Sample 4 
Prior to birinapant infusion 
Sample 5 
4 hours after completion birinapant infusion 
 
All blood samples will be collected from the arm opposite the site of infusion or distal to 
the site of infusion, in collection tubes containing K2EDTA. If there is a delay in 
completion of birinapant infusion, this must be noted in the CRF. If birinapant infusion is 
resumed to completion, PK sample collection will continue with end of infusion and post-
infusion timepoints. 
 
Blood samples (2mL) for pharmacokinetic analyses will be drawn into pre-labeled tubes 
containing K2EDTA anticoagulant at the time points specified in Table 16. Within 30 
minutes of collection, blood samples will be centrifuged under refrigeration 
(approximately +4°C at 1500 g RCF) for approximately 10 minutes. Plasma will be 
harvested and divided into 2 separate aliquots. Samples will be stored frozen (-70oC 
preferred, or -20 oC - for specifications see Laboratory Manual) in pre-labeled cryovials 
prior to bioanalysis. 
 STATISTICAL CONSIDERATIONS 
12.1 
General Considerations 
Details of the scope and nature of statistical analyses to be utilized in analyzing data from 
this study will be found in the Statistical Analysis Plan (SAP). The analysis of all the 
safety and pharmacodynamic parameters will be performed by Medivir or its designee. 
Safety analyses will include all patients who receive at least one dose of either 
investigational product. All data collected for these patients will be used in the analyses, 
and no imputation will be performed for missing data.  AEs that are unrelated to 
treatment and that occur more than 30 days after treatment administration will not be 
reported or analyzed. The statistical methods employed in this protocol will be primarily 


 
 
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descriptive since the study was not sized for a specific level of power. No inferential 
statistics will be utilized in the safety analyses. 
For all analyses, baseline is defined as the last measurement for a variable before the dose 
of pembrolizumab or birinapant.  All data collected on the eCRF will be included in data 
listings.  Routine data listing or tabulation review during the study conduct will be 
performed to identify missing data, anomalies, and outliers.   
Unless otherwise stated, continuous variables will be summarized using number of 
observations, mean standard deviation, median (as appropriate), minimum, and maximum.  
Categorical variables will be tabulated with frequencies and percentages.   
All analyses will be performed using SAS® version 9.3 or later (SAS Institute, Cary NC), 
or comparable software.  A complete description of data handling rules and planned 
statistical analyses will be detailed in a separate SAP before conducting any planned 
analysis. 
12.2 
Determination of Sample Size 
No formal sample size or power calculations will be performed for the dose-escalation 
phase of the study.  A sample size of 3 to 6 patients per cohort is a feasible sample size to 
assess safety for dose escalation and dose-limiting toxicity.  Additional patients may be 
needed for cohort expansion during dose escalation, for the replacement of non-evaluable 
patients. Only patients who do not complete the first cycle due to study drug related 
toxicity will be replaced. 
Once the RP2D of birinapant combined with pembrolizumab is defined, additional 
patients with relapsed or refractory carcinoma will be enrolled in the dose-expansion 
phase of the study.   
The dose expansion phase will comprise 4 cohorts of 26-30 patients, as follows:   
• 
Colorectal cancer (28 patients) 
• 
Ovarian cancer (27 patients) 
• 
Cervical cancer (26 patients) 
• 
Various solid tumors (30 patients, including 5 patients with each of the 6 
following tumor types: (Small cell lung cancer; Cholangiocarcinoma; 
Gastroesophageal carcinoma; Mesothelioma; Head and Neck Squamous 
Cell Carcinoma (HNSCC)-checkpoint inhibitor-naïve; and HNSCC 
checkpoint inhibitor-experienced) 
A Simon’s 2-stage design (Simon 1989) will be used for each of the cohorts in colorectal 
cancer, ovarian cancer and cervical cancer, as outlined in Table 17. A predefined interim 
analysis allowing stopping each of these cohorts for futility and safety will be conducted 
in the first stage to limit undue exposure before further inclusion into a given cohort. 
The interim analyses will be based on at least 6 and most 13 patients having completed 
from 9 up to 27 weeks of treatment (3 to 9 cycles) in the colorectal cancer cohort and 
based on at least 6 and at most 16 and 15 patients in the ovarian cancer cohort and 


 
 
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cervical cancer cohort, respectively. Note that one additional patient will be included in 
each cohort. This patient will only be included in the interim analysis in case a patient 
drops out in that cohort. Thus, the number of included patients in each cohort will be 27+ 
1 (CRC), 26+1 (ovarian) and 25+1 (cervical). In all cases this extra patient will be 
included in the main/end analysis. If the predefined level for success in a given cohort is 
reached prior to the stipulated number of patients being enrolled/completed, enrollment in 
that cohort may be discontinued.   
The Simon’s two-stage design yields a type I error rate of 0.05 and statistical power of 
0.80 for each of the three main cohorts described above using a one-sided test when the 
true response rate is 20% for colorectal cancer, 25% for ovarian cancer and 30% for 
cervical cancer. No formal sample size or power calculation will be performed for the 
fourth cohort. 
12.3 
Randomization and Stratification 
No randomization or stratification will be utilized in this study. 
12.4 
Analysis Population 
The following four populations will be defined for this study: 
• Intent-to-Treat Population (ITT): will comprise any patient that is enrolled to the 
study and receives a dose of pembrolizumab and birinapant. Note that the ITT 
population can be considered equivalent to the Full Analysis Set population as no 
randomization is done in this study. 
• Safety Population: will be the same as the ITT population. 
• Efficacy Evaluable Population: will comprise all patients in the ITT population 
who have baseline and at least one post-baseline efficacy assessment, unless the 
patient dies or experiences an AE that results in study drug termination prior to 
assessment. At that point, the patient will be considered to have progressed in the 
absence of other data.  
• Pharmacodynamic Population: The pharmacodynamic population will include all 
treated patients for whom pre- and post- infusion pharmacodynamic data are 
available. 
12.5 
Demographics and Baseline Characteristics 
Descriptive statistics will be provided to summarize demographics and baseline 
characteristics. 
12.6 
Analysis of Safety Data 
The safety and tolerability of pembrolizumab and birinapant will be based on results of 
DLT incidence, reported SAEs, AEs, vital sign measurements, physical examinations, 
clinical laboratory information, ECOG performance status, and concomitant medications. 
Exposure to study drug and reasons for discontinuation will be tabulated.  These data will 


 
 
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be summarized descriptively for the dose escalation phase and for the dose expansion 
phase of the protocol separately for the ITT population. Safety data will be summarized 
descriptively by cohort and also summarized descriptively over cohorts within each of the 
two phases of the protocol. 
For parameters measured over time, data and changes from baseline will be summarized 
for each time point.  Adverse events will be coded using the current Medical Dictionary 
for Regulatory Activities (MedDRA) classification system, and will be summarized by 
system organ class and preferred term.  
Additional safety analyses may be determined in order to most clearly describe toxicity 
rates and to further define the safety profile of pembrolizumab and birinapant. 
12.7 
Efficacy Analysis  
Efficacy, as measured by the ORR, will be assessed through RECIST v1.1 and iRECIST 
measurements and clinical response per Investigator.  Results will be summarized 
descriptively (See SAP for further details). 
In the dose expansion phase of the protocol, the null hypothesis that the true response rate 
is 𝑝𝑝0 will be tested against the one-sided alternative 𝐻𝐻𝐴𝐴: 𝑂𝑂𝑂𝑂𝑂𝑂> 𝑝𝑝0 in each of the three 
cohorts in Simon’s two-stage design (Simon 1989). The statistical test will be performed 
for each cohort with 𝑝𝑝0 , 𝑝𝑝1, 𝑛𝑛1, 𝑛𝑛, 𝑟𝑟1 and 𝑟𝑟2 as in Table 17 as follows. In the first stage, 
𝑛𝑛1 patients will be accrued. If there are 𝑟𝑟1 or fewer responses in these 𝑛𝑛1 patients, the 
study will be stopped. Otherwise, n - 𝑛𝑛1 additional patients will be accrued for a total of n 
patients. The null hypothesis will be rejected if 𝑟𝑟2+1 or more responses are observed in n 
patients. This design yields a type I error rate of 0.05 and power of 0.80 when the true 
response rate is 𝑝𝑝1  for each of the three main cohorts. No correction for multiple 
comparisons are done.  
Table 17 
 Simon’s two-stage design settings in each of the three main cohorts  
Indication 
Response rate 
(ORR) 
𝑛𝑛1 
 (# patient in 
the 1st stage) 
n 
(Total 
#patients) 
𝑟𝑟1  
(Continue 
with stage 
2 if >𝑟𝑟1 
responses 
in stage 1) 
𝑟𝑟2 
(p-value 
<=0.05 if 
>𝑟𝑟2 
responses 
after 
stage 2) 
Poor drug 
(𝑝𝑝0) 
Good 
drug (𝑝𝑝1) 
Colorectal 
cancer  
<=5% 
>=20% 
13 
27 
0 
3 
Ovarian 
cancer 
<=7% 
>=25% 
16 
26 
1 
4 
Cervical 
cancer 
<=10% 
>=30% 
15 
25 
1 
5 


 
 
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Note that one additional patient will be included in each cohort. This patient will only be 
included in the interim analysis in case a patient drops out in that cohort. Thus, the 
number of included patients in in each cohort will be 27+1 (CRC), 26+1 (ovarian) and 
25+1 (cervical). In all cases this extra patient will be included in the main/end analysis. 
The final statistical analysis will take account of the actual number of patients evaluable 
for efficacy. 
12.8 
Analysis of Pharmacodynamic Parameters 
Descriptive statistics will be provided to summarize pharmacodynamic parameters. For 
parameters measured over time, observed data and changes from baseline will be 
summarized for each time point. 
 Descriptive statistics will be provided to summarize pharmacodynamic parameters. For 
parameters measured over time, observed data and changes from baseline will be 
summarized for each time point. 
12.9 
Analysis of Pharmacokinetic data 
The plasma PK data of birinapant will be summarized descriptively. Population PK 
modeling may also be applied to analyze the data and will, in that case, be reported 
separately. 
 DATA COLLECTION, STUDY MONITORING AND DATA 
DISCLOSURE 
Data will be collected using CRFs that are specifically designed for this study.  The data 
collected on the CRFs will be captured in a clinical data management system (CDMS) 
that meets the technical requirements described in US 21 Code of Federal Regulations 
(CFR) Part 11.  The CDMS will be fully validated to ensure that it meets the scientific, 
regulatory, and logistical requirements of the study before it is used to capture data from 
this study.  Before using the CDMS, all users will receive training on the system and 
study specific training.  After they are trained, users will be provided with individual 
system access rights. 
All required study data will be collected from primary source documents (or direct 
electronic capture from validated instrument operating systems, where applicable) by 
appropriately designated and trained personnel at the clinical facility, and CRFs must be 
completed for each patient screened consistent with the data source.  Patients’ actual 
identity will be coded appropriately and should not be discernible from the data provided 
on the CRF.  CRF content will be verified against data sources by the study monitor, and 
reviewed for consistency by Data Management using both automated logical checks and 
manual review.  All data collected will be approved by the Investigator at the clinical site.  
This approval acknowledges the Investigator’s review and declaration that the data are 
complete and accurate. 


 
 
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Queries regarding study data in CRFs will be provided to the clinical site and will be 
reviewed and responded to, based on all raw study data, in the manner dictated by the 
Sponsor.   
 DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
The Investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented and the study data to be subsequently verified.  These 
documents include Investigator’s Study Files and patients’ clinical source documents. 
The Investigator will ensure the Study Files are maintained with copies of the CRFs and 
data query forms, protocol/amendments, IRB and regulatory approvals with associated 
correspondence, all versions of informed consent templates, all original, signed informed 
consents, study drug shipment and accountability records, staff curricula vitae and 
training records, authorization forms, all correspondence, and all other appropriate 
documents.  The Study File will be inspected by the study monitor periodically and as 
part of the study closeout visit and must be made available in the event of a regulatory 
inspection or Sponsor’s quality assurance audit. 
Patients’ clinical source documents may include, but need not be limited to, patient’s 
hospital/clinic records, physicians’ and nurses’ notes, study visit appointment book, 
original laboratory reports, ECG, radiograph, laboratory, pathology and special 
assessment reports, and consultant communications, including all information relating to 
study patient referrals from other medical institutions or individuals. 
Financial information related to conduct of the study by both the Sponsor and the 
Investigator are to be kept separate from files relating to study conduct and are 
confidential, privileged information with respect to regulatory audits. 
 QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with GCP and all applicable regulatory requirements, a quality 
assurance audit may be performed by the Sponsor or its designees.  Regulatory 
authorities may also conduct a regulatory inspection of this study.  Such 
audits/inspections can occur at any time during or after completion of the study.  If an 
audit or inspection occurs, the Investigator and institution agree to provide the 
auditors/inspectors direct access to all relevant documents and to allocate his/her time and 
the time of his/her staff to the auditors/inspectors to discuss findings and any relevant 
issues. 
The Investigator and study staff are responsible for maintaining a comprehensive and 
accurate filing system of all study-related documentation in a manner suitable for 
inspection at any time by the Sponsor, its designees, and/or regulatory authorities.  By 
signing this protocol, the Investigator attests that he/she understands and agrees to 
provide access to the necessary documentation and files. 


 
 
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As applicable, both the Investigator and Sponsor are responsible for implementing and 
maintaining quality control and quality assurance systems, each with written standard 
operating procedures (SOPs), to ensure that this study is conducted and data are 
generated, documented, and reported in compliance with the protocol, accepted standards 
of GCP, and all applicable governmental legal/regulatory requirements of both the US 
and the country in which the study is conducted.   
 ETHICS AND GOOD CLINICAL PRACTICE COMPLIANCE 
This study will be carried out according to the Declaration of Helsinki, the Notes for 
Guidance on GCP (2000) (CPMP/ICH/135/95) and with ICH GCP. 
This protocol and any accompanying material, including information that will be 
provided to prospective patients (such as advertisements, patient information sheets, or 
study descriptions used to induce study participation or obtain informed consent) must be 
submitted by the Investigator to the IRB.  Approval of each such submission must be 
obtained from the committee before it may be used in the study and must be documented 
in a written notification to the Investigator specifying the protocol number, protocol 
version, documents reviewed, and date on which the committee met and granted the 
approval.  In particular, each informed consent document must bear clear evidence 
(written, stamp, date of approval, etc.) of IRB approval before it may be presented to 
prospective (or ongoing, as appropriate) study patients for signature. 
Written evidence of the approval must be made available to the Sponsor.  Any 
modifications made to the protocol and of correspondingly modified informed consent 
documents made after receipt of IRB approval must also be submitted to the committee 
for approval before implementation unless the modification is made on an emergency 
basis to protect the welfare of study patients.  In the latter case, the IRB must be notified 
promptly and their written approval must be obtained as soon after the fact as possible. 
Appropriate reports on the progress of the study will be made to the IRB and the Sponsor 
by the Investigator in accordance with applicable regulatory regulations and in 
conformity with policies established by both the IRB and the Sponsor.  The shortest time 
interval between required reports required by either party or by regulations will prevail. 
The Investigator at each investigative site, or his/her nominee, will be responsible for 
reporting any SAEs to the IRB as soon as possible, and in accordance with the guidelines 
of the IRB. 
The Sponsor or its designee will be responsible for reporting all serious, life threatening 
or fatal adverse study drug events with a causal relationship to the study drug to 
appropriate regulatory agencies within their required timelines. 
The Investigator will submit the site-specific informed consent to the Sponsor for 
approval before submitting to the IRB.  The Investigator is responsible for obtaining 
written, informed consent(s) from each prospective patient interested in participating in 
this study before performing any study-related procedures.  Written informed consent 
must be obtained after adequate, thorough, and clear explanation of the aims, methods, 


 
 
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objectives, and potential hazards of the study, as well as any use of the patient’s genetic 
information from the study.  The Investigator must use the most current IRB-approved 
consent form for documenting written informed consent.  Each informed consent will be 
appropriately signed and dated by the patient and the person obtaining consent and each 
page not signed must be initialed and dated by the patient.  The investigational site must 
retain the original signed consent and provide a copy to the patient.   
Information concerning the protocol, the study information, patent applications, and 
processes, scientific data, or other pertinent information is confidential and remains the 
property of the Sponsor.  The Investigator may use this information for the purpose of the 
study only and may not disseminate it in whole or in part to third parties except for a 
participating CRO, the IRB, regulatory authorities, or, after Sponsor approval, to others 
involved in study conduct. 
The Sponsor will use information developed in this clinical study in connection with the 
development of birinapant and, therefore, may disclose it as required to other clinical 
Investigators participating in other studies and to regulatory agencies.  In order to allow 
the use of the information derived from this clinical study, the Investigator understands 
that he/she has an obligation to provide all data produced during this study to the Sponsor. 
The Sponsor considers that clinical data (complete or incomplete) constitute financially 
sensitive information.  Consequently, the Sponsor requires that discussion of results in 
any form, electronic, verbal, or written before study completion and full reporting should 
only be undertaken with the Sponsor’s prior written consent. 
Individual patients’ medical information obtained as a result of this study is considered 
confidential.  The Investigator and the study center will adhere to all applicable laws 
relating to the protection of patient information.  To assure that patients’ confidentiality is 
maintained, patients’ data will be identified by a study-assigned number and date of birth 
only.  
All Sponsor personnel will handle patients’ data in a confidential manner in accordance 
with applicable regulations governing clinical research.  Patients’ records will be 
inspected only in connection with this research project.  Information generated as a result 
of a patient’s participation in this study may be disclosed to third parties for research and 
regulatory purposes in any country as determined by the Sponsor.  However, patients will 
not be individually identified but will be referred to only by the study assigned number 
and the patient’s date of birth. 
16.1 
Patient Information and Consent 
All patients will receive written and verbal information regarding the study. This 
information will emphasize that participation in the study is voluntary and that the patient 
may withdraw from the study at any time and for any reason. All patients will be given 


 
 
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the opportunity to ask questions about the study and will be given sufficient time to 
decide whether to participate in the study. 
Before any study-related procedures will be performed the ICF will be signed and 
personally dated by the patient (or their legally acceptable representative and/or witness, 
as applicable) and by the qualified person who conducted the informed consent 
discussion. Local regulations and laws regulate who is authorized to conduct the 
informed consent procedure. 
The consent includes information that the patient’s identity will be kept confidential, 
except as required by the law, and except for inspections by Agencies that regulate 
experimental drug studies, auditors, members of Independent Review Boards or Ethics 
Committees, and the study Sponsor or agents of the sponsor.  
A copy of the patient information including the signed consent form will be provided to 
the patient. 
The patient or his/her legally acceptable representative should be informed in a timely 
manner if new information becomes available that may be relevant to the subject’s 
willingness to continue participation in the trial. 
 STUDY SITE CLOSURE 
Upon completion or termination of the study, the Sponsor/CRO monitor will conduct site 
closure activities with the Investigator and site staff (as appropriate), in accordance with 
applicable regulations, GCP, and Medivir AB’s and the designee CRO’s SOPs. 
FDA can temporarily suspend or terminate the study upon receipt of information that 
raises doubts about the safety or scientific validity of the study. 
 Medivir AB reserves the right to temporarily suspend or to terminate the study or close a 
site at any time for reasons including (but not limited to) lack of recruitment, futility, 
safety issues, ethical issues, or severe noncompliance.  If Medivir AB determines that 
such action is required, Medivir AB will discuss the reasons for taking such action with 
the Investigator or head of the medical institution (where applicable).  When feasible, 
Medivir will provide advance notice to the Investigator or head of the medical institution 
of the impending action.  If a study is suspended or terminated for safety reasons, 
Medivir will promptly inform all Investigators, heads of the medical institutions (where 
applicable), and/or institutions conducting the study.  Medivir AB will also promptly 
inform the relevant regulatory authorities of the suspension/termination along with the 
reasons for such action.  Where required by applicable regulations, the Investigator or 
head of the medical institution must inform the IRB promptly and provide the reason(s) 
for the suspension/termination. 


 
 
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 RECORD RETENTION 
All clinical study documents must be secured and retained by the Investigator until at 
least two years after the last approval of a marketing application in an ICH region (i.e., 
US, Europe, or Japan) and until there are no pending or contemplated marketing 
applications in an ICH region; or, if no application is filed or if the application is not 
approved for such indication, until two (2) years after the investigation is discontinued 
and regulatory authorities have been notified.  Investigators may need to retain 
documents longer if required by applicable regulatory requirements or if requested by the 
Sponsor.  The Investigator must notify the Sponsor before destroying any clinical study 
records. 
The Investigator will notify the Sponsor of the intended storage location for all study 
records.  Should the Investigator have reason to assign the study records to another party 
or move them to another location, the Sponsor must be notified in advance. 
If the Investigator cannot guarantee this archiving requirement at the investigative site for 
any or all of the documents, special arrangements must be made between the Investigator 
and the Sponsor to store these in sealed containers in an off-site storage location so that 
they can be returned to the Investigator in case of a regulatory audit.  Where source 
documents are required for the continued care of the patient, appropriate copies will be 
made for off-site storage. 
No study document should be destroyed without prior written agreement between the 
Sponsor and the Investigator. Should the Investigator wish to assign the study records to 
another party or move them to another location, the Investigator must notify the Sponsor 
in writing of the new responsible person and/or the new location. 
 PROVISION OF STUDY RESULTS AND INFORMATION TO 
INVESTIGATORS  
A Clinical Study Report (CSR) will be prepared after the study has been completed, and 
all data have been entered, reviewed, and analyzed. The CSR will be signed off by the 
Sponsor’s representative, and where required by applicable regulatory requirements, the 
Investigator.  
The sponsor reserves the right to collate preliminary data from this open label study as ad 
hoc analyses that enables update reporting at scientific conferences. In such cases, the 
data will be handled as outlined in the SAP and protocol sections 12 as well as 13. 
The Investigator must submit to the Sponsor, any proposed publication or presentation, 
along with information about the scientific journal or presentation forum, at least 30 days 
before submission of the publication or presentation (2 weeks for abstracts). The 
Investigator will comply with requests from the Sponsor to delete references to its 
confidential information (other than the study results) in any publication or presentation 
and agrees to withhold publication or presentation for an additional 60 days in order to 
obtain patent protection if deemed necessary. 


 
 
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No such interim communication, presentation or publication will include the Sponsor’s 
confidential information. 
After conclusion of the study, the Investigator may make oral presentations of study 
results or publish such results in scientific journals or other scholarly media without prior 
written approval from the Sponsor, only after the following conditions have been met: 
• The results of the study in their entirety have been publicly disclosed by or with 
the consent of the Sponsor in an abstract, manuscript, or presentation forum; 
• The Investigator has complied with all requests from the Sponsor to delete any 
references to its confidential information (other than study results); 
• The study has been completed for at least 2 years. 
 FINANCING AND INSURANCE  
Agreements about the appropriate payment will be made between the Sponsor and the 
Investigator(s) and will be known as the Clinical Trial Agreement. Payment will relate to 
the number of patients as well as the cost of clinical visits, laboratory investigations, and 
other services outside of normal routine examinations and specifically connected with the 
conduct of this study. This agreement will cover payment for CRFs fully completed in 
conformity with the protocol. The fee for participants who withdraw prematurely from 
the study will be on a pro-rata basis reflecting the percentage of study activities 
completed. 
Patients may be compensated for the time that they spend participating in the study using 
a formula determined by the investigative site. 
Insurance will be provided in conformity with US guidelines and institutional 
requirements for all patients involved in the study. The patient should not take part in any 
other clinical study while enrolled in this study. The patient should report any health 
injury that could have occurred as a result of the clinical study to the Investigator without 
delay. 
 STUDY ADMINISTRATIVE INFORMATION 
21.1 
Protocol Amendments 
Alterations to study procedures not previously provided for in the protocol will require a 
protocol amendment. The amendment must be approved in writing by the IRB before 
implementation and may require a revised informed consent document to be signed by all 
patients who are ongoing or about to enroll in the study. 
An exception will be made only if immediate changes to treatment are necessary to 
protect the health and welfare of study patients. In such a case, the IRB will be notified 
promptly and the protocol will be amended and submitted for IRB approval as promptly 
as possible. 


 
 
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21.2 
Biological Specimens 
The identity and contact information for the laboratories responsible for analyzing 
biological specimens (e.g., pharmacodynamic samples) is located in the study reference 
documents.  Instructions for handling and shipment of biological samples will be 
provided in the study reference documents. 
 
 


 
 
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 APPENDICES 
Appendix 1 Blood Volume 
During the study blood will be drawn at the study visit. Limited blood volumes will be 
taken at each single occasion. Approximate blood volume per study visit have been listed 
below:  
 
Study Procedures 
Screening 
 
Cycle 1 
Subsequent Cycles 
Follow up  
Day
 1 
Day 
2 
Day 
8 
Day 
1 
Day 
8  
Every 
6 
weeks 
Every 
12 
weeks 
Safety 
Follow up 
Visit  
PD/ 
Study Drug 
Discontinua
tion 
Serum Chemistry 
X 
X 
 
X 
X 
X 
 
 
X 
X 
Hematology 
X 
X 
 
X 
X 
X 
 
 
X 
X 
Pregnancy test serum at 
screening 
X 
 
 
 
 
 
 
 
 
 
PD blood sampling 
 
X 
X 
X 
 
 
 
 
 
 
CD3+, CD4+, CD8+, CD19+ 
ANC, ALC 
 
X 
 
X 
 
 
 
 
 
 
ANC, ALC 
 
 
X 
 
 
 
 
 
 
 
Serology (HSV, VZV) 
X 
 
 
 
 
 
 
 
 
 
Hepatitis C antibody 
X 
 
 
 
 
 
 
 
 
 
PK blood sampling 
 
X 
X 
X 
 
 
 
 
 
 
Hepatitis C antibody 
X 
 
 
 
 
 
 
 
 
 
Thyroid testing 
X 
 
 
 
 
 
X 
 
 
 
CEA for CRC patients 
X 
 
 
 
 
 
 
X 
X 
 
MSI for CRC patients 
X 
 
 
 
 
 
 
 
 
 
CA-125 for Ovarian cancer 
patients 
X 
X 
 
 
X 
 
 
 
X 
 
Approximate Blood 
Volume per visit (mL) 
45 
60 
45 
45 
45 
45 
15 
15 
45 
45 
 
 
 
 


 
 
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Appendix 2 
Inclusion/Exclusion criteria for individual cohorts 
Appendix 2.1 Inclusion/Exclusion criteria Dose Escalation Phase 
NB: Inclusion/exclusion criteria numbering is derived from the complete set of criteria 
defined in sections 4.1 and 4.2. 
Inclusion criteria 
Patients will be eligible for study participation if they meet ALL of the following 
inclusion criteria, after patient has provided written informed consent.  
1. The patient is male or female ≥ 18 years of age on the day of signing informed 
consent. 
2. The patient is able to understand and voluntarily sign a written informed consent, and 
is willing and able to comply with the protocol requirements. 
3. The patient must have a histologically confirmed solid malignancy that is metastatic 
or unresectable and for which standard curative or palliative measures do not exist or 
are no longer effective.  Patients with tumors with mutations for which there are 
FDA-approved therapies must have progressed following these therapies in order to 
be eligible for this study.  Patients with metastatic colorectal cancer should have 
progressed on prior fluoropyrimidine-based therapies, and have no curative therapies 
available to them, in order to be eligible for this study. Colorectal cancer patients 
should be assessed for microsatellite instability (MSI) status as per the local site 
routines. (Dose Escalation Phase only) 
4. Patients must have measurable disease based on RECIST 1.1 as determined by the 
site study team.  Tumor lesions situated in a previously irradiated area are considered 
measurable if progression has been demonstrated in such lesions.  
5. Patients must have an Eastern Cooperative Oncology Group (ECOG) score of 0 or 1 
at screening.   
6. Patients must have a life expectancy of greater than 12 weeks. 
7. Patients must have amylase and lipase values < ULN. 
8. Patients must demonstrate adequate organ function as defined in Table A2.1.  All 
screening labs should be performed within 10 days of treatment initiation. 
 
Table A2.1 
Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L  


 
 
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Renal 
Creatinine OR 
Measured 
or 
calculateda 
creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤1.5xULN OR 
≥60 mL/min for patient with  
creatinine levels >1.5x institutional ULN 
Hepatic 
Total bilirubin 
≤1.5xULN OR 
Direct bilirubin ≤ULN for patients with total 
bilirubin levels >1.5xULN), unless known Gilbert’s 
Syndrome has been diagnosed 
AST (SGOT) and ALT (SGPT) 
≤2.5xULN OR 
≤5.0xULN for patients with liver metastases 
Coagulation 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
 
Activated Partial Thromboplastin Time 
(aPTT) 
≤1.5xULN unless patient is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic 
range of intended use of anticoagulants 
≤1.5xULN unless patient is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic 
range of intended use of anticoagulants 
a Creatinine clearance should be calculated per institutional standard. 
9. Female patients of childbearing potential must have a negative urine or serum serum 
pregnancy test will be required.   
10. Female patients of childbearing potential must be willing to use an adequate 
pregnancy test within 72 hours prior to receiving the first dose of study medication. 
If the urine test is positive or cannot be confirmed as negative, a method of 
contraception for the course of the study through 120 days after the last dose of study 
medication. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the patient. 
11. Male patients with female partners of childbearing potential must agree to use an 
adequate method of contraception, starting with the first dose of study therapy 
through 120 days after the last dose of study therapy.  
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the patient. 
12. A tumor tissue sample for PD-L1 biomarker analysis from archival material, a newly 
obtained core or excisional biopsy is available for submission.  Repeat samples may 
be required if adequate tissue is not provided.   
13. Have resolution of toxic effect(s) of the most recent prior chemotherapy to Grade 1 
or less (except neuropathy or alopecia). If patients have received major surgery or 
radiation therapy of > 30 Gy, they must have recovered from the toxicity and/or 
complications from the intervention.  


 
 
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Exclusion Criteria 
 A patient will be excluded from the study for any one or more of the following reasons: 
1. Patients who have had a prior anti-cancer monoclonal antibody (mAb) within 4 
weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) 
from adverse events due to agents administered more than 4 weeks earlier prior to 
study Day 1. 
2. Patients who have had prior chemotherapy, targeted small molecule therapy, or 
radiation therapy within 2 weeks prior to study Day 1 or who have not recovered (i.e., 
≤ Grade 1 or at baseline) from adverse events due to a previously administered agent. 
Note:  Patients with ≤ Grade 2 neuropathy or ≤ Grade 2 alopecia are an exception to this 
criterion and may qualify for the study. 
Note:  If patients have received major surgery, they must have recovered adequately from 
the toxicity and/or complications from the intervention prior to starting therapy.   
3. Patients who are currently participating and receiving study therapy or who have 
participated in a study of an investigational agent and received study therapy or who 
have used an investigational device within 4 weeks of the first dose of treatment. 
4. Patients who have received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, 
anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) 
antibody (including ipilimumab or any other antibody or drug specifically targeting 
T-cell co-stimulation or checkpoint pathways) or if the patient has previously 
participated in Merck MK-3475 clinical trials. (Not applicable for various solid 
tumors cohort, head and neck squamous cell carcinoma check-point inhibitor 
experienced group) 
5. Patients with known active central nervous system (CNS) metastases and/or 
carcinomatous meningitis.   
Note:  Patients with previously treated brain metastases may participate provided they are 
stable (without evidence of progression by imaging (using the identical imaging 
modality for each assessment, either MRI or CT scan) for at least four weeks prior to 
the first dose of trial treatment and any neurologic symptoms have returned to 
baseline), have no evidence of new or enlarging brain metastases, and are not using 
systemic steroids for at least 7 days prior to trial treatment.  This exception does not 
include carcinomatous meningitis which is excluded regardless of clinical stability. 
6. Patients with a known additional malignancy that is progressing or requires active 
treatment.  Exceptions include basal cell carcinoma of the skin, squamous cell 
carcinoma of the skin that has undergone potentially curative therapy or in situ 
cervical cancer. 


 
 
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7. Patients who have a history of allergic reactions attributed to compounds of similar 
chemical or biologic composition to birinapant or pembrolizumab or their 
constituents. 
8. Patients requiring the use of anti-tumor necrosis factor (anti-TNF) therapies, such as 
infliximab, or patients who have received treatment with anti-TNF therapies within 5 
half-lives of the drug. 
9. Patients with a diagnosis of immunodeficiency or who are receiving systemic steroid 
therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other 
form of immunosuppressive therapy within 7 days before the first dose of study drug. 
The use of physiologic doses of corticosteroids may be approved after consultation 
with the Sponsor.  
10. Patients with an uncontrolled intercurrent illness including, but not limited to, 
symptomatic congestive heart failure, hypertension, unstable angina pectoris, cardiac 
arrhythmia, autoimmune or inflammatory diseases, or psychiatric illness that would 
limit compliance with study requirements. 
11. Patients with an active autoimmune disease that has required systemic treatment in 
the past 2 years (i.e., with use of disease modifying agents, corticosteroids or 
immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) 
is not considered a form of systemic treatment. 
 
12. Patients who have evidence of active, non-infectious pneumonitis. Patients with a 
history of (non-infectious) pneumonitis that required steroids or current pneumonitis.  
 
13. Patients with a history of interstitial lung disease. 
 
14. Patients who are pregnant or breastfeeding, or expecting to conceive or father 
children within the projected duration of the trial, starting with the screening visit 
through 120 days after the last dose of trial treatment. Pregnant women and men who 
want to conceive a child are excluded from this study because birinapant and 
pembrolizumab are agents with unknown potential for teratogenic or abortifacient 
effects in humans. Because there is an unknown risk for AEs in nursing infants 
secondary to treatment of the mother with birinapant and pembrolizumab, 
breastfeeding should be discontinued if the mother is treated on this study.  
15. Patients who have a known history of Human Immunodeficiency Virus (HIV) (HIV 
1/2 antibodies), or active Hepatitis B (e.g., HBsAg reactive). Patients with active 
Hepatitis C (e.g., HCV RNA [qualitative] is detected).  
16. Patients who have received a live-virus vaccination within 30 days of planned 
treatment start. Seasonal flu vaccines that do not contain live virus are permitted. 


 
 
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Confidential 
17. Patients who have disease that is suitable for local therapy administered with curative 
intent. 
18. Patients who have received transfusion of blood products (including platelets or red 
blood cells) or administration of colony stimulating factors (including G-CSF, GM-
CSF or recombinant erythropoietin) within 4 weeks prior to study Day 1.  
19. Patients who have a history or current evidence of any condition, therapy, or 
laboratory abnormality that might confound the results of the trial, interfere with the 
patient’s participation for the full duration of the trial, or it is not in the best interest 
of the patient to participate, in the opinion of the treating investigator.  
20. Patients who have known psychiatric or substance abuse disorders that would 
interfere with cooperation with the requirements of the trial. 
21. Patients who have severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any 
of its excipients. 
23. Patients who have previously received birinapant treatment.  
 
 
 


 
 
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Appendix 2.2 Inclusion/Exclusion criteria Dose Expansion Phase Colorectal cancer 
cohort 
NB: Inclusion/exclusion criteria numbering is derived from the complete set of criteria 
defined in sections 4.1 and 4.2. 
Inclusion Criteria 
Patients will be eligible for study participation if they meet ALL of the following 
inclusion criteria, after patient has provided written informed consent.  
1. The patient is male or female ≥ 18 years of age on the day of signing informed 
consent. 
2. The patient is able to understand and voluntarily sign a written informed consent, and 
is willing and able to comply with the protocol requirements.  
4. Patients must have measurable disease based on RECIST 1.1 as determined by the 
site study team.  Tumor lesions situated in a previously irradiated area are considered 
measurable if progression has been demonstrated in such lesions.  
5. Patients must have an Eastern Cooperative Oncology Group (ECOG) score of 0 or 1 
at screening.   
6. Patients must have a life expectancy of greater than 12 weeks. 
7. Patients must have amylase and lipase values < ULN. 
8. Patients must demonstrate adequate organ function as defined in Table A2.2.  All 
screening labs should be performed within 10 days of treatment initiation. 
 
Table A2.2 
Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L  
Renal 
Creatinine OR 
Measured 
or 
calculateda 
creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤1.5xULN OR 
≥60 mL/min for patient with  
creatinine levels >1.5x institutional ULN 
Hepatic 
Total bilirubin 
≤1.5xULN OR 
Direct bilirubin ≤ULN for patients with total 
bilirubin levels >1.5xULN), unless known Gilbert’s 
Syndrome has been diagnosed 


 
 
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AST (SGOT) and ALT (SGPT) 
≤2.5xULN OR 
≤5.0xULN for patients with liver metastases 
Coagulation 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
 
Activated Partial Thromboplastin Time 
(aPTT) 
≤1.5xULN unless patient is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic 
range of intended use of anticoagulants 
≤1.5xULN unless patient is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic 
range of intended use of anticoagulants 
a Creatinine clearance should be calculated per institutional standard. 
9. Female patients of childbearing potential must have a negative urine or serum 
pregnancy test within 72 hours prior to receiving the first dose of study medication. 
If the urine test is positive or cannot be confirmed as negative, a serum pregnancy 
test will be required.   
10. Female patients of childbearing potential must be willing to use an adequate method 
of contraception for the course of the study through 120 days after the last dose of 
study medication. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the patient. 
11. Male patients with female partners of childbearing potential must agree to use an 
adequate method of contraception, starting with the first dose of study therapy 
through 120 days after the last dose of study therapy.  
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the patient. 
12. A tumor tissue sample for PD-L1 biomarker analysis from archival material, a newly 
obtained core or excisional biopsy is available for submission.  Repeat samples may 
be required if adequate tissue is not provided. 
13. Have resolution of toxic effect(s) of the most recent prior chemotherapy to Grade 1 
or less (except neuropathy or alopecia). If patients have received major surgery or 
radiation therapy of > 30 Gy, they must have recovered from the toxicity and/or 
complications from the intervention.  
14. Patients with metastatic colorectal cancer with no available therapy options that are 
known to provide clinical benefit per institutional standard of care.  Patients with 
tumors with mutations for which there are available therapies that are known to 
provide clinical benefit, as defined by national authority and/or ratified by national 
guidelines or equivalent, must have progressed following these therapies in order to 
be eligible for this study. 
15. Patients with histological or cytologically confirmed metastatic colorectal cancer 
which is Microsatellite Stable (MSI-Stable) accordingly to local laboratory testing.   


 
 
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Exclusion Criteria 
A patient will be excluded from the study for any one or more of the following reasons: 
1. Patients who have had a prior anti-cancer monoclonal antibody (mAb) within 4 
weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) 
from adverse events due to agents administered more than 4 weeks earlier prior to 
study Day 1. 
2. Patients who have had prior chemotherapy, targeted small molecule therapy, or 
radiation therapy within 2 weeks prior to study Day 1 or who have not recovered (i.e., 
≤ Grade 1 or at baseline) from adverse events due to a previously administered agent. 
Note:  Patients with ≤ Grade 2 neuropathy or ≤ Grade 2 alopecia are an exception to this 
criterion and may qualify for the study. 
Note:  If patients have received major surgery, they must have recovered adequately from 
the toxicity and/or complications from the intervention prior to starting therapy.   
3. Patients who are currently participating and receiving study therapy or who have 
participated in a study of an investigational agent and received study therapy or who 
have used an investigational device within 4 weeks of the first dose of treatment. 
4. Patients who have received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, 
anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) 
antibody (including ipilimumab or any other antibody or drug specifically targeting 
T-cell co-stimulation or checkpoint pathways) or if the patient has previously 
participated in Merck MK-3475 clinical trials. (Not applicable for Head and Neck 
Squamous Cell Carcinoma Check point inhibitor experienced group) 
5. Patients with known active central nervous system (CNS) metastases and/or 
carcinomatous meningitis.   
Note:  Patients with previously treated brain metastases may participate provided they are 
stable (without evidence of progression by imaging (using the identical imaging 
modality for each assessment, either MRI or CT scan) for at least four weeks prior to 
the first dose of trial treatment and any neurologic symptoms have returned to 
baseline), have no evidence of new or enlarging brain metastases, and are not using 
systemic steroids for at least 7 days prior to trial treatment.  This exception does not 
include carcinomatous meningitis which is excluded regardless of clinical stability. 
6. Patients with a known additional malignancy that is progressing or requires active 
treatment.  Exceptions include basal cell carcinoma of the skin, squamous cell 
carcinoma of the skin that has undergone potentially curative therapy or in situ 
cervical cancer. 
7. Patients who have a history of allergic reactions attributed to compounds of similar 
chemical or biologic composition to birinapant or pembrolizumab or their 


 
 
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16 Aug 2018 
 
Confidential 
constituents. 
8. Patients requiring the use of anti-tumor necrosis factor (anti-TNF) therapies, such as 
infliximab, or patients who have received treatment with anti-TNF therapies within 5 
half-lives of the drug. 
9. Patients with a diagnosis of immunodeficiency or who are receiving systemic steroid 
therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other 
form of immunosuppressive therapy within 7 days before the first dose of study drug. 
The use of physiologic doses of corticosteroids may be approved after consultation 
with the Sponsor.  
10. Patients with an uncontrolled intercurrent illness including, but not limited to, 
symptomatic congestive heart failure, hypertension, unstable angina pectoris, cardiac 
arrhythmia, autoimmune or inflammatory diseases, or psychiatric illness that would 
limit compliance with study requirements. 
11. Patients with an active autoimmune disease that has required systemic treatment in 
the past 2 years (i.e., with use of disease modifying agents, corticosteroids or 
immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) 
is not considered a form of systemic treatment. 
 
12. Patients who have evidence of active, non-infectious pneumonitis. Patients with a 
history of (non-infectious) pneumonitis that required steroids or current pneumonitis.  
 
13. Patients with a history of interstitial lung disease. 
 
14. Patients who are pregnant or breastfeeding, or expecting to conceive or father 
children within the projected duration of the trial, starting with the screening visit 
through 120 days after the last dose of trial treatment. Pregnant women and men who 
want to conceive a child are excluded from this study because birinapant and 
pembrolizumab are agents with unknown potential for teratogenic or abortifacient 
effects in humans. Because there is an unknown risk for AEs in nursing infants 
secondary to treatment of the mother with birinapant and pembrolizumab, 
breastfeeding should be discontinued if the mother is treated on this study.  
15. Patients who have a known history of Human Immunodeficiency Virus (HIV) (HIV 
1/2 antibodies), or active Hepatitis B (e.g., HBsAg reactive). Patients with active 
Hepatitis C (e.g., HCV RNA [qualitative] is detected).  
16. Patients who have received a live-virus vaccination within 30 days of planned 
treatment start. Seasonal flu vaccines that do not contain live virus are permitted. 
17. Patients who have disease that is suitable for local therapy administered with curative 
intent. 


 
 
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18. Patients who have received transfusion of blood products (including platelets or red 
blood cells) or administration of colony stimulating factors (including G-CSF, GM-
CSF or recombinant erythropoietin) within 4 weeks prior to study Day 1.  
19. Patients who have a history or current evidence of any condition, therapy, or 
laboratory abnormality that might confound the results of the trial, interfere with the 
patient’s participation for the full duration of the trial, or it is not in the best interest 
of the patient to participate, in the opinion of the treating investigator.  
20. Patients who have known psychiatric or substance abuse disorders that would 
interfere with cooperation with the requirements of the trial. 
21. Patients who have severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any 
of its excipients.  
23. Patients who have previously received birinapant treatment.  
 
 


 
 
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Appendix 2.3 Inclusion/Exclusion criteria Dose Expansion Phase Ovarian cancer 
cohort 
NB: Inclusion/exclusion criteria numbering is derived from the complete set of criteria 
defined in sections 4.1 and 4.2. 
Inclusion Criteria 
Patients will be eligible for study participation if they meet ALL of the following 
inclusion criteria, after patient has provided written informed consent.  
1. The patient is male or female ≥ 18 years of age on the day of signing informed 
consent. 
2. The patient is able to understand and voluntarily sign a written informed consent, and 
is willing and able to comply with the protocol requirements. 
4.  Patients must have measurable disease based on RECIST 1.1 as determined by the 
site study team.  Tumor lesions situated in a previously irradiated area are considered 
measurable if progression has been demonstrated in such lesions.  
5. Patients must have an Eastern Cooperative Oncology Group (ECOG) score of 0 or 1 
at screening.   
6. Patients must have a life expectancy of greater than 12 weeks. 
7. Patients must have amylase and lipase values < ULN. 
8. Patients must demonstrate adequate organ function as defined in Table A2.3.  All 
screening labs should be performed within 10 days of treatment initiation. 
 
Table A2.3 
Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L  
Renal 
Creatinine OR 
Measured 
or 
calculateda 
creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤1.5xULN OR 
≥60 mL/min for patient with  
creatinine levels >1.5x institutional ULN 
Hepatic 
Total bilirubin 
≤1.5xULN OR 
Direct bilirubin ≤ULN for patients with total 
bilirubin levels >1.5xULN), unless known Gilbert’s 
Syndrome has been diagnosed 
AST (SGOT) and ALT (SGPT) 
≤2.5xULN OR 
≤5.0xULN for patients with liver metastases 


 
 
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Coagulation 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
 
Activated Partial Thromboplastin Time 
(aPTT) 
≤1.5xULN unless patient is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic 
range of intended use of anticoagulants 
≤1.5xULN unless patient is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic 
range of intended use of anticoagulants 
a Creatinine clearance should be calculated per institutional standard. 
9. Female patients of childbearing potential must have a negative urine or serum 
pregnancy test within 72 hours prior to receiving the first dose of study medication. 
If the urine test is positive or cannot be confirmed as negative, a serum pregnancy 
test will be required.   
10. Female patients of childbearing potential must be willing to use an adequate method 
of contraception for the course of the study through 120 days after the last dose of 
study medication. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred 
contraception for the patient. 
11. A tumor tissue sample for PD-L1 biomarker analysis from archival material, a newly 
obtained core or excisional biopsy is available for submission.  Repeat samples may 
be required if adequate tissue is not provided.   
12. Have resolution of toxic effect(s) of the most recent prior chemotherapy to Grade 1 
or less (except neuropathy or alopecia). If patients have received major surgery or 
radiation therapy of > 30 Gy, they must have recovered from the toxicity and/or 
complications from the intervention.  
13. Patients must have a histologically confirmed epithelial ovarian cancer, primary 
peritoneal cancer or fallopian tube solid tumor cancer that is locally advanced or 
metastatic with no available therapy options that are known to provide clinical 
benefit per institutional standard of care.  Patients with tumors with mutations for 
which there are available therapies that are known to provide clinical benefit, as 
defined by national authority and/or ratified by national guidelines or equivalent, 
must have progressed following these therapies in order to be eligible for this study.  
16. Patients must have a histologically confirmed epithelial ovarian cancer, primary 
peritoneal cancer or fallopian tube solid tumor cancer that is locally advanced 
or metastatic with no available therapy options that are known to provide 
clinical benefit per institutional standard of care.  Patients with tumors with 
mutations for which there are available therapies that are known to provide 
clinical benefit, as defined by national authority and/or ratified by national 
guidelines or equivalent, must have progressed following these therapies in 
order to be eligible for this study. 


 
 
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Exclusion Criteria 
A patient will be excluded from the study for any one or more of the following reasons: 
1. Patients who have had a prior anti-cancer monoclonal antibody (mAb) within 4 
weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) 
from adverse events due to agents administered more than 4 weeks earlier prior to 
study Day 1. 
2. Patients who have had prior chemotherapy, targeted small molecule therapy, or 
radiation therapy within 2 weeks prior to study Day 1 or who have not recovered (i.e., 
≤ Grade 1 or at baseline) from adverse events due to a previously administered agent. 
Note:  Patients with ≤ Grade 2 neuropathy or ≤ Grade 2 alopecia are an exception to this 
criterion and may qualify for the study. 
Note:  If patients have received major surgery, they must have recovered adequately from 
the toxicity and/or complications from the intervention prior to starting therapy.   
3. Patients who are currently participating and receiving study therapy or who have 
participated in a study of an investigational agent and received study therapy or who 
have used an investigational device within 4 weeks of the first dose of treatment. 
4. Patients who have received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, 
anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) 
antibody (including ipilimumab or any other antibody or drug specifically targeting 
T-cell co-stimulation or checkpoint pathways) or if the patient has previously 
participated in Merck MK-3475 clinical trials.  
5. Patients with known active central nervous system (CNS) metastases and/or 
carcinomatous meningitis.   
Note:  Patients with previously treated brain metastases may participate provided 
they are stable (without evidence of progression by imaging (using the identical 
imaging modality for each assessment, either MRI or CT scan) for at least four 
weeks prior to the first dose of trial treatment and any neurologic symptoms have 
returned to baseline), have no evidence of new or enlarging brain metastases, and are 
not using systemic steroids for at least 7 days prior to trial treatment.  This exception 
does not include carcinomatous meningitis which is excluded regardless of clinical 
stability. 
6. Patients with a known additional malignancy that is progressing or requires active 
treatment.  Exceptions include basal cell carcinoma of the skin, squamous cell 
carcinoma of the skin that has undergone potentially curative therapy or in situ 
cervical cancer. 


 
 
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7. Patients who have a history of allergic reactions attributed to compounds of similar 
chemical or biologic composition to birinapant or pembrolizumab or their 
constituents. 
8. Patients requiring the use of anti-tumor necrosis factor (anti-TNF) therapies, such as 
infliximab, or patients who have received treatment with anti-TNF therapies within 5 
half-lives of the drug. 
9. Patients with a diagnosis of immunodeficiency or who are receiving systemic steroid 
therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other 
form of immunosuppressive therapy within 7 days before the first dose of study drug. 
The use of physiologic doses of corticosteroids may be approved after consultation 
with the Sponsor.  
10. Patients with an uncontrolled intercurrent illness including, but not limited to, 
symptomatic congestive heart failure, hypertension, unstable angina pectoris, cardiac 
arrhythmia, autoimmune or inflammatory diseases, or psychiatric illness that would 
limit compliance with study requirements. 
11. Patients with an active autoimmune disease that has required systemic treatment in 
the past 2 years (i.e., with use of disease modifying agents, corticosteroids or 
immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) 
is not considered a form of systemic treatment. 
 
12. Patients who have evidence of active, non-infectious pneumonitis. Patients with a 
history of (non-infectious) pneumonitis that required steroids or current pneumonitis.  
 
13. Patients with a history of interstitial lung disease. 
 
14. Patients who are pregnant or breastfeeding, or expecting to conceive or father 
children within the projected duration of the trial, starting with the screening visit 
through 120 days after the last dose of trial treatment. Pregnant women and men who 
want to conceive a child are excluded from this study because birinapant and 
pembrolizumab are agents with unknown potential for teratogenic or abortifacient 
effects in humans. Because there is an unknown risk for AEs in nursing infants 
secondary to treatment of the mother with birinapant and pembrolizumab, 
breastfeeding should be discontinued if the mother is treated on this study.  
15. Patients who have a known history of Human Immunodeficiency Virus (HIV) (HIV 
1/2 antibodies), or active Hepatitis B (e.g., HBsAg reactive). Patients with active 
Hepatitis C (e.g., HCV RNA [qualitative] is detected).  
16. Patients who have received a live-virus vaccination within 30 days of planned 
treatment start. Seasonal flu vaccines that do not contain live virus are permitted. 


 
 
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17. Patients who have disease that is suitable for local therapy administered with curative 
intent. 
18. Patients who have received transfusion of blood products (including platelets or red 
blood cells) or administration of colony stimulating factors (including G-CSF, GM-
CSF or recombinant erythropoietin) within 4 weeks prior to study Day 1.  
19. Patients who have a history or current evidence of any condition, therapy, or 
laboratory abnormality that might confound the results of the trial, interfere with the 
patient’s participation for the full duration of the trial, or it is not in the best interest 
of the patient to participate, in the opinion of the treating investigator.  
20. Patients who have known psychiatric or substance abuse disorders that would 
interfere with cooperation with the requirements of the trial. 
21. Patients who have severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any 
of its excipients.  
23. Patients who have previously received birinapant treatment. 
 
 


 
 
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Appendix 2.4 Inclusion/Exclusion criteria Dose Expansion Phase Cervical cancer 
cohort 
NB: Inclusion/exclusion criteria numbering is derived from the complete set of criteria 
defined in sections 4.1 and 4.2. 
Inclusion Criteria 
Patients will be eligible for study participation if they meet ALL of the following 
inclusion criteria, after patient has provided written informed consent.  
1. The patient is male or female ≥ 18 years of age on the day of signing informed 
consent. 
2. The patient is able to understand and voluntarily sign a written informed consent, and 
is willing and able to comply with the protocol requirements. 
4. Patients must have measurable disease based on RECIST 1.1 as determined by the 
site study team.  Tumor lesions situated in a previously irradiated area are considered 
measurable if progression has been demonstrated in such lesions.  
5. Patients must have an Eastern Cooperative Oncology Group (ECOG) score of 0 or 1 
at screening.   
6. Patients must have a life expectancy of greater than 12 weeks. 
7. Patients must have amylase and lipase values < ULN. 
8. Patients must demonstrate adequate organ function as defined in Table A2.4.  All 
screening labs should be performed within 10 days of treatment initiation. 
 
Table A2.4 
Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L  
Renal 
Creatinine OR 
Measured 
or 
calculateda 
creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤1.5xULN OR 
≥60 mL/min for patient with  
creatinine levels >1.5x institutional ULN 
Hepatic 
Total bilirubin 
≤1.5xULN OR 
Direct bilirubin ≤ULN for patients with total 
bilirubin levels >1.5xULN), unless known Gilbert’s 
Syndrome has been diagnosed 


 
 
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AST (SGOT) and ALT (SGPT) 
≤2.5xULN OR 
≤5.0xULN for patients with liver metastases 
Coagulation 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
 
Activated Partial Thromboplastin Time 
(aPTT) 
≤1.5xULN unless patient is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic 
range of intended use of anticoagulants 
≤1.5xULN unless patient is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic 
range of intended use of anticoagulants 
a Creatinine clearance should be calculated per institutional standard. 
9. Female patients of childbearing potential must have a negative urine or serum 
pregnancy test within 72 hours prior to receiving the first dose of study medication. 
If the urine test is positive or cannot be confirmed as negative, a serum pregnancy 
test will be required.   
10. Female patients of childbearing potential must be willing to use an adequate method 
of contraception for the course of the study through 120 days after the last dose of 
study medication. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the patient.  
12. A tumor tissue sample for PD-L1 biomarker analysis from archival material, a newly 
obtained core or excisional biopsy is available for submission.  Repeat samples may 
be required if adequate tissue is not provided.   
13. Have resolution of toxic effect(s) of the most recent prior chemotherapy to Grade 1 
or less (except neuropathy or alopecia). If patients have received major surgery or 
radiation therapy of > 30 Gy, they must have recovered from the toxicity and/or 
complications from the intervention.  
17. Patients must have histologically or cytologically confirmed cervical squamous cell 
carcinoma that is locally advanced or metastatic with no available therapy options 
that are known to provide clinical benefit per institutional standard of care. Patients 
with tumors with mutations for which there are available therapies that are known to 
provide clinical benefit, as defined by national authority and/or ratified by national 
guidelines or equivalent, must have progressed following these therapies in order to 
be eligible for this study. 
Exclusion Criteria 
A patient will be excluded from the study for any one or more of the following reasons: 
1. Patients who have had a prior anti-cancer monoclonal antibody (mAb) within 4 
weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) 
from adverse events due to agents administered more than 4 weeks earlier prior to 
study Day 1. 


 
 
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2. Patients who have had prior chemotherapy, targeted small molecule therapy, or 
radiation therapy within 2 weeks prior to study Day 1 or who have not recovered (i.e., 
≤ Grade 1 or at baseline) from adverse events due to a previously administered agent. 
Note:  Patients with ≤ Grade 2 neuropathy or ≤ Grade 2 alopecia are an exception to 
this criterion and may qualify for the study. 
Note:  If patients have received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting therapy.   
3. Patients who are currently participating and receiving study therapy or who have 
participated in a study of an investigational agent and received study therapy or who 
have used an investigational device within 4 weeks of the first dose of treatment. 
4. Patients who have received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, 
anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) 
antibody (including ipilimumab or any other antibody or drug specifically targeting 
T-cell co-stimulation or checkpoint pathways) or if the patient has previously 
participated in Merck MK-3475 clinical trials.  
5. Patients with known active central nervous system (CNS) metastases and/or 
carcinomatous meningitis.   
Note:  Patients with previously treated brain metastases may participate provided 
they are stable (without evidence of progression by imaging (using the identical 
imaging modality for each assessment, either MRI or CT scan) for at least four 
weeks prior to the first dose of trial treatment and any neurologic symptoms have 
returned to baseline), have no evidence of new or enlarging brain metastases, and are 
not using systemic steroids for at least 7 days prior to trial treatment.  This exception 
does not include carcinomatous meningitis which is excluded regardless of clinical 
stability. 
6. Patients with a known additional malignancy that is progressing or requires active 
treatment.  Exceptions include basal cell carcinoma of the skin, squamous cell 
carcinoma of the skin that has undergone potentially curative therapy or in situ 
cervical cancer. 
7. Patients who have a history of allergic reactions attributed to compounds of similar 
chemical or biologic composition to birinapant or pembrolizumab or their 
constituents. 
8. Patients requiring the use of anti-tumor necrosis factor (anti-TNF) therapies, such as 
infliximab, or patients who have received treatment with anti-TNF therapies within 5 
half-lives of the drug. 
9. Patients with a diagnosis of immunodeficiency or who are receiving systemic steroid 
therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other 


 
 
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form of immunosuppressive therapy within 7 days before the first dose of study drug. 
The use of physiologic doses of corticosteroids may be approved after consultation 
with the Sponsor.  
10. Patients with an uncontrolled intercurrent illness including, but not limited to, 
symptomatic congestive heart failure, hypertension, unstable angina pectoris, cardiac 
arrhythmia, autoimmune or inflammatory diseases, or psychiatric illness that would 
limit compliance with study requirements. 
11. Patients with an active autoimmune disease that has required systemic treatment in 
the past 2 years (i.e., with use of disease modifying agents, corticosteroids or 
immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) 
is not considered a form of systemic treatment. 
 
12. Patients who have evidence of active, non-infectious pneumonitis. Patients with a 
history of (non-infectious) pneumonitis that required steroids or current pneumonitis.  
 
13. Patients with a history of interstitial lung disease. 
 
14. Patients who are pregnant or breastfeeding, or expecting to conceive or father 
children within the projected duration of the trial, starting with the screening visit 
through 120 days after the last dose of trial treatment. Pregnant women and men who 
want to conceive a child are excluded from this study because birinapant and 
pembrolizumab are agents with unknown potential for teratogenic or abortifacient 
effects in humans. Because there is an unknown risk for AEs in nursing infants 
secondary to treatment of the mother with birinapant and pembrolizumab, 
breastfeeding should be discontinued if the mother is treated on this study.  
15. Patients who have a known history of Human Immunodeficiency Virus (HIV) (HIV 
1/2 antibodies), or active Hepatitis B (e.g., HBsAg reactive). Patients with active 
Hepatitis C (e.g., HCV RNA [qualitative] is detected).  
16. Patients who have received a live-virus vaccination within 30 days of planned 
treatment start. Seasonal flu vaccines that do not contain live virus are permitted. 
17. Patients who have disease that is suitable for local therapy administered with curative 
intent. 
18. Patients who have received transfusion of blood products (including platelets or red 
blood cells) or administration of colony stimulating factors (including G-CSF, GM-
CSF or recombinant erythropoietin) within 4 weeks prior to study Day 1.  
19. Patients who have a history or current evidence of any condition, therapy, or 
laboratory abnormality that might confound the results of the trial, interfere with the 
patient’s participation for the full duration of the trial, or it is not in the best interest 
of the patient to participate, in the opinion of the treating investigator.  


 
 
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20. Patients who have known psychiatric or substance abuse disorders that would 
interfere with cooperation with the requirements of the trial. 
21. Patients who have severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any 
of its excipients.  
23. Patients who have previously received birinapant treatment. 
 
 
 


 
 
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Appendix 2.5 Inclusion/Exclusion criteria Dose Expansion Phase various solid 
tumors cohort 
Appendix 2.5.1  
Inclusion/Exclusion criteria Dose Expansion Phase various 
solid tumors cohort, head and neck squamous cell carcinoma (HNSCC)-check-
point-inhibitor naïve group  
NB: Inclusion/exclusion criteria numbering is derived from the complete set of criteria 
defined in sections 4.1 and 4.2. 
Inclusion criteria 
Patients will be eligible for study participation if they meet ALL of the following 
inclusion criteria, after patient has provided written informed consent.  
1. The patient is male or female ≥ 18 years of age on the day of signing informed 
consent. 
2. The patient is able to understand and voluntarily sign a written informed consent, and 
is willing and able to comply with the protocol requirements. 
4. Patients must have measurable disease based on RECIST 1.1 as determined by the 
site study team.  Tumor lesions situated in a previously irradiated area are considered 
measurable if progression has been demonstrated in such lesions.  
5. Patients must have an Eastern Cooperative Oncology Group (ECOG) score of 0 or 1 
at screening.   
6. Patients must have a life expectancy of greater than 12 weeks. 
7. Patients must have amylase and lipase values < ULN. 
8. Patients must demonstrate adequate organ function as defined in A2.5.1.  All 
screening labs should be performed within 10 days of treatment initiation. 
 
Table A2.5.1 Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L  
Renal 
Creatinine OR 
Measured 
or 
calculateda 
creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤1.5xULN OR 
≥60 mL/min for patient with  
creatinine levels >1.5x institutional ULN 
Hepatic 
Total bilirubin 
≤1.5xULN OR 
Direct bilirubin ≤ULN for patients with total 


 
 
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bilirubin levels >1.5xULN), unless known Gilbert’s 
Syndrome has been diagnosed 
AST (SGOT) and ALT (SGPT) 
≤2.5xULN OR 
≤5.0xULN for patients with liver metastases 
Coagulation 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
 
Activated Partial Thromboplastin Time 
(aPTT) 
≤1.5xULN unless patient is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic 
range of intended use of anticoagulants 
≤1.5xULN unless patient is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic 
range of intended use of anticoagulants 
a Creatinine clearance should be calculated per institutional standard. 
9. Female patients of childbearing potential must have a negative urine or serum 
pregnancy test within 72 hours prior to receiving the first dose of study medication. 
If the urine test is positive or cannot be confirmed as negative, a serum pregnancy 
test will be required.   
10. Female patients of childbearing potential must be willing to use an adequate method 
of contraception for the course of the study through 120 days after the last dose of 
study medication. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the patient. 
11. Male patients with female partners of childbearing potential must agree to use an 
adequate method of contraception, starting with the first dose of study therapy 
through 120 days after the last dose of study therapy.  
Note: Abstinence is acceptable if this is the usual lifestyle and preferred 
contraception for the patient. 
12. A tumor tissue sample for PD-L1 biomarker analysis from archival material, a newly 
obtained core or excisional biopsy is available for submission.  Repeat samples may 
be required if adequate tissue is not provided. 
13. Have resolution of toxic effect(s) of the most recent prior chemotherapy to Grade 1 
or less (except neuropathy or alopecia). If patients have received major surgery or 
radiation therapy of > 30 Gy, they must have recovered from the toxicity and/or 
complications from the intervention.  
18. Patients must have histologically or cytologically confirmed head and neck 
squamous cell carcinoma that is locally advanced or metastatic with no available 
therapy options that are known to provide clinical benefit per institutional standard of 
care. Patients with tumors with mutations for which there are available therapies that 
are known to provide clinical benefit, as defined by national authority and/or ratified 
by national guidelines or equivalent, must have progressed following these therapies 
in order to be eligible for this study. 


 
 
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Exclusion Criteria 
A patient will be excluded from the study for any one or more of the following reasons: 
1. Patients who have had a prior anti-cancer monoclonal antibody (mAb) within 4 
weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) 
from adverse events due to agents administered more than 4 weeks earlier prior to 
study Day 1. 
2. Patients who have had prior chemotherapy, targeted small molecule therapy, or 
radiation therapy within 2 weeks prior to study Day 1 or who have not recovered (i.e., 
≤ Grade 1 or at baseline) from adverse events due to a previously administered agent. 
Note:  Patients with ≤ Grade 2 neuropathy or ≤ Grade 2 alopecia are an exception to 
this criterion and may qualify for the study. 
Note:  If patients have received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting therapy.   
3. Patients who are currently participating and receiving study therapy or who have 
participated in a study of an investigational agent and received study therapy or who 
have used an investigational device within 4 weeks of the first dose of treatment. 
4. Patients who have received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, 
anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) 
antibody (including ipilimumab or any other antibody or drug specifically targeting 
T-cell co-stimulation or checkpoint pathways) or if the patient has previously 
participated in Merck MK-3475 clinical trials. 
5. Patients with known active central nervous system (CNS) metastases and/or 
carcinomatous meningitis.   
Note:  Patients with previously treated brain metastases may participate provided 
they are stable (without evidence of progression by imaging (using the identical 
imaging modality for each assessment, either MRI or CT scan) for at least four 
weeks prior to the first dose of trial treatment and any neurologic symptoms have 
returned to baseline), have no evidence of new or enlarging brain metastases, and are 
not using systemic steroids for at least 7 days prior to trial treatment.  This exception 
does not include carcinomatous meningitis which is excluded regardless of clinical 
stability. 
6. Patients with a known additional malignancy that is progressing or requires active 
treatment.  Exceptions include basal cell carcinoma of the skin, squamous cell 
carcinoma of the skin that has undergone potentially curative therapy or in situ 
cervical cancer. 
7. Patients who have a history of allergic reactions attributed to compounds of similar 


 
 
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chemical or biologic composition to birinapant or pembrolizumab or their 
constituents. 
8. Patients requiring the use of anti-tumor necrosis factor (anti-TNF) therapies, such as 
infliximab, or patients who have received treatment with anti-TNF therapies within 5 
half-lives of the drug. 
9. Patients with a diagnosis of immunodeficiency or who are receiving systemic steroid 
therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other 
form of immunosuppressive therapy within 7 days before the first dose of study drug. 
The use of physiologic doses of corticosteroids may be approved after consultation 
with the Sponsor.  
10. Patients with an uncontrolled intercurrent illness including, but not limited to, 
symptomatic congestive heart failure, hypertension, unstable angina pectoris, cardiac 
arrhythmia, autoimmune or inflammatory diseases, or psychiatric illness that would 
limit compliance with study requirements. 
11. Patients with an active autoimmune disease that has required systemic treatment in 
the past 2 years (i.e., with use of disease modifying agents, corticosteroids or 
immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) 
is not considered a form of systemic treatment. 
 
12. Patients who have evidence of active, non-infectious pneumonitis. Patients with a 
history of (non-infectious) pneumonitis that required steroids or current pneumonitis.  
 
13. Patients with a history of interstitial lung disease. 
 
14. Patients who are pregnant or breastfeeding, or expecting to conceive or father 
children within the projected duration of the trial, starting with the screening visit 
through 120 days after the last dose of trial treatment. Pregnant women and men who 
want to conceive a child are excluded from this study because birinapant and 
pembrolizumab are agents with unknown potential for teratogenic or abortifacient 
effects in humans. Because there is an unknown risk for AEs in nursing infants 
secondary to treatment of the mother with birinapant and pembrolizumab, 
breastfeeding should be discontinued if the mother is treated on this study.  
15. Patients who have a known history of Human Immunodeficiency Virus (HIV) (HIV 
1/2 antibodies), or active Hepatitis B (e.g., HBsAg reactive). Patients with active 
Hepatitis C (e.g., HCV RNA [qualitative] is detected).  
16. Patients who have received a live-virus vaccination within 30 days of planned 
treatment start. Seasonal flu vaccines that do not contain live virus are permitted. 
17. Patients who have disease that is suitable for local therapy administered with curative 
intent. 


 
 
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18. Patients who have received transfusion of blood products (including platelets or red 
blood cells) or administration of colony stimulating factors (including G-CSF, GM-
CSF or recombinant erythropoietin) within 4 weeks prior to study Day 1.  
19. Patients who have a history or current evidence of any condition, therapy, or 
laboratory abnormality that might confound the results of the trial, interfere with the 
patient’s participation for the full duration of the trial, or it is not in the best interest 
of the patient to participate, in the opinion of the treating investigator.  
20. Patients who have known psychiatric or substance abuse disorders that would 
interfere with cooperation with the requirements of the trial. 
21. Patients who have severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any 
of its excipients.  
23. Patients who have previously received birinapant treatment. 
 
 


 
 
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Appendix 2.5.2  
Inclusion/Exclusion criteria Dose Expansion Phase various 
solid tumors cohort, HNSCC check-point -inhibitor experienced group  
NB: Inclusion/exclusion criteria numbering is derived from the complete set of criteria 
defined in sections 4.1 and 4.2. 
Inclusion Criteria 
Patients will be eligible for study participation if they meet ALL of the following 
inclusion criteria, after patient has provided written informed consent.  
1. The patient is male or female ≥ 18 years of age on the day of signing informed 
consent. 
2. The patient is able to understand and voluntarily sign a written informed consent, and 
is willing and able to comply with the protocol requirements. 
4. Patients must have measurable disease based on RECIST 1.1 as determined by the 
site study team.  Tumor lesions situated in a previously irradiated area are considered 
measurable if progression has been demonstrated in such lesions.  
5. Patients must have an Eastern Cooperative Oncology Group (ECOG) score of 0 or 1 
at screening.   
6. Patients must have a life expectancy of greater than 12 weeks. 
7. Patients must have amylase and lipase values < ULN. 
8. Patients must demonstrate adequate organ function as defined in Table A.2.5.2.  All 
screening labs should be performed within 10 days of treatment initiation. 
 
Table A2.5.2 Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L  
Renal 
Creatinine OR 
Measured 
or 
calculateda 
creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤1.5xULN OR 
≥60 mL/min for patient with  
creatinine levels >1.5x institutional ULN 
Hepatic 
Total bilirubin 
≤1.5xULN OR 
Direct bilirubin ≤ULN for patients with total 
bilirubin levels >1.5xULN), unless known Gilbert’s 
Syndrome has been diagnosed 
AST (SGOT) and ALT (SGPT) 
≤2.5xULN OR 
≤5.0xULN for patients with liver metastases 


 
 
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Coagulation 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
 
Activated Partial Thromboplastin Time 
(aPTT) 
≤1.5xULN unless patient is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic 
range of intended use of anticoagulants 
≤1.5xULN unless patient is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic 
range of intended use of anticoagulants 
a Creatinine clearance should be calculated per institutional standard. 
9. Female patients of childbearing potential must have a negative urine or serum 
pregnancy test within 72 hours prior to receiving the first dose of study medication. 
If the urine test is positive or cannot be confirmed as negative, a serum pregnancy 
test will be required.   
10. Female patients of childbearing potential must be willing to use an adequate method 
of contraception for the course of the study through 120 days after the last dose of 
study medication. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred 
contraception for the patient. 
11. Male patients with female partners of childbearing potential must agree to use an 
adequate method of contraception, starting with the first dose of study therapy 
through 120 days after the last dose of study therapy. (Not applicable for Ovarian 
cancer cohort or Cervical cancer cohort) 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred 
contraception for the patient. 
12. A tumor tissue sample for PD-L1 biomarker analysis from archival material, a newly 
obtained core or excisional biopsy is available for submission.  Repeat samples may 
be required if adequate tissue is not provided. 
13. Have resolution of toxic effect(s) of the most recent prior chemotherapy to Grade 1 
or less (except neuropathy or alopecia). If patients have received major surgery or 
radiation therapy of > 30 Gy, they must have recovered from the toxicity and/or 
complications from the intervention.  
18. Patients must have histologically or cytologically confirmed head and neck 
squamous cell carcinoma that is locally advanced or metastatic with no available 
therapy options that are known to provide clinical benefit per institutional standard of 
care. Patients with tumors with mutations for which there are available therapies that 
are known to provide clinical benefit, as defined by national authority and/or ratified 
by national guidelines or equivalent, must have progressed following these therapies 
in order to be eligible for this study (various solid tumor cohort: head and neck 
squamous cell carcinoma groups only). 


 
 
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19. Patients with Head and Neck Squamous Cell Carcinoma who are to participate in the 
group of Checkpoint inhibitor experienced patients must have received prior therapy 
with an anti-PD-1 or anti-PD-L1 antibody administered either as monotherapy, or in 
combination with other therapies. Patients must have received at least two doses of 
an approved anti-PD-1/anti-PD-L1 antibody and have experienced documented 
radiographic progression of disease by RECIST v1.1. The initial evidence of disease 
progression is to be confirmed by a second assessment no less than four weeks from 
the date of the first documented disease progression in the absence of rapid clinical 
progression. The date for documentation of initial progression will be considered the 
date for disease progression. Progressive disease must have been documented during 
or within 12 weeks after last dose of such treatment. (various solid tumor cohort 
head and neck squamous cell carcinoma, check-point inhibitor experienced group 
only). 
Exclusion Criteria 
A patient will be excluded from the study for any one or more of the following reasons: 
1. Patients who have had a prior anti-cancer monoclonal antibody (mAb) within 4 
weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) 
from adverse events due to agents administered more than 4 weeks earlier prior to 
study Day 1. 
2. Patients who have had prior chemotherapy, targeted small molecule therapy, or 
radiation therapy within 2 weeks prior to study Day 1 or who have not recovered (i.e., 
≤ Grade 1 or at baseline) from adverse events due to a previously administered agent. 
Note:  Patients with ≤ Grade 2 neuropathy or ≤ Grade 2 alopecia are an exception to 
this criterion and may qualify for the study. 
Note:  If patients have received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting therapy.   
3. Patients who are currently participating and receiving study therapy or who have 
participated in a study of an investigational agent and received study therapy or who 
have used an investigational device within 4 weeks of the first dose of treatment. 
5. Patients with known active central nervous system (CNS) metastases and/or 
carcinomatous meningitis.   
Note:  Patients with previously treated brain metastases may participate provided 
they are stable (without evidence of progression by imaging (using the identical 
imaging modality for each assessment, either MRI or CT scan) for at least four 
weeks prior to the first dose of trial treatment and any neurologic symptoms have 
returned to baseline), have no evidence of new or enlarging brain metastases, and are 
not using systemic steroids for at least 7 days prior to trial treatment.  This exception 


 
 
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does not include carcinomatous meningitis which is excluded regardless of clinical 
stability. 
6. Patients with a known additional malignancy that is progressing or requires active 
treatment.  Exceptions include basal cell carcinoma of the skin, squamous cell 
carcinoma of the skin that has undergone potentially curative therapy or in situ 
cervical cancer. 
7. Patients who have a history of allergic reactions attributed to compounds of similar 
chemical or biologic composition to birinapant or pembrolizumab or their 
constituents. 
8. Patients requiring the use of anti-tumor necrosis factor (anti-TNF) therapies, such as 
infliximab, or patients who have received treatment with anti-TNF therapies within 5 
half-lives of the drug. 
9. Patients with a diagnosis of immunodeficiency or who are receiving systemic steroid 
therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other 
form of immunosuppressive therapy within 7 days before the first dose of study drug. 
The use of physiologic doses of corticosteroids may be approved after consultation 
with the Sponsor.  
10. Patients with an uncontrolled intercurrent illness including, but not limited to, 
symptomatic congestive heart failure, hypertension, unstable angina pectoris, cardiac 
arrhythmia, autoimmune or inflammatory diseases, or psychiatric illness that would 
limit compliance with study requirements. 
11. Patients with an active autoimmune disease that has required systemic treatment in 
the past 2 years (i.e., with use of disease modifying agents, corticosteroids or 
immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) 
is not considered a form of systemic treatment. 
 
12. Patients who have evidence of active, non-infectious pneumonitis. Patients with a 
history of (non-infectious) pneumonitis that required steroids or current pneumonitis.  
 
13. Patients with a history of interstitial lung disease. 
 
14. Patients who are pregnant or breastfeeding, or expecting to conceive or father 
children within the projected duration of the trial, starting with the screening visit 
through 120 days after the last dose of trial treatment. Pregnant women and men who 
want to conceive a child are excluded from this study because birinapant and 
pembrolizumab are agents with unknown potential for teratogenic or abortifacient 
effects in humans. Because there is an unknown risk for AEs in nursing infants 
secondary to treatment of the mother with birinapant and pembrolizumab, 
breastfeeding should be discontinued if the mother is treated on this study.  


 
 
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15. Patients who have a known history of Human Immunodeficiency Virus (HIV) (HIV 
1/2 antibodies), or active Hepatitis B (e.g., HBsAg reactive). Patients with active 
Hepatitis C (e.g., HCV RNA [qualitative] is detected).  
16. Patients who have received a live-virus vaccination within 30 days of planned 
treatment start. Seasonal flu vaccines that do not contain live virus are permitted. 
17. Patients who have disease that is suitable for local therapy administered with curative 
intent. 
18. Patients who have received transfusion of blood products (including platelets or red 
blood cells) or administration of colony stimulating factors (including G-CSF, GM-
CSF or recombinant erythropoietin) within 4 weeks prior to study Day 1.  
19. Patients who have a history or current evidence of any condition, therapy, or 
laboratory abnormality that might confound the results of the trial, interfere with the 
patient’s participation for the full duration of the trial, or it is not in the best interest 
of the patient to participate, in the opinion of the treating investigator.  
20. Patients who have known psychiatric or substance abuse disorders that would 
interfere with cooperation with the requirements of the trial. 
21. Patients who have severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any 
of its excipients.  
22. Patients who have received anti-PD-L2, anti-CD137, or anti-Cytotoxic T-
lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any 
other antibody or drug specifically targeting T-cell co-stimulation or checkpoint 
pathways). 
23. Patients who have previously received birinapant treatment. 
 
 


 
 
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Appendix 2.5.3  
Inclusion/Exclusion criteria Dose Expansion Phase various 
solid tumor cohort, gastroesophageal carcinoma group  
NB: Inclusion/exclusion criteria numbering is derived from the complete set of criteria 
defined in sections 4.1 and 4.2. 
Inclusion Criteria 
Patients will be eligible for study participation if they meet ALL of the following 
inclusion criteria, after patient has provided written informed consent.  
1. The patient is male or female ≥ 18 years of age on the day of signing informed 
consent. 
2. The patient is able to understand and voluntarily sign a written informed consent, and 
is willing and able to comply with the protocol requirements. 
4. Patients must have measurable disease based on RECIST 1.1 as determined by the 
site study team.  Tumor lesions situated in a previously irradiated area are considered 
measurable if progression has been demonstrated in such lesions.  
5. Patients must have an Eastern Cooperative Oncology Group (ECOG) score of 0 or 1 
at screening.   
6. Patients must have a life expectancy of greater than 12 weeks. 
7. Patients must have amylase and lipase values < ULN. 
8. Patients must demonstrate adequate organ function as defined in A2.5.3.  All 
screening labs should be performed within 10 days of treatment initiation. 
 
Table A2.5.3 Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L  
Renal 
Creatinine OR 
Measured 
or 
calculateda 
creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤1.5xULN OR 
≥60 mL/min for patient with  
creatinine levels >1.5x institutional ULN 
Hepatic 
Total bilirubin 
≤1.5xULN OR 
Direct bilirubin ≤ULN for patients with total 
bilirubin levels >1.5xULN), unless known Gilbert’s 
Syndrome has been diagnosed 


 
 
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AST (SGOT) and ALT (SGPT) 
≤2.5xULN OR 
≤5.0xULN for patients with liver metastases 
Coagulation 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
 
Activated Partial Thromboplastin Time 
(aPTT) 
≤1.5xULN unless patient is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic 
range of intended use of anticoagulants 
≤1.5xULN unless patient is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic 
range of intended use of anticoagulants 
a Creatinine clearance should be calculated per institutional standard. 
9. Female patients of childbearing potential must have a negative urine or serum 
pregnancy test within 72 hours prior to receiving the first dose of study medication. 
If the urine test is positive or cannot be confirmed as negative, a serum pregnancy 
test will be required.   
10. Female patients of childbearing potential must be willing to use an adequate method 
of contraception for the course of the study through 120 days after the last dose of 
study medication. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred 
contraception for the patient. 
11. Male patients with female partners of childbearing potential must agree to use an 
adequate method of contraception, starting with the first dose of study therapy 
through 120 days after the last dose of study therapy. (Not applicable for Ovarian 
cancer cohort or Cervical cancer cohort) 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the patient. 
12. A tumor tissue sample for PD-L1 biomarker analysis from archival material, a newly 
obtained core or excisional biopsy is available for submission.  Repeat samples may 
be required if adequate tissue is not provided.   
13. Have resolution of toxic effect(s) of the most recent prior chemotherapy to Grade 1 
or less (except neuropathy or alopecia). If patients have received major surgery or 
radiation therapy of > 30 Gy, they must have recovered from the toxicity and/or 
complications from the intervention.  
23. Patients must have histologically or cytologically confirmed carcinoma of the 
esophagus including the gastroesophageal junction that is locally advanced or 
metastatic with no available therapy options that are known to provide clinical 
benefit per institutional standard of care.  Patients with tumors with mutations for 
which there are available therapies that are known to provide clinical benefit, as 
defined by national authority and/or ratified by national guidelines or equivalent, 
must have progressed following these therapies in order to be eligible for this study.  


 
 
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Exclusion Criteria 
A patient will be excluded from the study for any one or more of the following reasons: 
1. Patients who have had a prior anti-cancer monoclonal antibody (mAb) within 4 
weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) 
from adverse events due to agents administered more than 4 weeks earlier prior to 
study Day 1. 
2. Patients who have had prior chemotherapy, targeted small molecule therapy, or 
radiation therapy within 2 weeks prior to study Day 1 or who have not recovered (i.e., 
≤ Grade 1 or at baseline) from adverse events due to a previously administered agent. 
Note:  Patients with ≤ Grade 2 neuropathy or ≤ Grade 2 alopecia are an exception to 
this criterion and may qualify for the study. 
Note:  If patients have received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting therapy.   
3. Patients who are currently participating and receiving study therapy or who have 
participated in a study of an investigational agent and received study therapy or who 
have used an investigational device within 4 weeks of the first dose of treatment. 
4. Patients who have received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, 
anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) 
antibody (including ipilimumab or any other antibody or drug specifically targeting 
T-cell co-stimulation or checkpoint pathways) or if the patient has previously 
participated in Merck MK-3475 clinical trials.  
5. Patients with known active central nervous system (CNS) metastases and/or 
carcinomatous meningitis.   
Note:  Patients with previously treated brain metastases may participate provided 
they are stable (without evidence of progression by imaging (using the identical 
imaging modality for each assessment, either MRI or CT scan) for at least four 
weeks prior to the first dose of trial treatment and any neurologic symptoms have 
returned to baseline), have no evidence of new or enlarging brain metastases, and are 
not using systemic steroids for at least 7 days prior to trial treatment.  This exception 
does not include carcinomatous meningitis which is excluded regardless of clinical 
stability. 
6. Patients with a known additional malignancy that is progressing or requires active 
treatment.  Exceptions include basal cell carcinoma of the skin, squamous cell 
carcinoma of the skin that has undergone potentially curative therapy or in situ 
cervical cancer. 
7. Patients who have a history of allergic reactions attributed to compounds of similar 


 
 
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chemical or biologic composition to birinapant or pembrolizumab or their 
constituents. 
8. Patients requiring the use of anti-tumor necrosis factor (anti-TNF) therapies, such as 
infliximab, or patients who have received treatment with anti-TNF therapies within 5 
half-lives of the drug. 
9. Patients with a diagnosis of immunodeficiency or who are receiving systemic steroid 
therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other 
form of immunosuppressive therapy within 7 days before the first dose of study drug. 
The use of physiologic doses of corticosteroids may be approved after consultation 
with the Sponsor.  
10. Patients with an uncontrolled intercurrent illness including, but not limited to, 
symptomatic congestive heart failure, hypertension, unstable angina pectoris, cardiac 
arrhythmia, autoimmune or inflammatory diseases, or psychiatric illness that would 
limit compliance with study requirements. 
11. Patients with an active autoimmune disease that has required systemic treatment in 
the past 2 years (i.e., with use of disease modifying agents, corticosteroids or 
immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) 
is not considered a form of systemic treatment. 
 
12. Patients who have evidence of active, non-infectious pneumonitis. Patients with a 
history of (non-infectious) pneumonitis that required steroids or current pneumonitis.  
 
13. Patients with a history of interstitial lung disease. 
 
14. Patients who are pregnant or breastfeeding, or expecting to conceive or father 
children within the projected duration of the trial, starting with the screening visit 
through 120 days after the last dose of trial treatment. Pregnant women and men who 
want to conceive a child are excluded from this study because birinapant and 
pembrolizumab are agents with unknown potential for teratogenic or abortifacient 
effects in humans. Because there is an unknown risk for AEs in nursing infants 
secondary to treatment of the mother with birinapant and pembrolizumab, 
breastfeeding should be discontinued if the mother is treated on this study.  
15. Patients who have a known history of Human Immunodeficiency Virus (HIV) (HIV 
1/2 antibodies), or active Hepatitis B (e.g., HBsAg reactive). Patients with active 
Hepatitis C (e.g., HCV RNA [qualitative] is detected).  
16. Patients who have received a live-virus vaccination within 30 days of planned 
treatment start. Seasonal flu vaccines that do not contain live virus are permitted. 
17. Patients who have disease that is suitable for local therapy administered with curative 
intent. 


 
 
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18. Patients who have received transfusion of blood products (including platelets or red 
blood cells) or administration of colony stimulating factors (including G-CSF, GM-
CSF or recombinant erythropoietin) within 4 weeks prior to study Day 1.  
19. Patients who have a history or current evidence of any condition, therapy, or 
laboratory abnormality that might confound the results of the trial, interfere with the 
patient’s participation for the full duration of the trial, or it is not in the best interest 
of the patient to participate, in the opinion of the treating investigator.  
20. Patients who have known psychiatric or substance abuse disorders that would 
interfere with cooperation with the requirements of the trial. 
21. Patients who have severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any 
of its excipients.  
23. Patients who have previously received birinapant treatment. 
 
 


 
 
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Appendix 2.5.4  
Inclusion/Exclusion criteria Dose Expansion Phase various 
solid tumor cohort, mesothelioma group  
NB: Inclusion/exclusion criteria numbering is derived from the complete set of criteria 
defined in sections 4.1 and 4.2. 
Inclusion Criteria 
Patients will be eligible for study participation if they meet ALL of the following 
inclusion criteria, after patient has provided written informed consent.  
1. The patient is male or female ≥ 18 years of age on the day of signing informed 
consent. 
2. The patient is able to understand and voluntarily sign a written informed consent, and 
is willing and able to comply with the protocol requirements. 
4. Patients must have measurable disease based on RECIST 1.1 as determined by the 
site study team.  Tumor lesions situated in a previously irradiated area are considered 
measurable if progression has been demonstrated in such lesions.  
5. Patients must have an Eastern Cooperative Oncology Group (ECOG) score of 0 or 1 
at screening.   
6. Patients must have a life expectancy of greater than 12 weeks. 
7. Patients must have amylase and lipase values < ULN. 
8. Patients must demonstrate adequate organ function as defined in Table A2.5.4.  All 
screening labs should be performed within 10 days of treatment initiation. 
 
Table A2.5.4 Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L  
Renal 
Creatinine OR 
Measured 
or 
calculateda 
creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤1.5xULN OR 
≥60 mL/min for patient with  
creatinine levels >1.5x institutional ULN 
Hepatic 
Total bilirubin 
≤1.5xULN OR 
Direct bilirubin ≤ULN for patients with total 
bilirubin levels >1.5xULN), unless known Gilbert’s 
Syndrome has been diagnosed 
AST (SGOT) and ALT (SGPT) 
≤2.5xULN OR 
≤5.0xULN for patients with liver metastases 


 
 
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Coagulation 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
 
Activated Partial Thromboplastin Time 
(aPTT) 
≤1.5xULN unless patient is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic 
range of intended use of anticoagulants 
≤1.5xULN unless patient is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic 
range of intended use of anticoagulants 
a Creatinine clearance should be calculated per institutional standard. 
9. Female patients of childbearing potential must have a negative urine or serum 
pregnancy test within 72 hours prior to receiving the first dose of study medication. 
If the urine test is positive or cannot be confirmed as negative, a serum pregnancy 
test will be required.   
10. Female patients of childbearing potential must be willing to use an adequate method 
of contraception for the course of the study through 120 days after the last dose of 
study medication. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred 
contraception for the patient. 
11. Male patients with female partners of childbearing potential must agree to use an 
adequate method of contraception, starting with the first dose of study therapy 
through 120 days after the last dose of study therapy. (Not applicable for Ovarian 
cancer cohort or Cervical cancer cohort) 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred 
contraception for the patient. 
12. A tumor tissue sample for PD-L1 biomarker analysis from archival material, a newly 
obtained core or excisional biopsy is available for submission.  Repeat samples may 
be required if adequate tissue is not provided.  
13. Have resolution of toxic effect(s) of the most recent prior chemotherapy to Grade 1 
or less (except neuropathy or alopecia). If patients have received major surgery or 
radiation therapy of > 30 Gy, they must have recovered from the toxicity and/or 
complications from the intervention.  
22. Patients must have histologically or cytologically confirmed pleural mesothelioma 
that is locally advanced or metastatic with no available therapy options that are 
known to provide clinical benefit per institutional standard of care. Patients with 
tumors with mutations for which there are available therapies that are known to 
provide clinical benefit, as defined by national authority and/or ratified by national 
guidelines or equivalent, must have progressed following these therapies in order to 
be eligible for this study.  
 


 
 
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Exclusion Criteria 
A patient will be excluded from the study for any one or more of the following reasons: 
1. Patients who have had a prior anti-cancer monoclonal antibody (mAb) within 4 
weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) 
from adverse events due to agents administered more than 4 weeks earlier prior to 
study Day 1. 
2. Patients who have had prior chemotherapy, targeted small molecule therapy, or 
radiation therapy within 2 weeks prior to study Day 1 or who have not recovered (i.e., 
≤ Grade 1 or at baseline) from adverse events due to a previously administered agent. 
Note:  Patients with ≤ Grade 2 neuropathy or ≤ Grade 2 alopecia are an exception to 
this criterion and may qualify for the study. 
Note:  If patients have received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting therapy.   
3. Patients who are currently participating and receiving study therapy or who have 
participated in a study of an investigational agent and received study therapy or who 
have used an investigational device within 4 weeks of the first dose of treatment. 
4. Patients who have received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, 
anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) 
antibody (including ipilimumab or any other antibody or drug specifically targeting 
T-cell co-stimulation or checkpoint pathways) or if the patient has previously 
participated in Merck MK-3475 clinical trials.  
5. Patients with known active central nervous system (CNS) metastases and/or 
carcinomatous meningitis.   
Note:  Patients with previously treated brain metastases may participate provided 
they are stable (without evidence of progression by imaging (using the identical 
imaging modality for each assessment, either MRI or CT scan) for at least four 
weeks prior to the first dose of trial treatment and any neurologic symptoms have 
returned to baseline), have no evidence of new or enlarging brain metastases, and are 
not using systemic steroids for at least 7 days prior to trial treatment.  This exception 
does not include carcinomatous meningitis which is excluded regardless of clinical 
stability. 
6. Patients with a known additional malignancy that is progressing or requires active 
treatment.  Exceptions include basal cell carcinoma of the skin, squamous cell 
carcinoma of the skin that has undergone potentially curative therapy or in situ 
cervical cancer. 
7. Patients who have a history of allergic reactions attributed to compounds of similar 


 
 
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16 Aug 2018 
 
Confidential 
chemical or biologic composition to birinapant or pembrolizumab or their 
constituents. 
8. Patients requiring the use of anti-tumor necrosis factor (anti-TNF) therapies, such as 
infliximab, or patients who have received treatment with anti-TNF therapies within 5 
half-lives of the drug. 
9. Patients with a diagnosis of immunodeficiency or who are receiving systemic steroid 
therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other 
form of immunosuppressive therapy within 7 days before the first dose of study drug. 
The use of physiologic doses of corticosteroids may be approved after consultation 
with the Sponsor.  
10. Patients with an uncontrolled intercurrent illness including, but not limited to, 
symptomatic congestive heart failure, hypertension, unstable angina pectoris, cardiac 
arrhythmia, autoimmune or inflammatory diseases, or psychiatric illness that would 
limit compliance with study requirements. 
11. Patients with an active autoimmune disease that has required systemic treatment in 
the past 2 years (i.e., with use of disease modifying agents, corticosteroids or 
immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) 
is not considered a form of systemic treatment. 
 
12. Patients who have evidence of active, non-infectious pneumonitis. Patients with a 
history of (non-infectious) pneumonitis that required steroids or current pneumonitis.  
 
13. Patients with a history of interstitial lung disease. 
 
14. Patients who are pregnant or breastfeeding, or expecting to conceive or father 
children within the projected duration of the trial, starting with the screening visit 
through 120 days after the last dose of trial treatment. Pregnant women and men who 
want to conceive a child are excluded from this study because birinapant and 
pembrolizumab are agents with unknown potential for teratogenic or abortifacient 
effects in humans. Because there is an unknown risk for AEs in nursing infants 
secondary to treatment of the mother with birinapant and pembrolizumab, 
breastfeeding should be discontinued if the mother is treated on this study.  
15. Patients who have a known history of Human Immunodeficiency Virus (HIV) (HIV 
1/2 antibodies), or active Hepatitis B (e.g., HBsAg reactive). Patients with active 
Hepatitis C (e.g., HCV RNA [qualitative] is detected).  
16. Patients who have received a live-virus vaccination within 30 days of planned 
treatment start. Seasonal flu vaccines that do not contain live virus are permitted. 
17. Patients who have disease that is suitable for local therapy administered with curative 
intent. 


 
 
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18. Patients who have received transfusion of blood products (including platelets or red 
blood cells) or administration of colony stimulating factors (including G-CSF, GM-
CSF or recombinant erythropoietin) within 4 weeks prior to study Day 1.  
19. Patients who have a history or current evidence of any condition, therapy, or 
laboratory abnormality that might confound the results of the trial, interfere with the 
patient’s participation for the full duration of the trial, or it is not in the best interest 
of the patient to participate, in the opinion of the treating investigator.  
20. Patients who have known psychiatric or substance abuse disorders that would 
interfere with cooperation with the requirements of the trial. 
21. Patients who have severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any 
of its excipients.  
23. Patients who have previously received birinapant treatment. 
 
 


 
 
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Appendix 2.5.5  
Inclusion/Exclusion criteria Dose Expansion Phase various 
solid tumor cohort, Small cell lung cancer group  
NB: Inclusion/exclusion criteria numbering is derived from the complete set of criteria 
defined in sections 4.1 and 4.2. 
Inclusion Criteria 
Patients will be eligible for study participation if they meet ALL of the following 
inclusion criteria, after patient has provided written informed consent.  
1. The patient is male or female ≥ 18 years of age on the day of signing informed 
consent. 
2. The patient is able to understand and voluntarily sign a written informed consent, and 
is willing and able to comply with the protocol requirements. 
4. Patients must have measurable disease based on RECIST 1.1 as determined by the 
site study team.  Tumor lesions situated in a previously irradiated area are considered 
measurable if progression has been demonstrated in such lesions.  
5. Patients must have an Eastern Cooperative Oncology Group (ECOG) score of 0 or 1 
at screening.   
6. Patients must have a life expectancy of greater than 12 weeks. 
7. Patients must have amylase and lipase values < ULN. 
8. Patients must demonstrate adequate organ function as defined in TableA2.5.5.  All 
screening labs should be performed within 10 days of treatment initiation. 
 
Table A2.5.5 Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L  
Renal 
Creatinine OR 
Measured 
or 
calculateda 
creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤1.5xULN OR 
≥60 mL/min for patient with  
creatinine levels >1.5x institutional ULN 
Hepatic 
Total bilirubin 
≤1.5xULN OR 
Direct bilirubin ≤ULN for patients with total 
bilirubin levels >1.5xULN), unless known Gilbert’s 
Syndrome has been diagnosed 
AST (SGOT) and ALT (SGPT) 
≤2.5xULN OR 
≤5.0xULN for patients with liver metastases 


 
 
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Coagulation 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
 
Activated Partial Thromboplastin Time 
(aPTT) 
≤1.5xULN unless patient is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic 
range of intended use of anticoagulants 
≤1.5xULN unless patient is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic 
range of intended use of anticoagulants 
a Creatinine clearance should be calculated per institutional standard. 
9. Female patients of childbearing potential must have a negative urine or serum 
pregnancy test within 72 hours prior to receiving the first dose of study medication. 
If the urine test is positive or cannot be confirmed as negative, a serum pregnancy 
test will be required.   
10. Female patients of childbearing potential must be willing to use an adequate method 
of contraception for the course of the study through 120 days after the last dose of 
study medication. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred 
contraception for the patient. 
11. Male patients with female partners of childbearing potential must agree to use an 
adequate method of contraception, starting with the first dose of study therapy 
through 120 days after the last dose of study therapy. (Not applicable for Ovarian 
cancer cohort or Cervical cancer cohort) 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred 
contraception for the patient. 
12. A tumor tissue sample for PD-L1 biomarker analysis from archival material, a newly 
obtained core or excisional biopsy is available for submission.  Repeat samples may 
be required if adequate tissue is not provided.   
13. Have resolution of toxic effect(s) of the most recent prior chemotherapy to Grade 1 
or less (except neuropathy or alopecia). If patients have received major surgery or 
radiation therapy of > 30 Gy, they must have recovered from the toxicity and/or 
complications from the intervention.  
20. Patients must have histologically or cytologically confirmed small cell lung 
carcinoma that is locally advanced or metastatic with no available therapy options 
that are known to provide clinical benefit per institutional standard of care. Patients 
with tumors with mutations for which there are available therapies that are known to 
provide clinical benefit, as defined by national authority and/or ratified by national 
guidelines or equivalent, must have progressed following these therapies in order to 
be eligible for this study. 
 


 
 
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Exclusion Criteria 
A patient will be excluded from the study for any one or more of the following reasons: 
1. Patients who have had a prior anti-cancer monoclonal antibody (mAb) within 4 
weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) 
from adverse events due to agents administered more than 4 weeks earlier prior to 
study Day 1. 
2. Patients who have had prior chemotherapy, targeted small molecule therapy, or 
radiation therapy within 2 weeks prior to study Day 1 or who have not recovered (i.e., 
≤ Grade 1 or at baseline) from adverse events due to a previously administered agent. 
Note:  Patients with ≤ Grade 2 neuropathy or ≤ Grade 2 alopecia are an exception to 
this criterion and may qualify for the study. 
Note:  If patients have received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting therapy.   
3. Patients who are currently participating and receiving study therapy or who have 
participated in a study of an investigational agent and received study therapy or who 
have used an investigational device within 4 weeks of the first dose of treatment. 
4. Patients who have received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, 
anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) 
antibody (including ipilimumab or any other antibody or drug specifically targeting 
T-cell co-stimulation or checkpoint pathways) or if the patient has previously 
participated in Merck MK-3475 clinical trials.  
5. Patients with known active central nervous system (CNS) metastases and/or 
carcinomatous meningitis.   
Note:  Patients with previously treated brain metastases may participate provided 
they are stable (without evidence of progression by imaging (using the identical 
imaging modality for each assessment, either MRI or CT scan) for at least four 
weeks prior to the first dose of trial treatment and any neurologic symptoms have 
returned to baseline), have no evidence of new or enlarging brain metastases, and are 
not using systemic steroids for at least 7 days prior to trial treatment.  This exception 
does not include carcinomatous meningitis which is excluded regardless of clinical 
stability. 
6. Patients with a known additional malignancy that is progressing or requires active 
treatment.  Exceptions include basal cell carcinoma of the skin, squamous cell 
carcinoma of the skin that has undergone potentially curative therapy or in situ 
cervical cancer. 
7. Patients who have a history of allergic reactions attributed to compounds of similar 


 
 
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chemical or biologic composition to birinapant or pembrolizumab or their 
constituents. 
8. Patients requiring the use of anti-tumor necrosis factor (anti-TNF) therapies, such as 
infliximab, or patients who have received treatment with anti-TNF therapies within 5 
half-lives of the drug. 
9. Patients with a diagnosis of immunodeficiency or who are receiving systemic steroid 
therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other 
form of immunosuppressive therapy within 7 days before the first dose of study drug. 
The use of physiologic doses of corticosteroids may be approved after consultation 
with the Sponsor.  
10. Patients with an uncontrolled intercurrent illness including, but not limited to, 
symptomatic congestive heart failure, hypertension, unstable angina pectoris, cardiac 
arrhythmia, autoimmune or inflammatory diseases, or psychiatric illness that would 
limit compliance with study requirements. 
11. Patients with an active autoimmune disease that has required systemic treatment in 
the past 2 years (i.e., with use of disease modifying agents, corticosteroids or 
immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) 
is not considered a form of systemic treatment. 
 
12. Patients who have evidence of active, non-infectious pneumonitis. Patients with a 
history of (non-infectious) pneumonitis that required steroids or current pneumonitis.  
 
13. Patients with a history of interstitial lung disease. 
 
14. Patients who are pregnant or breastfeeding, or expecting to conceive or father 
children within the projected duration of the trial, starting with the screening visit 
through 120 days after the last dose of trial treatment. Pregnant women and men who 
want to conceive a child are excluded from this study because birinapant and 
pembrolizumab are agents with unknown potential for teratogenic or abortifacient 
effects in humans. Because there is an unknown risk for AEs in nursing infants 
secondary to treatment of the mother with birinapant and pembrolizumab, 
breastfeeding should be discontinued if the mother is treated on this study.  
15. Patients who have a known history of Human Immunodeficiency Virus (HIV) (HIV 
1/2 antibodies), or active Hepatitis B (e.g., HBsAg reactive). Patients with active 
Hepatitis C (e.g., HCV RNA [qualitative] is detected).  
16. Patients who have received a live-virus vaccination within 30 days of planned 
treatment start. Seasonal flu vaccines that do not contain live virus are permitted. 
17. Patients who have disease that is suitable for local therapy administered with curative 
intent. 


 
 
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18. Patients who have received transfusion of blood products (including platelets or red 
blood cells) or administration of colony stimulating factors (including G-CSF, GM-
CSF or recombinant erythropoietin) within 4 weeks prior to study Day 1.  
19. Patients who have a history or current evidence of any condition, therapy, or 
laboratory abnormality that might confound the results of the trial, interfere with the 
patient’s participation for the full duration of the trial, or it is not in the best interest 
of the patient to participate, in the opinion of the treating investigator.  
20. Patients who have known psychiatric or substance abuse disorders that would 
interfere with cooperation with the requirements of the trial. 
21. Patients who have severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any 
of its excipients.  
23. Patients who have previously received birinapant treatment. 
 
 


 
 
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Appendix 2.5.6  
Inclusion/Exclusion criteria Dose Expansion Phase various 
solid tumor cohort, cholangiocarcinoma group  
NB: Inclusion/exclusion criteria numbering is derived from the complete set of criteria 
defined in sections 4.1 and 4.2. 
Inclusion Criteria 
Patients will be eligible for study participation if they meet ALL of the following 
inclusion criteria, after patient has provided written informed consent.  
1. The patient is male or female ≥ 18 years of age on the day of signing informed 
consent. 
2. The patient is able to understand and voluntarily sign a written informed consent, and 
is willing and able to comply with the protocol requirements. 
4. Patients must have measurable disease based on RECIST 1.1 as determined by the 
site study team.  Tumor lesions situated in a previously irradiated area are considered 
measurable if progression has been demonstrated in such lesions.  
5. Patients must have an Eastern Cooperative Oncology Group (ECOG) score of 0 or 1 
at screening.   
6. Patients must have a life expectancy of greater than 12 weeks. 
7. Patients must have amylase and lipase values < ULN. 
8. Patients must demonstrate adequate organ function as defined in TableA2.5.6.  All 
screening labs should be performed within 10 days of treatment initiation. 
 
Table A2.5.6 Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L  
Renal 
Creatinine OR 
Measured 
or 
calculateda 
creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤1.5xULN OR 
≥60 mL/min for patient with  
creatinine levels >1.5x institutional ULN 
Hepatic 
Total bilirubin 
≤1.5xULN OR 
Direct bilirubin ≤ULN for patients with total 
bilirubin levels >1.5xULN), unless known Gilbert’s 
Syndrome has been diagnosed 
AST (SGOT) and ALT (SGPT) 
≤2.5xULN OR 
≤5.0xULN for patients with liver metastases 


 
 
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Coagulation 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
 
Activated Partial Thromboplastin Time 
(aPTT) 
≤1.5xULN unless patient is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic 
range of intended use of anticoagulants 
≤1.5xULN unless patient is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic 
range of intended use of anticoagulants 
a Creatinine clearance should be calculated per institutional standard. 
9. Female patients of childbearing potential must have a negative urine or serum 
pregnancy test within 72 hours prior to receiving the first dose of study 
medication. If the urine test is positive or cannot be confirmed as negative, a 
serum pregnancy test will be required.   
10. Female patients of childbearing potential must be willing to use an adequate 
method of contraception for the course of the study through 120 days after the 
last dose of study medication. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred 
contraception for the patient. 
11. Male patients with female partners of childbearing potential must agree to use an 
adequate method of contraception, starting with the first dose of study therapy 
through 120 days after the last dose of study therapy. (Not applicable for Ovarian 
cancer cohort or Cervical cancer cohort) 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred 
contraception for the patient. 
12. A tumor tissue sample for PD-L1 biomarker analysis from archival material, a newly 
obtained core or excisional biopsy is available for submission.  Repeat samples may 
be required if adequate tissue is not provided.   
13. Have resolution of toxic effect(s) of the most recent prior chemotherapy to Grade 1 
or less (except neuropathy or alopecia). If patients have received major surgery or 
radiation therapy of > 30 Gy, they must have recovered from the toxicity and/or 
complications from the intervention.  
21. Patients must have histologically or cytologically confirmed cholangiocarcinoma that 
is locally advanced or metastatic with no available therapy options that are known to 
provide clinical benefit per institutional standard of care. Patients with tumors with 
mutations for which there are available therapies that are known to provide clinical 
benefit, as defined by national authority and/or ratified by national guidelines or 
equivalent, must have progressed following these therapies in order to be eligible for 
this study.  
 


 
 
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Exclusion Criteria 
A patient will be excluded from the study for any one or more of the following reasons: 
1. Patients who have had a prior anti-cancer monoclonal antibody (mAb) within 4 
weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) 
from adverse events due to agents administered more than 4 weeks earlier prior to 
study Day 1. 
2. Patients who have had prior chemotherapy, targeted small molecule therapy, or 
radiation therapy within 2 weeks prior to study Day 1 or who have not recovered (i.e., 
≤ Grade 1 or at baseline) from adverse events due to a previously administered agent. 
Note:  Patients with ≤ Grade 2 neuropathy or ≤ Grade 2 alopecia are an exception to 
this criterion and may qualify for the study. 
Note:  If patients have received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting therapy.   
3. Patients who are currently participating and receiving study therapy or who have 
participated in a study of an investigational agent and received study therapy or who 
have used an investigational device within 4 weeks of the first dose of treatment. 
4. Patients who have received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, 
anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) 
antibody (including ipilimumab or any other antibody or drug specifically targeting 
T-cell co-stimulation or checkpoint pathways) or if the patient has previously 
participated in Merck MK-3475 clinical trials.  
5. Patients with known active central nervous system (CNS) metastases and/or 
carcinomatous meningitis.   
Note:  Patients with previously treated brain metastases may participate provided 
they are stable (without evidence of progression by imaging (using the identical 
imaging modality for each assessment, either MRI or CT scan) for at least four 
weeks prior to the first dose of trial treatment and any neurologic symptoms have 
returned to baseline), have no evidence of new or enlarging brain metastases, and are 
not using systemic steroids for at least 7 days prior to trial treatment.  This exception 
does not include carcinomatous meningitis which is excluded regardless of clinical 
stability. 
6. Patients with a known additional malignancy that is progressing or requires active 
treatment.  Exceptions include basal cell carcinoma of the skin, squamous cell 
carcinoma of the skin that has undergone potentially curative therapy or in situ 
cervical cancer. 
7. Patients who have a history of allergic reactions attributed to compounds of similar 


 
 
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chemical or biologic composition to birinapant or pembrolizumab or their 
constituents. 
8. Patients requiring the use of anti-tumor necrosis factor (anti-TNF) therapies, such as 
infliximab, or patients who have received treatment with anti-TNF therapies within 5 
half-lives of the drug. 
9. Patients with a diagnosis of immunodeficiency or who are receiving systemic steroid 
therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other 
form of immunosuppressive therapy within 7 days before the first dose of study drug. 
The use of physiologic doses of corticosteroids may be approved after consultation 
with the Sponsor.  
10. Patients with an uncontrolled intercurrent illness including, but not limited to, 
symptomatic congestive heart failure, hypertension, unstable angina pectoris, cardiac 
arrhythmia, autoimmune or inflammatory diseases, or psychiatric illness that would 
limit compliance with study requirements. 
11. Patients with an active autoimmune disease that has required systemic treatment in 
the past 2 years (i.e., with use of disease modifying agents, corticosteroids or 
immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) 
is not considered a form of systemic treatment. 
 
12. Patients who have evidence of active, non-infectious pneumonitis. Patients with a 
history of (non-infectious) pneumonitis that required steroids or current pneumonitis.  
 
13. Patients with a history of interstitial lung disease 
 
14. Patients who are pregnant or breastfeeding, or expecting to conceive or father 
children within the projected duration of the trial, starting with the screening visit 
through 120 days after the last dose of trial treatment. Pregnant women and men who 
want to conceive a child are excluded from this study because birinapant and 
pembrolizumab are agents with unknown potential for teratogenic or abortifacient 
effects in humans. Because there is an unknown risk for AEs in nursing infants 
secondary to treatment of the mother with birinapant and pembrolizumab, 
breastfeeding should be discontinued if the mother is treated on this study.  
15. Patients who have a known history of Human Immunodeficiency Virus (HIV) (HIV 
1/2 antibodies), or active Hepatitis B (e.g., HBsAg reactive). Patients with active 
Hepatitis C (e.g., HCV RNA [qualitative] is detected).  
16. Patients who have received a live-virus vaccination within 30 days of planned 
treatment start. Seasonal flu vaccines that do not contain live virus are permitted. 
17. Patients who have disease that is suitable for local therapy administered with curative 
intent. 


 
 
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18. Patients who have received transfusion of blood products (including platelets or red 
blood cells) or administration of colony stimulating factors (including G-CSF, GM-
CSF or recombinant erythropoietin) within 4 weeks prior to study Day 1.  
19. Patients who have a history or current evidence of any condition, therapy, or 
laboratory abnormality that might confound the results of the trial, interfere with the 
patient’s participation for the full duration of the trial, or it is not in the best interest 
of the patient to participate, in the opinion of the treating investigator.  
20. Patients who have known psychiatric or substance abuse disorders that would 
interfere with cooperation with the requirements of the trial. 
21. Patients who have severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any 
of its excipients.  
23. Patients who have previously received birinapant treatment. 
 
 

SAP_001.pdf: 
Statistical Analysis Plan 
Title: A Phase 1/2, Multicenter, Single-Arm, Open-Label, 
Dose-Escalation Study of Birinapant in Combination with 
Pembrolizumab (KEYTRUDA™) in Patients with Relapsed or 
Refractory Solid Tumors 
Date: 13 June 2018 
NCT number: NCT02587962 
 


 
 
 
Statistical Analysis Plan 
 
 
 
 
 
Client Study Code: 
BPT-201 
Study Title: 
A Phase 1/2, Multicenter, Single-Arm, Open-Label, Dose-Escalation Study of 
Birinapant in Combination with Pembrolizumab (KEYTRUDA™) in Patients with 
Relapsed or Refractory Solid Tumors 
SDS Project Code: 
 
 
 




 
BPT-201_SAP_final 
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Table of Contents 
Signatures ........................................................................................................................................................ 2 
Abbreviations ................................................................................................................................................... 5 
1. 
Introduction ......................................................................................................................................... 7 
2. 
Study Objectives .................................................................................................................................. 7 
2.1 
Study Objectives Dose Escalation Phase ..................................................................................................................7 
2.1.1 
Primary Objective ................................................................................................................................................................. 7 
2.1.2 
Secondary Objective ............................................................................................................................................................. 7 
2.1.3 
Exploratory Objectives ......................................................................................................................................................... 7 
2.2 
Study Objectives Dose Expansion Phase ..................................................................................................................7 
2.2.1 
Primary Objective ................................................................................................................................................................. 7 
2.2.2 
Secondary Objectives ............................................................................................................................................................ 8 
2.2.3 
Exploratory Objectives ......................................................................................................................................................... 8 
3. 
Study Details ........................................................................................................................................ 8 
3.1 
Study Design and Study Population .........................................................................................................................8 
3.1.1 
Dose-escalation phase ........................................................................................................................................................... 8 
3.1.2 
Dose expansion phase ........................................................................................................................................................... 9 
3.1.3 
Study Flow Chart ................................................................................................................................................................ 10 
3.2 
Randomization and Blinding ..................................................................................................................................10 
3.3 
Number of Patients .................................................................................................................................................10 
3.3.1 
Sample Size Calculation ..................................................................................................................................................... 10 
 
Dose escalation phase ................................................................................................................................................. 10 
 
Dose expansion phase ................................................................................................................................................. 10 
4. 
Assessments ........................................................................................................................................ 11 
4.1 
Disposition and Other Supporting Assessments .....................................................................................................11 
4.1.1 
Patient Compliance ............................................................................................................................................................. 11 
4.1.2 
Protocol Deviations ............................................................................................................................................................. 11 
4.1.3 
Demographic and Baseline Characteristics ......................................................................................................................... 11 
4.1.4 
Medical History .................................................................................................................................................................. 11 
4.1.5 
Prior and Concomitant Medications .................................................................................................................................... 11 
4.1.6 
Eastern Cooperative Oncology Group-Performance Status ................................................................................................. 12 
4.2 
Efficacy Endpoints .................................................................................................................................................12 
4.2.1 
Dose Escalation Phase ........................................................................................................................................................ 12 
 
Primary Efficacy Endpoint .......................................................................................................................................... 12 
 
Secondary Efficacy Endpoints .................................................................................................................................... 12 
 
Exploratory Efficacy Variable .................................................................................................................................... 12 
4.2.2 
Dose Expansion Phase ........................................................................................................................................................ 12 
 
Primary Efficacy Endpoint .......................................................................................................................................... 12 
 
Secondary Efficacy Endpoints .................................................................................................................................... 13 
 
Exploratory Efficacy Variable .................................................................................................................................... 13 
4.2.3 
Definition of Efficacy Endpoints ........................................................................................................................................ 13 
 
Overall response (and ORR) assessed through RECIST 1.1 ....................................................................................... 14 
 
Progression Free Survival (PFS) ................................................................................................................................. 15 
 
Clinical Benefit Rate (CBR) ....................................................................................................................................... 15 
 
Time to response ......................................................................................................................................................... 15 
 
Duration of response ................................................................................................................................................... 15 
 
Overall Survival (OS) ................................................................................................................................................. 15 
 
Overall response assessed through iRECIST .............................................................................................................. 15 
 
Immune Best Overall Response (iBOR) ..................................................................................................................... 16 
 
Duration of iBOR ........................................................................................................................................................ 16 
 Time to iCPD .............................................................................................................................................................. 17 
 Immune Clinical Benefit Rate (iCBR) ........................................................................................................................ 17 
 Time to immune response ........................................................................................................................................... 17 
 Duration of immune response ..................................................................................................................................... 17 
4.3 
Safety Endpoints .....................................................................................................................................................17 
4.3.1 
Adverse Events ................................................................................................................................................................... 17 
4.3.2 
Clinical Laboratory Tests .................................................................................................................................................... 17 
 
Hematology, Serum Chemistry, Immunology and Urinalysis, Serology ..................................................................... 17 
 
Pregnancy Testing ....................................................................................................................................................... 18 
 
Histology .................................................................................................................................................................... 18 
4.3.3 
Physical Examination .......................................................................................................................................................... 18 
4.3.4 
Vital Signs .......................................................................................................................................................................... 18 
4.3.5 
ECGs................................................................................................................................................................................... 18 
4.4 
Pharmacokinetic Assessments ................................................................................................................................18 


 
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5. 
Analysis Methods ............................................................................................................................... 19 
5.1 
Clean File and Timing of Analysis .........................................................................................................................19 
5.2 
Analysis Populations ..............................................................................................................................................19 
5.2.1 
Intent-to-Treat Population (ITT) ......................................................................................................................................... 19 
5.2.2 
Efficacy Evaluable Population ............................................................................................................................................ 19 
5.2.3 
Safety Population ................................................................................................................................................................ 19 
5.2.4 
Pharmacodynamic Evaluable Population ............................................................................................................................ 19 
5.2.5 
Pharmacokinetic Analysis Population ................................................................................................................................. 19 
5.3 
General Principles for Presenting Study Data .........................................................................................................19 
5.4 
Statistical/Analytical issues ....................................................................................................................................20 
5.4.1 
Missing Data and Handling of Dropouts ............................................................................................................................. 20 
5.4.2 
Data Transformations and Derived Variables ..................................................................................................................... 21 
 
Calculation of change from baseline ........................................................................................................................... 21 
5.4.3 
Interim Analysis and Data Monitoring ................................................................................................................................ 21 
 
Colorectal Cancer Cohort ............................................................................................................................................ 21 
 
Ovarian Cancer Cohort ............................................................................................................................................... 21 
 
Cervical Cancer Cohort ............................................................................................................................................... 21 
5.4.4 
Multiple Comparisons/Multiplicity ..................................................................................................................................... 21 
5.4.5 
Examination of Subgroups .................................................................................................................................................. 22 
5.5 
Patient Disposition Summary .................................................................................................................................22 
5.5.1 
Patient Disposition .............................................................................................................................................................. 22 
5.5.2 
Protocol Deviations ............................................................................................................................................................. 22 
5.5.3 
Demographic and Baseline Characteristics ......................................................................................................................... 22 
5.5.4 
Medical History .................................................................................................................................................................. 22 
5.5.5 
Prior and Concomitant Medications .................................................................................................................................... 22 
5.5.6 
Exposure to Study Treatment .............................................................................................................................................. 22 
5.5.7 
Premature Termination ....................................................................................................................................................... 23 
5.6 
Efficacy Analyses ...................................................................................................................................................23 
5.6.1 
Primary Efficacy Analysis .................................................................................................................................................. 23 
5.6.2 
Secondary Efficacy Analyses .............................................................................................................................................. 24 
5.6.3 
Exploratory Efficacy Analyses............................................................................................................................................ 24 
5.6.4 
Subgroup Analyses ............................................................................................................................................................. 24 
5.6.5 
Sensitivity Analyses ............................................................................................................................................................ 24 
5.7 
Safety Analyses ......................................................................................................................................................25 
5.7.1 
Adverse Events ................................................................................................................................................................... 25 
5.7.2 
Clinical Laboratory Tests .................................................................................................................................................... 25 
5.7.3 
Physical Examination .......................................................................................................................................................... 25 
5.7.4 
Vital Signs .......................................................................................................................................................................... 26 
5.7.5 
Electrocardiogram ............................................................................................................................................................... 26 
5.8 
Pharmacokinetic Analyses ......................................................................................................................................26 
5.9 
Changes to Planned Analysis ..................................................................................................................................26 
6. 
References .......................................................................................................................................... 27 
7. 
Appendix 1 ......................................................................................................................................... 28 
 
 
 


 
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Abbreviations 
Abbreviation 
Term 
AE 
Adverse Event 
ALAT 
Alanine Transaminase 
ALP 
Alkaline Phosphatase 
ANCOVA 
Analysis of Covariance 
ASAT 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemicals 
CI 
Confidence Interval 
CBR 
Clinical Benefit Rate 
CR 
Complete Response 
CRP 
C-reactive protein 
DLT 
Dose Limiting Toxicity 
DSMB 
Data and Safety Monitoring Board 
FAS 
Full Analysis Set 
HDL 
High Density Lipoprotein 
IAP 
Interim Analysis Plan 
iBOR 
Immune Best Overall Response 
iCBR 
Immune Clinical Benefit Rate 
ICH 
International Conference on Harmonization 
iCPD 
Immune Confirmed Progressive Disease 
iCR 
Immune Complete Response 
IMP 
Investigational Medicinal Product 
iPR 
Immune Partial Response 
iRECIST 
Immune Response Evaluation Criteria in Solid Tumours 
iSD 
Immune Stable Disease 
iUPD 
Immune Unconfirmed Progressive Disease 
LLOQ 
Lower Limit Of Quantification 
LSmeans 
Least Square Means 
Max 
Maximum 
MedDRA 
Medical Dictionary for Regulatory Activities 
Min 
Minimum 
N 
Number of observations 
Nmiss 
Number of Missing Observations 
ORR 
Overall Response Rate 
OS 
Overall Survival 
OTC 
Over-the-counter 
PFS 
Progression Free Survival 
PD 
Progressive Disease 
PR 
Partial Response 
PT 
Preferred Term 
RBC 
Red Blood Cells 
RECIST 
Response Evaluation Criteria in Solid Tumours 
RP2D 
Recommended Phase 2 Dose 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 


 
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SD 
Stable Disease 
SOC 
System Organ Class 
SD 
Standard Deviation 
SRC 
Safety Review Committee 
TEAE 
Treatment Emergent Adverse Event 
TLF 
Tables Listing Figures 
WBC 
White Blood Cells 
 
 
 


 
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1. 
Introduction 
This Statistical Analysis Plan (SAP) provides a detailed and technical description of the 
planned statistical evaluation of the Medivir study BPT-201: “A Phase 1/2, Multicenter, 
Single-Arm, Open-Label, Dose-Escalation Study of Birinapant in Combination with 
Pembrolizumab (KEYTRUDA™) in Patients with Relapsed or Refractory Solid Tumors”. 
The study consists of two phases, a dose-escalation phase followed by a dose-expansion 
phase. 
  
Mock-up TFLs and an analysis plan for the exploratory objectives regarding biomarkers will 
be provided in separate documents. 
 
Details regarding the investigational plan, patient selection criteria, dose administration, and 
schedule of assessments are given in the Clinical Study Protocol (CSP) ”BPT-201 v4.0/incl 
amendment 03”. 
 
2. 
Study Objectives  
2.1 
Study Objectives Dose Escalation Phase  
2.1.1 Primary Objective 
To determine the safety and tolerability of the recommended phase 2 dose (RP2D) of 
birinapant when given in combination with pembrolizumab IV. 
2.1.2 Secondary Objective 
To assess preliminary efficacy of the combination of pembrolizumab and birinapant in 
patients with relapsed or refractory cancer by effects on tumor size as measured by imaging 
(CT or MRI) assessed by RECIST 1.1. 
2.1.3 Exploratory Objectives 
1. To assess preliminary efficacy of the combination of pembrolizumab and birinapant in patients 
with relapsed or refractory cancer by effects on tumor size as measured by imaging (CT or MRI) 
assessed by iRECIST. 
2. To determine the pharmacodynamic markers of birinapant and of pembrolizumab when given 
in combination at the schedule and dose as defined by the protocol, to include but not to be 
limited to mechanism of action (inhibition of cIAP1), and of immune surveillance and 
activation. 
3. To assess biomarkers that might predict for responders to the combination treatment and allow 
comparison to known potential predictive biomarkers of pembrolizumab response. 
4. To evaluate birinapant pharmacokinetics in plasma when administered in combination with 
pembrolizumab. 
2.2 
Study Objectives Dose Expansion Phase 
2.2.1 Primary Objective 
The primary objective in each of the cohorts is as follows: 
 
1. To determine whether the combination of pembrolizumab and birinapant has sufficient 
antitumor activity, as assessed by ORR, against colorectal cancer to warrant more extensive 
development.  


 
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2. To determine whether the combination of pembrolizumab and birinapant has sufficient 
antitumor activity, as assessed by ORR, against ovarian cancer to warrant more extensive 
development.  
3. To determine whether the combination of pembrolizumab and birinapant has sufficient 
antitumor activity, as assessed by ORR, against cervical cancer to warrant more extensive 
development. 
4. To determine the safety and tolerability of the RP2D of birinapant when given in combination 
with pembrolizumab to patients in the various solid tumors cohort  
2.2.2 Secondary Objectives 
1. To assess the safety and tolerability of the combination of pembrolizumab and birinapant; 
Overall and in the defined tumor types, colorectal cancer, ovarian cancer and cervical cancer. 
2. To assess clinical activity of the combination of pembrolizumab and birinapant in the defined 
tumor types by effects on tumor response, including CBR, time to response and duration of 
response, assessed by RECIST 1.1  
3. To assess clinical activity of the combination of pembrolizumab and birinapant in the defined 
tumor types by effect on overall survival 
4. To assess clinical activity of the combination of pembrolizumab and birinapant in the defined 
tumor types by effect on progression free survival. 
2.2.3 Exploratory Objectives 
1. To assess clinical activity of the combination of pembrolizumab and birinapant in the defined 
tumor types by effects on tumor response, including: CBR, time to response, duration of 
response, iBOR, duration of iBOR and time to iCPD, assessed by iRECIST. 
2. To assess the pharmacodynamic markers of birinapant and of pembrolizumab when given in 
combination at the schedule and dose as defined by the protocol, to include but not to be limited 
to mechanism of action (inhibition of cIAP1), and of immune surveillance and activation. 
3. To determine biomarkers that might predict for response and/or indicate response to the 
combination treatment and allow comparison to known potential predictive biomarkers of 
pembrolizumab response. 
4. To evaluate birinapant pharmacokinetics in plasma when administered in combination with 
pembrolizumab. 
3. 
Study Details 
Details of the study design, inclusion/exclusion criteria applicable to the dose escalation phase 
and for each tumor type of the dose expansion phase are given in the CSP. 
3.1 
Study Design and Study Population 
This is a phase 1/2, multicenter, single-arm, open-label, dose-escalation, safety, tolerability, 
pharmacokinetic and pharmacodynamic study of birinapant and pembrolizumab, conducted in 
male and female patients, ≥18 years of age, who have relapsed or refractory solid tumors.  
 
The study will have two parts, one dose escalation part followed by a dose-expansion phase.  
3.1.1 Dose-escalation phase 
The dose escalation part employs a sequential group dose-escalation design to determine the 
dose-limiting toxicity (DLT) and recommended phase 2 dose (RP2D) of birinapant 
administered in combination with pembrolizumab, both administered as a 30-minute 


 
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intravenous (IV) infusion. Pembrolizumab will be administered first on Day 1. The birinapant 
infusion will begin 30 minutes (+10 minutes) following the completion of the pembrolizumab 
infusion on Day 1. An additional dose of birinapant only will be administered on Day 8. The 
dose levels of birinapant and pembrolizumab are outlined in Table 1.  
Table 1 Dose Escalation Schedule 
Dose-Escalation Schedule 
Dose Level 
Pembrolizumab + Birinapant (per 21-day cycle)*  
Level -1 
200 mg pembrolizumab on Day 1 + birinapant 2.8 mg/m2/week on Days 
1 and 8  
Level 1 
200 mg pembrolizumab on Day 1 + birinapant 5.6 mg/m2/week on Days 
1 and 8 
Level 2 
200 mg pembrolizumab on Day 1 + birinapant 11 mg/m2/week on Days 
1 and 8 
Level 3 
200 mg pembrolizumab on Day 1 + birinapant 17 mg/m2/week on Days 
1 and 8 
Level 4 
200 mg pembrolizumab on Day 1 + birinapant 22 mg/m2/week on Days 
1 and 8 
*Note: A week without treatment (i.e., Days 15-21) will follow the second week of treatment, immediately after which the 
next 21-day cycle commences. 
 
A minimum of 3 and up to 6 evaluable patients will be enrolled per dose level. For patients 
enrolled in Dose Level 1, the birinapant starting dose will be 5.6 mg/m2/week. Dose 
escalation of birinapant will occur in up to three steps. The Safety Review Committee (SRC) 
will review all the cumulative safety data up to and including completion of Day 21 for the 
last patient in a cohort from that treatment group prior to dose escalation. Upon review of the 
safety data the SRC will determine whether or not the safety data supports dose escalation to 
the next sequential dose level. If the first dose level (5.6 mg/m2) is deemed intolerable, 
defined as ≥2 patients from 3-6 experiencing a DLT, the SRC may decrease the starting dose 
of the next dosing cohort to 2.8 mg/m2 (dose level -1). 
 
If 1 of the 3 to 6 patients enrolled at a given dose level experiences a DLT, enrollment at the 
next dose level will proceed, if the next highest dose has not already been declared 
intolerable. However, if 1 of these 3 to 6 patients experiences a DLT at the given dose level 
and the next highest dose has already been declared intolerable, a minimum of 6 patients are 
to be enrolled at the given level and the dose at the given level may be the RP2D. A separate 
safety review will be performed by the SRC to determine the RP2D of the combination of 
birinapant and pembrolizumab and to begin the dose-expansion phase of the study.  
 
3.1.2 Dose expansion phase 
Once the RP2D of birinapant combined with pembrolizumab is defined, additional patients 
with relapsed or refractory carcinoma will be enrolled in the dose-expansion phase of the 
study.  
Table 2. Dose Expansion Phase 
Pembrolizumab + Birinapant (per 21-day cycle)*  
200 mg pembrolizumab on Day 1 + birinapant at the RP2D 
mg/m2/week on Days 1 and 8  
 
The dose expansion phase will comprise of four patient cohorts defined as follows: 
• Colorectal cancer (28 patients) 


 
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• Ovarian cancer (27 patients) 
• Cervical cancer (26 patients) 
• Various solid tumors (30 patients, including 5 patients with each of the following 6 
tumor types: Small cell lung cancer; Cholangiocarcinoma; Gastroesophageal 
carcinoma; Mesothelioma; Head and Neck Squamous Cell Carcinoma (HNSCC)-
checkpoint inhibitor-naïve; and HNSCC checkpoint inhibitor-experienced) 
Predefined interim analyses for futility and safety will be conducted in each of the three main 
cohorts, i.e. in colorectal cancer, ovarian cancer and cervical cancer, to limit undue exposure 
before further inclusion into a given cohort. The design of the various solid tumors cohort will 
limit undue exposure in any of the selected tumor types by virtue of the fact that it limits the 
number of enrolled patient to five in each tumor type  
3.1.3 Study Flow Chart 
An overview of the study including the different periods (screening, baseline visit, treatment 
period and follow-up period) overview of the time points of measurements for each 
assessment are given in Table 5 (Schedule of Study Procedures and Assessments) in 
Appendix 1. 
 
3.2 
Randomization and Blinding 
This study is an open-label study, no randomization and blinding are needed. 
 
3.3 
Number of Patients 
3.3.1 Sample Size Calculation 
 Dose escalation phase 
 
No formal sample size or power calculations will be performed for the dose-escalation phase 
of the study. A sample size of 3 to 6 patients per cohort is a feasible sample size to assess 
safety for dose escalation and dose-limiting toxicity.  
 
 Dose expansion phase 
The dose expansion phase will comprise 4 cohorts of 26-30 patients, as follows:   
1. Colorectal cancer (28 patients will be recruited)  
2. Ovarian cancer (27 patients will be recruited) 
3. Cervical cancer (26 patients will be recruited)  
4. Various solid tumors (30 patients will be recruited, including 5 patients with each of the 6 
following tumor types: (Small cell lung cancer; Cholangiocarcinoma; Gastroesophageal 
carcinoma; Mesothelioma; Head and Neck Squamous Cell Carcinoma (HNSCC)-
checkpoint inhibitor-naïve; and HNSCC checkpoint inhibitor-experienced) 
A Simon’s 2-stage design (Simon 1989) will be used for each of the cohorts in colorectal 
cancer, ovarian cancer and cervical cancer, as outlined in Table 4. A predefined interim 
analysis allowing stopping each of these cohorts for futility and safety will be conducted in 
the first stage to limit undue exposure before further inclusion into a given cohort. 
 


 
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The interim analyses will be based on at least 6 and most 13 patients having completed from 9 
up to 27 weeks of treatment (3 to 9 cycles) in the colorectal cancer cohort and based on at 
least 6 and at most 16 and 15 patients in the ovarian cancer cohort and cervical cancer cohort, 
respectively.  
 
The Simon’s two-stage design as outlined in Table 4 yields a type I error rate of 0.05 and 
statistical power of 0.80 for each of the three main cohorts described above using a one-sided 
test when the true response rate is 20% for colorectal cancer, 25% for ovarian cancer and 30% 
for cervical cancer. No formal sample size or power calculation will be performed for the fourth 
cohort. 
 
Note that one additional patient will be included in each cohort compared to what is stated in 
Table 4. This patient will only be included in the interim analysis in case a patient drops out 
in that cohort. Thus, the number of included patients in each cohort will be 27+ 1 (CRC), 
26+1 (ovarian) and 25+1 (cervical). In all cases this extra patient will be included in the 
main/end analysis. If the predefined level for success in a given cohort is reached prior to the 
stipulated number of patients being enrolled/completed, enrollment in that cohort may be 
discontinued.  
 
4. 
Assessments 
An overview of the time points of measurements for each assessment is given in Table 5 
(Schedule of Study Procedures and Assessments) in Appendix 1.  
 
4.1 
Disposition and Other Supporting Assessments 
4.1.1 Patient Compliance 
Investigational product will be administered as an IV infusion by study staff and 
administration information will be recorded in the appropriate CRF. There will be no self-
administration of investigational product by the study patients. 
4.1.2 Protocol Deviations 
Protocol deviations will be classified into minor and major and logged as described in the Protocol 
Deviation Plan.  
4.1.3 Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be collected at the screening visit and will include age, 
gender, ethnicity, race, height, weight and body surface area. 
 
4.1.4 Medical History 
A complete medical history will include evaluation for past or present cardiovascular, 
respiratory, gastrointestinal, renal, hepatic, neurological, endocrine, metabolic, lymphatic, 
hematologic, immunologic, dermatologic, psychiatric, and genitourinary disorders, 
medication and surgical history, and review of any other diseases or disorders 
4.1.5 Prior and Concomitant Medications 
Prior medication is defined as medication stopped prior to baseline.  
 
Concomitant medication refers to medication, or therapy, other than the study medication, 
taken during the study treatment period. 
 


 
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All prescribed drugs, herbal products, vitamins, minerals, and OTC medications are regarded 
as prior/concomitant medications.  
 
Concomitant therapy or medication usage will be monitored throughout the study.  
4.1.6 Eastern Cooperative Oncology Group-Performance Status 
Eastern Cooperative Oncology Group Performance (ECOG) Status will be assessed throughout the 
study. 
4.2 
Efficacy Endpoints 
Details of the assessment of efficacy endpoints are given in Section 9 in the CSP. Definitions of the 
endpoints are given in Section 4.2.3. 
4.2.1 Dose Escalation Phase 
 
 Primary Efficacy Endpoint 
The primary objective of the dose escalation phase concerns safety and tolerability.  
 
 Secondary Efficacy Endpoints 
Tumor response and progression evaluated using RECIST v 1.1 
Measures defined by the ORR, will be assessed through RECIST v 1.1 until response or 
progression and will be subsequently analyzed through iRECIST as an exploratory endpoint 
(see below). 
 
 Exploratory Efficacy Variable 
Tumor response and progression evaluated using iRECIST. 
a) iBOR 
b) Duration of iBOR  
c) Time to iCPD 
Efficacy, as defined by the ORR, will be assessed through RECIST v 1.1 until response or 
progression and will be subsequently analyzed through iRECIST (iCR, or iPR or iSD or after 
iUPD iCR, iPR or iSD or iCPD). iBOR will also be assessed.  
Overall survival will also be assessed. 
4.2.2 Dose Expansion Phase 
 
 Primary Efficacy Endpoint 
The primary endpoint in each of the three main cohorts is as follows: 
1. The overall response assessed through RECIST v.1.1 until response or progression in 
colorectal cancer 
2. The overall response assessed through RECIST v1.1 until response or progression in 
ovarian cancer 
3. The overall response assessed through RECIST v1.1 until response or progression in 
cervical cancer 
 
The primary objective for the cohort with various tumor types concerns safety and tolerability 
of the RP2D dose of birinapant when given in combination with pembrolizumab. 


 
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Measures of tumor response will be evaluated using RECIST v1.1 until response or 
progression and will be subsequently analyzed through iRECIST as an exploratory endpoint 
(see below). 
 
 Secondary Efficacy Endpoints 
Clinical Activity: Tumor response will be assessed in all four cohorts by monitoring: 
• 
Progression Free Survival (PFS) 
• 
Clinical Benefit Rate (CBR) defined as CR+PR+SD 
• 
Time to response 
• 
Duration of response 
• 
Overall Survival (OS) 
Measures of tumor response will be evaluated using RECIST v1.1 until response or progression 
and will be subsequently analyzed through iRECIST as an exploratory endpoint (see below). 
 Exploratory Efficacy Variable 
Tumor response and progression evaluated in all four cohorts using iRECIST: 
• 
Overall response 
• 
iBOR 
• 
Duration of iBOR  
• 
Time to iCPD 
• 
Clinical Benefit Rate (CBR) defined as iCR+iPR+iSD  
• 
Time to response 
• 
Duration of response 
4.2.3 Definition of Efficacy Endpoints 
All patients will have a tumor measurement after cycle 3 (week 9) and subsequently after 
every third cycle. Measures will be assessed through RECIST 1.1 until whichever of the 
following occurs first: 
• Site-assessed disease progression is documented 
• The start of new anti-cancer treatment 
• Withdrawal of consent 
• Death  
• The end of the study 
After progression, measures will subsequently be analyzed through iRECIST as an 
exploratory endpoint.  
 
The outcome of a tumor measurement for RECIST 1.1 is a categorization into one of the 
following categories: 
• CR – Complete Response 
• PR – Partial Response 
• SD – Stable Disease 
• PD – Progressive Disease 
• Non-CR/Non-PD 
• Not Evaluable 


 
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For iRECIST, a tumor measurement is categorized into one of the following: 
• iCR 
• iPR 
• iSD 
• iUPD 
• iCPD 
• Non-iCR/Non-iPD 
• Not Evaluable 
Note that RECIST 1.1 and iRECIST is equivalent until Progressive Disease (PD). 
 
There will be two RECIST 1.1 and iRECIST categorizations, one made in the clinic and one 
made by an independent radiologist at MEDIAN Technologies. The categorization by the 
independent radiologist is the one that will be used in the analyses detailed in this SAP. The 
categorizations at the clinic will be reported descriptively as pure explorative purpose. 
 
A tumour measurement may consist of scans conducted at different days (during the visit 
window) but there will be only one date associated to the categorization for each visit. That 
date will be set by the independent radiologist and will be the date used in the derivation of 
the time to event endpoints below. The overall process for image receipt, review and reporting 
conducted by MEDIAN Technologies is detailed in the Imaging Review Charter -01, dated 7 
February 2018. 
 
 Overall response (and ORR) assessed through RECIST 1.1 
The primary endpoint in the dose expansion phase is the overall response assessed through 
RECIST v.1.1 until response or progression. A patient with a best overall response of either 
CP or PR is defined as a patient with an overall response according to RECIST 1.1. A tumor 
measurement categorized as CP or PR needs a confirmed response of either CP or PR at least 
4 weeks after the intial response assessment to be classified as best overall response CP or 
PR. Examples of patients with an overall response are the following (observations in cycle 3 
(week 9) and subsequent every 3rd cycles (9 weeks between each measurement):  
• SD, SD, PR, PR, ; SD, SD, PD (overall response as PR in cycle 9 which is confirmed 
in cycle 12 (9 weeks after)) 
• SD, SD, SD, CR, CR (overall response as CR in cycle 12) 
 
Example of patients with no overall response as assessed through RECIST 1.1: 
• SD, SD, SD, SD, SD, SD, SD, SD, SD 
• SD, PD(iUPD), iSD, iSD, iCPD 
• SD, PD(iUPD), iSD, iSD 
• SD, SD, PR, SD, SD, PD (PR in cycle 9 is not confirmed) 
• SD, PD(iUPD), iPR, iSD, iSD (no overall response according to RECIST 1.1) 
The overall respose rate (ORR) is defined as the proportion of patients that are classified as 
overall responders assessed through RECIST 1.1 as described above.  
 


 
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 Progression Free Survival (PFS) 
The PFS is defined as the length of time from the start of treatment the patient lives and does 
not progress (PD as assessed by RECIST 1.1). Patients who do not die or progress will be 
censored at the date “last known to be alive”, i.e. the latest date of contact with the patient 
based on all collected evaluation dates. 
 
 Clinical Benefit Rate (CBR) 
The CBR is defined as the percentage  of patients with the best measurement of response 
categorized as CR, PR or SD. Note that SD requires no confirmation as is required for the 
best overall response of either CR or PR. The first tumor assessment is planned to occur 9 
weeks after first dose and therefore, iSD documented at the first assessment would typically 
qualify as iSD. However, an iSD with actual assessment time less than 6 weeks after first dose 
will not be qualifyed as iSD. Patients with no post-baseline tumor assessments are considered 
to have achieved no clinical benefit.   
 
 Time to response 
The time to response is defined as the length of time from start of treatment until the date of 
the first documented CRor PR assessed through RECIST 1.1. CR or PR requires confirmation 
on imaging dates that are at least 4 weeks apart. Once it is confirmed, the first documented 
CR or PR will be considered the start of the response.   
 
Patients not obtaining an overall response (CR or PR) will be censored at the the date of their 
last tumor assessment.  
 
 Duration of response 
 
Duration of response will be calculated as the length of time from the first date of confirmed 
CR/PR to the date of death or the date of first documented tumor progression (PD), whichever 
is earlier, using RECIST v1.1. Patients who remain alive and do not progress are censored on 
the date of their last tumor assessment. Response duration is only evaluated in patients with 
an overall response of CR or PR. 
 
 Overall Survival (OS) 
 
Overall survival (OS) is defined as the time from the first dose of study treatment to the date 
of death due to any cause. For patients who do not die, the OS time will be censored on the 
date when the patient was last known to be alive. The date “last known to be alive” will be 
defined as the latest date of contact with the patient based on all collected evaluation dates, 
including the telephone contacts for the survival follow-up. 
 
 Overall response assessed through iRECIST 
The categorization using iRECIST is equivalent with the categorization using RECIST 1.1 
until PD. Once PD is obtained, RECIST 1.1 will stop whereas iRECIST will continue to 
characterize disease state also in cycles after PD.  
 
A patient with a best overall response of either iCP or iPR is defined as a patient with an 
overall response according to iRECIST. A tumor measurement categorized as iCP or iPR 
needs a confirmed response of either iCP or iPR at least 4 weeks after the intial response 
assessment to be classified as best overall response iCP or iPR.  
 


 
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Examples of patients with an overall response are patients with the following outcome of 
iRECIST at cycle 3 (week 9) and subsequent every 3rd cycles:  
• iSD, iSD, iPR, iPR, iSD; iPD (overall response as iPR in cycle 9 and confirmed in cycle 
12) 
• iSD, iSD, iSD, iCR, iCR (overall response as iCR in cycle 4) 
• iSD, PD(iUPD), iPR, iPR, iSD (overall response as iPR as assessed by iRECIST in cycle 
9 and confirmed in cycle 12) 
Example of patients with no overall response: 
• iSD, iSD, iSD, iSD, iSD, iSD, iSD, iSD, iSD 
• iSD, (iUPD), iSD, iSD, iCPD 
• iSD, iSD, iPR, iSD, iSD, iUPD (iPR in cycle 9 is not confirmed) 
• iSD, (iUPD), iSD,  
The overall respose rate (ORR) using iRECIST is defined as the percentages of patients that 
are classified as overall responders assessed through iRECIST as described above. 
 
 Immune Best Overall Response (iBOR) 
The immune best overall response (iBOR) is the best timepoint response recorded from the 
start of the study treatment until the last assessment of tumor response recorded during study 
period or the start of post treatment cancer therapy (whichever is sooner), taking into account 
any requirement for confirmation. iUPD will not override a subsequent best overall response 
of iSD, iPR, or iCR, meaning that iPR or iSD can be assigned (timepoint response or iBOR) 
even if new lesions have not regressed, or if unequivocal progression (non-target lesions) 
remains unchanged, providing that the criteria for iCPD are not met. Table 3 gives scenarios 
for assignment of iBOR (Seymour (2017)).  
 
Table 3 Scenarios of assignments of best overall response using iRECIST 
 
 
 Duration of iBOR 
The duration of iBOR is defined as the length of time from the date when iBOR is first 
documented until the date of death or the date when a change in disease state using iRECIST 
is objectively documented, whichever is earlier. Patients who remain alive and do not change 
from iBOR in disease state are censored on the date of their last tumor assessment. Patients 
who start a new therapy and do not change from iBOR in disease state are censored at the last 
tumor assessment prior to initiating the subsequent anticancer therapy. Duration of iBOR is 
only evaluated in patients with a documented diease state. 
 


 
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 Time to iCPD 
The time to immune Clinical Progressive Disease (iCPD) is the length of time from start of 
treatment until the date iCPD assessed through iRECIST is obtained. Patients not obtaining 
iCPD will be sensored on the date of their last tumor assessment. 
 
 Immune Clinical Benefit Rate (iCBR) 
The iCBR is defined as the percentage of patients with the best measurement of response 
categorized as iCR, iPR or iSD. Note that iSD requires no confirmation as is required for the 
immune best overall response of either iCR or iPR. The first tumor assessment is planned to 
occur 9 weeks after first dose and therefore, iSD documented at the first assessment would 
typically qualify as iSD. However, an iSD with actual assessment time less than 6 weeks after 
first dose will not be qualifyed as iSD. Patients with no post-baseline tumor assessments are 
considered to have achieved no clinical benefit according to iRECIST.   
 
 Time to immune response 
 
The time to immune response is defined as the length of time from start of treatment until the 
date of the first documented iCRor iPR assessed through iRECIST. iCR or iPR requires 
confirmation on imaging dates that are at least 4 weeks apart. Once it is confirmed, the first 
documented iCR or iPR will be considered the start of the response. 
 
Patients not obtaining an overall response (iCR or iPR) will be censored at the the date of 
their last tumor assessment.  
 
 Duration of immune response 
 
Duration of immune response is defined as the length of time from the first date of confirmed 
iCR/iPR to the date of death or the date of first documented tumor progression (iUPD) 
provided that iCPD is confirmed at the next assessment, whichever is earlier, using iRECIST. 
Patients who remain alive and do not progress are censored on the date of their last tumor 
assessment. Patients who start a new therapy without a prior iUPD are censored at the last 
tumor assessment prior to initiating the subsequent anticancer therapy. Response duration is 
only evaluated in patients with an overall immune response of iCR or iPR. 
4.3 
Safety Endpoints 
4.3.1 Adverse Events 
All adverse events (AEs) and serious adverse events (SAEs) will be reported by the 
investigator as specified in Section 8 in the CSP.  
4.3.2 Clinical Laboratory Tests 
 Hematology, Serum Chemistry, Immunology and Urinalysis, Serology 
The following samples will be analyzed by the local laboratory.   
 
Hematology with Differential: to include; hemoglobin, hematocrit, red blood cells (RBCs), 
white blood cells (WBCs), platelet count, WBC subset count (neutrophils, eosinophils, 
basophils, lymphocytes, and monocytes), mean corpuscular volume (MCV), mean 
corpuscular hemoglobin (MCH), mean cell hemoglobin concentration (MCHC). 
 
Clinical Chemistry - to include; lipase, amylase, albumin, total protein, blood glucose (non-
fasting), sodium, potassium, chloride, bicarbonate, magnesium, calcium, blood urea nitrogen 


 
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(BUN), creatinine, AST, ALT, alkaline phosphatase (ALP), total bilirubin, direct bilirubin, 
lactate dehydrogenase (LDH), gamma glutamyltransferase (GGT), and phosphate, thyroid 
function testing (triiodothyronine (T3) or free triiodothyronine (FT3), Thyroxine (T4) or free 
thyroxine (FT4), TSH). 
 
Immunology:  to include CD3, CD4, CD8 and CD19 
 
Urinalysis – Urine collected to determine pH, blood, protein, ketones, leukocyte elastase, 
nitrite, glucose, specific gravity, urobilinogen, and bilirubin.  If blood, leukocytes or nitrites 
are detected, microscopy will be completed. 
 
Serology: to include Hepatitis C Antibody 
 Pregnancy Testing 
For women of childbearing potential, the following tests are performed: 
• At screening: serum β-HCG pregnancy test (a negative test is required to confirm 
eligibility).  
• Before dosing on Days 1 of each cycle: urine pregnancy test (a negative test is required 
before dosing).  
 Histology 
Submission of formalin-fixed paraffin embedded tumor tissue sample blocks are preferred; if 
submitting unstained slides, the slides should be freshly cut and submitted to the testing 
laboratory within 7 days from site slide sectioning date otherwise a new specimen will be 
requested. See laboratory manual. 
4.3.3 Physical Examination 
The physical examination will include examination of the following: general appearance, 
head, ears, eyes, nose, throat, neck (including thyroid), skin, cardiovascular system, 
respiratory system, gastrointestinal system, musculoskeletal system, lymph nodes and nervous 
system. Any findings made during the physical examination will be noted regardless of if they 
are part of the patient’s medical history. 
 
4.3.4 Vital Signs 
Vital signs include sitting blood pressure, heart rate, respiratory rate, and temperature. 
4.3.5 ECGs 
12-lead ECGs will be taken in the supine position, after the patient has been lying down for at 
least three minutes. 
The following parameters will be assessed: heart rate; PR, QRS, QT, QTcF (Fridericia’s 
correction) intervals. The Investigator (or a qualified observer at the investigational site) will 
interpret the ECG using one of the following categories: within normal limits, abnormal but not 
clinically significant, or abnormal and clinically significant. 
4.4 
Pharmacokinetic Assessments 
Pharmacokinetic blood samples will be collected at four different time points during Cycle 1: 
• Day 1, 4 hours after completion of birinapant infusion. 
• Day 2, 24 hours after completion of birinapant infusion. 
• Day 8, before the infusion of birinapant. 


 
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• Day 8, 4 hours after completion of birinapant infusion. 
See Section 11 in the CSP for more details. 
5. 
Analysis Methods 
5.1 
Clean File and Timing of Analysis 
When the database has been declared to be complete and accurate, the database will be locked 
and declared clean file. Any changes to the database after that time can only be made by joint 
written agreement between the project manager, the data manager and the statistician.  
 
The final analysis will be performed after declared clean file, and after finalization and 
approval of this SAP document. 
5.2 
Analysis Populations 
The analysis of data will be based on different subsets according to the purpose of 
analysis, i.e. for efficacy and safety respectively. The classification of each patient with 
respect to each analysis population will be done prior to database lock. 
5.2.1 Intent-to-Treat Population (ITT) 
Will comprise any patient that is enrolled to the study and receives a dose of pembrolizumab 
and birinapant. Note that the ITT population can be considered equivalent to the FAS 
population, which is also the safety population, as no randomization is done in this study. 
5.2.2 Efficacy Evaluable Population  
Will comprise all patients in the ITT population who have baseline and at least one post-
baseline efficacy assessment, unless the patient dies or experiences an AE that results in study 
drug termination prior to assessment. At that point, the patient will be considered to have 
progressed in the absence of other data.  
5.2.3 Safety Population 
Will be the same as the ITT population. 
5.2.4 Pharmacodynamic Evaluable Population 
The pharmacodynamic population will include all treated patients for whom pre- and post- 
infusion pharmacodynamic data are available.   
5.2.5 Pharmacokinetic Analysis Population 
The PK population will include all treated patients for whom at least one pharmacokinetic 
sample is quantified.  
5.3 
General Principles for Presenting Study Data 
All statistical analyses will be performed at SDS using SAS® (Version 9.3 or higher, SAS 
Institute Inc., Cary, NC, USA). All statistical analyses will be performed after this SAP is 
finalised and approved and the study database is locked. 
 
Continuous data will be summarized using descriptive statistics where the following 
parameters will be reported: 
• 
Number of observations (n), 
• 
Mean, 
• 
Median, 
• 
Standard deviation (SD), 


 
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• 
Range (Min, Max) 
Categorical data will be presented as the number and percentage of patients. 
 
Time to event endpoints defined in Section 4.2.3 (e.g. duration of response, OS and time to 
iCPD) will be analysed using Kaplain-Meier methods taking censoring into account. The 
Kaplain-Meier plot and corresponding estimate of the median value with 95% confidence 
interval will be reported. 
 
All tests will be one-sided and performed at the 5% significance level. When reporting the 
results of significance tests, p-values will be reported together with 2-sided 90% confidence 
intervals.  
 
Throughout the report, the number of decimal places given for the summary statistics; mean, 
STD, confidence interval and median values will exceed that of the source data by one. 
Minimum and maximum will have the same number of decimal places as the source data. For 
relative frequencies, integer with one decimal and %-sign will be presented and for p-values 
four (three) decimals will be reported.  
 
Percentages will be based on number of patients with data at a certain time point with the 
exception of presentations of medical history, medications and AEs where the percentages 
will be based on the number of patients in the study population. 
 
In general, all data will be listed, sorted by phase of study, cohort and patient, and when 
appropriate by cycle within patient. All summary tables will be structured with a column for 
cohort and will be annotated with the total population size relevant to that table/cohort, 
including any missing observations. Summary tables will include summaries for visits for 
Cycle 1 (Screening, Day 1 pre dose, Day 1 post dose, Day 8 pre dose, Day 8 post dose and 
Day 22 End of Cycle 1 as appropriate) whereas subsequent cycles will be summarized with 
summary statistics for the minimum and maximum observed value during the subsequent 
cycles. 
 
The two phases of the study will be summarized separately. In addition, cohorts from phase 1 
and phase 2 may be combined and summarized if appropriate.  
5.4 
Statistical/Analytical issues 
5.4.1 Missing Data and Handling of Dropouts 
Missing values will not be imputed/replaced in the efficacy analysis.  
 
Laboratory values which are greater/smaller than a stated value will be replaced by the stated 
value (for example <1 will be replaced by 1) when summarized in tables. 
 
If the start and/or stop dates for medication, AEs and medical history are unknown the date 
will be imputed to calculate the duration of AE or to decide if the medication was ongoing at 
baseline or not. No imputation will be presented in individual patient listings. An unknown 
date will be imputed as follows: 
• If the month and date are unknown, the date will be set to June 30th.  
• If the day is unknown, the day will be set to the 15th.  
• If the year is unknown, the date will not be imputed.  
 


 
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5.4.2 Data Transformations and Derived Variables 
 Calculation of change from baseline 
Baseline is defined as the last measurement before the first dose of pembrolizumab or 
birinapant. The change from baseline value for visit X is derived as ‘value at visit X’ minus 
‘value at baseline’.  
5.4.3 Interim Analysis and Data Monitoring 
An independent Data Monitoring Committee (DMC) will meet approximately biannually 
during the dose expansion phase to review the complete analysis of combined observed 
toxicities including emerging safety reports and reported SAEs.  
 
Predefined interim analyses for futility and safety will be conducted in each of the cohorts in 
colorectal cancer, ovarian cancer and cervical cancer to limit undue exposure before further 
inclusion into a given cohort. 
 
The interim analysis constitutes the first stage in Simon’s two-stage design controlling the 
overall type I error to 5% within each cohort. The interim analysis for each of the three 
cohorts will be as follows:  
 
 Colorectal Cancer Cohort 
The interim analysis will be based on at least 6 and most 13 patients having completed from 9 
up to 27 weeks of treatment (3 to 9 cycles) in the colorectal cancer cohort. 
 
The second stage will continue, i.e. the remaining patients in the cohort will be recruited 
according to the plan, if at least 1 patient (out of 6-13 patients) responds in the overall tumor 
response assessed through RECIST v1.1. (provided the DMC decides not to stop the second 
stage because of safety issues). 
 
 Ovarian Cancer Cohort 
The interim analysis will be based on at least 6 and most 16 patients having completed from 9 
up to 27 weeks of treatment (3 to 9 cycles) in the ovarian cancer cohort. 
 
The second stage will continue if at least 2 patients (out of 6-16 patients) respond in the 
overall tumor response assessed through RECIST v1.1. (provided the DMC decides not to 
stop the second stage because of safety issues).  
 
 Cervical Cancer Cohort 
The interim analysis will be based on at least 6 and most 15 patients having completed from 9 
up to 27 weeks of treatment (3 to 9 cycles) in the cervical cancer cohort. 
 
The second stage will continue if at least 2 patients (out of 6-16 patients) respond in the 
overall tumor response assessed through RECIST v1.1. (provided the DMC decides not to 
stop the second stage because of safety issues). 
 
5.4.4 Multiple Comparisons/Multiplicity 
The four cohorts will be handled separately, no adjustment for multiple comparisons will be 
made between cohorts. No adjustment for multiple comparisons will be performed within a 
cohort as there is only one primary endpoint in each of the three main cohorts.  
 


 
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For the secondary efficacy variables, no statistical inference will be performed. Thus, no 
adjustment for multiple comparisons will be made. 
 
5.4.5 Examination of Subgroups 
No pre-defined analysis on subgroups are planned. 
  
5.5 
Patient Disposition Summary 
Descriptive summaries for continuous data and for categorical data will be provided in 
accordance with Section 5.3 if other not stated. 
 
5.5.1 Patient Disposition 
Number of patients screened, enrolled, discontinued for treatment (by reason), continuing in 
follow-up, and discontinued from the study (by reason) will be summarized by cancer cohort. 
 
5.5.2 Protocol Deviations 
Protocol deviations will be displayed in listings. 
 
5.5.3 Demographic and Baseline Characteristics 
Demographics and baseline characteristics (gender, age, ethnicity, race, height, weight and 
body surface area) will be presented as a table for the screening visit. 
 
5.5.4 Medical History 
Medical history and medical conditions ongoing at Screening will be coded by system organ 
class (SOC) and preferred term (PT) using MedDRA (version 20.0) and presented as number 
and percentage of patients in each SOC and PT by cancer cohort and in total over cohorts.  
 
5.5.5 Prior and Concomitant Medications 
Prior and concomitant medication will be coded according to the WHO-Drug Dictionary 
Enhanced (Version Mar 2017) and ATC classification. Prior and concomitant medication will 
be reported as a listing for all enrolled patients and tabulated by ACT level 1 and level 3 by 
cancer cohort and in total over cohorts.  
Prior anti cancer therapies, prior medications and concomitant medications will be tabulated 
separately.  
5.5.6 Exposure to Study Treatment 
The Investigational products will be administered as IV infusions by study staff and 
administration information will be recorded in the appropriate CRF.  
 
The following variables will be derived for birinapant and Pembrolizumab separately: 
• Cumulative dose = Sum of all administred doses.  
• Treatment duration (weeks) = (Date of last dose – date of first dose + planned treatment 
duration(days))/7. 
• Dose intensity = Cumulative dose/Treatment duration 
• Relative dose intensity (%) = 100*Dose intensity/Planned dose intensity 


 
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Planned treatment duration(days) is 21 days for Pembrolizab and 13 days (21-8) for 
birinapant (this is the number of days between the last dose of a treatment cycle and the first 
dose in the subsequent cycle).  
 
The unit of the dose will be in milligram (mg) for Pembrolizumab and in mg/m2 for 
birinapant. For birinapant, the total dose in ‘mg’ is divided by the patient body surface area 
(m2) to get dose expressed as mg/ m2. 
 
Cumulative dose, treatment duration, dose intensity, relative dose intensity, number of 
infusions administered, number of cycles started, and infusion time per administration will be 
summarized using descriptive statistics by cohort, treatment (Pembrolizumab) and cycle 
(cycle 1 and the minimum and maximum observed value during the subsequent cycles) and in 
total over cycles as appropriate.  
 
5.5.7 Premature Termination 
Patients who terminated prematurely will be summarized by reason for early termination and 
cancer cohort. 
 
5.6 
Efficacy Analyses 
The only formal statistical analysis in the study concerns the ORR, assessed through RECIST 
1.1, in each of the three main cancer cohort in the dose expansion phase of the study. That 
analysis is detailed in Section 5.6.1. The remaining efficacy endpoints will be summarized 
using descriptive statistics in accordance with Section 5.3 if other not stated. 
 
5.6.1 Primary Efficacy Analysis 
The primary endpoint will be summarized for the Efficacy Evaluable Population in 
accordance with Section 5.3. 
The primary efficacy analysis for each of the three main cohorts in the dose expansion phase of 
the protocol will be evaluated using Simon’s two-stage design (Simon 1989). The null 
hypothesis that the true response rate (π) is 𝜋0 will be tested against the one-sided alternative 
𝐻𝐴: 𝜋> 𝜋0 in each of the three cohorts with 𝜋0 , 𝜋1, 𝑛1, 𝑛, 𝑟1 and 𝑟2 as in Table 4 as follows. 
In the first stage, 𝑛1 patients will be accrued. If there are 𝑟1 or fewer responses in these 𝑛1 
patients, the cohort will be stopped and the p-value for the test will be reported as not significant 
(no p-value will be calculated). Otherwise, n - 𝑛1 additional patients will be accrued for a total 
of n patients. The null hypothesis will be rejected if 𝑟2+1 or more responses are observed in n 
patients.  
Table 4 Simon’s two-stage design settings in each of the three main cohorts 
Indication 
Response rate 
(ORR) 
𝑛1 
 (# patient in 
the 1st stage) 
n 
(Total 
#patients) 
𝑟1  
(Continue 
with stage 
2 if >𝑟1 
responses 
in stage 1) 
𝑟2 
(p-value 
<=0.05 if 
>𝑟2 
responses 
after stage 
2) 
Poor drug 
(𝜋0) 
Good 
drug (𝜋1) 
Colorectal 
cancer  
<=5% 
>=20% 
13 
27 
0 
3  


 
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Ovarian 
cancer 
<=7% 
>=25% 
16 
26 
1 
4 
Cervical 
cancer 
<=10% 
>=30% 
15 
25 
1 
5 
 
In case the total number of evaluable patients do not equal the planned number of patients (n 
in Table 4), the statistical inference of the ORR will take account of the actual total number of 
evaluable patients, 𝑛∗, as suggested in Koyama and Chen (2007). With a modified stage 2 
sample size, the p-value will be calculated as follows.  
 
i. Find 𝜋∗ such that 𝑃𝜋(𝑋2 > 𝑟2 −𝑥1|𝑛2) = 𝑃𝜋0(𝑋2 ≥𝑥2|𝑛2
∗) 
ii. Compute the p-value by  
∑𝑃𝜋0(𝑋1 = 𝑥|𝑛1)
𝑛1
𝑥=𝑟1+1
𝐴(𝑥, 𝑛2, 𝜋∗) 
Here 𝑛2(= 𝑛−𝑛1) denotes the planned number of patients in the second stage, 𝑛2
∗ the actual 
number of patients in the second stage and 𝑋2 denotes the number of responses among those 
𝑛2 patients. The p-value will be calculated as above even if 𝑛2
∗= 𝑛2 . In that case it simplifies 
to the original Simon’s 2-stage design with rejection regions as in Table 4. 
 
The point estimate of response rate and the corresponding 90% confidence interval will be 
obtained by inverting the hypothesis testing. Compute the p-value for testing 𝐻0: 𝜋≤𝜋′0 
versus 𝐻𝐴: 𝜋> 𝜋′0 as above. The 90% confidence interval for π  is the collection of 𝜋′0 such 
that the corresponding p-value is within [0.05, 0.95]. The value of 𝜋′0 which gives a p-value 
of 0.5 will be the point estimate of the response rate (π). 
 
5.6.2 Secondary Efficacy Analyses 
The secondary endpoints will be summarized with descriptive statistics in accordance with 
Section 5.3 for the Efficacy Evaluable Population. 
 
5.6.3 Exploratory Efficacy Analyses 
The exploratory endpoints will be summarized with descriptive statistics in accordance with 
Section 5.3 for the Efficacy Evaluable Population. 
 
5.6.4 Subgroup Analyses 
No pre-defined analysis on subgroups are planned. 
 
5.6.5 Sensitivity Analyses 
A sensitivity analysis of the primary endpoint will be conducted if there are patients that are 
wrongly included into the study and receives a dose of pembrolizumab and birinapant. In that 
case, the primary efficacy analysis will be repeated when those patients are excluded from the 
efficacy evaluable population, for the cohorts it concerns, as a sensitivity analysis. Also other 
major protocol deviations may be considered in this sensitivity analysis.  
 


 
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5.7 
Safety Analyses 
No formal statistical analyses will be performed, although descriptive summaries for 
continuous data and for categorical data will be provided in accordance with Section 5.3 if 
other not stated. Complete listings of all patient safety evaluations will be provided to support 
each summary table. 
 
All presentations will be based on the safety analysis set. 
 
5.7.1 Adverse Events 
Adverse Events (AEs) will be coded by system organ class (SOC), preferred term (PT) and 
Verbatim name using MedDRA Version 20.0 
 
All AEs will be listed whereas the treatment emergent AEs (TEAEs), i.e. any AE with onset 
or worsening on or after the first dose of any IMP and within 30 days after the last dose of 
IMP, will be summarized as follows.The number of TEAEs, as well as the number and 
percentage of patients reporting any TEAE will be summarised for Cycle 1, subsequent cycles 
and Safety follow-up by cohort. Separate summary tables will be produced for the following: 
1. 
TEAEs related to IMP by Verbatim names  
2. 
TEAEs related to IMP by SOC and PT 
3. 
TEAEs not related to IMP by Verbatim name  
4. 
TEAEs not related to IMP by SOC and PT 
5. 
Serious Adverse Events (SAEs) by Verbatim name 
6. 
SAEs by SOC and PT.  
7. 
TEAEs related to IMP by AE grade 
8. 
TEAEs not related to IMP by AE grade 
AEs leading to withdrawals or death will be presented by cohort. 
 
All percentages will be based on the number of patients in the safety set. 
 
5.7.2 Clinical Laboratory Tests 
All laboratory parameters for individual patients will be listed and patients with abnormal 
values (out of normal range reported by the laboratory) and with clinically significant 
abnormalities (according to the Investigator’s criteria) will be flagged. 
 
Clinical Laboratory Tests (hematology, clinical chemistry, immunology, serology, urinalysis, 
pregnancy testing and histology) will be summarized regarding observed values, change from 
baseline and abnormal findings in accordance with Section 5.3 by cancer cohort and in total 
over cohorts. In addition, the categorization of the observed values into ‘low’, ‘normal’ and 
‘high’ will be summarized in max/min shift from baseline tables by cohort and in total over 
cohorts. There will be two variants of each shift table, one where the max/min is taken over 
the samples taken after the first dose but before the 2nd dose and one where the max/min is 
taken over all samples taken after the first dose. 
 
5.7.3 Physical Examination 


 
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Physical examination will be presented as the number and percentage of patients with normal, 
abnormal not clinically significant, abnormal clinically significant result over time by Body 
System and cancer cohort. 
 
Findings that are present during screening and prior to drug administration will be included 
under Medical History. Significant findings made after drug administration that meet the 
definition of an AE will be reported under the AE section. 
 
5.7.4 Vital Signs 
Vital signs will be summarized regarding observed values and change from baseline in 
accordance with Section 5.3 by cancer cohort and in total over cohorts. 
 
In case several measurements are taken for the same planned sample time, average values will 
be used. 
 
5.7.5 Electrocardiogram 
ECG results will be summarized regarding observed values, change from baseline values and 
findings (normal, abnormal not clinically significant and abnormal clinical significant) in 
accordance with Section 5.3 by cancer cohort. 
 
If one of the measurements within a triplicate ECGs is classified as abnormal the value for 
that visit is classified as abnormal. 
 
5.8 
Pharmacokinetic Analyses 
The raw PK data (actual drug concentrations ) will be summarized in accordance with Section 
5.3. The PK data will be summarized by dose and (nominal) sampling time in the dose 
escalation phase of the study. Whereas in the dose expansion phase, the data will be 
summarized by cohort and scheduled (nominal) sampling time and over cohorts by scheduled 
(nominal) sampling time, as appropriate. A sample with actual sample time outside the 
acceptable time window will not be included in the summary statistics, but will appear in the 
listings. 
 
Concentration-time data that are below lower limit of quantification (LLOQ) will be treated 
as zero for PK analysis. The number (and the percentage) of samples below LLOQ will be 
shown in the summary tables. 
 
Individual graphs on PK (plasma concentration versus actual time point) will be reported for 
each patient  separately, and summarized by cohort/dose group.  
 
The PK analysis will be performed on the PK population set.  
 
Population PK modeling may also be applied to analyze the PK data and will, in that case, be 
reported separately. 
 
5.9 
Changes to Planned Analysis 
The statistical analysis of the primary endpoint has been supplemented with how the analysis 
will be done in case of the number of patients evaluable for efficacy differs from the planned 
number of patients in the Simon’s design.  


 
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6. 
References 
BPT-201 v4.0/incl amendment 03, final version dated 18 January 2018. 
 
Eisenhauer, EA, Therasse, P, Bogaerts, J, Schwartz, LH, Sargent, D, Ford, R, et al. New response 
evaluation criteria in solid tumours: Revised recist guideline (version 1.1). Eur J Cancer. 
2009;45(2):228-247. 
 
Imaging Review Charter for BPT-201, MEDIAN Technologies, 7 February 2018. 
 
Koyama T, Chen H. Proper inference from Simon’s two-stage designs. Stat. Med. 2008;27:3145–154 
 
Seymour, L, Bogaerts, J, Perrone, A, Ford, R, Schwartz, LH, Mandrekar, S, et al. Irecist: Guidelines 
for response criteria for use in trials testing immunotherapeutics. Lancet Oncol. 2017;18(3):e143-e152. 
 
Simon R. Optimal two-stage designs for phase II clinical trials. Controlled Clinical Trials. 1989; 
10(1):1–10. [PubMed: 2702835] 
 
Statistical Principles for Clinical Trials (ICH Topic E 9). EMEA. September 1998, 
CPMP/ICH/363/96. 
 
 


 
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7. 
Appendix 1 
 
Table 5 
 Schedule of Study Procedures and Assessments  
Study Procedures 
Screening 
(Within 
28 Days of 
Cycle 1 
Day 1) 
Cycle 1 
Subsequent 
Cycles 
 
 
 
Follow up  
Day 1 Day 2 
Day 8 
Day 1 
Day 8  
End of 
the Third 
Week of 
Every 
Third 21-
Day Cycle 
Every 
six 
weeks 
Every 
12 
weeks 
Safety Follow up Visit 
(30 Days After Study 
Drug Discontinuation) 
Progressive Disease/ 
Study Drug 
Discontinuation20 
Overall 
Survival 
Follow-up21 
Visit Window 
 
 
 
± 2 Days 
 
± 2 Days 
± 3 Days 
 
 
+7 Days 
± 3 Days 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
 
 
 
 
Medical History and 
Disease 
Characteristics1 
X 
 
 
 
 
 
 
 
 
 
 
 
ECOG Performance 
Status 
X 
X 
 
 
X 
 
 
 
 
X 
X 
 
Serology2 (HSV, 
VZV) 
X 
 
 
 
 
 
 
 
 
 
 
 
Review Prior/ 
Concomitant 
Medications 
X 
X 
 
X 
X 
X 
 
 
 
X 
 
 
Measurement of 
Vital Signs3 
X 
X 
 
X 
X 
X 
 
 
 
X 
 
 
Physical 
Examination 
X 
X 
 
 
X 
 
 
 
 
X 
 
 
Weight and Height4 
X 
X 
 
 
X 
 
 
 
 
 
 
 


 
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Study Procedures 
Screening 
(Within 
28 Days of 
Cycle 1 
Day 1) 
Cycle 1 
Subsequent 
Cycles 
 
 
 
Follow up  
Day 1 Day 2 
Day 8 
Day 1 
Day 8  
End of 
the Third 
Week of 
Every 
Third 21-
Day Cycle 
Every 
six 
weeks 
Every 
12 
weeks 
Safety Follow up Visit 
(30 Days After Study 
Drug Discontinuation) 
Progressive Disease/ 
Study Drug 
Discontinuation20 
Overall 
Survival 
Follow-up21 
Visit Window 
 
 
 
± 2 Days 
 
± 2 Days 
± 3 Days 
 
 
+7 Days 
± 3 Days 
 
BSA Calculation5 
 
X 
 
 
X 
 
 
 
 
 
 
 
Serum Chemistry6 
X 
X 
 
X 
X 
X 
 
 
 
X 
X 
 
Hematology7 
X 
X 
 
X 
X 
X 
 
 
 
X 
X 
 
Urinalysis8 
X 
X 
 
 
X 
 
 
 
 
X 
 
 
Hepatitis C antibody 
X 
 
 
 
 
 
 
 
 
 
 
 
CA-125 (Ovarian 
Cancer patients only) 
X 
X 
 
 
X 
 
 
 
 
X 
 
 
CEA (CRC patients 
only) 
X 
 
 
 
 
 
 
 
X 
X 
 
 
MSI for CRC 
patients16 
X 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test 9 
X 
X 
 
 
X 
 
 
 
 
X 
 
 
12-Lead 
Electrocardiogram 
X 
X 
 
X 
X 
X 
 
 
 
X 
 
 
Adverse Events10 
 
X 
X 
X 
X 
X 
 
 
 
X 
 
 
Administration of 
pembrolizumab11 
 
X 
 
 
X 
 
 
 
 
 
 
 
Administration of 
NSAIDs12 
 
X 
 
X 
X 
X 
 
 
 
 
 
 
Administration of 
birinapant13 
 
X 
 
X 
X 
X 
 
 
 
 
 
 
Pharmacodynamic 
Blood Sampling14 
 
X 
X 
X 
 
 
 
 
 
 
 
 


 
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Study Procedures 
Screening 
(Within 
28 Days of 
Cycle 1 
Day 1) 
Cycle 1 
Subsequent 
Cycles 
 
 
 
Follow up  
Day 1 Day 2 
Day 8 
Day 1 
Day 8  
End of 
the Third 
Week of 
Every 
Third 21-
Day Cycle 
Every 
six 
weeks 
Every 
12 
weeks 
Safety Follow up Visit 
(30 Days After Study 
Drug Discontinuation) 
Progressive Disease/ 
Study Drug 
Discontinuation20 
Overall 
Survival 
Follow-up21 
Visit Window 
 
 
 
± 2 Days 
 
± 2 Days 
± 3 Days 
 
 
+7 Days 
± 3 Days 
 
CD3+, CD4+, CD8+, 
CD19+, ANC, ALC 
Blood Sampling 
 
X15 
 
X17 
 
 
 
 
 
 
 
 
Archival Tumor 
Tissue Sample for 
Pharmacodynamic 
Analysis18 
X 
 
 
 
 
 
 
 
 
 
 
 
Optional Tumor 
Biopsy Sample for 
Pharmacodynamic 
Analysis 
X18 
 
 
 
X18 
 
 
 
 
 
 
 
Radiological Tumor 
Assessment 19 
X 
 
 
 
 
 
X 
 
 
 
X 
 
ANC and ALC 
 
 
X 
 
 
 
 
 
 
 
 
 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
X 
Pharmacokinetic 
Blood Sampling22 
 
X 
X 
X 
 
 
 
 
 
 
 
 
Thyroid testing6 
X 
 
 
 
 
 
 
X 
 
 
 
 
1 
Medical history and disease characteristics should include the date of the initial cancer diagnosis, a listing of relevant past and current diseases, and the details of active disease. 
2 
For those patients that may develop cranial nerve palsy, a second sample will be collected at the time of the event to assess for HSV (herpes simplex virus) and VZV (varicella zoster virus) 
viral titers.   
3 
Vital signs will be collected at Screening and on Days 1, and 8 of every 21-day cycle and will include blood pressure, respiration rate, heart rate, and body temperature. Vital signs should 
be collected pre- and post-administration of pembrolizumab, and; pre- and post-administration of birinapant). 
4 
Height and weight is to be measured at screening. Weight should be measured for each BSA calculation. 
5 
If a patient’s BSA is > 2.5, then 2.5 will be used to calculate the patient’s study-drug dose. If the patient’s body weight has changed > 10% from that used to calculate the prior BSA, the 
BSA will be recalculated and the dose adjusted. 
6 
Serum chemistry will be performed at screening (within 10 days of Cycle 1 Day 1) and on Days 1 and 8 of every cycle beginning with Cycle 1 Day 1.  Chemistry panel is to include the 
following parameters:  lipase, amylase, albumin, total protein, blood glucose (non-fasting), sodium, potassium, chloride, bicarbonate, magnesium, calcium, blood urea nitrogen (BUN), 
creatinine, AST, ALT, alkaline phosphatase (ALP), total bilirubin, direct bilirubin, lactate dehydrogenase (LDH), gamma glutamyltransferase (GGT), and phosphate.  If screening 


 
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chemistry is performed within 72 hours of Cycle 1 Day 1, the sample does not need to be repeated.  Thyroid function testing includes triiodothyronine (T3) or free triiodothyronine (FT3), 
Thyroxine (T4) or free thyroxine (FT4), and TSH 
7  
Hematology will include CBC and differentials. Hematology will be performed at screening (within 10 days of Cycle 1 Day1) and on Days 1 and 8 of every cycle beginning with Cycle 1 
Day 1. If screening hematology is performed within 72 hours of Cycle 1 Day 1, the sample does not need to be repeated  
8  
Urinalysis will be performed at screening and on Day 1 of every 21-day cycle. If screening urinalysis is performed within 72 hours of Cycle 1 Day 1, the sample does not need to be 
repeated 
9 
For women of child bearing potential, a serum pregnancy test must be performed at screening only. Urine or serum pregnancy tests must be done within 72 hours before the first dose of 
study drug.  A urine pregnancy test can be performed at all other study visits.  Monthly pregnancy testing should be conducted as per local regulations where applicable. 
10 
The adverse event reporting period is from the time the patient signs consent until 30 days after study-drug discontinuation. 
Adverse events that lead to study-drug discontinuation should be followed until resolution or stabilization.  
11 
Pembrolizumab 200 mg will be administered first on Day 1 of each 21-day cycle.  
12 
All patients will be required to be administered All patients will be required to be administered 800 mg of ibuprofen (or equipotent and equivalent alternative NSAID) prior to 
administration of birinapant on Day 1 and Day 8 as prophylaxis for possible events of cranial nerve palsy associated with the administration of birinapant. 
13 
Birinapant will be administered 30 minutes (+10 minutes) after pembrolizumab on Day 1 and by itself on Day 8 of each 21-day cycle.   
14 
Pharmacodynamic blood samples will be collected from all patients in Cycle 1.  These samples will be sent to a central laboratory for analysis. 
• 
Day 1: prior to pembrolizumab (sample 1) and 4 hours post-birinapant dose (sample 2) 
• 
Day 2: 24 hours post-birinapant dose (from Day 1) (sample 3) 
• 
Day 8: prior to birinapant (sample 4) and 4 hours post-birinapant dose (sample 5) 
15 
A peripheral blood sample will be collected to assess for CD3+, CD4+, CD8+, CD19+, ANC and ALC on cycle 1 day 1 prior to the pembrolizumab infusion A CBC is required prior to 
dosing.  This sample will be analyzed locally.  
16 
MSI testing for CRC patients done at local laboratory. Results from an historical sample can be used if done within 24 months of C1D1 
17 
A peripheral blood sample will be collected to assess for CD3+, CD4+, CD8+, CD19+, ANC and ALC on cycle 1 day 8 4 hours after the completion of the birinapant infusion. A CBC is 
required prior to dosing. This sample will be analyzed locally. 
18 
Archival tumor tissue sample for biomarkers should be obtained during screening (pre-dose; paraffin embedded archival); if no archival sample is available, a fresh biopsy, though not 
required, may be obtained. A subsequent second optional fresh tumor biopsy may be requested at any time during Cycle 2 (time of sampling post-dose will be recorded) or after to assess 
the pharmacodynamics of birinapant and pembrolizumab in this patient population. For further information, consult the laboratory manual. 
19 
All patients will be required to have a CT scan of their chest, abdomen and pelvis during screening.  MRIs will be allowed but the same radiological modality must be used at each repeat 
assessment.  Repeat radiological assessments will be performed every 9 weeks (last week of every 3rd cycle).  In the event of a response, a confirmatory scan must be performed 4 weeks 
following initial assessment of response.  All radiological assessments will be reviewed according to both RECIST v 1.1 and iRECIST criteria.   
20 
Patients who discontinue from study treatment due to reasons other than disease progression will need to be followed every 30 days until documentation of disease progression or initiation 
of a new therapy for their disease. Once disease progression is documented or new therapy is initiated the patient will move into the survival follow up stage of the protocol.  
21 
Patients will be contacted by telephone every 3 months after last study-drug treatment for survival information and subsequent therapy information 
22  
Pharmacokinetic blood samples will be collected from all patients in Cycle 1.  These samples will be sent to a bioanalytical laboratory for analysis. 
• 
Day 1: 4 hours after completion of birinapant infusion (sample 2) 
• 
Day 2: 24 hours after completion of birinapant infusion (from Day 1) (sample 3) 
• 
Day 8: prior to birinapant (sample 4) and 4 hours after completion of birinapant infusion (sample 5)