Clinical trial NCT03637491
Conditions: Pancreatic Cancer
Keywords: KRAS NRAS PDAC Pancreatic Cancer
Sponsor: Pfizer
Start date: 2018-08-15; Completion date: 2021-02-02
Enrollment: 36 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This Phase 1b/2 study will examine the effects of the study drugs, avelumab, binimetinib and talazoparib when given in a 2 (doublet) or 3 (triplet) drug combination, in patients with locally advanced or metastatic RAS-mutant solid tumors. The Phase 1b part of the study will assess if the different study drugs can be given together safely and which doses to use for further research. Phase 2 will test if the study treatments have an effect on tumor size and growth, and gather more information about potential side effects.

Detailed description:
This is a Phase 1b/2, open label, multi-center, safety, clinical activity, pharmacokinetic (PK), and pharmacodynamics (PD) study of combinations of avelumab, binimetinib and talazoparib in adult patients with metastatic pancreatic ductal adenocarcinoma and other locally advanced or metastatic KRAS- or NRAS-mutant solid tumors.

The Phase 1b part of this study will initially assess doublet drug combinations to determine a recommended dose for further investigation. Following this, the recommended dose for the combination of avelumab, binimetinib and talazoparib (triplet) will be determined. The recommended doses for the doublet and triplet combinations will be used in the Phase 2 part of the study, which will assess the safety and preliminary anti-tumor activity of the study treatments.

Arms: arm 1: Open label arm 2: Open label arm 3: Open label.
Interventions: intervention 1: Avelumab intervention 2: Binimetinib intervention 3: Talazoparib
Intervention descriptions: intervention 1: IV treatment intervention 2: Oral treatment intervention 3: Oral treatment

Protocol documents:
Prot_000.pdf: 
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A PHASE 1B/2 STUDY TO EVALUATE SAFETY AND CLINICAL ACTIVITY OF 
COMBINATIONS OF AVELUMAB, BINIMETINIB AND TALAZOPARIB IN 
PATIENTS WITH LOCALLY ADVANCED OR METASTATIC RAS-MUTANT 
SOLID TUMORS
Investigational Product Number:
MSB0010718C
MDV3800, BMN 673
MEK162
Investigational Product Name:
Avelumab (MSB0010718C) 
Talazoparib (PF-06944076)
Binimetinib (MEK162)
United States (US) Investigational New 
Drug (IND) Number:
138,057
European Clinical Trials Database 
(EudraCT) Number:
2018-000124-34
Protocol Number:
B9991033
Phase:
1b/2
This document and accompanying materials contain confidential information belonging to Pfizer.  Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this 
information in confidence and not copy or disclose it to others (except where required by applicable law) or 
use it for unauthorized purposes.  In the event of any actual or suspected breach of this obligation, Pfizer 
must be promptly notified.


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Document History
Document
Version Date
Summary of Changes and Rationale
Protocol 
Amendment 3
24 September 2019
1. The study title has been updated to reflect 
the updated study design.
2. Due to dose-limiting toxicities seen with 
the doublet of avelumab and continuous 
daily binimetib dosing, the study design 
has been updated: 

The dosing schedule for binimetinib 
has been modified to an intermittent 
schedule (seven days on 
treatment/seven days off treatment).

Phases 1b and 2 doublet combinations 
have been modified to study 
binimetinib and talazoparib. 

Estimates for total enrollment in 
Phases 1b and 2 were revised to 
reflect the updated study design.
3. Phase 2 design has been modified to 
remove the randomized NSCLC cohort 
due to enrollment concerns (ie, anticipated 
slow enrollment of these patients).  
NSCLC will instead be included as an 
eligible tumor type in the RAS-mutation 
positive ‘tumor agnostic’ cohort, which 
does not pre-specify a minimum or 
maximum number of any given tumor 
type.  This tumor agnostic cohort was also 
increased in size from 
20 to 30 patients to accommodate this 
change. 
4. Schedule of Activities have been updated 
to include:

The Day 7 visit has been clarified to 
be Day 8, and the visit window has 
been removed to allow for a PK 


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assessment following a single dose of 
binimetinib.  

TNM staging and date of progression 
during or following each prior 
regimen as part of cancer history.  

Pharmacokinetic (PK) sampling 
timepoints were revised to reflect the 
updated study design and to enable a 
Cmax assessment for binimetinib.  If 
indicated, an additional sample may 
also be drawn to investigate a 
potential exposure-toxicity 
relationship for any given patient.  

Triplicate ECGs corresponding to PK 
sampling have been removed as this is 
no longer required and did not align to 
Tmax at steady state for all study drugs.  
However, a triplicate ECG will be 
performed at screening and pre-dose 
on Cycle 1 Day 1. Single ECGs will 
be performed as a standard safety 
assessment on Day 1 of all other 
cycles. 
5. The protocol background section has been 
updated:

Avelumab background information 
has been clarified and upated per 
updates included in the current 
Investigator’s Brochure (June 2019).

Rationale has been provided for the 
decision to discontinue the doublet 
combination of avelumab and 
binimetinib and replace this with the 
doublet combination of binimetinib 
and talazoparib. 

A preliminary summary of the 
available safety data for the doublet 


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combination of avelumab and 
binimetinib has been added.

Rationale has been provided for the 
inclusion of the Phase 2 NSCLC 
patients into the ‘tumor agnostic’ 
cohort.

Rationale has been added for the 
change to an intermittent dosing 
schedule for binimetinib.

Regulatory approval information has 
been added for binimetinib and 
talazoparib.
6. Study objectives and endpoints have been 
updated accordingly: 

The doublet combination of 
binimetinib and talazoparib has been 
added.

The NSCLC specific patient reported 
outcomes have been removed.

PK parameters have been updated to 
reflect the current design. 
7. The maximum administered dose 
definition has been updated to reflect the 
intermittent schedule of binimetinib and 
the modified doublet combination of 
binimetinib and talazoparib.
8. Inclusion criteria were updated:

#1 (eligible tumor types) was updated 
such that NSCLC patients are only 
eligible for Phase 2.

#5 (tumor tissue requirements) was 
updated to clarify that bone lesion 
biopsies are not acceptable.
9. Exclusion criterion were updated:


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
#20 (concomitant medication 
restrictions) was revised in accordance 
with the current guidance relating to 
use of Pg-p inhibitors/inducers.

#22 (uncontrolled hypertension 
restriction) has been updated to clarify
that patients requiring 
anti-hypertensive medication must be 
on a stable regimen for at least 2 
weeks.
10. Section 5.5 has been updated to clarify the 
treatment administration procedures to be 
followed due to the updated study design.
11. The dose-limiting toxicity definitions 
have been updated to align with visit 
scheduling and the current guidance for 
binimetinib protocols.
a.
Hypertension criteria has been 
modified to allow 14 days for Grade 3 
hypertension to be controlled to Grade 
2 with or without ongoing medical 
therapy.
b. The duration of Grade 3 
lipase/amylase has been removed.
c.
Eye disorder criterion has been 
modified to Grade ≥3 uveitis, blurred 
vision, flashing lights or floaters.
d. Removed criterion: Grade 3 rash that 
does not improve to Grade 1 within 
14 days, limits self-care, or which is 
associated with infection.
12. The dose modification guidance has been 
updated to improve consistency and align 
with the guidance in the prescribing 
information and current protocol guidance 
for binimetinib, and the prescribing 
information for talazoparib and avelumab.  
The combined tables of dose 


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modifications have been removed to 
simplify the instructions for investigators 
and to ensure consistency with the 
prescribing guidance’s described above.
13. Section 5.8.3 has been updated to clarify 
requirements for use of steroids in the 
management of treatment-related adverse 
events.
14. Sections 5.8.6 and 5.8.7 have been 
updated based on current guidance for 
prohibited medications and those to be 
used with caution during treatment with 
talazoparib and binimetinib.
15. Section 6.4 has been updated to clarify 
that all patients are expected to enter 
survival follow-up, even if they 
discontinue short-term follow-up prior to 
completing the 90 day follow-up period.
16. Assessments (Section 7) have been 
updated:

Table 15 (required laboratory safety 
tests) was updated to confirm that 
glucose can be sampled regardless of 
fasting status as per standard protocol 
guidance, and that myoglobin may be 
measured in blood or urine 
(previously limited to urine) since 
some study centers do not have access 
to a urine myoglobin laboratory test.

12 Lead ECG requirements have been 
updated per changes in the Schedule 
of Assessments.
17. Section 8.3 has been updated to remove 
Grade 0 from the ‘Clinical Description of 
Severity’ table per the current Pfizer 
standard protocol template.
18. The statistical sections of the protocol 
(Section 9) was updated to reflect the 


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changes in study design, including the 
addition of Appendix 6. 
19. References have been updated to include 
new information.
20. Minor editorial changes have been made 
for consistency and readability.
Protocol 
Amendment 2
05 November 2018
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
3. Consistent with changes implemented in 
the updated talazoparib Investigator’s 
Brochure (dated August 2018), the 
protocol was revised to increase the 
duration of contraception use and 
concomitant medication restrictions.  
Requirements for male contraceptive use 
in relation to binimetinib was also 
clarified as per the current binimetinib IB 
(dated 20 March 2018) and regulatory 
guidance (Exclusion criterion #29, 
Section 4.1; Section 4.3; Section 5.8.6).  
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4. Consistent with changes implemented in 
the updated talazoparib Investigator’s 
Brochure (dated August 2018), 
background pharmacokinetic information 
was updated (Section 1.2.3.2).
5. Preliminary safety information that has 
become available from the B9991025 
study has been added in Section 1.2.3.3.
6. Permissible highly effective methods of 
contraception were updated as per current 
protocol standard, including the addition 
of sexual abstinence (Section 4.3).
7. Consistent with the Avelumab 
Investigator’s Brochure (version 8, 
16May2018), the recommendation for 
management of Grade 1 to 
2 immune-related rash was updated and 
Recommendations for the management of 
pulmonary irAEs was added as this had 
previously been omitted in error 
(Table 12, Section 5.5.7).
8. Required safety laboratory tests (Table 13, 
Section 7.1.4) were updated as follows:

As not all study centers have access to 
a complete CK isozyme panel 
(CK-MB, CK-MM and CK-BB) at 
their local laboratory, it was clarified 
that CK-MB is required and others
(CK-MM, CK-BB) should be 
performed if available (Table 13, 
Section 7.1.4).

As many centers perform an activated 
partial thromboplastin time 
assessment (aPTT) rather than PTT, 
aPTT was added as an alternate 
coagulation test.  

Given potential variation in reporting 
of PT results across study centers, PT 
has been removed as a reportable test 


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result in favor of collecting the INR 
result alone (Table 13, Section 7.1.4).
9. Study-required ECG assessments were 
clarified in order to specify that single 
ECG procedures should be performed 
prior to study drug dosing (Schedule of 
Assessments; Section 7.1.6).
10. Avelumab PK blood sample collection 
requirement for Cycle 1 Day 7 was 
clarified (Schedule of Assessments).
11. Requirements relating to tumor biopsy 
procedures were clarified 
(Section 7.4.1.1).
12. Section 8.4.1 Protocol-Specified Serious 
Adverse Events was added in accordance 
with the standard protocol template. 
13. Related editorial updates have been made 
for consistency and readability.
Protocol 
Amendment 1
05 June 2018
Revised as per request from United States 
Food and Drug Administration review.  

Summary and Study Design sections were 
clarified:

The Phase 1b portion of the study will 
only enroll patients with KRAS- or 
NRAS-mutant non-small cell lung 
cancer (NSCLC) and metastatic 
pancreatic ductal adenocarcinoma 
(mPDAC). 

Each dose cohort (doublet or triplet) 
may enroll both NSCLC and mPDAC 
patients without preference to tumor 
type (ie, separate dose cohorts by 
tumor type are not planned during 
Phase 1b).  

Example tumor types expected to be 
enrolled in the ‘other advanced solid 


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This amendment incorporates all revisions to date, including amendments made at the request
of country health authorities and institutional review boards (IRBs)/ethics committees (ECs).
tumors’ cohort in the Phase 2 portion 
of the study were added.

Inclusion criterion #1a was clarified that 
locally advanced or metastatic NSCLC 
includes stage IIIb and IV.

Exclusion criterion #8 was revised to 
exclude patients with a prior history of 
uveitis and iritis. 

DLT definition for eye disorders revised 
to specify the maximum duration (ie, 
≤21 days) of Grade 2 immune-related 
uveitis, eye pain, blurred vision or 
decreased visual acuity and to clarify that 
systemic treatment is corticosteroid based.
Original protocol
20 April 2018
Not applicable (N/A)


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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................17
APPENDICES .........................................................................................................................20
PROTOCOL SUMMARY.......................................................................................................21
SCHEDULE OF ACTIVITIES................................................................................................30
1. INTRODUCTION ...............................................................................................................40
1.1. Mechanism of Action/Indication.............................................................................40
1.1.1. Avelumab....................................................................................................40
1.1.2. Binimetinib .................................................................................................40
1.1.3. Talazoparib .................................................................................................41
1.2. Background and Rationale ......................................................................................41
1.2.1. Avelumab Clinical Experience...................................................................41
1.2.1.1. Clinical Efficacy in Patients with Solid Tumors.......................44
1.2.1.2. Pharmacokinetics of Avelumab in Humans..............................45
1.2.2. Binimetinib Clinical Experience.................................................................45
1.2.2.1. Clinical Efficacy in Patients with Solid Tumors.......................48
1.2.2.2. Pharmacokinetics of Binimetinib..............................................48
1.2.2.3. Avelumab in Combination with Binimetinib............................49
1.2.3. Talazoparib Clinical Experience.................................................................50
1.2.3.1. Clinical Efficacy in Patients with Advanced Solid Tumors......52
1.2.3.2. Pharmacokinetics of Talazoparib in Humans............................52
1.2.3.3. Talazoparib in Combination with Avelumab (Study 
B9991025) .........................................................................................53
1.2.4. Rationale for the Study...............................................................................54
1.2.4.1. Rationale for Combination Treatment.......................................54
1.2.4.2. Safety Considerations and Rationale for Phase 1b BLRM 
Design................................................................................................55
1.2.4.3. Drug-Drug Interaction Assessment...........................................56
1.2.5. Rationale for Patient Population.................................................................56
1.2.5.1. Rationale for KRAS- and NRAS-Mutant Tumors ....................56
1.2.5.2. Rationale for Tumor Types and Prospective Patient 
Selection ............................................................................................57
1.2.6. Rationale for the Investigational Product Doses ........................................57


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1.2.6.1. Avelumab 800 mg fixed Dose Q2W.........................................57
1.2.6.2. Binimetinib................................................................................58
1.2.6.3. Talazoparib................................................................................59
1.2.7. Summary of Benefit/Risk Assessment .......................................................59
................................................60
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................61
3. STUDY DESIGN.................................................................................................................62
3.1. Study Overview.......................................................................................................62
3.1.1. Phase 1b Design..........................................................................................63
3.1.2. Phase 2 Design............................................................................................65
3.2. Dose-Limiting Toxicity Definition .........................................................................66
3.2.1. Hematologic................................................................................................66
3.2.2. Non-Hematologic .......................................................................................66
3.2.3. Eye Disorders..............................................................................................67
3.2.4. Cardiac Disorders .......................................................................................67
3.2.5. Respiratory Disorders .................................................................................67
3.2.6. Skin and Subcutaneous Tissue Disorders...................................................68
3.2.7. Non-Adherence to Treatment Schedule......................................................68
3.2.8. Dose Reductions.........................................................................................68
3.3. Maximum Tolerated Dose Definition .....................................................................68
3.4. Maximum Administered Dose Definition...............................................................68
3.5. RP2D Definition......................................................................................................68
4. PATIENT ELIGIBILITY CRITERIA.................................................................................69
4.1. Inclusion Criteria.....................................................................................................69
4.2. Exclusion Criteria....................................................................................................71
4.3. Lifestyle Guidelines ................................................................................................74
4.4. Sponsor’s Qualified Medical Personnel..................................................................76
5. STUDY TREATMENTS.....................................................................................................76
5.1. Allocation to Treatment ..........................................................................................76
5.2. Treatment Duration .................................................................................................78
5.3. Patient Compliance .................................................................................................78
5.3.1. Avelumab Patient Compliance ...................................................................78
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5.3.2. Binimetinib and Talazoparib Patient Compliance......................................79
5.4. Investigational Product Supplies.............................................................................79
5.4.1. Dosage Forms and Packaging.....................................................................79
5.4.1.1. Avelumab ..................................................................................80
5.4.1.2. Binimetinib................................................................................80
5.4.1.3. Talazoparib................................................................................80
5.4.2. Preparation and Dispensing........................................................................80
5.4.2.1. Avelumab ..................................................................................80
5.4.2.2. Binimetinib................................................................................81
5.4.2.3. Talazoparib................................................................................81
5.5. Administration.........................................................................................................81
5.5.1. Combination Therapy Administration........................................................81
5.5.1.1. Avelumab and Binimetinib (doublet)........................................81
5.5.1.2. Binimetinib and Talazoparib (doublet) .....................................82
5.5.1.3. Avelumab, Binimetinib & Talazoparib (Triplet) ......................82
5.5.2. Binimetinib Administration........................................................................83
5.5.3. Talazoparib Administration........................................................................84
5.5.4. Avelumab Premedication............................................................................84
5.5.5. Avelumab Administration ..........................................................................85
5.5.5.1. Special Precautions for Avelumab Administration...................85
5.5.6. Food Requirements.....................................................................................85
5.5.7. Recommended Dose Modifications............................................................86
5.5.7.1. Dosing Interruptions..................................................................86
5.5.7.2. Dose Reductions - Binimetinib and Talazoparib ......................87
5.5.7.3. Toxicity Related Treatment Modifications ...............................87
5.5.7.4. Section A: Study Treatment Modifications for 
Talazoparib Drug-Related Toxicity...................................................88
5.5.7.5. Section B: Treatment Modifications for Binimetinib-
Related Adverse Events.....................................................................89
5.5.7.6. Section C: Treatment Modifications for Avelumab-
Related Toxicity ................................................................................94
5.5.8. Treatment After Initial Evidence of Radiological Disease 
Progression.....................................................................................................103


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5.6. Investigational Product Storage ............................................................................104
5.6.1. Avelumab Storage ....................................................................................105
5.6.2. Talazoparib Storage..................................................................................105
5.6.3. Binimetinib Storage..................................................................................105
5.7. Investigational Product Accountability.................................................................105
5.7.1. Destruction of Investigational Product Supplies ......................................105
5.8. Concomitant Medications .....................................................................................105
5.8.1. Supportive Care Guidelines......................................................................106
5.8.2. Anti-Inflammatory Therapy......................................................................107
5.8.3. Corticosteroids..........................................................................................107
5.8.4. Concomitant Surgery................................................................................107
5.8.5. Concomitant Radiotherapy.......................................................................108
5.8.6. Prohibited Concomitant Medications and Therapies................................108
5.8.7. Cautionary Use of Other Medication During Treatment With 
Binimetinib ....................................................................................................109
6. STUDY PROCEDURES ...................................................................................................110
6.1. Screening...............................................................................................................110
6.2. Treatment Period/ End of Treatment.....................................................................110
6.3. Patient Withdrawal................................................................................................110
6.4. Follow-up and Long-term Follow-up....................................................................111
7. ASSESSMENTS................................................................................................................112
7.1. Safety Assessments ...............................................................................................112
7.1.1. Pregnancy Testing ....................................................................................112
7.1.2. Contraceptive Check.................................................................................113
7.1.3. Adverse Events.........................................................................................113
7.1.4. Laboratory Safety Assessments................................................................113
7.1.5. Physical Examinations and Vital Signs....................................................115
7.1.6. (12-Lead) Electrocardiograms..................................................................115
7.1.7. Echocardiogram/Multigated Acquisition Scan.........................................116
7.1.8. Ophthalmic Assessments..........................................................................117
7.1.8.1. Additional Ophthalmology Assessments ................................117
7.2. Pharmacokinetic Assessments...............................................................................117


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7.2.1. Blood for PK Analysis of Avelumab........................................................118
7.2.2. Blood for PK Analysis of Binimetinib .....................................................118
7.2.3. Blood for PK analysis of Talazoparib ......................................................118
7.3. Immunogenicity Assessments...............................................................................118
7.4. Biomarker and Pharmacodynamic Assessments...................................................119
7.4.1. Tumor Biospecimens and De Novo Tumor Biopsies ...............................119
7.4.1.1. Tumor Biospecimens...............................................................120
7.4.2. Peripheral Blood Samples.........................................................................121
.................................................................................121
...........................................................................................122
..................................................................................123
7.6. Tumor Response Assessment................................................................................123
7.7. Tumor RAS Mutation Status.................................................................................124
...............................................................125
....................................................................................125
...............................................................................125
................................................................................125
8. ADVERSE EVENT REPORTING....................................................................................127
8.1. Requirements.........................................................................................................127
8.1.1. Additional Details On Recording Adverse Events on the CRF................128
8.1.2. Eliciting Adverse Event Information........................................................128
8.1.3. Withdrawal From the Study Due to Adverse Events (see also the 
Patient Withdrawal section)...........................................................................128
8.1.4. Time Period for Collecting AE/SAE Information....................................128
8.1.4.1. Reporting SAEs to Pfizer Safety.............................................129
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF ...............129
8.1.5. Causality Assessment ...............................................................................129
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities ................130
8.2. Definitions.............................................................................................................130
8.2.1. Adverse Events.........................................................................................130
8.2.2. Abnormal Test Findings ...........................................................................131
8.2.3. Serious Adverse Events ............................................................................131
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8.2.4. Hospitalization..........................................................................................132
8.3. Severity Assessment..............................................................................................133
8.4. Special Situations ..................................................................................................133
8.4.1. Protocol-Specified Serious Adverse Events.............................................133
8.4.2. Potential Cases of Drug-Induced Liver Injury..........................................133
8.4.3. Exposure to the Investigational Product During Pregnancy or 
Breastfeeding, and Occupational Exposure...................................................135
8.4.3.1. Exposure During Pregnancy....................................................135
8.4.3.2. Exposure During Breastfeeding ..............................................137
8.4.3.3. Occupational Exposure ...........................................................137
8.4.4. Medication Errors .....................................................................................137
9. DATA ANALYSIS/STATISTICAL METHODS.............................................................138
9.1. Analysis Sets .........................................................................................................138
9.1.1. Full Analysis Set.......................................................................................138
9.1.2. Safety Analysis Set...................................................................................138
9.1.3. DLT-evaluable Analysis Set.....................................................................139
.........................................................................139
9.1.5. Pharmacokinetics/Immunogenicity Analysis Set .....................................139
9.1.5.1. Pharmacokinetics Analysis Set ...............................................139
9.1.5.2. Immunogenicity Analysis Set .................................................139
9.1.5.3. Biomarker Analysis (BA) Set .................................................139
9.2. Statistical Methods and Properties ........................................................................140
9.2.1. Statistical Methods for Dose Finding: BLRM..........................................140
9.3. Sample Size Determination...................................................................................142
9.4. Efficacy Analysis ..................................................................................................143
9.4.1. Analysis of the Primary Endpoint.............................................................144
9.4.2. Analysis of the Secondary Endpoints.......................................................144
9.5. Analysis of Pharmacokinetics and Pharmacodynamics ........................................145
9.5.1. Analysis of Pharmacokinetics of Investigational Products ......................145
9.5.2. Population Pharmacokinetic Analysis or 
Pharmacokinetic/Pharmacodynamic (PK/Pharmacodynamic) Modeling......145
9.5.3. Analysis of Immunogenicity Data of Avelumab......................................145
9.6. Analysis of Biomarker Secondary
.............................146
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9.7. Safety Analysis......................................................................................................146
9.7.1. Analysis of the Primary Endpoint in Phase 1b .........................................146
9.7.2. Adverse Events.........................................................................................146
9.7.3. Laboratory Test Abnormalities.................................................................146
9.7.4. Electrocardiogram.....................................................................................147
.................................................................................147
...................................................147
........................................................................147
9.9. Interim Analysis ....................................................................................................148
9.10. Data Monitoring Committee ...............................................................................148
10. QUALITY CONTROL AND QUALITY ASSURANCE...............................................148
11. DATA HANDLING AND RECORD KEEPING ...........................................................149
11.1. Case Report Forms/Electronic Data Record .......................................................149
11.2. Record Retention.................................................................................................149
12. ETHICS............................................................................................................................150
12.1. Institutional Review Board/Ethics Committee....................................................150
12.2. Ethical Conduct of the Study ..............................................................................150
12.3. Patient Information and Consent.........................................................................150
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP .........................................................................................................................151
13. DEFINITION OF END OF TRIAL.................................................................................152
13.1. End of Trial in a Member State...........................................................................152
13.2. End of Trial in All Other Participating Countries...............................................152
14. SPONSOR DISCONTINUATION CRITERIA ..............................................................152
15. PUBLICATION OF STUDY RESULTS........................................................................152
15.1. Communication of Results by Pfizer ..................................................................152
15.2. Publications by Investigators ..............................................................................153
16. REFERENCES ................................................................................................................155
LIST OF TABLES
Table 1.
Avelumab and Binimetinib Dose Levels..................................................26
Table 2.
Binimetinib and Talazoparib Dose Levels ...............................................26
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Table 3.
Avelumab, Binimetinib and Talazoparib Dose Levels.............................27
Table 4.
Schedule of Activities: Safety and Efficacy Assessments........................32
Table 5.
Schedule of Activities: Tumor Tissue, Pharmacokinetic and 
Pharmacodynamic/Pharmacogenomic Assessments ................................37
Table 6.
Adverse Events Regardless of Causality Reported in ≥10.0% of 
Patients by Preferred Term (Pooled Data from Studies of Single-
agent Binimetinib 45 mg BID in Patients with Melanoma) .....................46
Table 7.
Avelumab and Binimetinib Dose Levels..................................................63
Table 8.
Binimetinib and Talazoparib Dose Levels ...............................................64
Table 9.
Avelumab, Binimetinib and Talazoparib Dose Levels.............................64
Table 10.
Treatment Modifications for Talazoparib Drug-Related Toxicity ...........88
Table 11.
Treatment Modifications for Binimetinib Drug-Related Toxicity ...........89
Table 12.
Treatment Modification for Avelumab Drug-Related Toxicity ...............94
Table 13.
Treatment Modification for Symptoms of IRRs Associated with 
Avelumab..................................................................................................95
Table 14.
Management of Immune-Related Adverse Events...................................96
Table 15.
Required Safety Laboratory Tests ..........................................................114
Table 16.
Objective Response Status at Each Assessment for Patients with 
Measurable Disease at Baseline..............................................................173
Table 17.
Historical Dose Limiting Toxicity Data from Study EMR100070-
001 ..........................................................................................................178
Table 18.
Prior Distributions for the Parameters of the MAP Model Used to 
Derive the Prior for the Single-Agent Avelumab Model Parameters.....178
Table 19.
Historical Dose Limiting Toxicity Data from Studies ARRAY-162-
111 and CMEK162X1101......................................................................179
Table 20.
Prior Distributions for the Parameters of the MAP Model Used to 
Derive the Prior for the Single-Agent Binimetinib Model 
Parameters...............................................................................................180
Table 21.
Historical Dose Limiting Toxicity data from study NCT01286987.......180
Table 22.
Prior Distributions for the Parameters of the MAP Model Used to 
Derive the Prior for the Single-Agent Talazoparib Model 
Parameters...............................................................................................181
Table 23.
Prior Distribution for the Model Parameters ..........................................182
Table 24.
Summary of Prior Distribution of Dose Limiting Toxicity Rates for 
the Doublet Combination of Avelumab in Combination with 
Binimetinib .............................................................................................182


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Table 25.
Summary of Prior Distribution of DLT Rates for the Triplet 
Combination of Avelumab in Combination with Binimetinib and 
Talazoparib .............................................................................................183
Table 26.
Doublet Combination: Data Scenarios, Next Dose 
Recommendation, and the Interval Probability of Target Toxicity 
and Overdosing at Next Dose.................................................................184
Table 27.
Triplet Combination: Clinically Meaningful Starting Dose Given 
Hypothetical Data from the Doublet Combination, and the Interval 
Probability of Target Toxicity and Overdosing at Starting Dose...........184
Table 28.
Triplet Combination: Data Scenarios (Given Hypothetical Doublet 
Data), Next Dose Recommendation, and the Interval Probability of 
Target Toxicity and Overdosing at Next Dose.......................................185
Table 29.
Doublet Combination: Dose Limiting Toxicity Rate Scenarios 
(Fixed Avelumab Dose 10mg/kg Every 2 Weeks).................................186
Table 30.
Triplet Combination: Dose Limiting Toxicity Rate Scenarios (Fixed 
Avelumab Dose 10mg/kg Every 2 Weeks) ............................................186
Table 31.
Doublet Combination: Operating Characteristics...................................188
Table 32.
Triplet Combination: Operating Characteristics.....................................188
Table 33.
Historical Dose Limiting Toxicity data from study NCT01286987.......192
Table 34.
Prior Distributions for the Parameters of the MAP Model Used to 
Derive the Prior for the Single-Agent Talazoparib Model 
Parameters...............................................................................................192
Table 35.
Historical Dose Limiting Toxicity Data from Studies ARRAY-162-
111 and CMEK162X1101......................................................................193
Table 36.
Prior Distributions for the Parameters of the MAP Model Used to 
Derive the Prior for the Single-Agent Binimetinib Model 
Parameters...............................................................................................194
Table 37.
Historical Dose Limiting Toxicity Data from Study EMR100070-
001 ..........................................................................................................195
Table 38.
Prior Distributions for the Parameters of the MAP Model Used to 
Derive the Prior for the Single-Agent Avelumab Model Parameters.....195
Table 39.
Prior Distribution for the Model Parameters ..........................................197
Table 40.
Summary of Prior Distribution of Dose Limiting Toxicity Rates for 
the Binimetinib (7d/7d) + Talazoparib Doublet .....................................197
Table 41.
Summary of Prior Distribution of DLT Rates for the Avelumab + 
Binimetinib + Talazoparib Triplet..........................................................198


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Table 42.
Binimetinib (7d/7d) + Talazoparib Doublet: Data Scenarios, Next 
Dose Recommendation, and the Interval Probability of Target 
Toxicity and Overdosing at Next Dose. .................................................199
Table 43.
Avelumab + Binimetinib (7d/7d) + Talazoparib Triplet: Clinically 
Meaningful Starting Dose Given Hypothetical Data from the 
Doublet, and the Interval Probability of Target Toxicity and 
Overdosing at Starting Dose...................................................................199
Table 44.
Avelumab + Binimetinib (7d/7d) + Talazoparib  Triplet: Data 
Scenarios (Given Hypothetical Doublet Data), Next Dose 
Recommendation, and the Interval Probability of Target Toxicity 
and Overdosing at Next Dose.................................................................200
Table 45.
Binimetinib (7d/7d) + Talazoparib Doublet: True Dose Limiting 
Toxicity Rate Scenarios..........................................................................202
Table 46.
Avelumab + Binimetinib (7d/7d) + Talazoparib Triplet: True Dose 
Limiting Toxicity Rate Scenarios...........................................................202
Table 47.
Binimetinib + Talazoparib (7d/7d) Doublet Combination: Operating 
Characteristics.........................................................................................204
Table 48.
Avelumab + Binimetinib (7d/7d) + Talazoparib Triplet: Operating 
Characteristics.........................................................................................204
APPENDICES
Appendix 1. Abbreviations and Definitions of Terms...........................................................162
Appendix 2. ECOG Performance Status................................................................................168
Appendix 3. Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1 Guidelines ...........................................................................169
Appendix 4. Cockroft-Gault Formula....................................................................................174
Appendix 5. Detailed Dose Escalation/De-escalation Scheme for BLRM Design – prior 
to implementation of Amendment 3.......................................................175
Appendix 6. Detailed Dose Escalation/De-escalation Scheme for BLRM Design -
Amendment 3..........................................................................................189
............................................................................................205
.......................................................................................207
.................................................................................................209
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PROTOCOL SUMMARY 
Background and Rationale:
Avelumab (MSB0010718C) is a human immunoglobulin (Ig) G1 monoclonal antibody 
(mAb) directed against programmed death-ligand 1 (PD-L1).  Avelumab selectively binds to 
PD-L1 and competitively blocks its interaction with programmed death receptor 1 (PD-1), 
thereby interfering with this key immune checkpoint inhibition pathway.  In March 2017, 
avelumab received accelerated approval by the United States (US) Food and Drug 
Administration (FDA) as the first approved treatment for metastatic merkel cell carcinoma 
(MCC) followed by approvals in Japan, Australia, European Union, Switzerland, and Israel.  
In May 2017, avelumab received accelerated approval by the US FDA for the treatment of 
patients with locally advanced or metastatic urothelial cancer (UC) with disease progression 
during or following platinum-containing chemotherapy, or within 12 months of neoadjuvant 
or adjuvant platinum-containing chemotherapy.  In January 2018, avelumab was approved 
for the same indication in Israel.  Avelumab is currently being investigated as a single-agent 
and in combination with other anti-cancer therapies in patients with locally advanced or 
metastatic solid tumors and various hematological malignancies. 
Binimetinib (MEK162) is an oral potent small molecule mitogen-activated protein kinase 
kinase (MEK) 1/2 inhibitor currently being developed by Array BioPharma for the treatment 
of B-Raf proto-oncogene serine/threonine-protein kinase (BRAF)-mutant melanoma (in 
combination with encorafenib, a novel oral BRAF kinase inhibitor) and BRAF-mutant 
colorectal cancer (CRC) (in combination with encorafenib and cetuximab).  The US FDA 
and European Medicines Agency approved the use of binimetinib and encorafenib for the 
treatment of BRAF-mutant, unresectable or metastatic melanoma on 27 June 2018 and 20 
September 2018, respectively.  MEK is a key protein kinase in the RAS/RAF/MEK/ERK 
signaling pathway, which regulates several key cellular activities including proliferation, 
differentiation, migration, survival and angiogenesis.  Inappropriate activation of this 
pathway has been shown to occur in many cancers, particularly through mutations in BRAF 
and RAS gene family members (including Kirsten rat sarcoma viral oncogene (KRAS) and 
neuroblastoma RAS viral oncogene homolog (NRAS).
Talazoparib (PF-06944076) is a potent, orally bioavailable poly (adenosine diphosphate 
[ADP]-ribose) polymerase (PARP) inhibitor, which is cytotoxic to human cancer cell lines 
harboring gene mutations that compromise deoxyribonucleic acid (DNA) repair, an effect 
referred to as synthetic lethality.  Talazoparib is currently being investigated as a single-agent 
and in combination with other anti-cancer therapies, including avelumab (Pfizer Study 
B9991025).  In a Phase 3 trial in patients with breast cancer susceptibility gene (BRCA) 
½-positive locally advanced and/or metastatic breast cancer (protocol no. 
673-301 [EMBRACA]), single-agent talazoparib demonstrated superior progression-free 
survival (PFS) versus physician choice chemotherapy.40  Median PFS was 8.6 months 
(95% confidence interval (CI): 7.2, 9.3) for patients treated with talazoparib and 5.6 months 
(95% CI: 4.2, 6.7) for those treated with chemotherapy [hazard ratio (HR): 0.54 (95% CI: 
0.41, 0.71), p<0.0001].  Based on this study, the US FDA and European Medicines Agency 
approved the use of talazoparib for the treatment of adult patients with germline breast cancer 
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(HER2)-negative locally advanced or metastatic breast cancer on 16 October 2018 and 20 
June 2019, respectively.  
Combinations of avelumab, binimetinib and talazoparib are expected to produce additive or 
synergistic anti-tumor activity relative to each drug used as a single-agent.  Studies suggest 
that oncogenic RAS signaling upregulates PD-L1 expression via the MEK-extracellular 
regulated signal kinase (ERK) pathway,41,47 and that inhibition of MEK in combination with 
checkpoint blockade promotes T-cell and anti-tumor activity.42  Consistent with this, the 
combination of binimetinib with an anti-PD-1 antibody improved anti-tumor activity and 
survival as compared to single-agent controls in a KRAS-mutant tumor model.43  Emerging 
data also indicate that the combination of PARP and MEK inhibition has synergistic anti-
tumor activity.  Combined treatment with the PARP inhibitor talazoparib and MEK inhibitor 
selumetinib induces synergistic cytotoxic effects in vitro and in vivo in multiple RAS-mutant 
tumor models across tumor lineages where RAS mutations are prevalent.44  The effects of the 
combination are independent of BRCA1/2 and p53 mutation status, suggesting that the 
synergistic activity is likely to be generalizable.
In conclusion, the above rationale supports the clinical investigation of combinations of 
PD-L1, MEK, and PARP inhibition in patients with locally advanced or metastatic KRAS- or 
NRAS-mutant tumors where there are few effective therapeutic options.  
The primary purpose of this study is to assess the safety and early signs of efficacy of 
combinations of avelumab, binimetinib and talazoparib in patients with metastatic pancreatic 
ductal adenocarcinoma (mPDAC) and other locally advanced or metastatic KRAS- or 
NRAS-mutant solid tumors.  The combinations to be studied include avelumab and 
binimetinib, binimetinib and talazoparib, and all 3 study drugs combined.  The primary tumor 
type of interest for this study - mPDAC - was selected based on the high frequency of RAS 
mutations in this tumor type,39,46 as well as an unmet medical need which is foreseen to 
continue into the future.  Given the high frequency of KRAS mutations in pancreatic cancer
(ie, over 90%),39,46 these patients will not be preselected based on KRAS/NRAS mutation 
status.
Study Objectives and Endpoints:
Primary Objectives

Phase 1b: To assess the dose-limiting toxicity (DLT) rate of the doublet and triplet 
combinations in patients with mPDAC in order to determine the recommended 
Phase 2 dose (RP2D) for the combinations.

Phase 2: To assess the objective response rate (ORR) of the doublet and triplet
combinations based on the Investigator assessment per Response Evaluation Criteria 
in Solid Tumors, version 1.1 (RECIST v1.1) in patients with mPDAC and other 
KRAS- or NRAS-mutant advanced solid tumors.


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Secondary Objectives
!
To assess the overall safety and tolerability of the doublet and triplet combinations.
!
To characterize the pharmacokinetics (PK) of avelumab, binimetinib and talazoparib 
when given in combination.
!
To evaluate the immunogenicity of avelumab when given in combination with the 
other study drugs.
!
To assess the anti-tumor activity of the doublet and triplet combinations.
!
To assess the correlation of anti-tumor activity of the doublet and triplet combinations 
with PD-L1 expression, DNA Damage Repair (DDR) gene alterations, and tumor 
mutational burden (TMB) in baseline tumor tissue.
Exploratory Objectives
 
 
 
  
 
 
.
Primary Endpoints
!
Phase 1b: DLT during the primary DLT evaluation period (Cycle 1). 
!
Phase 2: Confirmed objective response (OR) based on Investigator assessment per 
RECIST v1.1. 
Secondary Endpoints
!
Adverse Events (AEs) as characterized by type, severity (as graded by National 
Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] 
v4.03), timing, seriousness, and relationship to study treatment.
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!
Laboratory abnormalities as characterized by type, severity (as graded by NCI 
CTCAE v4.03) and timing.
!
PK parameters, ie, concentration at the end of the dosing interval (Ctrough) for 
avelumab, binimetinib and talazoparib, and maximum plasma concentration (Cmax) 
for avelumab and binimetinib, at various cycles.
!
Avelumab anti-drug antibody (ADA) levels and neutralizing antibodies (nAb) against 
avelumab.
!
Phase 1b: Confirmed OR based on Investigator assessment per RECIST v1.1. 
!
Time to tumor response (TTR), duration of response (DR), and PFS based on 
Investigator assessment per RECIST v1.1, and overall survival (OS). 
!
PD-L1 expression level, DDR gene alterations, and tumor mutational burden in 
baseline tumor tissue.
Exploratory Endpoints
 
 
 
 
 
 
 
 
 
Study Design:
This is a Phase 1b/2, open label, multi-center study of combinations of avelumab, binimetinib 
and talazoparib in eligible adult patients with mPDAC and other locally advanced or 
metastatic KRAS- or NRAS-mutant  solid tumors.
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Initially, this study examined avelumab given intravenously (IV) every 2 weeks (Q2W) and 
binimetinib given orally twice daily (BID) on a continuous dosing schedule with the 
objective of identifying an RP2D for this doublet combination before proceeding to assess 
the triplet combination of avelumab, binimetinib and talazoparib.  Due to observed dose-
limiting toxicities (DLTs) with continuous binimetinib dosing, the dosing schedule for 
binimetinib has been modified (Amendment 3) to an intermittent dosing schedule(s) which is 
expected to mitigate these potential toxicities.  
Given that recent clinical trial results for a combination of an anti-PD-L1 and a MEK 
inhibitor showed limited clinical activity69,70 and pre-clinical data support the combination of 
MEK and PARP inhibitors,44,72 this trial has also been modified (Amendment 3) to explore 
the doublet combination of binimetinib and talazoparib in addition to the triplet combination 
of avelumab, binimetinib and talazoparib.  This doublet combination is anticipated to have an 
acceptable safety profile, as seen with the combination of the MEK and PARP inhibitors, 
selumetinib and olaparib, respectively, which was well tolerated in an ongoing Phase 1 
study.71
Per Amendment 3, the study will include a sequential dose-finding phase (Phase 1b) for 
binimetinib in combination with talazoparib (doublet) and avelumab in combination with 
binimetinib and talazoparib (triplet), followed by Phase 2.  Approximately 122 patients will 
be enrolled into the study, including 52 patients in Phase 1b (inclusive of the 22 patients 
previously enrolled during Phase 1b prior to implementation of Protocol Amendment 3) and 
70 patients in Phase 2.  The actual number of patients will depend on the number of DLT 
events, dose levels/cohorts and dosing schedules that are tested during Phase 1b.
For Phase 1b, only patients with mPDAC will be enrolled.  The doublet combination of 
binimetinib (BID, 7 days on/7 days off; Schedule 7d/7d) and talazoparib will be evaluated 
first to determine the RP2D for this combination.  Upon the completion of the dose-finding 
for the doublet, the triplet of avelumab in combination with binimetinib and talazoparib will 
then be evaluated to determine the RP2D for this combination.
Guidance for Phase 1b dosing (dose level to be evaluated in the next cohort) and enrollment 
(number of patients to be enrolled in the next cohort) decisions will be based on a Bayesian 
Logistic Regression Model (BLRM).  The BLRM incorporates single-agent and available 
combination DLT data (historical and prospectively across dose cohorts) to estimate the 
posterior probability of underdosing, target dosing, and overdosing, thereby reducing patient 
risk and increasing efficiency and precision during dose finding with combination treatments.
Phase 1b Design
The dose levels for the combination of avelumab and continuous binimetinib prior to 
implementation of Amendment 3 are shown in Table 1 below.  The starting dose level (D0) 
was 800 mg avelumab  IV Q2W and 45 mg binimetinib orally (PO) twice daily, which 
satisfied the Escalation With Overdose Control (EWOC) criterion35 that the risk for excessive 
toxicity be less than 0.25.  (NOTE: For the starting dose level D0, the risk of excessive 
toxicity was estimated to be 0.10 based on information from prior single-agent Phase 1 


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studies and a pharmacokinetic (PK) assessment of no potential significant drug-drug 
interaction between avelumab and binimetinib.)
Table 1.
Avelumab and Binimetinib Dose Levels
Dose Level
Avelumab dose IV
(mg Q2W)
Binimetinib dose PO
(mg twice daily)
D0
800
45
D-1
800
30
D0= starting dose; D-1=reduced dose; IV= intravenous; mg= milligram; Q2W= every 2 weeks.
The potential dose levels for the combination of binimetinib and talazoparib are shown in 
Table 2.  The starting dose level (BT0) is 45 mg binimetinib orally BID, Schedule 7d/7d, and 
0.75 mg talazoparib orally once daily (QD) on a continuous dosing schedule, which satisfies 
the EWOC criterion35 that the risk for excessive toxicity be less than 0.25.  Of note, for BT0, 
the risk of excessive toxicity was estimated to be 0.189 based on the information from prior 
single-agent Phase 1 studies30,9 and a PK assessment of no potential drug-drug interaction 
between binimetinib and talazoparib (see Appendix 6, Table 40).  
Table 2.
Binimetinib and Talazoparib Dose Levels
Dose Levels
Binimetinib Dose (Oral)
(mg twice daily)*
Talazoparib Dose (Oral)
(mg daily)
BT1
45
1.0
BT0
45
0.75
BT-1
45
0.5
BT-2
30
1.0
BT-3
30
0.75
BT-4
30
0.5
Abbreviations: mg=milligram.
*In accordance with the assigned intermittent dosing schedule (ie, 7d/7d or 5 days on/2 days off (5d/2d)).
Dose-finding for the triplet combination of avelumab, binimetinib and talazoparib will begin 
once the RP2D for the doublet combination (with intermittent Schedule 7d/7d binimetinib 
dosing) has been confirmed in at least 9 DLT-evaluable patients.
The potential dose levels for the triplet combination are listed in Table 3.  The starting dose 
level will be determined at the completion of the dose finding for the doublet combinations
based on clinical data (including but not limited to safety and PK data) from the avelumab 
and binimetinib and binimetinib and talazoparib doublet dose-finding portions of this study 
and from the combination of avelumab and talazoparib (dose-finding phase of study 
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Table 3.
Avelumab, Binimetinib and Talazoparib Dose Levels
Avelumab Dose IV
(mg Q2W)
Binimetinib Dose PO
(mg twice daily, Schedule 
7d/7d)
Talazoparib Dose PO
(mg once daily)
800
30
0.5
800
30
0.75
800
30
1.0
800
45
0.5
800
45
0.75
800
45
1.0
IV= intravenous; mg= milligram; Q2W= every 2 weeks; PO=oral.
If the doublet of binimetinib and talazoparib is well tolerated using Schedule 7d/7d for 
binimetinib with an RP2D of at least 45 mg binimetinib and 0.75 mg talazoparib, the 
combination of binimetinib (BID) administered on a more intensive dosing schedule (ie, 
5 days on/2 days off; Schedule 5d/2d) with continuous talazoparib (QD) may also be 
explored in order to determine the RP2D for this combination.  In this case, possible dose 
levels include those indicated in Table 2, with a starting dose level that will be selected based 
on satisfying the EWOC criterion.  Patient enrollment into this doublet combination using 
Schedule 5d/2d for binimetinib dosing may occur in parallel with that of the triplet dose 
finding using Schedule 7d/7d for binimetinib dosing.
For each combination, beginning with the starting dose level, cohorts of 3-6 patients will be 
enrolled, treated, and monitored during the 28-day DLT evaluation period (Cycle 1).  Patients 
without DLTs who withdraw from study treatment before receiving at least 75% of the 
planned dose of the investigational products in Cycle 1 for reasons other than treatment 
related toxicity are not evaluable for DLT.  A minimum of 3 DLT-evaluable patients will be 
required; additional patients will be enrolled in the specific enrollment cohort to replace 
patients who are not considered DLT-evaluable, where required.  When all DLT-evaluable 
patients treated in a given enrollment cohort have completed the DLT observation period or 
experienced a DLT, whichever occurs first, the posterior distribution for the risk of DLT for 
new patients at different dose levels for the combination of interest will be evaluated.  The 
posterior distributions will be summarized to provide the posterior probability that the risk of 
DLT lies within the intervals shown below. 

Underdosing:
[0, 0.16);

Target toxicity:
[0.16, 0.33);

Excessive toxicity:
[0.33, 1].


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In addition to accumulating safety data and observed DLTs, decisions on further patient 
enrollment and dose level selection will be guided by the Escalation With Overdose Control
EWOC criterion.35  A combination dose may only be used for newly enrolled patients if the 
risk of excessive toxicity at that combination dose is less than 0.25.
A dose level combination is a potential candidate for being the maximum tolerated dose 
(MTD) level when all the following criteria are met:

≥6 patients have been treated at that dose;

Probability of target dosing >50%;

Probability of overdosing <25%.
An RP2D below the MTD may be determined based on other safety, clinical activity, PK, 
and pharmacodynamic (PD) data.  Before initiating the Phase 2, safety will be confirmed in 
at least 9 DLT-evaluable patients treated at the RP2D for each combination. Available PK 
data for approximately 6 patients treated with the doublet and triplet will be evaluated.  If the 
PK profile of each drug appears to be consistent with the PK profile of each drug given 
individually, Phase 2 will be initiated without waiting for complete PK data.
Phase 2 Design 
Once the Phase 1b part is completed and the RP2Ds for the doublet and triplet combinations 
have been determined, Phase 2 will be initiated to evaluate the safety and anti-tumor activity 
of the RP2D for each combination.  Up to 40 patients with mPDAC will be randomized in a 
1:1 ratio to the doublet and the triplet combinations (ie, 20 patients per combination) to 
reduce potential treatment selection bias.  In the case that an RP2D is determined for the 
doublet combination using more than 1 binimetinib dosing schedule (ie, Schedules 7d/7d and 
5d/2d), only one of the doublet schedules will be chosen to be evaluated in Phase 2 on the 
basis of all available safety, PK and anti-tumor activity data.
In addition to the above mPDAC tumor cohorts, 30 patients with other locally advanced or 
metastatic KRAS- or NRAS-mutant  solid tumors (such as NSCLC, CRC, melanoma and 
endometrial cancer) will be enrolled in a ‘tumor agnostic’ cohort  to receive the triplet 
combination as this may provide clinical benefit to a broader population of patients than 
primarily planned for this study (ie, mPDAC).  
In total, approximately 70 patients are expected to be treated in Phase 2. 
Study Treatments:
Eligible patients will be centrally assigned to a study treatment cohort after providing 
informed consent and completing the screening procedures.  Patients enrolled in Phase 1b 
prior to implementation of Amendment 3 will continue to receive the originally assigned 
study treatment, with subsequent dose adjustments made as allowed for study drug-related 
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Avelumab will be supplied as a sterile solution (20 mg/mL) and will be administered as a 
1-hour IV infusion Q2W on Days 1 and 15 of each 28-day cycle at a fixed dose of 800 mg.  
In order to mitigate infusion-related reactions (IRRs), patients will be premedicated with an 
antihistamine and paracetamol (acetaminophen) prior to the first 4 infusions of avelumab; 
thereafter, premedications should be administered based upon clinical judgment and the 
presence/severity of prior infusion reactions.
Binimetinib will be provided as 15 mg film-coated tablets for oral administration, and 
packaged in induction sealed, high density polyethylene bottles with child resistant caps.  
Patients should self-administer binimetinib, orally twice daily at the defined dose (either 
30 mg or 45 mg) and schedule, with or without food.  The first dose should be taken in the 
morning, with the second dose 12±2 hours later. 
Talazoparib will be supplied as 0.25 mg and 1.0 mg capsules for oral administration, and 
packaged in induction sealed, high density polyethylene bottles with child resistant caps.  
Patients should self-administer talazoparib, orally once daily at the defined dose level (either 
0.5 mg, 0.75 mg, or 1 mg), at approximately the same time each morning along with the first 
dose of binimetinib.
On the days when avelumab is administered, patients must be instructed not to administer 
the morning binimetinib dose and the talazoparib dose at home, but to take their medication 
to the clinic (ie, investigative site) on these days for administration after necessary 
procedures are completed.
Statistical Methods:
The primary endpoint for Phase 1b will be the occurrence of DLT during the primary DLT 
evaluation period (Cycle 1).  
The primary endpoint for Phase 2 will be confirmed OR.  OR is defined as a Complete 
Response (CR) or Partial Response (PR) per RECIST v1.1, occurring from the date of first 
dose of study treatment for non-randomized cohorts or date of randomization for randomized 
cohorts, until the date of first documentation of progressive disease (PD) or death due to any 
cause.  Both CR and PR must be confirmed by repeat assessments performed no less than 
4 weeks after the criteria for response are first met.  ORR is defined as the proportion of 
patients with a confirmed CR or PR based on the Investigator’s assessment according to 
RECIST v1.1.  Confirmed responses are those that persist on repeat tumor assessments for at 
least 4 weeks after initial documentation of response.  Otherwise, the patient will be counted 
as a non-responder in the assessment of ORR.  Additionally, patients with inadequate data for 
tumor assessment (eg, no baseline assessment or no follow-up assessments) will be 
considered as non-responders in the assessment of ORR.  Within each cohort and for each 
combination, ORR will be estimated and the two-sided exact 95% CIs for ORR will be 
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In the Phase 1b dose finding, it is estimated that approximately up to 18 and 12 patients will 
be enrolled in the doublet and triplet combination, respectively (in addition to the 22 patients 
previously enrolled during Phase 1b prior to implementation of Protocol Amendment 3).  
Each combination will include at least 6 patients treated at the MTD level and at least 
9 patients at the RP2D.  The actual number of patients will depend on the number of DLT 
events, dose levels/cohorts and dosing schedules that are tested.
In Phase 2, the primary objective is to assess the ORR of the doublet and the triplet 
combinations.  
With 20 treated patients per treatment group (doublet and triplet combinations) for mPDAC, 
ORR can be estimated with a maximum standard error of 0.112.

With 30 treated patients in the ‘tumor agnostic’ cohort of the triplet combination, 
ORR can be estimated with a maximum standard error of 0.091.  
Further, assuming a beta-binomial distribution for the ORR and a beta (0.5, 0.5) prior:

mPDAC cohort for the doublet combination: if 5 responders (out of 20 patients, ORR 
of 25%) are observed, the posterior probability of a true ORR 15% (considered a 
clinically relevant effect) will be 80% (89.0%). 

mPDAC cohort for the triplet combination: if 7 responders (out of 20 patients, ORR 
of 35%) are observed, the posterior probability of a true response rate 25% 
(considered a clinically relevant effect) will be 80% (84.9%).

‘Tumor agnostic’ KRAS- or NRAS-mutant solid tumor cohort for the triplet 
combination: if 12 responders (out of 30 patients, ORR of 40%) are observed, the 
posterior probability of a true ORR 30% (considered a clinically relevant effect) will 
be 80% (88.2%).
The determination of what constitutes a clinically meaningful response rate was based upon a 
review of historical ORR data for clinical studies in mPDAC, second line NSCLC, and 
CRC.49-58
SCHEDULE OF ACTIVITIES
The Schedule of Activities (SOA) table provides an overview of the protocol visits and 
procedures.  Refer to the STUDY PROCEDURES and ASSESSMENTS sections of the 
protocol for detailed information on each assessment required for compliance with the 
protocol.
The Investigator may schedule visits (unplanned visits) in addition to those listed in the SOA
table (Table 4) in order to conduct evaluations or assessments required to protect the 
well-being of the patient.


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This SOA will be followed for the entire study, including all study drug combinations and 
schedules to be studied in Phase 1b and Phase 2.  Further details can be found in Section 5, 
Section 6, and Section 7.


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Table 4.
Schedule of Activities: Safety and Efficacy Assessments
Protocol Activities
Screening
On-Treatment Period: (One Cycle =28 Days)
Post-Treatment Period
28 Days Prior to
Enrollment
Cycle 1
Cycle 2
Cycles 3
End of 
Treatment[1]
Short-Term Follow-Up 
(Day After Last Dose 
30±3, 60±3, 90±3)[2]
Long-Term 
Follow-Up 
(Every 12 
Weeks 
±14 days)[3]
Day 
1
Day 8
(Phase 1b 
ONLY)
Day 
15
Day 
1
Day 
15
Day 
1
Day 
15
Visit Window (Days)
2
2
2
2
2
+7
±3
±14
Informed Consent[4]
X
Cancer History[5]
X
Medical History[6]
X
Baseline Signs and Symptoms[7]
X
Height
X
Weight
X
X
X
X
X
Contraceptive Check[8]
X
X
X
X
X
X[8]
X[8]
Laboratory and Safety Assessments – Must be performed pre-dose during the Treatment Period.  Note: laboratory tests may be performed up to 3 days prior to the scheduled 
clinic visit so that results will be available for review. 
Physical Examination (including 
skin)
X
X
X
X
X
X (30 day visit only)
Vital Signs[9]
X
X
X
X
X
X
X
X
X
X (30 day visit only)
ECOG Performance Status[10]
X
X
X
X
X
X (30 day visit only)
Hematology[11]
X
X[12]
X
X
X
X
X
X
X
X (30 day visit only)
Blood Chemistry[11]
X
X[12]
X
X
X
X
X
X
X
X (30 day visit only)
Coagulation[11]
X
X[12]
X
X
X
X (30 day visit only)
Cardiac Troponin (cTn)[13]
X
If CK-MB is >ULN.  For new cardiac biomarker increase, see Table 14.
Blood or Urine Myoglobin 
X
If CK is Grade ≥3
ACTH and Thyroid Function 
Tests[11]
X
Every 
2 
cycles 
(C2, 4 
6, etc)
X
X (30 day visit only)
Urinalysis[14]
X
As clinically indicated.
Serum/Urine Pregnancy Test (for 
women of childbearing potential 
only)[15]
X
X
X
X
X
Hepatitis B and Hepatitis C Virus 
tests[16]
X


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Table 4.
Schedule of Activities: Safety and Efficacy Assessments
Protocol Activities
Screening
On-Treatment Period: (One Cycle =28 Days)
Post-Treatment Period
28 Days Prior to
Enrollment
Cycle 1
Cycle 2
Cycles 3
End of 
Treatment[1]
Short-Term Follow-Up 
(Day After Last Dose 
30±3, 60±3, 90±3)[2]
Long-Term 
Follow-Up 
(Every 12 
Weeks 
±14 days)[3]
Day 
1
Day 8
(Phase 1b 
ONLY)
Day 
15
Day 
1
Day 
15
Day 
1
Day 
15
Visit Window (Days)
2
2
2
2
2
+7
±3
±14
Triplicate 12-Lead ECG[17]
X
X
Single 12-Lead ECG[17]
X
X
X
Ophthalmic Examination
X[18]
X[18]
Every 8 
weeks (7 
days) eg, 
Cycle 4, 6, 
8 etc[18]
X
X (30 day visit only)[19]
ECHO/MUGA (LVEF 
Determination)
X
X
Cycle 5 
then every 
12 weeks 
(7 days) 
eg, Cycle 
8, 11, 14 
etc
X
Enrollment and Treatment
Enrollment/Treatment 
Assignment[20]
X
Talazoparib Administration[21]
Continuous once daily.
Binimetinib Administration[22]
Twice a day as per the assigned dosing schedule.
Premedication for Avelumab[23]
X
X
X
X
Optional 
Administration, at PI 
discretion, based on 
presence/severity of 
prior infusion 
reactions.
Avelumab Administration[24]
X
X
X
X
X
X
Other Clinical Assessments
Tumor Assessments (by RECIST 
for all tumor types)[25]
X
Every 8 weeks (7 days) after C1D1. 
After 52 weeks from C1D1, every 16 weeks (7 days) until progressive disease.
Serious and Non-Serious 
Adverse Event Monitoring[26]
X
Monitored and recorded continually
X
X[27]


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Table 4.
Schedule of Activities: Safety and Efficacy Assessments
Protocol Activities
Screening
On-Treatment Period: (One Cycle =28 Days)
Post-Treatment Period
∀28 Days Prior to
Enrollment
Cycle 1
Cycle 2
Cycles #3
End of 
Treatment[1]
Short-Term Follow-Up 
(Day After Last Dose 
30±3, 60±3, 90±3)[2]
Long-Term 
Follow-Up 
(Every 12 
Weeks 
±14 days)[3]
Day 
1
Day 8
(Phase 1b 
ONLY)
Day 
15
Day 
1
Day 
15
Day 
1
Day 
15
Visit Window (Days)
∃2
∃2
∃2
∃2
∃2
+7
±3
±14
Concomitant Treatments[28]
X
Monitored and recorded continually
X
X
Subsequent Anti-Cancer 
Treatment[29]
X
X
Survival[30]
X
X
Abbreviations: ACTH=adrenocorticotropic hormone, C=Cycle; C1D1=Cycle 1 Day 1; 
; ECG=electrocardiogram; 
ECHO=echocardiogram; ECOG PS=Eastern Cooperative Oncology Group performance status; 
; 
LVEF=Left Ventricular Ejection Fraction; MUGA=multigated acquisition; PI=Principal Investigator; 
.
Footnotes for Safety and Efficacy Assessments (Phase 1b and Phase 2) Schedule of Activities:
1.
End of Treatment: Perform tests/procedures if not completed during the previous 7 days.
2.
Short-Term Follow-up: All patients will be followed for safety every 30 days (∃3 days) through 90 days after the last dose of study treatment or until the start of new 
anti-cancer treatment, whichever occurs first.  If the patient has discontinued from study treatment for a reason other than disease progression, the patient should continue to 
undergo tumor assessments until disease progression regardless of initiation of a subsequent anti-cancer therapy.  Assessments during this period will be conducted according 
to the SOA or as clinically indicated.  See Section 6.4 for further details.
3.
Long-Term Follow-up: Follow-Up to continue until death unless lost to follow-up, consent withdrawal, or study discontinued by the Sponsor.  If the patient has withdrawn 
from study treatment for a reason other than disease progression, the patient should continue to undergo tumor assessments until disease progression regardless of initiation of 
a subsequent anti-cancer therapy.  See Section 6.4 for further details.
4.
Informed Consent: Must be obtained prior to undergoing any study-specific procedure and may be obtained >28 days prior to enrollment.  Upon providing written informed 
consent, the site should contact the IRT system so as to register the patient and receive a centrally assigned study identification code.
5.
Cancer History: Oncology-related history for the current malignancy under study, including information on prior regimens (duration of administration, best overall response 
[BOR] observed, and date of progression), current tumor, node, metastasis (TNM) stage, surgery, and radiation therapy. 
6.
Medical History: Includes history of diseases or injuries (active or resolved) and concomitant illnesses that are not considered to be the disease under study. 
7.
Baseline Signs and Symptoms: Patients will be asked about any signs and symptoms experienced within the 14 days prior to enrollment and record on the Medical History 
case report form (CRF) page. 
8.
Contraceptive Check: Investigator to confirm correct use of contraception, as applicable, for the duration of its required usage.  See Lifestyle Guidelines and Contraceptive 
Check Section 7.1.2 for additional details. 
9.
Vital Signs: Record blood pressure (BP), pulse heart rate (HR), and temperature.
10. ECOG Performance Status: See Appendix 2 for the criteria to assign the ECOG Performance Status at each time point.
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11. Hematology, Coagulation, Blood Chemistry, ACTH and Thyroid Function Tests: Required safety laboratory test results that must be reviewed prior to study drug 
administration include, at a minimum, hematology (ie, hemoglobin, platelets, and white blood cells) and chemistry (ie, ALT, AST, alkaline phosphatase, creatine kinase, total 
bilirubin, blood urea nitrogen, creatinine, sodium, potassium, and glucose).  See Section 7.1.4 for the list of required Laboratory Tests and Section 5.5.7.3 for requirements to 
perform additional laboratory tests to monitor toxicity related to either investigational product. 
12. Hematology, Coagulation, Blood Chemistry, and Urinalysis: It is not necessary to repeat on Cycle 1 Day 1 (C1D1) if performed within 7 days prior to C1D1 as part of 
Screening.
13. Cardiac Troponin: During screening, clinically significant positive results in myocardial biomarkers should be further assessed as per local standard of care to rule out 
concurrent cardiac conditions which could make the patient ineligible for the study per the exclusion criteria. During the study, new laboratory cardiac biomarker elevations 
suggestive of myocarditis should be assessed as per Table 14. Additional tests should also be performed when clinically indicated.  See Section 7.1.4.
14. Urinalysis: Dipstick is acceptable.  Perform microscopic analyses if dipstick is positive for blood or protein.  See Section 7.1.4.
15. Serum/Urine Pregnancy Test (for women of childbearing potential only): Results of the pregnancy test should be available prior to dosing.  See Section 4.1 for criteria 
defining women of childbearing potential, as those patients who require pregnancy testing.  Serum or urine pregnancy tests must have a sensitivity of at least 25 mIU/mL. 
Additionally, perform pregnancy tests whenever one menstrual cycle is missed or when a potential pregnancy is otherwise suspected.  See Section 7.1.1 for additional 
pregnancy testing details.
16. Hepatitis B and Hepatitis C Virus tests: Includes HBV surface antigen and anti-HCV antibody tests.  If anti-HCV antibody test is positive, HCV RNA test must be to be 
performed.
17. 12-Lead ECG: Triplicate 12-lead ECGs will be performed at Screening and pre-dose on Cycle 1 Day 1.  On Day 1 of all other cycles, a single 12-lead ECG will be 
performed prior to any study drug dosing.  The parameters to be recorded are RR, QT, QTc, PR, and QRS.  See Section 7.1.6 for details regarding ECGs and the procedure to 
follow if QTc is prolonged (>500 msec).  If the patient experiences any cardiac AE or syncope, dizziness, seizures, or stroke, triplicate ECGs should be obtained at the time of 
the event. See Section 7.1.6.
18. Ophthalmic Examination: Full ophthalmic examination, including best corrected visual acuity for distance testing, automated visual field testing, slit lamp examination, 
intraocular pressure and dilated fundoscopy with attention to retinal abnormalities, especially RPED, serous detachment of the retina and RVO (or associated symptoms).  In 
the case of any suspected retinal abnormality optical coherence tomography (OCT) and/or fluorescein angiography will be performed. .
19. See Section 7.1.8.1.Only required if there was a clinically significant abnormality noted at the End of Treatment Visit.
20. Enrollment/Treatment Assignment: Managed by an Interactive Response Technology (IRT) system operated by Pfizer or designee.  In this study, the date of treatment 
assignment will be considered the “date of enrollment”, Investigational product administration should begin within 3 days after enrollment.  See Section 5.1 for information 
regarding the IRT system and allocation to treatment. 
21. Talazoparib Administration: See Section 5.5.3 for details on talazoparib administration.  On Day 1 and 15 of each cycle, and also on Cycle 1 Day 8 for Phase 1b patients,
the daily dose of talazoparib should not be taken prior to the study visit and will be taken at the clinic after all procedures/assessments have been completed (see Section 5.5.1
on the administration of the study combinations).
22. Binimetinib Administration: See Section 5.5.2 for details on binimetinib administration.  On Day 1 and 15 of each cycle, the first daily dose of binimetinib should not be 
taken prior to the study visit and will be taken at the clinic after all procedures/assessments have been completed (see Section 5.5.1 on the administration of the study 
combinations).  Phase 1b Only: At the Cycle 1 Day 8 visit, a single dose of binimetinib will be administered in the clinic for all patients after all pre-dose 
procedures/assessments have been completed; where applicable per the assigned dosing schedule, the morning dose of binimetinib on Cycle 1 Day 8 should not be taken prior 
to the study visit.
23. Premedication for Avelumab: An antihistamine and paracetamol (acetaminophen) must be administered prior to the first 4 avelumab infusions (See Section 5.5.4 for further 
details on the premedication and Section 5.5.1 on the administration of the study combinations). 
24. Avelumab Administration: See Section 5.5.5 for details on avelumab administration and Section 5.5.5.1 for special precautions for avelumab administration. 


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25. Tumor Assessments (for all tumor types): See Section 7.6 for details on tumor assessments, including tumor assessments to confirm CR or PR using RECIST version 1.1 
(See Appendix 3).  Bone imaging is required at baseline for all patients.  Brain CT or MRI scans are required at baseline for all patients with stable brain lesions and for those 
for whom Central Nervous System (CNS) involvement is suspected.  Baseline scans are to be performed within 28 days prior randomization (for randomized cohorts) or start 
of study treatment (for non-randomized cohorts).  Imaging should be performed with contrast agents unless contraindicated for medical reasons.  Timing of disease 
assessment should follow calendar days and should not be adjusted for delays in cycle starts.  Tumor assessments should also be performed whenever disease progression is 
suspected.  Bone imaging is required at a different frequency than other imaging (every 16 weeks during the first 52 weeks of study treatment and every 24 weeks thereafter) 
if bone metastases are present at baseline. 
26. Serious and Non-Serious Adverse Event Monitoring: AEs should be documented and recorded at each visit using the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE) version 4.03.  The time period for actively eliciting and collecting AEs and SAEs (“active collection period”) for each patient 
begins from the time the patient provides informed consent through and including a minimum of 90 calendar days after the last investigational product administration.  If the 
patient begins a new anti-cancer therapy, the period for recording non-serious AEs on the CRF ends at the time the new treatment is started.  However, any SAEs occurring 
during the active collection period must still be reported to Pfizer Safety and recorded on the CRF, irrespective of any intervening treatment.
27. Safety Follow-up Serious and Non-Serious Adverse Event Monitoring: Patients continuing to experience a study treatment-related AE following discontinuation of 
investigational products will continue to be followed at least every 4 weeks until resolution or determination, in the clinical judgment of the Investigator, that no further 
improvement is expected.
28. Concomitant Treatments: Includes all medications and non-drug supportive interventions (eg, transfusions) from 28 days prior to the start of study treatment and up to 
90 days after the last dose of investigational products.  If a patient begins a new anti-cancer therapy, reporting of concomitant medications should end at the time the new 
treatment is started.  See Section 5.8 for additional details, Section 5.8.6 for prohibited medications, and Section 5.8.7 for drugs that should be given with caution when 
patients are being treated with the investigational products, which should be discussed with the patient and appropriately managed. 
29. Subsequent Anti-Cancer Treatment: Subsequent anti-cancer therapy will be documented and recorded.
30. Survival: Contact patients via telephone or at the clinic for survival status independently of time of disease progression for at least 2 years after enrollment of the last patient 
or until death, lost-to-follow-up, patient withdrawal of consent, or study discontinued by the Sponsor, whichever comes first.  For those patients without evidence of disease 
progression at the time of treatment discontinuation who continue to be followed with tumor assessments at Long-Term Follow-Up, survival status will be collected at the 
time of the scheduled tumor assessments.
 
 
 
 
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Table 5.
Schedule of Activities: Tumor Tissue, Pharmacokinetic and Pharmacodynamic/Pharmacogenomic Assessments
Protocol Activities
Screening
Treatment Period (1 Cycle =28 Days)
Post Treatment
∀28 Days 
Prior to
Enrollment
Cycle 1
Cycle 2
Cycles #3
End of 
Treatment
Short-Term Follow-Up 
(Day 30, Day 60 and 
Day 90 after last dose)
Long-Term 
Follow-Up
(Every 3 months)
Day
1
Day
8
(Phase 1b 
ONLY)
Day
15
Day
1
Day 
15
Day
1
Day
15
Visit Window (Days)
∃2
∃2
∃2
∃2
∃2
+7
∃3
∃14
Tumor Tissue
KRAS/NRAS Mutation Status[1]
X
Tumor Sample/Biopsy
X[2]
Optional[3]
X[4]
PK & Immunogenicity 
Binimetinib PK[5]
X
X
X
X
Cycle 3 only
Talazoparib PK[6]
X
X
X
X
Cycle 3 only
Avelumab PK[7]
X
X
X
X
X
Cycles 3, 5, 9, 
and 12 only
Immunogenicity (ADA) 
Testing[8]
X
X
X
X
Cycles 3, 5, 9, 
and 12 only
PD/PG Blood Sampling[9]
 
Circulating tumor (ct)DNA[12]
X
X
Cycles 3-5 only
X
 
 
 
 
Abbreviations: ADA=anti-drug antibodies; DNA=deoxyribonucleic acid; PD=pharmacodynamic; PG=pharmacogenomic; PK=pharmacokinetic; 
.
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Footnotes for Pharmacokinetic, Pharmacodynamic, and Pharmacogenomic Assessments Schedule of Activities:
Please refer to Laboratory Manual for instructions on sample collection, processing and shipment for all Pharmacokinetic, Pharmacodynamic, and 
Pharmacogenomic tests listed in Table 5.
1.
KRAS/NRAS Mutation Status: For NSCLC patients, as well as the patients enrolled in the ‘KRAS or NRAS mutation positive’ Phase 2 cohort, a positive KRAS or NRAS 
mutation status must have been previously documented through local laboratory testing.  Any Clinical Laboratory Improvement Amendments (CLIA)-approved test (or 
comparable local validation) using either tumor tissue or ctDNA may have been used for this analysis.  For NSCLC patients not previously tested locally or for whom the 
tumor mutation status is unknown, then a tumor tissue sample (specified in footnote #2) may be sent to the central laboratory to determine the KRAS and NRAS status; to 
allow for adequate turnaround time (~14 days), this sample may be submitted prior to the 28 day screening period but after informed consent has been obtained.  See 
Section 7.7.  
2.
Tumor Biopsy: A mandatory tumor core needle or excisional biopsy from a locally recurrent or metastatic tumor site that is not the only RECIST v1.1 target lesion must be 
performed during screening to provide a FFPE tumor tissue block.  If tumor tissue is available from a biopsy/surgery that was performed within 1 year prior to study 
enrollment and the patient did not receive any intervening systemic anti-cancer treatment, this tumor tissue may be submitted without repeating a tumor biopsy during the 
screening period.  In all instances, if a block cannot be provided due to documented local/institutional regulations, at least 20 unstained slides are required.  See 
Section 7.4.1.1.  
3.
Tumor Biopsy during Treatment Period (Optional): Optional biopsies are encouraged between Cycle 2 Day 1 and Cycle 3 Day 1.  In addition, tumor tissue is requested 
for study purposes for patients who undergo tumor biopsy or resection as part of routine clinical care at any time during the treatment period.  See Section 7.4.1.1.  
4.
Tumor Biopsy at End of Treatment: Every effort should be made to obtain an EOT (∃14 days) biopsy if a patient discontinues study treatment due to RECIST v1.1 
confirmed disease progression, except in instances where the procedure, as performed in the clinical research setting, poses an unacceptable risk to the patient.  See 
Section 7.4.1.1.
5.
Blood Draw for Binimetinib PK: Phase 1b Only: Blood samples (3-mL whole blood) will be collected at pre-dose, 1, 2 and 3 hours post-dose on Day 1 and Day 8 of 
Cycle 1.  All patients (Phase 1b and Phase 2): Pre-dose on Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1 and Cycle 3 Day 1.  If indicated, an additional PK sample may also 
be drawn with agreement between the Investigator and Sponsor (eg, to investigate a potential exposure-toxicity relationship for a particular patient).  See Section 7.2.2.
6.
Blood Draw for Talazoparib PK: Blood samples (3-mL whole blood) will be collected at pre-dose on Day 1, Day 8 (Phase 1b Only) and Day 15 of Cycle 1, and Day 1 of 
Cycle 2 and Cycle 3.  If indicated, an additional PK sample may also be drawn with agreement between the Investigator and Sponsor (eg, to investigate a potential exposure-
toxicity relationship for a particular patient).  See Section 7.2.3.
7.
Blood Draw for Avelumab PK (not applicable for binimetinib and talazoparib doublet combination patients): Blood samples (3.5-mL whole blood) will be collected at 
pre-dose and at the end of infusion (within 10 minutes after the avelumab infusion ends) on Day 1, and Day 15 of Cycle 1; Day 1 and Day 15 of Cycle 2; and Day 1 of Cycles 
3, 5, 9 and 12.  An additional single sample will also be obtained at the Cycle 1, Day 8 visit for Phase 1b patients.  If indicated, an additional PK sample may also be drawn 
with agreement between the Investigator and Sponsor (eg, to investigate a potential exposure-toxicity relationship for a particular patient).  See Section 7.2.1.
8.
Blood Draw for Avelumab Immunogenicity (ADA) Testing (not applicable for binimetinib and talazoparib doublet combination patients): Blood samples (3.5-mL whole 
blood) for avelumab immunogenicity testing will be collected pre-dose on Day 1 and Day 15 of Cycle 1 and Cycle 2; on Day 1 of Cycle 3, 5, 9, and 12.  See Section 7.3.
9.
PD/PG Blood Sampling: PD/PG time points may be adjusted based on emerging data during the course of the study; however, the total number of samples drawn during the 
study will not be increased.
 
 
12. ctDNA: A 20-mL blood sample (for plasma preparation) will be collected prior to dosing on Day 1 of Cycles 1 through 5, and at the EOT.  See Section 7.4.2.
 
 
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1. INTRODUCTION
This is a Phase 1b/2 study to assess the safety and early signs of efficacy of combinations of 
avelumab (MSB0010718C), binimetinib (also known as MEK162 or ARRY-438162) and 
talazoparib (also known as PF-06944076, BMN 673, or MDV38003) in patients with 
metastatic pancreatic ductal adenocarcinoma (mPDAC) and other locally advanced or 
metastatic KRAS- or NRAS-mutant solid tumors. 
1.1. Mechanism of Action/Indication
1.1.1. Avelumab
Avelumab (MSB0010718C) is a human immunoglobulin (Ig)G1 mAb directed against 
PD-L1.  Avelumab selectively binds to PD-L1 and competitively blocks its interaction with 
programmed death receptor 1 (PD-1), thereby interfering with this key immune checkpoint 
inhibition pathway.  Compared with anti-PD-1 antibodies that target T-cells, avelumab 
targets tumor cells, and therefore is expected to have fewer side effects, including a lower 
risk of autoimmune-related safety issues, as blockade of PD-L1 leaves the programmed death 
ligand 2 (PD-L2)/PD-1 pathway intact to promote peripheral self-tolerance.1,2  For complete 
details of the in vitro and nonclinical studies, refer to the avelumab Investigator’s Brochure 
(IB) v9.0.3  
In March 2017, avelumab received accelerated approval by the United States (US) Food and 
Drug Administration (FDA) as the first approved treatment for metastatic Merkel cell 
carcinoma (MCC) followed by approvals in Japan, Australia, European Union, Switzerland, 
and Israel.  In May 2017, avelumab received accelerated approval by the US FDA for the 
treatment of patients with locally advanced or metastatic Urothelial Cancer (UC) with disease 
progression during or following platinum-containing chemotherapy, or within 12 months of 
neoadjuvant or adjuvant platinum-containing chemotherapy.  In January, 2018 avelumab was 
approved for the same indication in Israel.  
Avelumab is currently being investigated as single-agent and in combination with other 
anti-cancer therapies in patients with locally advanced or metastatic solid tumors and various 
hematological malignancies.
Additional information for avelumab may be found in the single reference safety document 
(SRSD), which for this study is the avelumab Investigator Brochure (IB).3
1.1.2. Binimetinib
Binimetinib is an oral potent small molecule mitogen-activated protein kinase kinase (MEK) 
1/2 inhibitor.  In cell-free systems, binimetinib inhibits MEK1 and MEK2 with half maximal 
inhibitory concentrations (IC50) of 12 nM and 46 nM, respectively.  In vivo, single-agent 
binimetinib inhibits the growth of tumors in numerous xenograft models, including those 
derived from NSCLC, colorectal, pancreatic and melanoma cancers.  Binimetinib is currently 
being developed by Array BioPharma for the treatment of B-Raf proto-oncogene 
serine/threonine-protein kinase (BRAF)-mutant melanoma (in combination with encorafenib, 
a novel oral BRAF kinase inhibitor) and BRAF-mutant CRC (in combination with 
encorafenib and cetuximab).  The US FDA and European Medicines Agency approved the 


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use of binimetinib and encorafenib for the treatment of BRAF-mutant, unresectable or 
metastatic melanoma on 27 June 2018 and 20 September 2018, respectively.  
Additional information for binimetinib may be found in the SRSD, which for this study is the 
binimetinib IB.30
1.1.3. Talazoparib
Talazoparib is a potent, orally bioavailable poly (adenosine diphosphate [ADP]-ribose) 
polymerase (PARP) inhibitor, which is cytotoxic to human cancer cell lines harboring gene 
mutations that compromise deoxyribonucleic acid (DNA) repair, an effect referred to as 
synthetic lethality, by inhibiting PARP catalytic activity and possibly by trapping PARP 
protein on DNA, thereby preventing DNA repair, replication, and transcription.5,6,7  Although 
other PARP inhibitors also possess both activities, in vitro studies demonstrated that 
talazoparib has more potent PARP trapping activity than other PARP inhibitors in clinical 
development.6,8  
DNA damage promotes inflammation via the NF-κB pathway10 and the stimulation of 
interferon genes (STING) pathway,11,12 and has been shown to increase the intrinsic 
immunogenicity of tumor cells via up-regulation of major histocompatibility complex 
(MHC), natural killer group 2 member D Ligand (NKG2DL), and inducible costimulator 
ligand (ICOSL).13,14  As such, increased DNA damage via PARP inhibition is expected to 
enhance effective recognition and infiltration of tumors by immune cells.  In keeping with 
this expectation, talazoparib has been shown to promote T-cell and natural killer (NK) cell 
infiltration and activation in a mouse model of ovarian cancer.15  Additionally, talazoparib 
treatment has been shown to lead to increased expression of PD-L1 by tumor cells,16
suggesting that this may represent a means by which tumors function to inhibit 
talazoparib-mediated anti-tumor immunity. 
Talazoparib is currently being investigated as a single-agent and in combination with other 
anti-cancer therapies, including avelumab (Pfizer Study B9991025).  Based on this study, the 
US FDA and European Medicines Agency approved the use of talazoparib for the treatment 
of adult patients with germline breast cancer susceptibility gene (gBRCA)-mutated human 
epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast 
cancer on 16 October 2018 and 20 June 2019, respectively.
Additional information for talazoparib may be found in the SRSD, which for this study is the 
talazoparib IB.9  
1.2. Background and Rationale
1.2.1. Avelumab Clinical Experience
Avelumab is being developed jointly by Pfizer and Merck KGaA/EMD Serono and is 
indicated for the treatment of adults and pediatric patients 12 years and older with metastatic 
MCC and in adult patients having UC with disease progression during or following 
platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant 
platinum-containing chemotherapy.  Avelumab is also being studied in a wide variety of 


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cancers, including NSCLC, gastric cancer, renal cell carcinoma (RCC), ovarian cancer, UC, 
Hodgkin’s Lymphoma, and relapsed or refractory diffuse B-cell lymphoma, as a single-agent 
or in combination with chemotherapy, tyrosine kinase inhibitors, or other 
immune-modulating agents.
The safety profile of avelumab administered intravenously (IV) as single-agent at a dose of 
10 mg/kg every 2 weeks (Q2W) has been characterized primarily in 1738 adult patients from 
studies EMR100070-001 in various solid tumors (N=1650) and EMR100070-003 Part A in 
MCC (N=88).  Study EMR100070-001 consists of 2 parts, a dose escalation phase and a dose 
expansion phase, which is performed in selected tumor types. 
As of 05 November 2015, 53 patients were treated in the dose escalation phase of the 
EMR100070-001 study, with 4, 13, 15, and 21 patients treated with avelumab doses of 1, 3, 
10, and 20 mg/kg Q2W, respectively.  According to the study protocol, the DLT assessment 
was performed on 19 patients who participated in the 3 + 3 dose-escalation algorithm (1 
mg/kg [n = 4], 3 mg/kg [n = 3], 10 mg/kg [n = 6], and additional patients were enrolled to 
further assess safety and other study endpoints but without a formal DLT assessment.4  
Among the 19 patients in the DLT analysis set, none of the patients treated with doses up to 
10 mg/kg experienced a DLT, and the 10 mg/kg dose of avelumab was thus considered a safe 
and well tolerated dose for further investigation in the dose expansion cohorts.  One DLT (a 
Grade 3 immune-related adverse event (irAE) characterized by increased creatine kinase 
(CK), myositis, and myocarditis) was observed in 1 patient at the dose of 20 mg/kg.
The dose expansion phase of study EMR100070-001 included patients with NSCLC, gastric 
cancer, breast cancer, CRC, castration resistant prostate cancer (CRPC), adrenocortical 
carcinoma, melanoma, mesothelioma, UC, ovarian cancer, RCC, and squamous cell cancer 
of the head and neck.  Study EMR100070-003 Part A was conducted in patients with MCC. 
A summary of pooled safety data as of the data cutoff date of 09 June 2016 from patients 
treated at 10 mg/kg Q2W in studies EMR100070-001 and EMR100070-003 (N=1738) is 
provided here. 
Treatment-emergent adverse events (TEAEs) were observed in 1697 (97.6%) patients, with 
the most frequent (10%) being fatigue (32.4%), nausea (25.1%), diarrhea (18.9%), 
constipation (18.4%), decreased appetite (18.4%), IRR (17.1%), weight decreased (16.6%), 
vomiting (16.2%), anemia (14.9%), abdominal pain (14.4%), cough (13.8%), pyrexia 
(13.6%), dyspnea (13.2%), edema peripheral (11.9%), back pain (11.8%), and arthralgia 
(10.4%). 
Treatment-related TEAEs were observed in 1164 (67.0%) patients, and the most frequent 
(5%) were fatigue (17.7%), IRR (17.0%), nausea (8.6%), diarrhea (7.1%), chills (6.7%),
pyrexia (6.1%), decreased appetite (5.2%), and hypothyroidism (5.0%). 


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A total of 177 patients (10.2%) experienced Grade 3 treatment-related TEAEs, and the most 
frequent (0.5%) were fatigue (1.0%), increased lipase (1.0%), increased gamma-glutamyl 
transferase (GGT) (0.6%), IRR (0.6%), and increased aspartate aminotransferase (AST) 
(0.5%). 
A total of 777 (44.7%) patients had at least 1 serious TEAE.  Treatment-related serious 
TEAEs were reported in 108 (6.2%) patients, with the most frequent (0.2%) being IRR 
(0.9%), pneumonitis (0.6%), pyrexia (0.3%), adrenal insufficiency (0.3%), and 
hypothyroidism, diarrhea, vomiting, autoimmune disorder, autoimmune hepatitis, 
transaminases increased, dyspnea, and colitis (0.2% each). 
There were 911 deaths (52.4%) in the pooled safety data set.  The majority of deaths were 
due to progressive disease (744, 42.8%).  There were 59 deaths (3.4%) attributed to TEAEs 
not related to trial treatment, and 4 deaths (0.2%) attributed to a treatment-related TEAE by 
the Investigator and which occurred up to 30 days after the last dose of avelumab: 
pneumonitis (1 case), acute liver failure (1 case), respiratory distress (in the context of sepsis) 
(1 case), and autoimmune hepatitis with hepatic failure (1 case).  In addition, 1 patient died 
with acute respiratory failure (in the context of lung cancer progression) considered related to 
avelumab by the Investigator 37 days after the last dose of avelumab.  The cause of death 
was marked as “other” or “unknown” in 17 (1.0%) and 83 (4.8%) cases, respectively. 
A total of 244 patients (14.0%) permanently discontinued avelumab treatment due to TEAEs, 
including 107 patients (6.2%) discontinuing because of treatment-related TEAEs.  The most 
frequent treatment-related TEAEs leading to treatment discontinuation were IRR (1.8%), 
GGT increased (0.4%), and diarrhea, fatigue, autoimmune disorder, alanine aminotransferase 
(ALT) increased, blood creatine phosphokinase (CPK) increased, lipase increased, arthralgia, 
and pneumonitis (0.2% each).
Immune-Related Adverse Events (irAEs): in the pooled safety data (N=1738), a total of 
247 patients (14.2%) experienced irAEs, defined as adverse events (AEs) requiring use of 
corticosteroids (and/or hormonal therapy for endocrinopathies), and no clear alternate 
etiology.  The median time to first onset of an irAE was 11.7 weeks.  The most frequent 
irAEs were thyroid disorders including hypothyroidism (5.2%), hyperthyroidism (0.4%) and 
thyroiditis (0.2%), immune-related rash (5.2%), immune-related colitis (1.5%), immune-
related pneumonitis (1.2%), immune-related hepatitis (0.9%), adrenal insufficiency (0.5%), 
and immune-related myositis (0.5%).  In addition, irAEs reported in 0.1% of patients in the 
pooled safety dataset included: type 1 diabetes mellitus, immune-related nephritis/renal 
dysfunction, hypopituitarism, uveitis, and Guillain-Barre Syndrome.  The majority of irAEs 
were Grade 1 or Grade 2 in severity, with 39 (2.2%) being of Grade 3 severity.  Fatal 
outcome was reported in 1 patient (0.1%) with immune-related pneumonitis, and 2 patients 
(0.1%) with immune-related hepatitis.  Other relevant irAEs reported with avelumab outside 
the pooled safety dataset as of 22 March 2019 included 12 cases of potential myocarditis 
(including 1 case of fatal outcome), 7 cases of potential pancreatitis (including 1 with fatal 
outcome), 3 cases of non-fatal graft versus host disease, and 1 case of immune 
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IRRs: a total of 439 patients (25.3%) experienced at least 1 IRR, defined as a TEAE coded 
under the preferred terms of IRR, drug hypersensitivity, hypersensitivity, anaphylactic 
reaction, type I hypersensitivity, chills, pyrexia, back pain, dyspnea, hypotension, flushing, 
and abdominal pain according to a predefined case definition.  The most common preferred 
terms that met the definition for an IRR included:  infusion-related reaction (17.0%), chills 
(5.4%), and pyrexia (3.6%).  Most of the events were of Grade 1 or Grade 2 severity.  
Grade 3 IRRs occurred in 12 patients (0.7%) including 3 patients (0.2%) who experienced 
Grade 4 IRRs.  No Grade 5 IRRs were reported.  In most cases, the first occurrence of an 
IRR was related to the first infusion, with only 6 patients experiencing the first IRR at the 
fifth or later infusion.  All Grade 3 IRRs occurred with the first (7 patients) or second 
(5 patients) infusion.  Overall, 21.6% of patients had 1 IRR, 2.6% of patients had 2 IRRs, 
14 patients (0.8%) had 3 IRRs, and 3 patients had >3 IRRs.  IRR recurrence after the fourth 
infusion was rare (15 patients) and all recurrent IRRs were of Grade 1 or 2 severity.  
In 35 patients (2.0%), treatment was permanently discontinued because of an IRR.
Immunogenicity of avelumab in humans: immunogenicity assessment included all subjects 
from Studies EMR100070-001 and EMR100070-003 treated with 10 mg/kg of avelumab 
Q2W and who had at least one valid anti-drug antibody (ADA) result as of the data cut-off 
date of 09 June 2016.  Of the 1738 patients treated with avelumab, 1627 were evaluable for 
treatment-emergent ADAs, 96 (5.9%) tested positive for ADAs and 41 (2.5%) tested positive 
for neutralizing antibodies.  Titers were generally low across ADA ever-positive subjects, 
with no clear relationship between the duration of immunogenicity response and the 
maximum observed titer.  Current data suggest there is no clinically meaningful impact of 
ADA positivity on the pharmacokinetics (PK), efficacy, or safety of avelumab.
Clinical Experience in mPDAC 
The primary patient population of interest for this current study (B9991033) are those with 
pancreatic cancer.  Seven patients with pancreatic cancer were enrolled in the phase 1a dose 
escalation phase of Study EMR100070-001, at dose levels ranging from 1 mg/kg to 
20 mg/kg; no objective responses were reported among these 7 patients.61  
1.2.1.1. Clinical Efficacy in Patients with Solid Tumors
Study EMR 100070-001 is an ongoing global, open-label Phase 1 study to investigate the 
safety, tolerability, pharmacokinetics (PK), and biological and clinical activity of avelumab 
in subjects with metastatic or locally advanced solid tumors.  The study has various tumor 
type specific expansion cohorts, including NSCLC, RCC, urothelial carcinoma, gastric and 
gastro-esophageal junction cancer, metastatic breast cancer, colorectal cancer, 
castrate-resistant prostate cancer, melanoma, ovarian cancer, adrenocortical carcinoma, head 
and neck carcinoma, and mesothelioma.  As reported in the Investigator’s Brochure,3
confirmed and unconfirmed objective response rates (ORRs) in the first-line advanced 
NSCLC, second-line advanced NSCLC, ovarian cancer, second-line gastric/gastroesophageal 
junction cancer, urothelial carcinoma, mesothelioma, and adrenocortical carcinoma 
expansion cohorts were 19.9% (31 of 156 patients), 14.1% (26 of 184), 7.0% (16 of 
228 patients in secondary and efficacy expansion cohorts combined), 6.7% (4 of 60), 
16.1% (39 of 242), 9.4% (5 of 53), and 10.5% (2 of 19), respectively.  


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1.2.1.2. Pharmacokinetics of Avelumab in Humans
Available PK data from Study EMR100070-001 show that the concentration at the end of the 
dosing interval (Ctrough) increased more than proportionally to dose between 1 to 10 mg/kg, 
and proportionally to dose for doses above 10 mg/kg.  The terminal half-life (t1/2) also 
increased with dose; however, the geometric mean values for t1/2 were similar for the 
10 mg/kg and 20 mg/kg dose levels, at 94.6 hours (3.96 days) and 99.1 hours (4.1 days), 
respectively.  This PK characteristic suggests that target-mediated drug disposition is 
involved in the clearance of avelumab, and that high PD-L1 target receptor occupancy (TO) 
is likely achieved throughout the dosing interval at doses of 10 mg/kg and 20 mg/kg given 
Q2W.
The 10 mg/kg dose Q2W achieved high TO (mean TO >90%) of PD-L1 in peripheral blood 
mononuclear cells (PBMC) during the entire dosing interval, as determined from ex vivo
studies.  Based on the in vitro TO data and the observed trough serum avelumab levels in the 
dose escalation cohorts of Study EMR100070-001, TO was predicted to reach or exceed 
95% throughout the entire dosing interval in more subjects in the 10 mg/kg dose group than 
in the 3 mg/kg dose group.
Avelumab is eliminated by intracellular lysosomal proteolytic degradation throughout the 
entire body and therefore is not expected to be affected by small molecule drugs that are 
cytochrome P450 (CYP450) enzyme modulators or by transporter modulators.  Furthermore, 
avelumab itself is not expected to interfere with either absorption or elimination of small 
molecule drugs that are substrates of transporters, are metabolized via CYP450, hydrolysis or 
conjugation, and/or are renally excreted.  
Population PK analysis did not show any meaningful effects on clearance of avelumab from 
premedication with paracetamol (acetaminophen) or diphenhydramine, nor from concomitant 
medication with ibuprofen, acetylsalicylic acid, opioids, corticosteroids, and biological 
therapies evaluated to date.
1.2.2. Binimetinib Clinical Experience
As of 20 January 2018, a total of 2816 healthy subjects and patients have received at least 
1 dose of binimetinib either as monotherapy or in combination with other agents.  This 
includes 229 healthy subjects, 164 patients with rheumatoid arthritis, 17 patients with 
hepatic dysfunction, 6 patients with renal dysfunction, and 2400 patients with advanced 
cancer. 
Binimetinib has been/is being extensively studied in combination with other targeted and 
standard chemotherapy agents, including targeted inhibitors of protein kinase C (PKC; 
sotrastaurin), cyclin dependent kinase (CDK) 4/6 (ribociclib), phosphatidylinositol-3 kinases 
(PI3K; BYL719, buparlisib), RAF (encorafenib), epidermal growth factor receptor (EGFR; 
erlotinib, cetuximab) and insulin-like growth factor (IGF)-1R (ganitumab), as well as with 
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Available clinical data indicate a predictable safety profile consistent with that reported for 
other allosteric MEK1/2 inhibitors.  The most frequent TEAEs by Medical Dictionary for 
Regulatory Activities (MedDRA) preferred term in patients receiving binimetinib include 
rash, dermatitis acneiform, nausea, vomiting, diarrhea, peripheral edema, fatigue, and 
creatine kinase (CK) elevation.  Other clinically relevant toxicities are retinal events, 
increased blood pressure, decreased cardiac ejection fraction, and noninfectious 
pneumonitis/interstitial lung disease, all of which should be monitored closely with 
appropriate diagnostic evaluations.  These observed AEs are generally reversible and 
manageable by appropriate supportive medical care and/or dose modifications.
As of the data cutoff date of 20 January 2018, the experience of binimetinib as a single-agent 
in patients with advanced cancer -includes 943 patients who received at least 1 dose of 
binimetinib in 7 clinical studies.  In the Phase 1 Study ARRAY-162-111, binimetinib doses 
were escalated from 30 mg to 80 mg twice daily (BID) and the recommended single-agent 
dose for further development was 45 mg BID.  
Pooled AE data from 2 single-agent clinical studies of binimetinib in patients with metastatic 
melanoma (Study CMEK162X2201 and CMEK162A2301) are presented in Table 6 and 
provides a safety assessment of the recommended single-agent dose (“binimetinib 45 mg 
population;” N = 427).  All 427 patients (100%) included in the analysis reported at least 
1 AE, the most common (≥20.0% of patients) of which were blood CK increased (44.7%), 
diarrhea (42.6%), acneiform dermatitis (41.5%), peripheral edema (40.7%), rash (34.2%), 
nausea (30.0%), and fatigue (26.7%).  Most of these events were Grade 1 or 2 in severity.  
Two hundred eighty-five patients (66.7%) in the binimetinib 45 mg population experienced 
at least 1 Grade 3/4 AE; those reported for >2.0% of patients were blood CK increased 
(20.8%), hypertension (8.0%), ejection fraction decreased, fatigue and general physical 
health deterioration (3.5% each), rash (3.0%), dermatitis acneiform (2.6%), ALT increased 
and anemia (2.3% each), and AST increased and hypokalemia (2.1% each).
Table 6.
Adverse Events Regardless of Causality Reported in ≥10.0% of Patients by 
Preferred Term (Pooled Data from Studies of Single-agent Binimetinib 
45 mg BID in Patients with Melanoma)
Preferred term
45 mg BID
N = 427
All Grades
n (%)
Grade 3/4
n (%)
Any AE
427 (100)
285 (66.7)
Blood CK increased
191 (44.7)
89 (20.8)
Diarrhea
182 (42.6)
8 (1.9)
Dermatitis acneiform
177 (41.5)
11 (2.6)
Oedema peripheral
174 (40.7)
3 (0.7)
Rash
146 (34.2)
13 (3.0)
Nausea
128 (30.0)
5 (1.2)


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Preferred term
45 mg BID
N = 427
All Grades
n (%)
Grade 3/4
n (%)
Fatigue
114 (26.7)
15 (3.5)
Vomiting
84 (19.7)
8 (1.9)
Constipation
65 (15.2)
2 (0.5)
Hypertension
64 (15.0)
34 (8.0)
Asthenia
60 (14.1)
8 (1.9)
AST increased
59 (13.8)
9 (2.1)
Pruritus
58 (13.6)
4 (0.9)
Decreased appetite
55 (12.9)
2 (0.5)
Pyrexia
53 (12.4)
0
Dry skin
45 (10.5)
0
Dyspnoea
44 (10.3)
6 (1.4)
Ejection fraction decreased
44 (10.3)
15 (3.5)
Retinal detachment
44 (10.3)
0
Abbreviations: AE = adverse event; AST = aspartate aminotransferase; CK = creatinine phosphokinase; 
mg = milligram(s); n or N = number.
Data cutoff date CMEK162A2301 18 Mar 2016; CMEK162X2201 06 Nov 2015.
One hundred three patients (24.1%) in the binimetinib 45 mg population experienced AEs 
that resulted in discontinuation of binimetinib treatment.  The most frequently reported AEs 
leading to discontinuation (>1.0% of patients) were ejection fraction decreased (16 patients 
[3.7%]), blood CK increased (8 patients [1.9%]), retinal vein occlusion (7 patients [1.6%]), 
and edema peripheral, dermatitis acneiform and general physical health deterioration 
(5 patients [1.2%] each).
One hundred forty-one patients (33.0%) in the binimetinib 45 mg population reported at least 
1 serious adverse event (SAE) on study or within 30 days of the last dose of binimetinib.  
The most frequently reported SAEs (>1.0% of patients) by PT were general physical health 
deterioration (3.7%), RVO (1.4%) and blood CK increased, diarrhea, dyspnea and vomiting 
(1.2% each).
In the binimetinib 45 mg population, 46 patients (10.8%) died on study or within 30 days of 
the last dose of binimetinib.  The majority of on-treatment deaths (40 patients [9.4%]) were 
due to progression of malignant melanoma.  Adverse events resulting in death for patients in 
the binimetinib 45 mg population were sepsis (2 patients) and dyspnea, embolism, euthanasia 
and multi-organ failure (1 patient each).
Please refer to the binimetinib IB30 for a detailed discussion of the safety profile of 
binimetinib.


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Clinical Experience in mPDAC 
Study CMEK162X1101, conducted in Japanese patients with advanced solid tumors, 
included 3 with pancreatic cancer.  Of these 3 patients, 1 experienced a SAE of Grade 4 CPK 
increased and 1 discontinued study treatment due to Grade 4 lipase increase; both of these 
events were considered to be related to study treatment.  No objective responses (CR or PR) 
were observed in any of these patients.
1.2.2.1. Clinical Efficacy in Patients with Solid Tumors
Anti-tumor activity with single-agent binimetinib was demonstrated among 269 patients with 
NRAS-mutant melanoma enrolled in the Phase 3 NEMO study.  In that study, the observed 
ORR was 15% (95% CI: 11, 20%) with a median duration of response of 6.9 months.48
Binimetinib has also demonstrated clinical activity when used in combination with 
encorafenib.  In the Phase 3 COLUMBUS trial for the treatment of patients with 
BRAF-mutant advanced, unresectable or metastatic melanoma, the median progression-free
survival for patients treated with the combination of encorafenib (450 mg daily) plus 
binimetinib (45 mg twice daily) was 14.9 months versus 7.3 months for patients treated with 
vemurafenib alone (960 mg twice daily) HR 0.54 (95% CI: 0.41–0.71, p<0.0001).60
1.2.2.2. Pharmacokinetics of Binimetinib
The pharmacokinetics (PK) of binimetinib are characterized to be a moderate to high 
variability drug.  Increases in exposure are generally dose proportional over the dose range of 
5 to 80 mg.  The area under the curve (AUC) accumulation ratio was 1.31 at the 45-mg twice 
daily (BID) dose level in cancer patients (Study CMEK162X2201).  Steady-state 
concentrations were reached within 15 days with an accumulation of approximately 1.5 fold 
with BID dosing.  The median terminal half-life (t1/2) was approximately 9 hours following a 
single 45 mg oral dose of 14C-binimetinib in healthy male subjects (CMEK162A2102).  
Binimetinib and its metabolites were primarily eliminated by way of feces (62%).
The effect of food on binimetinib PK was evaluated in 2 studies, ARRAY-162- 104 and 
CMEK162A2103.  No clinically significant food effect was observed in either study, 
therefore binimetinib may be administered without regard to food.  Furthermore, a 
drug-interaction study (ARRAY-162-105) with the proton-pump inhibitor rabeprazole 
indicates binimetinib can be administered in the presence of stomach pH-altering agents. 
Binimetinib is primarily metabolized by glucuronidation pathways (mainly via uridine 
diphosphate glucuronosyl transferase [UGT]1A1, 1A3 and 1A9); however, the impact of 
UGT1A1 inhibitors or inducers has not been clinically assessed.  In vitro studies also 
demonstrated that binimetinib is a substrate of P-glycoprotein (P-gp) and breast cancer 
resistance protein (BCRP), but the effects of inhibitors of these transporters on the PK of 
binimetinib are unknown.


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In vitro, binimetinib reversibly inhibits CYP2B6; however based on the inhibitory constant 
(Ki) and IC50 values for inhibition, the in vivo inhibition of CYP2B6 is not anticipated to be 
clinically relevant.  Binimetinib has also induced CYP3A in vitro; however, in a drug-drug 
interaction study (CMEK162A2105) in healthy subjects, binimetinib did not alter the 
exposure of midazolam, indicating this induction is not clinically relevant. 
Clinical Study CMEK162A2104 is a completed Phase 1 study investigating the PK of 
binimetinib in hepatic impairment subjects versus healthy subjects.  Six subjects with mild 
hepatic impairment, 6 subjects with moderate impairment, 5 subjects with severe impairment 
and 10 subjects with normal hepatic function were enrolled.  Data indicate that binimetinib 
exposure was not significantly altered in subjects with mild hepatic impairment compared to 
healthy subjects, but may be potentially increased up to 2-fold in subjects with moderate and 
severe hepatic impairment.  
Clinical Study ARRAY-162-106 is a completed Phase 1 study investigating the PK of 
binimetinib in renal impairment subjects versus healthy subjects.  The study was to be 
divided into 2 parts.  In Part 1, a total of 12 subjects were enrolled: 6 subjects with severe 
renal impairment [estimated glomerular filtration rate (eGFR) ≤29 mL/min/1.73 m2] and 
6 matching healthy subjects (eGFR ≥80 mL/min/1.73 m2).  The Part 1 results indicated the 
exposure of binimetinib in severely impaired subjects was 20% to 30% higher compared with 
healthy subjects.  A review of the Part 1 PK data determined Part 2 (evaluation of subjects 
with moderate and mild renal impairment and matching healthy subjects) was not required to 
be conducted since the increase in binimetinib exposure in subjects with severe renal 
impairment compared with the matching healthy subjects was below the protocol-specified 
50% increase.
In a population PK analysis, apparent oral clearance (CL/F) and apparent volume of 
distribution (V/F) decreased by about 1% and 8%, respectively, in typical elderly subject in 
the 95th percentile of age (79 years old) on study, compared with a typical younger patient 
(59 years old).  Binimetinib exposure has not been evaluated in adolescents or children less 
than 18 years of age. 
For further details on the PK and metabolism of binimetinib, please refer to the current 
binimetinib IB.30
1.2.2.3. Avelumab in Combination with Binimetinib
Preliminary safety results for the doublet combination of avelumab with binimetinib that was 
examined within this current study (B9991033) are provided in this section.  The initial 
Phase 1b study examined the safety of avelumab administered at a fixed dose of 800 mg 
Q2W in combination with binimetinib administered orally BID on a continuous daily dosing 
schedule.  Two dose levels were studied, including a first dose level with binimetinib at 
45 mg BID (Dose Level D0) and a reduced dose level with binimetinib at 30 mg BID (Dose 
Level D-1).  As of the database cut-off date of 31 July 2019, a total of 22 patients with 
mPDAC received study treatment.  


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Initially, a total of 12 patients were treated at the starting dose of avelumab (800 mg Q2W) 
and binimetinib at 45 mg BID.  Of these 12 patients, 11 were determined to be 
DLT-evaluable; 1 patient discontinued treatment prior to completing the DLT evaluation 
period due to disease progression and was not evaluable.  Among the 11 DLT-evaluable 
patients, 5 experienced AEs that met DLT criteria, including 1 patient each with Grade 3 
hypertension, Grade 4 increased blood creatinine phosphokinase (CPK), and Grade 3 
pustular rash; 1 patient with a combination of gastrointestinal toxicities (ie, Grade 2 nausea, 
Grade 2 vomiting, Grade 2 abdominal pain, and Grade 1 diarrhea); and 1 patient with two 
DLTs, including Grade 3 retinal pigment epithelium detachment (RPED) that fully resolved 
following treatment discontinuation and a Grade 3 pneumonitis that was also reported as a 
serious adverse event (SAE).  Based on these DLTs, avelumab Q2W in combination with this 
binimetinib dose administered on a continuous schedule was assessed as having exceeded the 
probability of overdosing and, therefore, enrollment proceeded at the lower dose level (D-1).  
A total of 10 patients were treated at the avelumab 800mg Q2W and binimetinib 30 mg BID 
dose level, all of whom were determined to be DLT-evaluable.  In total, 3 of the 10 patients 
experienced study treatment-related AEs that met DLT criteria, including 1 patient each with 
Grade 3 increased blood CPK, Grade 3 acneiform dermatitis, and Grade 3 mucosal 
inflammation (mucositis).  Of these DLTs, the Grade 3 mucositis also met SAE criteria as the 
patient was hospitalized due to this event.
As of the database cut-off date of 31 July 2019, the most frequently reported TEAEs among 
all 22 patients, regardless of study drug relationship, included rash (9 patients); AST 
increased, acneiform dermatitis, CPK increased, and fatigue (7 patients each); ALT 
increased, pyrexia, diarrhea, nausea, and vomiting (6 patients each); abdominal pain, 
hypertension, and peripheral edema (5 patients each); and infusion-related reaction,
dehydration, and pruritis (4 patients each).  Most reported TEAEs were Grade 1-2 in severity, 
however most (18 of 22) of the patients experienced at least one Grade ≥3 TEAE, including 
3 patients with Grade 5 (fatal) TEAEs of disease progression that were not related to study 
drug.
Although the rate of DLTs was higher than expected, the overall safety profile remained 
consistent with the individual study drugs and the study population.  Given the observed 
DLT rates when avelumab was combined with either 30 or 45 mg BID continuous 
binimetinib, enrollment into any of the planned triplet combination dose levels (avelumab, 
binimetinib and talazoparib) was not feasible according to the BLRM and no further patients 
will be enrolled using the continuous binimetinib dosing schedule.
1.2.3. Talazoparib Clinical Experience
As of 30 November 2016, approximately 439 patients have received talazoparib in 
company-sponsored studies in hematologic malignancies and solid tumors.  Studies in solid 
tumors include a Phase 1 study (PRP-001) in advanced or recurrent solid tumors, a Phase 1 
study in advanced malignancies (PRP-002), a Phase 2 study (673-201) in locally advanced 
and/or metastatic breast cancer patients with a germline breast cancer gene (BRCA) defect, a 
Phase 3 study (673-301) in locally advanced or metastatic breast cancer with a germline 
BRCA defect, a Phase 1 hepatic impairment study (MDV3800-02), a Phase 1 absorption, 


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distribution, metabolism and excretion (ADME) study (MDV3800-03) and a Phase 1 study 
on cardiac repolarization (MDV3800-14).
As of 30 November 2016, aggregate safety data from 3 company-sponsored clinical studies 
evaluating talazoparib monotherapy at the recommended single-agent dose of 1 mg once 
daily (QD) in patients with advanced malignancies (Phase 1 studies PRP-001 and 
MDV3800-14 and Phase 2 study 673-201; 164 patients total) provide the basis for the most 
common TEAEs (occurring in ≥20% of patients), which were fatigue (47.6%), anemia 
(45.7%), nausea (41.5%), thrombocytopenia (26.8%), diarrhea (26.2%), alopecia (22.6%), 
neutropenia (22.6%), constipation (22.0%), and headache (21.3%).  Study drug-related 
TEAEs occurring in ≥20% of patients included anemia (42.1%), fatigue (36.6%), nausea 
(29.3%), thrombocytopenia (25.6%), neutropenia (20.7%), and alopecia (20.1%).  The most 
common Grade 3 or higher drug-related TEAEs occurring in 5% of patients were anemia 
(28.0%), thrombocytopenia (16.5%), and neutropenia (12.2%). 
Serious adverse events (SAEs) occurred in 52 of 164 patients (31.7%) who received 1 mg 
QD talazoparib.  Serious adverse events occurring in 2% of patients were pleural effusion 
(4.3%), anemia and dyspnea (3.7% each), and neoplasm progression and thrombocytopenia 
(2.4% each).  Fourteen patients had SAEs considered related to talazoparib, which included 
anemia (3.0%); thrombocytopenia (2.4%); platelet count decreased (1.2%); and increased 
transaminases, neutropenic sepsis, and vomiting (0.6% each).
A total of 12 of 164 patients (18.8%) who received 1 mg QD talazoparib had a TEAE that led 
to death (6 associated with the underlying malignancy including 1 also associated with 
bronchopneumonia; 2 dyspnea; and 1 each disease progression, lung infection, hypoxia, and 
respiratory failure).  Of these events, none were assessed as related to talazoparib.  
Among the 164 patients who received 1 mg QD talazoparib, 19.5% had a TEAE that led to 
dose reduction and 57.3% had a TEAE that led to dose interruption.  The most common 
TEAEs that led to dose reduction or interruption were associated with myelosuppression.
Five of 164 patients (3.0%) treated with talazoparib at a dose of 1 mg QD permanently 
discontinued talazoparib due to a TEAE.  The TEAEs that led to study drug discontinuation 
were anemia, increased ALT, increased AST, metastatic breast cancer, and dyspnea.
In the ongoing Phase 3, open-label, randomized, parallel-group study (protocol no. 
673-301 [EMBRACA]), talazoparib is being evaluated in patients with germline BRCA 1/2 
mutations who received no more than 3 prior chemotherapy regimens for locally advanced or 
metastatic breast cancer.  Based on this study, a NDA for talazoparib as a treatment for this 
patient population was submitted to US FDA on 06 April 2018.  For this submission, a 
pooled safety analysis for 494 patients with solid tumors in Phase 1-3 studies who received 
talazoparib 1 mg QD was provided, with a data cut-off date of 15 September 2017.62  AEs 
reported for ≥20% of patients were anemia (49.2%), fatigue (47.6%), nausea (44.3%), 
headache (26.5%), neutropenia (22.9%), diarrhea (22.7%), alopecia and vomiting 
(22.3% each), constipation (20.6%), and decreased appetite (20.2%).  The results are 


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consistent with the pooled safety analysis reported in the current Investigator’s Brochure for 
talazoparib and summarized above.  
Clinical Experience in mPDAC 
Thirteen patients with pancreatic cancer received talazoparib in study PRP-001, including 
3 patients in the dose escalation phase (Part 1) and 10 patients receiving 1.0 mg/day in a 
tumor expansion cohort (Part 2).  Treatment-related AEs reported in 2 or more of the 
13 pancreatic patients included anemia (2 patients), neutropenia (3 patients), and flatulence 
(2 patients). Of these events, 2 each of anemia and neutropenia were Grade 3 or 4 in 
severity. Six (6) patients experienced a SAE, including 1 patient each with bacteremia, 
malignant ovarian cyst, pancreatic carcinoma, tumor associated fever, disease progression, 
and hyperbilirubinemia. None of these SAEs was considered by the investigator to be related 
to study drug.  
Among 10 patients with pancreatic cancer receiving 1.0 mg/day in the dose-expansion 
(Part 2) phase of study, the objective response rate was 20.0% (2 patients with a PR) and 
clinical benefit rate (CR, PR, or stable disease lasting at least 16 weeks) was 
30.0% (3 patients). In addition, there were 3 pancreatic cancer patients treated in dose 
escalation (Part 1) phase of the study, including 1 enrolled at 0.025 mg/day and 2 enrolled at 
0.05 mg/day; no objective response was observed among these 3 patients.
1.2.3.1. Clinical Efficacy in Patients with Advanced Solid Tumors
Talazoparib, as a single-agent, has demonstrated anti-tumor activity in patients with multiple 
types of solid tumors with DNA repair pathway abnormalities, particularly those associated 
with BRCA and phosphatase and tensin homolog gene (PTEN) dysfunction, including breast 
cancer, ovarian/peritoneal cancer, and pancreatic cancer in the Phase 1 Study PRP-001.  In 
patients with advanced breast cancer, ovarian/peritoneal cancer and pancreatic cancer, ORRs 
of 50.0% (7 of 14), 41.7% (5 of 12) and 20% (2 of 10) were observed, respectively.9  
In the ongoing Phase 3 EMBRACA study in patients with BRCA 1/2-positive locally 
advanced and/or metastatic breast cancer, single-agent talazoparib demonstrated superior 
PFS versus physician choice chemotherapy.  Median PFS was 8.6 months (95% CI: 7.2, 9.3) 
for patients treated with talazoparib and 5.6 months (95% CI: 4.2, 6.7) for those treated with 
chemotherapy [HR: 0.54 (95% CI: 0.41, 0.71), p<0.0001].40
1.2.3.2. Pharmacokinetics of Talazoparib in Humans
Talazoparib plasma exposure was dose proportional in the dose range of 0.025 mg to 2 mg 
QD suggesting linear PK.  Talazoparib absolute bioavailability is at least 54.6%.  After 
administration of a single 1 mg dose of talazoparib to cancer patients, the median Tmax ranged 
from 0.5 to 2.0 hours across studies.  Administration of talazoparib with food (a high-fat, 
high-calorie meal) had no impact on the AUC while reduced the Cmax by 46%.  The reduction 
in the rate of absorption with food is not expected to be clinically relevant as efficacy is 
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Mean talazoparib binding to human plasma proteins is 74%.  Population PK analysis showed 
that talazoparib apparent steady-state volume of distribution (Vss/F) was 420 L, which is 
greater than total body water (42 L), indicating that talazoparib distributes to peripheral 
tissues.
Talazoparib undergoes minimal hepatic metabolism.  Based on population PK analysis, there 
was no effect of mild hepatic impairment (total bilirubin ≤upper limit of normal [ULN] and 
aspartate aminotransferase [AST] >ULN, or total bilirubin >1.0 to 1.5 x ULN and any AST) 
on talazoparib exposure.  No dose adjustment is necessary for patients with mild hepatic 
impairment.  The effect of hepatic impairment on talazoparib PK is being investigated in the 
ongoing study MDV3800-02.
Talazoparib was eliminated slowly with a mean terminal plasma half-life (t1/2) of 89.8 hours.  
Talazoparib accumulated after 1 mg QD dosing with a median accumulation ratio ranging 
from 2.33 to 5.15, consistent with its t1/2.  Population PK analysis showed that talazoparib 
CL/F was 6.45 L/hr.  Excretion of unchanged talazoparib in urine was the major route of 
elimination accounting for 54.6% of the administered dose.  Population PK analysis showed 
that talazoparib CL/F was reduced by 14.4% and 37.1% in patients with mild renal 
impairment (creatinine clearance [CrCl], 60-89 mL/min) and moderate renal impairment 
(30 mL/min ≤CrCl <60 mL/min), respectively, compared to that of patients with normal 
renal function (CrCl >90 mL/min).  No dose adjustment is recommended for patients with 
mild renal impairment.  The starting dose of talazoparib for patients with moderate renal 
impairment should be reduced to 0.75 mg.  The effect of renal impairment on talazoparib PK 
is being investigated in the ongoing study MDV3800-01.
In vitro studies showed that talazoparib is a substrate for the efflux transporters 
P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).  Population PK analysis 
indicated that concomitant administration of strong P-gp inhibitors with talazoparib increased 
talazoparib exposure by 44.7% relative to talazoparib administered alone.  Details of 
prohibited medications for this study are provided in Section 5.8.6.
1.2.3.3. Talazoparib in Combination with Avelumab (Study B9991025) 
The combination of avelumab with talazoparib is currently being studied in Pfizer study 
B9991025 (JAVELIN Parp Medley).  This Phase 1b/2 study will examine the safety and 
anti-tumor activity of avelumab administered at a fixed dose of 800 mg Q2W in combination 
with talazoparib (0.5 mg, 0.75 mg, or 1.0 mg) administered orally once daily in patients with 
advanced solid tumors.  The starting dose level of talazoparib was 1.0 mg once daily.  
Preliminary safety data are available for the Phase 1b portion of this study, following 
evaluation of the first 12 enrolled patients.  All patients had completed their first cycle with 
treatment of avelumab at 800 mg IV Q2W in combination with talazoparib 1 mg PO QD and 
were evaluable for DLT.  The most frequently reported TEAEs were anemia (8 patients, 
66.7%), neutropenia (7 patients, 58.3%), and chills and thrombocytopenia (both 5 patients, 
41.7%).  The most frequently reported Grade 3 TEAEs were thrombocytopenia (4 patients, 
33.3%), anemia (3 patients 25.0%), and neutropenia (2 patients, 16.7%).  


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A DLT rate of 0.25 was observed with no unexpected toxicities: a total of 3 DLTs occurred 
that warranted dose interruption and reduction (two cases of Grade 3 thrombocytopenia and 
one case of Grade 3 neutropenia).68  
The safety profile of the combination of avelumab with talazoparib at full dose remained 
aligned to the safety profiles for the individual monotherapies.  The RP2D for talazoparib in 
combination with avelumab at 800 mg IV Q2W was established at 1 mg PO QD.
1.2.4. Rationale for the Study
1.2.4.1. Rationale for Combination Treatment
Based on the mechanisms of action discussed in Sections 1.1.1, 1.1.2 and 1.1.3, avelumab,
binimetinib and talazoparib have the potential to produce additive or synergistic anti-tumor 
activity relative to each drug used as a single-agent, with (i) avelumab functioning to
overcome PD-L1-mediated inhibition of anti-tumor immune response, (ii) binimetinib 
enhancing the antitumor activity of anti-PD-1/PD-L1 antibodies, (iii) talazoparib functioning 
to promote immune priming and tumor immunogenicity, and (iv) talazoparib and binimetinib 
having a potential synergistic cytotoxic effects when administered in combination.
The activity of avelumab depends on generation of a productive immune response, composed 
of effective antigen presentation, T-cell priming, infiltration of tumors, and recognition and 
killing of tumor cells.18  Studies suggest that oncogenic RAS signaling upregulates PD-L1 
expression via the MEK-ERK pathway,41,47 and that inhibition of MEK in combination with 
checkpoint blockade promotes T-cell and anti-tumor activity.42  Consistent with this, the 
combination of binimetinib with an anti-PD-1 antibody improved anti-tumor activity and 
survival as compared to single-agent controls in a KRAS-mutant tumor model.43  
In addition to upregulating PD-L1, MEK has also been identified as a negative regulator of 
MHC-I expression in multiple cancer cell lines.  As demonstrated with the MEK inhibitor 
(MEKi) trametinib and the V600E BRAF inhibitor vemurafenib, binimetinib also increases 
basal interferon (IFN)-gamma induced MHC Class I expression in NRAS-and BRAF-mutant 
melanoma cell lines.33  In syngeneic CT26 CRC engrafted BALB/C mice, the MEKi 
trametinib + anti-PD-1 antibody inhibited tumor growth more effectively than their 
single-agent controls.  In addition, the combination increased tumor infiltrating CD8+ T cells 
in vivo, with no significant alterations in the numbers and expression levels of CD3, CD4, 
CD25, CD69, and PD-1.34
Talazoparib, via its ability to promote increased DNA damage, has the potential to promote 
several key stages of the immune response that may synergize with PD-L1 blockade by 
avelumab.  Firstly, talazoparib-mediated cell death, via either PARP trapping or via increased
DNA damage, has the potential to release antigens into the tumor microenvironment, 
promoting effective antigen presentation; this has been described for other therapies that 
lead; to increased tumor cell death.19  Secondly, DNA damage promotes inflammation via 
2 alternative pathways, the first being activation of the NF-κB pathway via 
ataxia-telangiectasia mutated (ATM)-mediated phosphorylation of the NF-κB essential 
modulator (NEMO),10 and the second being activation of the STING pathway via generation 


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and detection of cytosolic DNA.11,12  Activation of these pathways leads to increased 
pro-inflammatory signaling that enhances effective recognition and infiltration of tumors by 
immune cells, and has recently been shown to be critical to the response to checkpoint 
inhibition in mice.20  Finally, DNA damage has been shown to lead to upregulation of MHC, 
NKG:2DL, and ICOSL,13,14 which would be expected to increase the intrinsic 
immunogenicity of tumor cells and enhance their recognition and killing by T -cells and 
NK -cells. 
Emerging data also indicate that the combination of PARP and MEK inhibition has 
synergistic anti-tumor activity.  Combined treatment with the PARP inhibitor talazoparib and 
MEK inhibitor selumetinib induces synergistic cytotoxic effects in vitro and in vivo in 
multiple RAS-mutant tumor models across tumor lineages where RAS mutations are 
prevalent.44  The effects of the combination are independent of BRCA1/2 and p53 mutation 
status, suggesting that the synergistic activity is likely to be generalizable.
Given that recent clinical trial results for a similar combination of an anti-PD-L1 and a MEK 
inhibitor showed limited clinical activity69,70 and pre-clinical data support the combination of 
MEK and PARP inhibitors,44,72 this trial has been modified (Amendment 3) to explore the 
doublet combination of binimetinib and talazoparib in addition to the triplet combination of 
avelumab, binimetinib and talazoparib.  This doublet combination is anticipated to have an 
acceptable safety profile, as seen with the combination of the MEK and PARP inhibitors, 
selumetinib and olaparib, respectively, which was well tolerated in an ongoing Phase 1 
study.71
In conclusion, the above rationale supports the clinical investigation of combinations of 
PD-L1, MEK, and PARP inhibition in patients with locally advanced or metastatic KRAS- or 
NRAS-mutant tumors where there are few effective therapeutic options.  
1.2.4.2. Safety Considerations and Rationale for Phase 1b BLRM Design
The relatively distinct safety profile of avelumab, binimetinib and talazoparib also supports 
the clinical evaluation of the doublet  and triplet combinations.  While there are no 
overlapping DLTs observed in the single-agent Phase 1 trials of these agents, common 
toxicities observed with all 3 agents includes fatigue, nausea, and diarrhea, however these 
were generally mild or moderate in severity.  Additionally, the relatively short half-life of 
binimetinib may allow for more effective toxicity management in the context of the 
combination treatments.
Guidance for dosing (dose level to be evaluated in the next cohort) and enrollment (number 
of patients to be enrolled in the next cohort) decisions will be based on a Bayesian Logistic 
Regression Model (BLRM).  The BLRM provides an optimal design for dose finding with 
combination treatments as it incorporates single-agent and available combination DLT data 
(historical and prospectively across dose cohorts) to estimate the posterior probability of 
underdosing, target dosing, and overdosing, thereby reducing patient risk and increasing 
efficiency and precision during dose finding with combination treatments.


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1.2.4.3. Drug-Drug Interaction Assessment
Based on the characteristics of each compound, the drug-drug interaction (DDI) potential 
among avelumab, binimetinib, and talazoparib is considered to be minimal for the following 
reasons: i) the DDI between small molecules (binimetinib and talazoparib) and biologics 
(avelumab) is uncommon; ii) the 3 drugs do not share metabolic/elimination pathways: 
Avelumab is an immunoglobulin G1 (IgG1) mAb eliminated by intracellular lysosomal 
proteolytic degradation, binimetinib is metabolized primarily by glucoronidation, and 
talazoparib is mostly renally eliminated; and iii) although both binimetinib and talazoparib 
are substrates of P-gp and BCRP, neither drug was found to be an in vitro inhibitor of these 
transporters.  Therefore, the potential of metabolic interaction between these drugs is 
minimal.  
To assess for potential DDI, the concentrations of avelumab, binimetinib and talazoparib will 
be measured in all patients enrolled in this study and compared with historical PK data for 
each agent when administered alone, including a real time PK assessment during the 
Phase 1b part of the study.
1.2.5. Rationale for Patient Population
1.2.5.1. Rationale for KRAS- and NRAS-Mutant Tumors
Oncogenic RAS mutations are common drivers of cancer cell proliferation and survival, yet 
therapies which specifically target RAS-mutant tumors are not currently available in the 
clinic.  While the proposed combination treatments may also have clinical utility against 
BRAF-mutant tumors that also activate the MEK-ERK pathway, drugs specifically targeting 
BRAF are currently available and/or are actively being studied; as such, BRAF-mutant 
tumors were not considered for inclusion in this current study.  
Section 1.2.4 presents the mechanistic rationale for targeting RAS-mutant tumors with the 
combinations of avelumab, binimetinib and talazoparib:

RAS mediates upregulation of PD-L1 via the MEK-ERK signaling pathway.47

MEK is a negative regulator of MHC-I expression in multiple cancer cell lines.

Concurrent PARP and MEK inhibition has synergistic anti-tumor activity in 
RAS-mutant tumor models.
Thus, combinations of PD-L1, MEK, and PARP inhibition may confer clinical benefit in 
patients with RAS-mutant tumors. 
Given that different RAS proteins may potentially activate different pathways outside of 
MEK/ERK, as well as the small sample size planned for this study, the study population will 
be limited to those with KRAS- or NRAS-mutant tumors.


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1.2.5.2. Rationale for Tumor Types and Prospective Patient Selection
The primary tumor type of interest for this study - mPDAC - was selected based on the high 
frequency of RAS mutations in this tumor type as well as an unmet medical need which is 
foreseen to continue into the future.  
As anti-PD-1/L1 therapy is anticipated to become more commonly administered in the 
first- and second-line settings for patients with NSCLC, this population will be limited to 
those who have progressed following 1 prior treatment line with these agents in order to 
explore the anti-tumor activity of each combination treatment.  The rationale for the 
combination treatment provided in Section 1.2.4.1 also supports studying this population by 
providing a basis for potentially overcoming resistance to immune checkpoint blockade, such 
as by: (i) increasing IFN-gamma induced MHC-I expression and T-cell infiltration (ie, via 
MEK inhibition with binimetinib), and (ii) increasing antigen presentation and 
pro-inflammatory signaling (ie, via PARP inhibition with talazoparib). 
KRAS- and NRAS-mutations are prevalent in mPDAC, occurring at a frequency of over 
90% in pancreatic cancer.39,46  While patients with mPDAC will be enrolled in a tumor-
specific cohort in the Phase 2 portion of this trial, eligible patients with advanced NSCLC 
will be enrolled in a ‘tumor agnostic’ cohort of patients bearing either KRAS- or NRAS-
mutant tumors.  While it was initially planned to include a tumor-specific NSCLC cohort, 
this was removed in Amendment 3 due to patient recruitment concerns (ie, anticipated slow 
enrollment of these patients).  In addition to NSCLC, it is anticipated that the ‘tumor 
agnostic’ cohort will enroll patients with CRC (~50% are positive for KRAS/NRAS 
mutations) as well as patients with melanoma, endometrial and stomach cancers (~10 - 30% 
positive).46  For this cohort, only the triplet combination of avelumab, binimetinib and 
talazoparib will be studied as this combination may provide clinical benefit to a broader 
population of patients than primarily planned for this study (ie, mPDAC). 
Patients in the ‘tumor agnostic’ cohort must be positive for KRAS or NRAS mutations in 
order to be eligible for participation in this study.  To facilitate patient enrollment and study 
conduct, previous positive test results obtained at any time for the current diagnosis under 
study, as well as by prospective local laboratory testing, may be used to determine patient 
eligibility.  Given the high frequency of KRAS mutations in pancreatic cancer, these patients 
will not be preselected based on KRAS/NRAS mutation status.  Nevertheless, tumor samples 
for all patients will be submitted to a central laboratory for a retrospective confirmation of 
RAS mutation status.
1.2.6. Rationale for the Investigational Product Doses
1.2.6.1. Avelumab 800 mg fixed Dose Q2W
To date, avelumab has been administered at the clinically active, safe, and tolerable dose of 
10 mg/kg Q2W to more than 1700 patients across multiple indications.  Furthermore, this 
10 mg/kg Q2W avelumab dosing regimen has been approved by the FDA as the first 
treatment for MCC and also for the treatment of UC following platinum-containing 
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Avelumab was originally dosed on a mg/kg basis in order to reduce inter-subject variability 
in drug exposure.  However, emerging data for mAbs, including the marketed PD-1 and 
PD-L1 immune checkpoint inhibitors nivolumab, pembrolizumab and atezolizumab, reveal 
that body weight-based dosing regimens do not result in less variability in measures of 
exposure over fixed (ie, body-weight independent) dosing regimens.21,22,23  Additionally, 
fixed dosing offers the advantages of less potential for dispensing errors, shorter dose 
preparation times in a clinical setting, and greater ease of administration.
Population PK analysis was conducted based on the acquired PK data across 3 single-agent 
avelumab studies in patients with 14 different types of cancer.  Pharmacokinetic simulations 
suggest that exposures to avelumab across the available range of body weights are similar 
with 800 mg Q2W compared with 10 mg/kg Q2W; exposures were similar near the 
population median weight.  Low-weight subjects tended towards marginally lower exposures 
relative to the rest of the population when weight-based dosing was used, and marginally 
higher exposures when flat dosing was applied.  However, the implications of these exposure 
differences are not expected to be clinically meaningful at any weight across the whole 
population.  Furthermore, the 800 mg Q2W and every 3 weeks (Q3W) dosing regimens are 
expected to result in Ctrough >1 g/mL which is required to maintain avelumab serum 
concentrations at >90% TO throughout the entire dosing interval in all weight categories.
Therefore, in this clinical trial, a fixed dosing regimen of 800 mg administered as a 1-hour IV 
infusion Q2W will be utilized for avelumab. 
1.2.6.2. Binimetinib
The dose levels of binimetinib to be evaluated in this study are supported by clinical studies 
in patients with advanced solid tumors.  A summary of pooled safety data from
2 single-agent clinical studies of binimetinib in patients with metastatic melanoma (Study 
CMEK162X2201 and CMEK162A2301) treated at the recommended dose of 45 mg twice 
daily has demonstrated an acceptable safety profile.  
As of the data cutoff date of 20 January 2018, the experience of binimetinib in combination 
with other targeted agents, standard chemotherapy agents or immunomodulating agents in 
1457 patients with advanced cancer in 16 clinical studies.  The 45 mg twice daily dose has 
been used in a triple combination with encorafenib and ribociclib, and has also been studied 
in combination with other investigational agents (RAF265, buparlisib, BEZ235, sotrastaurin 
and ganitumab).
Initially, this study (B9991033) examined avelumab and continuous binimetinib with the 
objective of identifying an RP2D for the doublet combination of avelumab and binimetinib.  
Due to observed DLTs, the dosing schedule for binimetinib has been modified (Amendment 
3) to an intermittent schedule of 7 days on treatment/7 days off (Schedule 7d/7d).  As most of 
the DLTs observed with the continuous binimetinib dosing schedule were consistent with 
binimetinib’s safety profile (eg, rash, CPK increase, RPED), an intermittent dosing schedule 
is expected to mitigate these potential toxicities.  This schedule is also supported by 
preclinical data that have shown that pulsatile (Schedule 7d/7d) dosing of the MEKi 


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selumetinib resulted in superior efficacy as compared with continuous dosing, potentially 
through improved activation of tumor infiltrating lymphocytes.73  
In the event that the doublet combination of binimetinib and talazoparib is well tolerated 
using Schedule 7d/7d for binimetinib with an RP2D of at least 45 mg binimetinib and 
0.75 mg talazoparib, the combination of binimetinib (BID) administered on a more intensive 
dosing schedule (ie, 5 days on treatment/2 days off treatment [Schedule 5d/2d]) with 
continuous talazoparib (QD) may also be explored for this doublet combination (Note: the 
triplet combination will only use Schedule 7d/7d binimetinib dosing).  Similar intermittent 
dosing schedules have also been administered with other MEK inhibitors in order to reduce 
treatment-related toxicity, including selumetinib (4 days on treatment/3 days off treatment) 
and PD-0325901 (5 days on treatment/2 days off treatment).74,75
1.2.6.3. Talazoparib
The dose levels of talazoparib to be evaluated in this study are supported by clinical studies 
in patients with advanced malignancies.  In the PRP-001 Phase 1 study in patients with 
advanced or recurrent solid tumors, talazoparib was escalated from 0.025 to 1.1 mg daily and 
the recommended dose for further development was determined to be 1 mg daily.  Data from 
this study at 1 mg/day demonstrated objective responses or clinical benefit (CR, PR, or stable 
disease 24 weeks) in patients with breast, ovarian/peritoneal, pancreatic cancer, small cell 
lung cancer (SCLC), and Ewing sarcoma.  Aggregate safety data for 164 patients enrolled in 
3 open-label, company-sponsored clinical studies evaluating talazoparib monotherapy at 
1 mg/day (PRP-001, 673-201, and MDV3800-14) have demonstrated an acceptable safety 
profile.  Additionally, the dose level of 1 mg daily was used in the randomized Phase 3 study 
673-301 in patients with locally advanced or metastatic breast cancer.
1.2.7. Summary of Benefit/Risk Assessment
An evaluation of the anticipated benefits and risks as required in Article 3(2)(a) of Directive 
2001/20/EC (cf. Article 6(3)(b) of Directive 2001/20/EC) has been conducted.
The benefit-risk relationship has been carefully considered in the planning of this trial.  
Responses to avelumab have been observed in a broad range of other tumor types, including 
NSCLC, ovarian cancer, gastric/gastroesophageal junction cancer, urothelial carcinoma, 
mesothelioma, adrenocortical carcinoma, gastric cancer, and merkel cell carcinoma.3  The 
clinical safety data available to date with single-agent avelumab in patients with advanced 
solid tumors suggest an acceptable safety profile, as described in Section 1.2.1.  Most of the 
observed AEs were either in line with those expected in patients with advanced solid tumors 
or with similar class effects of mAbs blocking the PD-1/PD-L1 axis.  Infusion-related 
reactions including hypersensitivity and irAEs/autoimmune disorders have been identified as
important risks for avelumab.  Respective risk mitigation measures have been implemented 
in all ongoing clinical studies with avelumab, including this clinical trial protocol.  These 
include guidelines for treatment interruption and discontinuation in case of irAEs, as well as 
mandatory pre-treatment with an antihistamine and acetaminophen prior to the first 
4 avelumab infusions (Cycles 1-2) and as clinically indicated thereafter.


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Based upon the observed anti-tumor activity as a single agent in NRAS-mutant melanoma in 
combination with its clinical safety profile, binimetinib continues to have a favorable 
benefit-risk profile to support current clinical development in patients with selected 
advanced/metastatic malignancies.  In pooled safety data from 2 single-agent clinical studies 
(N=427), the most common (≥20.0% of patients) AEs were blood CK increased (44.7%), 
diarrhea (42.6%), dermatitis acneiform (41.5%), edema peripheral (40.7%), rash (34.2%), 
nausea (30.0%), and fatigue (26.7%).  Anti-tumor activity with single-agent binimetinib was 
demonstrated among 269 patients with NRAS-mutant melanoma enrolled in the Phase 3 
NEMO study.  In that study, the observed ORR was 15% (95% CI: 11, 20%) with a median 
DR of 6.9 months.48
As described in Section 1.2.2.3, the overall safety profile of binimetinib administered 
continuously in combination with avelumab remained consistent with the individual study 
drugs and the study population.  However, due to the DLT rate observed among patients 
receiving avelumab and continuous binimetinib dosing in this study, the dosing schedule for 
binimetinib proposed for evaluation in the doublet and triplet combinations has been 
modified (Amendment 3) to an intermittent dosing schedule(s) which is expected to mitigate 
these potential toxicities.
As described in Section 1.2.3.1, talazoparib has shown anti-tumor activity in patients with 
breast, ovarian, peritoneal and pancreatic cancers.  The clinical safety profile of talazoparib 
supports its use as both a single-agent and in combination with cancer therapies.  The most 
common TEAEs associated with single-agent talazoparib administration (>20% of patients) 
were myelosuppression (eg, anemia, thrombocytopenia, neutropenia), gastrointestinal 
toxicity (eg, nausea, diarrhea, vomiting), fatigue, alopecia, and headache; Grade ≥3 TEAEs 
in ≥5% of patients were associated with myelosuppression.  These AEs were primarily 
Grade 1 or 2 severity and typically resolved with temporary dose interruptions or reductions.9  
The anti-tumor activity of single-agent talazoparib has been demonstrated in the ongoing 
EMBRACA study in BRCA1/2-positive patients with locally advanced and/or metastatic 
breast cancer, in which talazoparib provided a significantly superior ORR and PFS benefit as 
compared to standard chemotherapy.40
Based on the manageable safety profiles of avelumab, binimetinib and talazoparib 
administered as single-agents, the expected low incidence of overlapping severe toxicities, 
and the anticipated enhanced anti-tumor activity, the projected benefit-risk relationship of the 
proposed combinations are expected to be favorable for investigation in this population of 
patients with advanced solid tumors.  
 
 
 
 
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2. STUDY OBJECTIVES AND ENDPOINTS
Primary Objective(s): 
Primary Endpoint(s): 
!
Phase 1b: To assess the DLT rate of the doublet 
and triplet combinations in patients with 
mPDAC in order to determine the 
recommended Phase 2 dose (RP2D) for the 
combinations.
!
Phase 2: To assess the ORR of the doublet and 
triplet combinations based on Investigator 
assessment per RECIST v1.1 in patients with 
mPDAC and other KRAS- or NRAS-mutant 
advanced solid tumors.
!
Phase 1b: DLT during the primary DLT 
evaluation period (Cycle 1). 
!
Phase 2: Confirmed OR based on Investigator 
assessment per RECIST v1.1 (see Appendix 3).
Secondary Objective(s): 
Secondary Endpoint(s): 
!
To assess the overall safety and tolerability of 
the doublet and triplet combinations.
!
To characterize the PK of avelumab, 
binimetinib and talazoparib when given in 
combination.
!
To evaluate the immunogenicity of avelumab 
when given in combination with the other study 
drugs.
!
To assess the anti-tumor activity of the doublet 
and triplet combinations.
!
To assess the correlation of anti-tumor activity 
of the doublet and triplet combinations with 
PD-L1 expression, DDR gene alterations, and 
TMB in baseline tumor tissue.
!
Adverse Events as characterized by type, 
severity (as graded by NCI CTCAE v4.03), 
timing, seriousness, and relationship to study 
treatment.
!
Laboratory abnormalities as characterized by 
type, severity (as graded by NCI CTCAE 
v4.03) and timing.
!
PK parameters, ie, Ctrough for avelumab, 
binimetinib, and talazoparib, and Cmax for 
avelumab and binimetinib, at various cycles.
!
Avelumab ADA levels and nAb against 
avelumab.
!
Phase 1b: Confirmed OR based on Investigator 
assessment per RECIST v1.1. 
!
TTR, DR, and PFS based on Investigator 
assessment per RECIST v1.1 and OS. 
!
PD-L1 expression level, DDR gene alterations, 
and TMB in baseline tumor tissue.
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Exploratory Objective(s)
Exploratory Endpoint(s)
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3. STUDY DESIGN
3.1. Study Overview
This is a Phase 1b/2, open label, multi-center, study of combinations of avelumab, 
binimetinib and talazoparib in eligible adult patients with mPDAC (regardless of KRAS 
status) and other locally advanced or metastatic KRAS- or NRAS-mutant solid tumors.
Initially, this study examined avelumab given IV Q2W and binimetinib given BID on a 
continuous dosing schedule with the objective of identifying an RP2D for this doublet 
combination before proceeding to assess the triplet combination of avelumab, binimetinib 
and talazoparib. Due to observed DLTs with continuous binimetinib dosing, the dosing 
schedule for binimetinib has been modified (Amendment 3) to an intermittent dosing 
schedule(s) which is expected to mitigate these potential toxicities.  
Per Amendment 3, the study will include a sequential dose-finding phase (Phase 1b) for 
binimetinib in combination with talazoparib (doublet) and avelumab in combination with 
binimetinib and talazoparib (triplet) followed by Phase 2.  Approximately 122 patients will
be enrolled into the study, including 52 patients in Phase 1b (inclusive of the 22 patients 
previously enrolled during Phase 1b enrolled prior to implementation of Amendment 3) and 
70 patients in Phase 2.  The actual number of patients will depend on the number of DLT 
events, dose levels/cohorts and dosing schedules that are tested during Phase 1b.
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For Phase 1b, only patients with mPDAC will be enrolled.  The doublet combination of 
binimetinib BID (Schedule 7d/7d) and talazoparib will be evaluated first to determine the 
RP2D for this combination.  Upon the completion of the dose-finding for the doublet, the 
triplet of avelumab in combination with binimetinib and talazoparib will then be evaluated to 
determine the RP2D for this combination.
Guidance for Phase 1b dosing (dose level to be evaluated in the next cohort) and enrollment 
(number of patients to be enrolled in the next cohort) decisions will be based on a BLRM.  
The BLRM incorporates single-agent and available combination DLT data (historical and 
prospectively across dose cohorts) to estimate the posterior probability of under-dosing, 
target dosing and overdosing, thereby reducing patient risk and increasing efficiency and 
precision during dose finding with combination treatments.  
3.1.1. Phase 1b Design
The dose levels of avelumab and continuous binimetinib studied prior to implementation of 
Amendment 3 are included in Table 7.  The starting dose level (D0) was 800 mg avelumab 
IV Q2W and 45 mg binimetinib orally twice daily, which satisfied the EWOC criterion35 that 
the risk for excessive toxicity be less than 0.25.  Of note, for the D0, the risk of excessive 
toxicity was estimated to be 0.10 based on the information from prior single-agent Phase 1 
studies and a PK assessment of no potential drug-drug interaction between avelumab and 
binimetinib. 
Table 7.
Avelumab and Binimetinib Dose Levels
Dose Level
Avelumab dose IV
(mg Q2W)
Binimetinib dose oral
(mg twice daily)
D0
800
45
D-1
800
30
Abbreviations: D0= starting dose; D-1=reduced dose; IV= intravenous; mg= milligram; Q2W= every 2 weeks.
The potential dose levels for the combination of binimetinib and talazoparib are shown in 
Table 8.  The starting dose level (BT0) is 45 mg binimetinib orally BID, Schedule 7d/7d, and 
talazoparib 0.75 mg orally, QD on a continuous dosing schedule, which satisfies the EWOC 
criterion35 that the risk for excessive toxicity be less than 0.25.  Of note, for BT0, the risk of 
excessive toxicity was estimated to be 0.189 based on the information from prior single-agent 
Phase 1 studies30,9 and a PK assessment of no potential drug-drug interaction between 
binimetinib and talazoparib (see Appendix 6 Table 40). 


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Table 8.
Binimetinib and Talazoparib Dose Levels
Dose 
Levels
Binimetinib Dose (Oral)
(mg twice daily)*
Talazoparib Dose (Oral)
(mg daily)
BT1
45
1.0
BT0
45
0.75
BT-1
45
0.5
BT-2
30
1.0
BT-3
30
0.75
BT-4
30
0.5
Abbreviations: mg= milligram.
*In accordance with the assigned intermittent dosing schedule (ie, Schedule 7d/7d or 5d/2d).
Dose-finding for the triplet of avelumab, binimetinib and talazoparib will begin once the 
RP2D for the doublet combination (Schedule 7d/7d binimetinib dosing) has been confirmed 
in at least 9 DLT-evaluable patients (see Section 9.1.3).
The potential dose levels for the triplet combination of avelumab, binimetinib, and 
talazoparib are listed in Table 9.  The starting dose level for the triplet will be determined at 
the completion of the dose finding for the doublet combinations based on all available 
clinical data (including but not limited to safety and PK data) from the avelumab and 
binimetinib and binimetinib and talazoparib doublet dose-finding portions of this study and 
from the combination of avelumab and talazoparib (dose-finding component of study 
B9991025).
Table 9.
Avelumab, Binimetinib and Talazoparib Dose Levels
Avelumab Dose 
(IV)
(mg Q2W)
Binimetinib Dose (Oral)
(mg twice daily, Schedule 
7d/7d)
Talazoparib Dose (Oral)
(mg daily)
800
30
0.5
800
30
0.75
800
30
1.0
800
45
0.5
800
45
0.75
800
45
1.0
Abbreviations: IV= intravenous; mg= milligram; Q2W= every 2 weeks.
If the doublet of binimetinib and talazoparib is well tolerated using Schedule 7d/7d for 
binimetinib with an RP2D of at least 45 mg binimetinib and 0.75 mg talazoparib, the 
combination of binimetinib (BID) administered on a more intensive dosing schedule (ie, 
5 days on/2 days off; Schedule 5d/2d) with continuous talazoparib (QD) may also be 
explored in order to determine the RP2D for this combination.  In this case, possible dose 


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levels include those indicated in Table 8, with a starting dose level that will be selected based 
on satisfying the EWOC criterion.  Patient enrollment into this doublet combination using 
Schedule 5d/2d for binimetinib dosing may occur in parallel with that of the triplet dose 
finding using Schedule 7d/7d for binimetinib dosing.
For each combination, beginning with the starting dose level, cohorts of 3-6 patients will be 
enrolled, treated, and monitored during the 28 day DLT evaluation period (Cycle 1).  Patients 
without DLTs who withdraw from study treatment before receiving at least 75% of the 
planned dose of the investigational products in Cycle 1 for reasons other than treatment 
related toxicity are not evaluable for DLT.  A minimum of 3 DLT-evaluable patients will be 
required; additional patients will be enrolled in the specific enrollment cohort to replace 
patients who are not considered DLT-evaluable, where required.  When all DLT-evaluable 
patients treated in a given enrollment cohort have completed the DLT observation period or 
experienced a DLT, whichever occurs first, the posterior distribution for the risk of DLT for 
new patients at different dose levels for the combination of interest will be evaluated.  The 
posterior distributions will be summarized to provide the posterior probability that the risk of 
DLT lies within the intervals shown below: 

Underdosing:
[0, 0.16);

Target toxicity:
[0.16, 0.33);

Excessive toxicity:
[0.33, 1].
In addition to accumulating safety data and observed DLTs, decisions on further patient 
enrollment and dose level selection will be guided by the EWOC criterion.35  A combination 
dose may only be used for newly enrolled patients if the risk of excessive toxicity at that 
combination dose is less than 25% (0.25).
Available PK data for approximately 6 patients treated with the doublet and triplet 
combinations will be evaluated.  If the PK profile of each drug appears to be consistent with 
the PK profile of each drug given individually, Phase 2 will be initiated without waiting for 
complete PK data.
Before expanding into Phase 2, available PK data will be reviewed and safety will be 
confirmed in at least 9 DLT-evaluable patients treated at the RP2D for each combination.  
3.1.2. Phase 2 Design 
Once the Phase 1b part is completed and the RP2Ds for the doublet and triplet combinations 
have been determined, Phase 2 will be initiated to evaluate the safety and anti-tumor activity 
of the RP2D for each drug combination.  Up to 40 patients with mPDAC will be randomized 
in a 1:1 ratio to the doublet and triplet combinations, respectively (ie, 20 patients per 
combination) to reduce potential treatment selection bias.  In the case that an RP2D is 
determined for the doublet combination using more than 1 binimetinib dosing schedule 
(ie, Schedules 7d/7d and 5d/2d), only one will be chosen to be evaluated in Phase 2 on the 
basis of all available safety, PK and anti-tumor activity data.  


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In addition to the above mPDAC tumor cohorts, 30 patients with other locally advanced or 
metastatic KRAS- or NRAS-mutant solid tumors (such as NSCLC, CRC, melanoma and 
endometrial cancer) will be enrolled in a ‘tumor agnostic’ cohort to receive the triplet 
combination as this may provide clinical benefit to a broader population of patients than 
primarily planned for this study (ie, mPDAC).  
In total, approximately 70 patients are expected to be treated in Phase 2. 
3.2. Dose-Limiting Toxicity Definition
The study drug combinations will be administered in 28 day cycles and the DLT evaluation 
period will be 28 days after treatment start (ie, Cycle 1).  The severity of AEs will be graded 
according to CTCAE v 4.03.  For the purpose of dose finding, any of the following AEs 
occurring in the first cycle of treatment which are attributable to any or all agents in the 
combination will be classified as DLTs:
3.2.1. Hematologic

Grade 4 neutropenia (absolute neutrophil count [ANC] <500/mm3 or <0.5 x 109/L) 
lasting >5 days.

Febrile neutropenia, defined as ANC <1000/mm3 with a single temperature of
>38.3C (>101F) or a sustained temperature of 38C (100.4F) for more than 
1 hour.

Neutropenic infection (ANC <1,000/mm3 or <1.0 x 109/L, and Grade >3 infection).

Grade 3 thrombocytopenia (platelet count <50,000 mm3 or <50.0 × 109/L) with 
bleeding.

Grade 4 thrombocytopenia (platelet count <25,000/mm3 or <25.0 x 109/L).

Grade 4 anemia (life-threatening consequences; urgent intervention indicated).
3.2.2. Non-Hematologic

Grade 3 toxicities of any duration except:

Grade 3 nausea, vomiting, or diarrhea and Grade 4 vomiting or diarrhea in the 
absence of maximal medical therapy that resolves in 72 hours;

Grade 3 fatigue lasting <5 days;

Grade 3 hypertension that can be controlled to Grade 2 within 14 days with or 
without ongoing medical therapy;

Grade 3 serum lipase and/or serum amylase without clinical signs or symptoms of 
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
Grade ≥3 laboratory abnormalities without a clinical correlate and that do not 
require medical intervention;

Grade ≥3 laboratory abnormalities that do not represent a clinically relevant shift 
from baseline;

Grade 3 endocrinopathies controlled with hormonal therapy.

CK elevation Grade ≥3 associated with an increase in creatinine ≥1.5 × the patient’s 
baseline creatinine. 

Grade 3 troponin increase associated with any sign of cardiac toxicity (as determined 
by a cardiac evaluation).

Potential Hy’s Law cases defined as: ALT or AST >3 x upper limit of normal (ULN) 
if normal at baseline OR >3 x ULN and doubling the baseline (if >ULN at baseline) 
associated with total bilirubin >2 x ULN and an alkaline phosphatase <2 x ULN.
3.2.3. Eye Disorders

Retinopathy or retinal detachment Grade ≥3, confirmed by ophthalmic examination.

Retinal vascular disorder including RVO, confirmed by ophthalmic examination.

Any Grade ≥3 uveitis, blurred vision, flashing lights, or floaters.

Any other eye disorder Grade ≥3 for >21 consecutive days.

Any other eye disorder Grade 4 confirmed by ophthalmic examination.
3.2.4. Cardiac Disorders

Absolute decrease of left ventricular ejection fraction (LVEF) >10% compared to 
baseline and the LVEF is below the institution’s lower limit of normal (LLN).

Symptomatic left ventricular systolic dysfunction Grade ≥3.

Other cardiac disorders Grade ≥3.
3.2.5. Respiratory Disorders

Interstitial lung disease/pneumonitis Grade ≥2.

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3.2.6. Skin and Subcutaneous Tissue Disorders

Rash, hand foot skin reaction (HFSR), or photosensitivity CTCAE Grade 3 for 
>14 consecutive days despite maximal skin toxicity treatment (as per local practice).

Rash, HFSR, or photosensitivity CTCAE Grade 4.
3.2.7. Non-Adherence to Treatment Schedule

Failure to deliver at least 75% of the planned doses of any study drug during the first 
cycle of treatment due to treatment-related toxicities.
3.2.8. Dose Reductions

Any AE that results in a dose reduction of talazoparib or binimetinib during the first 
cycle of treatment as per Section 5.5.7.2 and Section 5.5.7.3.
While the rules for adjudicating DLTs in the context of Phase 1b are specified above, an AE 
not listed above, or an AE meeting the DLT criteria above but occurring outside of the DLT 
observation period may be defined as a DLT following assessment, based on the emerging 
safety profile for the combinations.
3.3. Maximum Tolerated Dose Definition
A dose level combination is a potential candidate for being the maximum tolerated dose 
(MTD) level when all the following criteria are met:

≥6 patients have been treated at that dose; 

Probability of target dosing >50%; and

Probability of overdosing <25%.
3.4. Maximum Administered Dose Definition
The maximum administered dose (MAD) is the highest dose level of the combination 
administered.  In this clinical study, the MAD for the doublet combination will not exceed 
binimetinib 45 mg orally twice daily and talazoparib 1mg orally once daily.  The MAD for 
the triplet will not exceed avelumab 800 mg IV Q2W in combination with binimetinib 45 mg 
orally twice daily (Schedule 7d/7d) and talazoparib 1 mg orally once daily.
3.5. RP2D Definition
The RP2D is the dose level of the combination that will be chosen for further clinical 
development and for evaluation in Phase 2.
A RP2D below the MTD may be determined based on other safety, clinical activity, PK and 
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4. PATIENT ELIGIBILITY CRITERIA
This study can fulfill its objectives only if appropriate patients are enrolled.  The following 
eligibility criteria are designed to select patients for whom participation in the study is 
considered appropriate.  All relevant medical and non-medical conditions should be taken 
into consideration when deciding whether a particular patient is suitable for this protocol. 
For the purposes of determining patient eligibility, the date of treatment assignment will be 
considered the “date of enrollment” (see Section 5.1).
4.1. Inclusion Criteria
Patients must meet all of the following inclusion criteria to be eligible for enrollment in the 
study: 
1. Prior to Independent Ethics Committee/Institutional Review Board (IEC/IRB) approval 
of Amendment 3: Histological diagnosis of locally advanced (primary or recurrent) or 
metastatic solid tumors that are not amenable for treatment with curative intent as 
follows:
a.
Stage IIIb/IV NSCLC with documented positive KRAS or NRAS mutation status as 
determined using a validated test performed in a College of American Pathologists 
(CAP)/Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory 
(or other comparable local or regional certification); or
b. Metastatic pancreatic ductal adenocarcinoma; or
c.
Phase 2 only: other advanced solid tumors with documented positive KRAS or NRAS 
mutation as determined using a validated test performed in a CAP/CLIA-certified 
laboratory (or other comparable local or regional certification). 
Post IEC/IRB approval of Amendment 3: Histological diagnosis of locally advanced 
(primary or recurrent) or metastatic solid tumors that are not amenable for treatment with 
curative intent as follows:
a.
Metastatic pancreatic ductal adenocarcinoma; or
b. Phase 2 only: Stage IIIb/IV NSCLC or other advanced solid tumors with documented 
positive KRAS or NRAS mutation as determined using a validated test performed in 
a CAP/CLIA-certified laboratory (or other comparable local or regional certification). 
2. Have had disease progression during or following at least 1 and not more than 2 prior 
lines of treatment for advanced or metastatic disease.
3. Patients with NSCLC must have previously received treatment with an anti-PD-1 or 
anti-PD-L1 agent for advanced disease.


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4. Measurable disease as per RECIST v1.1 criteria (Appendix 3) with at least 1 target 
lesion.
5. Provision of a Baseline Tumor sample:
Mandatory primary or metastatic tumor biopsy to be performed within 28 days 
(45 days for patients requiring prospective biomarker testing for eligibility 
evaluation) prior to study enrollment to allow formalin-fixed paraffin-embedded 
(FFPE) tissue to be submitted for protocol-required testing.  Core needle or excisional 
biopsies are required, as fine needle aspirations will not yield enough tissue for 
protocol-specified testing.  Bone lesion biopsies are not acceptable. 
Exception: If an archival tumor tissue sample is available from a biopsy/surgery that 
was performed within 1 year prior to study enrollment and the patient did not receive 
any subsequent systemic anti-cancer treatment, the tumor tissue may be submitted 
without repeating a tumor biopsy during the screening period.  
6. Age 18 years (except in Japan, where patients must be 20 years old).
7. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1. 
8. Adequate Bone Marrow Function (without hematopoietic growth factor or transfusion 
support within 14 days prior to study enrollment), including:
a.
ANC 1,500/mm3 or 1.5 x 109/L;
b. Platelets 100,000/mm3 or 100 x 109/L;
c.
Hemoglobin 9 g/dL (5.6 mmol/L).
9. Adequate renal function defined by an estimated creatinine clearance (CLCR) 
60 mL/min according to the Cockcroft-Gault formula or by 24 hour urine collection for 
CLCR, or according to local institutional standard method.
10. Adequate Liver Function, including:
a.
Total serum bilirubin 1.5 × ULN; 
b. AST and ALT 2.5 × ULN.
11. Adequate Cardiac Function including: 
a.
Left ventricular ejection fraction (LVEF) ≥50% or above institutional normal value as 
determined by a multigated acquisition (MUGA) scan or echocardiography; 
b. QTc ≤480 msec (mean from triplicate electrocardiograms [ECGs]).


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12. Female patients of childbearing potential must have negative serum pregnancy or urine
pregnancy test at screening.  Female patients of nonchildbearing potential must meet at 
least 1 of the following criteria:

Achieved postmenopausal status, defined as follows: cessation of regular menses for 
at least 12 consecutive months with no alternative pathological or physiological cause 
and have a serum follicle-stimulating hormone (FSH) level confirming the 
postmenopausal state;

Have undergone a documented hysterectomy and/or bilateral oophorectomy; 

Have medically confirmed ovarian failure. 

All other female patients (including female patients with tubal ligations) are 
considered to be of childbearing potential. 
13. Evidence of a personally signed and dated informed consent document indicating that the 
patient has been informed of all pertinent aspects of the study.
14. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and 
other procedures. 
4.2. Exclusion Criteria
Patients with any of the following characteristics/conditions will not be included in the study:
1. Prior treatment with avelumab, a PARP inhibitor or MEK inhibitor.  
2. Prior systemic anti-cancer therapy within 2 weeks prior to study enrollment.  
3. Persisting toxicity related to prior therapy NCI CTCAE v4.0 Grade >1; however, 
alopecia, sensory neuropathy Grade 2, or other Grade 2 adverse events not constituting 
a safety risk based on the investigator’s judgment are acceptable.
4. Prior radiation therapy within 2 weeks prior to enrollment.  Exception: Prior palliative 
radiotherapy is permitted, provided it has been completed at least 2 days prior to study 
enrollment and no clinically significant toxicities are expected (eg, mucositis, 
esophagitis).
5. Major surgery within 4 weeks prior to study enrollment.
6. Current use of immunosuppressive medication at the time of study enrollment, EXCEPT 
for the following permitted steroids (see Section 5.8.3):
a.
Intranasal, inhaled, topical steroids, eye drops or local steroid injection 
(eg, intra-articular injection);


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b. Systemic corticosteroids at physiologic doses 10 mg/day of prednisone or 
equivalent;
c.
Steroids as premedication for hypersensitivity reactions (eg, computed tomography 
(CT) scan premedication).
7. Known prior severe hypersensitivity to investigational products or any component in 
their formulations, including known severe hypersensitivity reactions to monoclonal 
antibodies (NCI CTCAE v4.03 Grade 3).
8. Known history of immune-mediated colitis, inflammatory bowel disease, pneumonitis, 
pulmonary fibrosis, uveitis or iritis.
9. Active or prior autoimmune disease that might deteriorate when receiving an 
immunostimulatory agent.  Patients with diabetes type I, vitiligo, psoriasis, or hypo- or 
hyperthyroid disease not requiring immunosuppressive treatment are eligible.
10. Prior organ transplantation including allogenic stem-cell transplantation.
11. Vaccination within 4 weeks of study enrollment and while on trials is prohibited except 
for administration of inactivated vaccines.
12. Diagnosis of Myelodysplastic Syndrome (MDS).
13. Known symptomatic brain metastases requiring steroids.  Patients with previously 
diagnosed brain metastases are eligible if they have completed their treatment and have 
recovered from the acute effects of radiation therapy or surgery prior to study enrollment, 
have discontinued corticosteroid treatment for these metastases for at least 4 weeks and 
are neurologically stable.
14. Participation in other studies involving investigational drug(s) within 4 weeks prior to 
study enrollment.
15. Known history of testing positive for human immunodeficiency virus (HIV) or known 
acquired immune deficiency syndrome (AIDS). 
16. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV 
surface antigen or HCV RNA if anti-HCV antibody screening test positive).
17. Active infection requiring systemic therapy.
18. Clinically significant (ie, active) cardiovascular disease: myocardial infarction 
(<6 months prior to enrollment), unstable angina, congestive heart failure (New York 
Heart Association Classification Class II) or a serious cardiac arrhythmia requiring 
medication.


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19. History of thromboembolic or cerebrovascular events ≤6 months prior to study 
enrollment, including transient ischemic attacks, cerebrovascular accidents, deep vein 
thrombosis or pulmonary emboli.
20. Prior to IEC/IRB approval of Amendment 3: Current or anticipated use of a P-gp 
inhibitor (amiodarone, carvedilol, clarithromycin, cobicistat, darunavir, dronedarone, 
erythromycin, indinavir , itraconazole, ketoconazole, lapatinib, lopinavir, propafenone, 
quinidine, ranolazine, ritonavir, saquinavir, telaprevir, tipranavir, valspodar, and 
verapamil), P-gp inducer (avasimibe, carbamazepine, phenytoin, rifampin, and St. John’s 
wort), or inhibitor of breast cancer resistance protein (BCRP) (curcumin, cyclosporine, 
elacridar [GF120918], and eltrombopag).  
Post IEC/IRB approval of Amendment 3: Current or anticipated use of strong P-gp 
inhibitor(s) and/or inducer(s) within 7 days prior to randomization.  For a list of strong 
P-gp inhibitors/inducers, refer to Section 5.8.6.
21. Inability to swallow or administer whole capsules or tablets, known intolerance to 
talazoparib or binimetinib or its excipients, known malabsorption syndrome, or other 
condition that may impair absorption of talazoparib or binimetinib.
22. Prior to IEC/IRB approval of Amendment 3: Uncontrolled hypertension defined as 
persistent systolic blood pressure ≥150 mmHg or diastolic blood pressure ≥100 mmHg 
despite current therapy.  
Post IEC/IRB approval of Amendment 3: uncontrolled hypertension defined as persistent 
systolic blood pressure ≥150 mmHg or diastolic blood pressure ≥100 mmHg despite 
current therapy.  Patients requiring anti-hypertensive therapy must be on a stable regimen 
for ≥2 weeks prior to commencing study treatment.   
23. Concurrent neuromuscular disorder that is associated with the potential of elevated CK 
(eg, inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal 
muscular atrophy).
24. Known history of Gilbert’s syndrome. 
25. History or current evidence of retinal degenerative disease, RVO or current risk factors 
for RVO (eg, uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or 
hypercoagulability syndromes). 
26. Bisphosphonate or denosumab dosage that was not stable (ie, not the same) for at least 
2 weeks before study enrollment for patients receiving these therapies.


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27. Other acute or chronic medical or psychiatric condition including recent (within the past 
year) or active suicidal ideation or behavior or laboratory abnormality that may increase 
the risk associated with study participation or investigational product administration or 
may interfere with the interpretation of study results and, in the judgment of the 
Investigator, would make the patient inappropriate for entry into this study.
28. Diagnosis of any other malignancy within 2 years prior to study enrollment, except for 
adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the breast, 
bladder or of the cervix, and low-grade (Gleason 6 or below) prostate cancer on 
surveillance with no plans for treatment intervention (eg, surgery, radiation, or castration) 
or prostate cancer that has been adequately treated with prostatectomy or radiotherapy 
and currently with no evidence of disease or symptoms is allowed.
29. Pregnant female patients; breastfeeding female patients; female patients of childbearing 
potential who are unwilling or unable to use a method of highly effective  contraception 
as outlined in this protocol during treatment and for at least 30 days after the last dose of 
avelumab or binimetinib and 7 months after the last dose of talazoparib; fertile male 
patients with female partners of reproductive potential or pregnant partners, unwilling to 
use a condom (even after vasectomy) during treatment and for at least 30 days after the 
last dose of binimetinib and 4 months after the last dose of talazoparib.
30. Investigator site staff members directly involved in the conduct of the study and their 
family members, site staff members otherwise supervised by the investigator, or patients 
who are Pfizer employees, including their family members, directly involved in the 
conduct of the study.
4.3. Lifestyle Guidelines
In this study, all patients will receive avelumab for which the teratogenic risk is currently 
unknown, in combination with binimetinib, which has been associated with teratogenic risk, 
with or without talazoparib, which has been associated with genotoxic and teratogenic risk.  
All female patients of childbearing potential who are, in the opinion of the Investigator, 
sexually active and at risk for pregnancy must agree to use highly effective contraception, 
preferably with low user dependency, during treatment and for at least 30 days after the last 
dose of avelumab or binimetinib and at least 7 months after the last dose of talazoparib.  
Fertile male patients with female partners of reproductive potential or pregnant partners, 
must agree to use a condom (even after vasectomy) during treatment and for at least 30 days 
after the last dose of binimetinib and for 4 months after the last dose of talazoparib.  Female 
partners of reproductive potential should use an additional highly effective contraceptive 
method for at least 4 months after the patient’s last dose of talazoparib.
The Investigator or his or her designee, in consultation with the patient, will confirm that the 
patient has selected an appropriate method of contraception for the individual patient from 
the list of permitted contraception methods (see below) and will confirm that the patient has 
been instructed in their consistent and correct use.  At time points indicated in the SOA, the 


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Investigator or designee will inform the patient of the need to use highly effective 
contraception consistently and correctly and document the conversation, and the patient’s 
affirmation, in the patient’s chart (patients need to affirm their consistent and correct use of at 
least 1 of the selected methods of contraception).  In addition, the Investigator or designee 
will instruct the patient to call immediately if the selected contraception method is 
discontinued or if pregnancy is known or suspected in the patient or partner. 
Contraception methods
Highly Effective Methods That Have Low User Dependency include:
Implantable progestogen only hormone contraception associated with inhibition of 
ovulation.
Intra-uterine device (IUD).
Intra-uterine hormone-releasing system (IUS).
Bilateral tubal occlusion.
Vasectomized partner.

Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the woman of child-bearing potential 
(WOCBP) and the absence of sperm has been confirmed.  If not, an additional 
highly effective method of contraception should be used.  
Highly Effective Methods That Are User Dependent Include:
Combined (estrogen- and progestogen-containing) hormonal contraception associated
with inhibition of ovulation:

Oral;

Intravaginal;

Transdermal;

Injectable.
Progestogen-only hormone contraception associated with inhibition of ovulation:

Oral;

Injectable.


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Sexual abstinence.  Sexual abstinence is considered a highly effective method only if 
defined as refraining from heterosexual intercourse during the entire period of risk 
associated with the trial intervention.  The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the trial and the preferred and usual lifestyle of 
the participant.
4.4. Sponsor’s Qualified Medical Personnel
The contact information for the Sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the Study Manual.
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, patients are provided with a contact card.  The contact card contains, 
at a minimum, protocol and investigational product identifiers, patient study numbers, 
contact information for the investigator site, and contact details for a contact center in the 
event that the investigator site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
patient’s participation in the study.  The contact number can also be used by investigator staff 
if they are seeking advice on medical questions or problems; however, it should be used only 
in the event that the established communication pathways between the investigator site and 
the study team are not available.  It is therefore intended to augment, but not replace, the 
established communication pathways between the investigator site and the study team for 
advice on medical questions or problems that may arise during the study.  The contact 
number is not intended for use by the patient directly, and if a patient calls that number, he or 
she will be directed back to the investigator site.
5. STUDY TREATMENTS
For the purposes of this study, and per International Council for Harmonisation (ICH) 
guidelines, investigational product is defined as a pharmaceutical form of an active 
ingredient or placebo being tested or used as a reference/comparator in a clinical trial, 
including a product with a marketing authorization when used or assembled (formulated or 
packaged) in a way different from the approved form, or when used for an unapproved 
indication, or when used to gain further information about an approved use (ICH E6 1.33).
For this study, the investigational products are avelumab, binimetinib and talazoparib.
5.1. Allocation to Treatment
Eligible patients will be centrally assigned to a treatment cohort after providing a written 
informed consent and completing the screening procedures.  For the purposes of determining 
patient eligibility, the date of treatment assignment will be considered the “date of 
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For the doublet combination (avelumab and binimetinib) in Phase 1b, mPDAC patients were 
treated with avelumab 800 mg Q2W and binimetinib 45 mg or 30 mg twice daily 
(continuous).  Patients enrolled in Phase 1b prior to the implementation of Amendment 3 will 
continue to receive the originally assigned study treatment, with subsequent dose adjustments 
made as allowed for study drug-related toxicity.
Per Amendment #3, the doublet combination of binimetinib and talazoparib will first be 
evaluated in Phase 1b with a starting dose level (BT0) of binimetinib 45 mg twice daily, 
Schedule 7d/7d, and talazoparib 0.75 mg once daily.  
Once the RP2D is established for the doublet combination (binimetinib and talazoparib), 
patients will be enrolled into the triplet Phase 1b to receive avelumab 800 mg Q2W, 
binimetinib (Schedule 7d/7d) and talazoparib at a starting dose level guided by the BLRM.  
In the case that a more intensive dosing schedule of binimetinib (ie, Schedule 5d/2d) is 
studied for the doublet of binimetinib and talazoparib, enrollment into this doublet and the 
triplet will occur in parallel by alternating enrollment of a complete cohort of patients to the 
doublet or triplet (ie, only a single dose level cohort will be open to enrollment at any given 
time). 
In the Phase 2 part, patients will be treated at the RP2Ds determined during Phase 1b.  If 
RP2Ds are established for both the doublet and triplet combinations, mPDAC patients will be 
randomized in a 1:1 ratio to either the doublet or triplet combination.  The ‘tumor agnostic’ 
KRAS- or NRAS- mutant solid tumor cohort will be enrolled into the triplet combination 
only. 
Assignment of patient number, patient enrollment (for Phase 1b patients and Phase 2 ‘tumor 
agnostic’ patients), and allocation of study treatment by dose level (Phase 1b) and 
randomization (for mPDAC patients) into cohorts at the RP2D (Phase 2) will be managed by 
an Interactive Response Technology (IRT) system.  At the time that a patient has signed 
informed consent and entered screening, the site should contact the IRT system to obtain the 
patient identification number.  Once a patient has met all eligibility criteria, the site then 
contacts the IRT system to enroll the patient and to obtain the study treatment allocation 
information (including randomization where applicable).  Study treatment should be initiated 
no later than 3 days after enrollment.
At the time of enrollment (for Phase 1b patients and Phase 2 ‘tumor agnostic’ cohort 
patients) or randomization (for Phase 2 mPDAC patients), site personnel (study coordinator 
or specified designee) will be required to enter into or select information from the IRT
system including but not limited to the user’s identification (ID) and password, the protocol 
number, the patient number, and the date of birth of the patient (in accordance with local data 
protection regulations and practices).  The IRT system will then provide a treatment 
assignment and dispensable unit (DU) or vial number.  The IRT system will also provide a 
confirmation report containing the patient number and DU or vial number assigned.  The 
confirmation report must be stored in the site’s files. 


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There is a 24-hour-a-day, 365-days-a-year IRT helpdesk available for any questions or 
issues.  The study-specific IRT reference manual will provide the contact information and 
further details on the use of the IRT system.
5.2. Treatment Duration
Patients will continue to receive study treatment until objective disease progression assessed 
by Investigator (see Section 5.5.8 for guidance on treatment beyond progression), patient 
refusal, unacceptable toxicity, or until the study is terminated by the Sponsor, or other 
withdrawal criteria are met (see Section 6.3).  
If the study was to be prematurely terminated, when patients may still derive benefit from the 
treatment under study, a roll over study or early access program will allow the patient to 
continue receiving study drug treatment until disease progression, or unacceptable toxicity or 
up to 2 years, whichever occurs first.
5.3. Patient Compliance
The information related to each trial drug administration, including the date, time, and dose 
of study drug, will be recorded in the case report form (CRF).  The Investigator will make 
sure that the information entered into the CRF regarding drug administration is accurate for 
each patient.  Any reason for noncompliance should be documented.
5.3.1. Avelumab Patient Compliance
All doses of avelumab will be administered at the investigational site by well-trained medical 
staff.  The start and stop times of the avelumab infusion, along with the total volume 
administered, will be recorded in the patients’ medical records.  Additionally, the start and 
stop times of any interruptions to infusions and/or changes in rate of avelumab infusion will 
also need to be recorded in the patients’ medical records.  The vials of avelumab that are 
assigned and prepared for patients will be recorded in the pharmacy records.  These records 
will all be available for Sponsor representatives to verify compliance. 
The site will complete the required dosage Preparation Record located in the Investigational 
Product manual (IP manual) for avelumab.  The use of the Preparation Record is preferred, 
but it does not preclude the use of an existing appropriate clinical site documentation system.  
The existing clinical site's documentation system should capture all pertinent/required 
information on the preparation and administration of the avelumab dose, including date of 
infusion, total dose administered, start and stop times of the infusion, and any reasons that a 
dose other than the protocol-specified dose or dosing schedule was administered.  This may 
be used in place of the Preparation Record after approval from the Sponsor and/or designee. 
Noncompliance is defined as a patient missing >1 infusion of avelumab for non-medical 
reasons.  If 1 infusion is missed and the interval between the subsequent infusion and the last 
administered treatment is longer than 4 weeks for non-medical reasons, then the patient 
would also be considered noncompliant.


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5.3.2. Binimetinib and Talazoparib Patient Compliance
Patients will be required to return all unused binimetinib tablets and talazoparib capsules (if 
applicable) every cycle.  The number of tablets or capsules returned by the patient will be 
counted, documented, and recorded by site personnel in the patient’s medical record and 
reconciled with the patient’s dosing diary to support the binimetinib/talazoparib 
accountability process.  Study site personnel must make reasonable efforts to obtain study 
drug packaging and any unused tablets or capsules from patients who do not routinely return 
them at study site visits. 
Additionally, a patient dosing diary will be provided to the patients to aid in patient 
compliance with the dosing instructions.  The diary will be maintained by the patient to 
include missed or changed binimetinib/talazoparib doses.  The time of each 
binimetinib/talazoparib dose administration and the total dose of binimetinib/talazoparib
taken each day will be recorded in the dosing diary.  Patients will be required to return the 
completed patient dosing diary on Day 1 and 15 of every cycle for timely review by site 
personnel and discussion of missed doses and/or compliance issues to ensure accurate data 
entry for the Dosing CRF.  On days when the patient’s binimetinib/talazoparib dose is given 
at the clinic due to scheduled PK sample collection, the time of binimetinib/talazoparib dose 
administration and the total dose of binimetinib/talazoparib taken will be recorded in the 
patient’s dosing records that are included in the medical chart.
Treatment compliance (reported as a percent) will be defined as the number of tablets or 
capsules taken during the study divided by the expected number of tablets or capsules, for 
binimetinib and talazoparib respectively multiplied by 100%.
5.4. Investigational Product Supplies 
Avelumab, binimetinib and talazoparib will be supplied for the study by Pfizer Global 
Clinical Supply, Worldwide Research and Development.  Drug supplies will be shipped to 
the study sites with a Drug Shipment and Proof of Receipt form.  This form will be 
completed, filed, and the shipment confirmed as directed on the bottom of the Drug Shipment 
and Proof of Receipt form.  The Investigator shall take responsibility for and shall take all 
steps to maintain appropriate records and ensure appropriate supply, storage, handling, 
distribution, and usage of investigational products in accordance with the protocol and any 
applicable laws and regulations.
5.4.1. Dosage Forms and Packaging
Packaging and labeling for all study drugs will be in accordance with applicable local 
regulatory requirements and applicable Good Manufacturing Practice (GMP) guidelines.  
The information on each study drug will be in accordance with approved submission 
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5.4.1.1. Avelumab
Avelumab is a sterile, clear, and colorless solution intended for IV administration.  It is 
presented at a concentration of 20 mg/mL in 10-mL glass vials closed with a rubber stopper 
and sealed with an aluminum polypropylene flip-off seal.  Each vial is intended for single use 
only. 
Avelumab will be packed in boxes each containing 1 vial. 
Avelumab will be shipped under refrigerated conditions (2C to 8C) that are monitored with 
temperature control monitoring devices.
5.4.1.2. Binimetinib
Binimetinib will be provided as 15 mg film-coated tablets for oral administration, packaged 
in induction sealed, high-density polyethylene bottles with child-resistant caps.  Each bottle 
will contain 60 tablets and will be appropriately labeled according to local regulatory 
requirements.
5.4.1.3. Talazoparib
Talazoparib will be provided as capsules for oral administration.  The 0.25 mg (opaque 
white, size 4) and 1.0 mg (opaque pale-pink, size 4) capsules will be supplied in separate 
bottles and labeled according to local regulatory requirements.  Talazoparib is packaged in 
induction sealed, high-density polyethylene bottles with child-resistant caps with 30 capsules 
of a single strength per bottle.
5.4.2. Preparation and Dispensing
Investigational products must not be used for any purpose other than the trial.  The 
administration of study treatment to patients who have not been enrolled into the trial is not 
covered by the trial insurance.
5.4.2.1. Avelumab
For administration in this trial, 4 vials of avelumab drug product must be diluted with 
0.9% saline solution (sodium chloride injection) to a volume of 250 mL.  See the IP manual 
for instructions on how to prepare avelumab for administration.  Investigational products 
should be prepared and dispensed by an appropriately qualified and experienced member of 
the study staff (eg, physician, nurse, physician’s assistant, nurse practitioner, or pharmacist) 
as allowed by local, state, and institutional guidance.
Detailed information on infusion bags and medical devices to be used for the preparation of 
the dilutions and subsequent administration will be provided in the IP Manual.
Any spills that occur should be cleaned up using the facility’s standard cleanup procedures 
for biologic products.
Any unused portion of the avelumab solution should be discarded in biohazard waste 
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5.4.2.2. Binimetinib
Binimetinib should be dispensed on the Day 1 Visit of every cycle.  A qualified staff member 
will dispense the investigational product in the bottles provided, in quantities of 60 tablets 
per bottle.  The patient/caregiver should be instructed to maintain the product in the bottle 
provided throughout the course of dosing, keep the investigational product away from 
children, and return the bottle to the site on the Day 1 Visit of every cycle.
Only qualified personnel who are familiar with procedures that minimize undue exposure to 
themselves and to the environment should undertake the dispensing, handling, and safe 
disposal of binimetinib.  Patients should be advised that oral anti-cancer agents are toxic 
substances and that other caregivers should always use gloves when handling the capsules.
5.4.2.3. Talazoparib
Talazoparib should be dispensed on the Day 1 Visit of every cycle.  A qualified staff member 
will dispense the investigational product in the bottles provided, in quantities of 30 capsules 
per bottle.  The patient/caregiver should be instructed to maintain the product in the bottle 
provided throughout the course of dosing, keep the investigational product away from 
children, and return the bottle to the site on the Day 1 Visit of every cycle.
Only qualified personnel who are familiar with procedures that minimize undue exposure to 
themselves and to the environment should undertake the dispensing, handling, and safe 
disposal of talazoparib.  Talazoparib is considered a cytotoxic and clastogenic agent; 
precautions regarding appropriate secure storage and handling must be used by healthcare 
professionals, including personal protective clothing, disposable gloves, and equipment.24  
Patients should be advised that oral anti-cancer agents are toxic substances and that other 
caregivers should always use gloves when handling the capsules.
5.5. Administration
5.5.1. Combination Therapy Administration
5.5.1.1. Avelumab and Binimetinib (doublet)
Binimetinib will be self-administered by the patient at home as per Section 5.5.2.  On the 
days when avelumab is administered, patients must be instructed not to administer the 
morning binimetinib dose at home, but to take their medication to the clinic on these days 
for administration after necessary procedures are completed.
On Days 1 and 15 of each cycle, when both avelumab and binimetinib are administered at the 
clinic, the following must occur in the order specified:
All required tests and assessments will be performed, as per the SOA and pre-dose 
blood will be drawn for PK and ADA assessments (when scheduled);
Binimetinib will be administered to the patient 30-60 minutes prior to the avelumab 
infusion by the qualified site personnel;


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Avelumab premedication will be administered, as described below in Section 5.5.4; 
Avelumab infusion will start after the avelumab premedications have been 
administered and after dosing with binimetinib; and
Blood will be drawn for PK assessments (when scheduled) prior to the avelumab 
infusion and immediately after the end of the avelumab infusion.
The exact dose administration date/time for both drugs should be documented in the patient’s 
notes and CRF.
5.5.1.2. Binimetinib and Talazoparib (doublet)
Binimetinib and talazoparib will be self-administered by the patient at home as per 
Section 5.5.2 and 5.5.3.  On the days when study drug dosing is required at the clinic per the 
SOA, patients must be instructed not to administer the morning binimetinib and the 
talazoparib dose at home, but to take their medication to the clinic on these days for 
administration after necessary procedures are completed.
On the applicable days, when both binimetinib and talazoparib are administered at the clinic, 
the following must occur in the order specified:
All required tests and assessments will be performed, as per the SOA and pre-dose 
blood will be drawn for PK assessments (when scheduled);
Binimetinib and talazoparib will be administered to the patient by the qualified site 
personnel;
Blood will be drawn for PK assessments (when scheduled). 
The exact dose administration date/time for both drugs should be documented in the 
patient’s notes and CRF.
5.5.1.3. Avelumab, Binimetinib & Talazoparib (Triplet)
Binimetinib and talazoparib will be self-administered by the patient at home as per 
Section 5.5.2 and 5.5.3.  On the days when  study drug dosing is required at the clinic per the 
SOA, patients must be instructed not to administer the morning binimetinib dose and the 
talazoparib dose at home, but to take their medication to the clinic on these days for 
administration after necessary procedures are completed.
On Days 1 and 15 of each cycle, when avelumab, binimetinib and talazoparib are 
administered at the clinic, the following must occur:
All required tests and assessments will be performed, as per the SOA and pre-dose 
blood will be drawn for PK and ADA assessments (when scheduled);


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Talazoparib and binimetinib will be co-administered to the patient prior to the 
avelumab infusion by the qualified site personnel.  Of note, on Cycle 1 Day 1, 
talazoparib and binimetinib should be administered 30-60 minutes prior to the start of 
the avelumab infusion;
Avelumab premedications will be administered as described in Section 5.5.4; 
Avelumab infusion will start after avelumab premedications have been administered 
and after dosing with binimetinib and talazoparib; and
Blood will be drawn for PK assessments (when scheduled) immediately after the end 
of the avelumab infusion.
The exact dose administration date/time for all three drugs should be documented in the 
patient's notes and CRF.
5.5.2. Binimetinib Administration
Binimetinib will be taken twice daily at the defined dose (either 30 mg or 45 mg) starting on 
Cycle 1 Day 1 (C1D1) in accordance with the assigned treatment schedule (eg, Schedule 
7d/7d) and treatment should continue until the ‘End of Treatment’ (EOT) visit.  On Days 1 
and 15 of each cycle, when the patient returns to the clinic for safety assessments and 
avelumab administration (if applicable), and on Cycle 1 Day 8 for Phase 1b patients, the 
patients must be reminded to take the medication to the clinic with them.  The first daily dose 
of binimetinib should NOT be taken prior to the study visit and will be taken at the clinic, 
after all procedures/assessments have been completed and before the avelumab infusion 
(if applicable).  In addition to the dosing schedule outlined, at the Cycle 1 Day 8 visit for 
Phase 1b patients, a single morning dose will be administered at the clinic and subsequent 
blood samples will be collected for PK.  
Patients should self-administer binimetinib orally twice daily in accordance with the assigned 
treatment schedule, with or without food.  The first dose should be taken in the morning, with 
the second dose 12±2 hours later.  The tablets should be swallowed whole with a glass of 
water without chewing or dissolving them prior to swallowing. 
Patients should be instructed to take each dose of binimetinib in the morning and evening at 
approximately the same time each day and to not take more than the prescribed dose at any 
time.
The oral dose of talazoparib (if applicable) should be taken at the same time as the 
binimetinib morning dose.
If a patient misses a dose or vomits any time after taking a dose, he/she must be advised that 
study drug should not be re-administered (patient should not “make it up”) but to resume 
subsequent doses either in the evening if a morning dose is affected, or, on the next morning 
as prescribed, if an evening dose is affected. 


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Patients should complete the Dosing Diary after taking each dose.  If the patient misses a day 
of treatment, a dose, or takes a dose different than was prescribed, the reason for the missed 
dose or different dose must be recorded in the Dosing Diary.  The Dosing Diary should be 
returned to the site at every visit.
5.5.3. Talazoparib Administration
Talazoparib will be taken once daily at the defined dose level (either 0.5 mg, 0.75 mg, or 
1 mg) starting on Cycle 1 Day 1 (C1D1) and treatment should continue until the EOT visit.  
On Days 1 and 15 of each cycle, when the patient returns to the clinic for safety assessments 
and avelumab administration (if applicable), and also on Cycle 1 Day 8 for Phase 1b patients, 
patients must be reminded to take the medication to the clinic with them.  The daily dose of 
talazoparib should NOT be taken prior to the study visit and will be taken at the clinic, after 
all procedures/assessments have been completed and before the avelumab infusion (if 
applicable).  
Patients should self-administer talazoparib orally once daily, in the morning, with or without 
food.  The capsules should be swallowed whole with a glass of water without chewing, 
dissolving, or opening them prior to swallowing. 
Patients should be instructed to take talazoparib at approximately the same time each 
morning along with the first dose of binimetinib (if applicable according to the dosing 
schedule) and to not take more than the prescribed dose at any time.
If a patient misses a day of treatment or vomits any time after taking a dose, he/she must be 
advised that study drug should not be re-administered (patient should not “make it up”) but to 
resume subsequent doses the next day as prescribed. 
Patients should complete the Dosing Diary after taking each dose.  If the patient misses a day 
of treatment or takes a dose different than was prescribed, the reason for the missed dose or 
different dose must be recorded in the Dosing Diary.  The Dosing Diary should be returned 
to the site at every visit.
5.5.4. Avelumab Premedication
In order to mitigate IRRs, premedication with an antihistamine and with paracetamol 
(acetaminophen) prior to the first 4 infusions of avelumab is mandatory.  Premedication 
should be administered for subsequent avelumab doses based on clinical judgment and 
presence/severity of prior infusion reactions.  The premedication regimen may be modified 
based on local treatment standards and guidelines, as appropriate.  Prophylactic 
corticosteroids are not permitted.
When avelumab and binimetinib (and talazoparib where applicable) are administered on the 
same day, premedications may be given either prior to, at the same time as, or after 
binimetinib (and talazoparib where applicable).  However, the avelumab infusion will start 
after the avelumab premedication is administered and after binimetinib and talazoparib 
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5.5.5. Avelumab Administration
Avelumab will be administered at 800 mg as a 1-hour IV infusion (-10/+20 minutes) starting 
after the binimetinib and talazoparib (where applicable) is administered, as per Section 5.5.4, 
at the investigational site on an outpatient basis on Day 1 and Day 15 of each 28-day cycle.  
The schedule for avelumab should be maintained: if avelumab cannot be given during the 
allowed visit window for any reason, the infusion should be skipped, and all other 
assessments should be completed for that visit as usual.  Investigational sites should make 
every effort to target the timing of the avelumab infusion to be as close to 1 hour as possible.  
The exact duration of infusion should be recorded in both the source documents and the 
CRFs.  Additionally, the start and stop times of any interruptions to infusion and/or changes 
in rate of avelumab infusion will also need to be recorded in source documents. 
After Cycle 1 Day 1, avelumab may be administered up to 2 days before or after the 
scheduled treatment day of each cycle for administrative reasons.
5.5.5.1. Special Precautions for Avelumab Administration
As with all mAb therapies, there is a risk of allergic reactions, including anaphylactic shock.  
Avelumab should be administered in a setting that allows for immediate access to an 
intensive care unit or equivalent environment and administration of therapy for anaphylaxis, 
such as the ability to implement immediate resuscitation measures.  Steroids (dexamethasone
10 mg), epinephrine (1:1,000 dilution), allergy medications (IV antihistamines), 
bronchodilators, or equivalents, and oxygen should be available for immediate access.  If a 
hypersensitivity reaction occurs, the patient must be treated according to the best available 
medical practice.  In order to mitigate avelumab IRRs, patients have to be premedicated, 
according to guidance in Section 5.5.4. 
Following the infusions of avelumab, patients must be observed for at least 30 minutes 
post-infusion for potential infusion-related reactions. 
Symptoms of avelumab infusion-related reactions include, but are not limited to, fever, chills, 
flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain, and urticaria.  
Management of avelumab IRRs is described in Table 13.  Patients should be instructed to 
immediately report to the Investigator any delayed reactions that may occur after they leave 
the clinic.
5.5.6. Food Requirements
The investigational products may be administered without regard to food.


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5.5.7. Recommended Dose Modifications
Every effort should be made to administer each investigational product at the planned dose 
and schedule. 
In the event of study treatment toxicity, dosing may be interrupted, delayed and/or reduced, 
only as described for each investigational product.  In the event of multiple toxicities, 
treatment/dose modifications should be based on the worst toxicity observed (CTCAE v4.03) 
and/or the most conservative recommendation for any given toxicity.  Patients are to be 
instructed to notify Investigators at the first occurrence of any adverse symptom.
Treatment/dose modifications may occur independently for each investigational product in 
the combination based on the observed toxicity and the general guidance, as follows: 

Avelumab: No dose reductions are permitted, but the next infusion may be omitted 
based on persisting toxicity.

Talazoparib: Dose modifications (dose interruptions or dose reductions) may be 
implemented to manage toxicities.

Binimetinib: Dose modifications (dose interruptions or dose reductions) may be 
implemented to manage toxicities.
See Section 5.5.7.3 for details regarding the specific protocol-permitted modifications for 
each investigational product.
All dose modifications must be clearly documented in the patient's medical chart and in the 
CRF.  Appropriate follow-up assessments should be done until adequate recovery occurs as 
assessed by the Investigator. 
In addition to dose modifications, Investigators are encouraged to employ best supportive 
care according to local institutional clinical practices.
5.5.7.1. Dosing Interruptions 
Guidelines for study treatment modifications for patients experiencing adverse events are 
provided in Section 5.5.7.3.
Dose interruptions for study treatment-related AEs are allowed as per the recommendations 
provided in Section 5.5.7.3.  Doses of any investigational product that were not administered 
due to toxicity will not be replaced within the same cycle.  In addition to dose interruption, 
the need for a dose reduction for binimetinib or talazoparib at the time of treatment 
resumption should also be considered based on recommendations provided in 
Section 5.5.7.3. 
In the event of a treatment interruption for reasons other than treatment-related toxicity 
(eg, elective surgery) for >7 consecutive days, treatment resumption will be decided in 
consultation with the Sponsor.  


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Dose interruptions due to treatment-related adverse events of more than 28 days for 
talazoparib or 21 days for binimetinib are not allowed and will result in permanent 
discontinuation unless resuming treatment is judged by the Investigator and the Sponsor to be 
in the best interest of the patient.
5.5.7.2. Dose Reductions - Binimetinib and Talazoparib
Following dosing interruption due to toxicity, the binimetinib or talazoparib dose may need 
to be resumed at a reduced dose as per the recommendations provided in Section 5.5.7.3.
Available dose levels for binimetinib are 45 and 30 mg twice daily per the assigned dosing 
schedule.
Available dose levels for talazoparib are 1, 0.75 and 0.5 mg once daily.  Dose reduction of 
talazoparib by 1 dose level at a time will be allowed depending on the starting dose. If a
talazoparib dose reduction is required, the patient may need to return to the clinic to receive a 
new drug supply since dosage strengths of the capsules may be different.  
Once the dose of binimetinib or talazoparib has been reduced for a given patient, all 
subsequent cycles should be administered at that dose level.  Intra-patient dose re-escalation 
is not allowed.
Site personnel must ensure the patient is instructed how to take the reduced dose and that the 
patient has the correct dosage strength for the reduced dose.  
5.5.7.3. Toxicity Related Treatment Modifications
Recommended dose modifications are presented in this section as follows:

Section A: Treatment Modifications for Talazoparib-Related Toxicity;

Section B: Treatment Modifications for Binimetinib-Related Toxicity;

Section C: Treatment Modifications for Avelumab-Related Toxicity.
The instructions should be followed in the table(s) regarding the investigational product(s) 
that toxicity is attributed to.  Patients who interrupt or permanently discontinue any of the 
investigational products due to toxicity may continue treatment with the investigational 
product(s) not considered to be responsible for the toxicity observed.  For patients receiving 
avelumab, any AE suspected to be immune-related should be managed according to the 
guidance for irAEs management (Table 12: Immune-Related Adverse Events Toxicity 
Management).  In addition, for suspected immune-related toxicities due to avelumab that 
require withholding avelumab or discontinuation (except for endocrinopathies), talazoparib 
and binimetinib should also be placed on hold until the toxicity is Grade ≤1 or baseline.  For 
toxicities attributed to talazoparib and/or binimetinib that require dosing interruption, 
avelumab may also be withheld until the toxicity is Grade ≤1 or baseline.


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5.5.7.4. Section A: Study Treatment Modifications for Talazoparib Drug-Related 
Toxicity
General treatment modifications in case of talazoparib related toxicity are shown in Table 10.
Table 10.
Treatment Modifications for Talazoparib Drug-Related Toxicity
Drug-related Adverse 
Reactions
Withhold Talazoparib 
until levels resolve to
Dose modification
Hemoglobin <8 g/dL
≥9 g/dL
Resume talazoparib at 1 reduced 
dose level
Platelet count <50,000/μL
≥75,000/μL
Neutrophil count 
<1,000/μL
≥1500/µL
Non-hematologic Grade 3 
or Grade 4
≤Grade 1
Consider resuming talazoparib at a 
reduced dose or discontinue


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5.5.7.5. Section B: Treatment Modifications for Binimetinib-Related Adverse Events
For cutaneous reactions, interstitial lung disease, cardiac events, rhabdomyolysis/CPK elevation, and liver toxicity that could represent 
an immune-related toxicity, the guidance for irAE management should also be followed for avelumab (Table 14: Management of 
Immune-Related Adverse Events).  If avelumab should be placed on hold or discontinued for a suspected irAE, binimetinib and 
talazoparib should also be placed on hold until the toxicity resolves to Grade ≤1 or baseline.  Treatment modifications for binimetinib 
related toxicity are shown below in Table 11.
Table 11.
Treatment Modifications for Binimetinib Drug-Related Toxicity
Dermatologic
Grade 2

If no improvement within 2 weeks, withhold until Grade ≤1. 

Resume at same dose if first occurrence or reduce dose if recurrent. 
Grade 3

Interrupt dosing of binimetinib until resolved to Grade ≤1.  

Then resume at current dose level for 1st occurrence or at reduced dose if recurrent.
Grade 4

Permanently discontinue binimetinib.
Ocular Events: Serous Retinopathy
Symptomatic serous 
retinopathy/Retinal
pigment epithelial 
detachments

Withhold binimetinib for up to 10 days.

If improves and becomes asymptomatic, resume treatment at current dose level.

If not improved, resume treatment at 1 reduced dose level or permanently discontinue binimetinib.


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Ocular Events: Uveitis
Grade 1-3
If Grade 1 or 2 does not respond to specific ocular therapy, or for Grade 3 uveitis, withhold binimetinib for up to 6 weeks.

If improved, resume at same or reduced dose.

If not improved, permanently discontinue binimetinib.
Grade 4
Permanently discontinue binimetinib.
Ocular Events: Retinal Vein Occlusion
Any Grade
Permanently discontinue binimetinib.
Other Eye Disorders: (ie, Non-retinal, Non-Uveitis Events)
Grade 1-2
Maintain dose level of binimetinib and increase frequency of ophthalmic monitoring to at least every 2 weeks until stabilization or 
resolution.
Grade 3
Interrupt dosing of binimetinib and refer patient to ophthalmologist within 1 week: 

If resolved to Grade ≤1 in ≤3 weeks, resume treatment at 1 reduced dose level. 

If not resolved to Grade ≤1 in ≤3 weeks, permanently discontinue and ensure close follow-up with ophthalmic monitoring until 
stabilization or resolution.
Grade 4
Permanently discontinue binimetinib and ensure immediate follow-up with ophthalmic monitoring until stabilization or resolution.
Cardiac Events: Cardiomyopathy
Asymptomatic, absolute 
decrease in LVEF of 
greater than 10% from 
Withhold binimetinib for up to 4 weeks and evaluate LVEF every 2 weeks. 


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baseline that is also 
below the lower limit of 
normal (LLN)
Resume treatment at 1 reduced dose level if the following are present:

LVEF is at or above the LLN; and 

Absolute decrease from baseline in 10% or less; and 

Patient is asymptomatic. 

If the LVEF does not recover within ≤4 weeks permanently discontinue binimetinib.
Grade 3-4 
(Symptomatic 
congestive heart failure
or absolute decrease in 
LVEF of > 20% from 
baseline that is also 
below LLN)
Permanently discontinue binimetinib.  Closely monitor LVEF until resolution or up to 16 weeks.  
Venous Thromboembolism
Uncomplicated Deep 
Venous Thrombosis or 
Pulmonary Embolism
Withhold binimetinib. 

If improves to Grade ≤1, resume at a reduced dose.

If no improvement, permanently discontinue binimetinib.
Life threatening 
Pulmonary Embolism 
Permanently discontinue binimetinib.
Interstitial Lung Disease
Grade 2
Withhold binimetinib for up to 4 weeks.  

If improved to Grade ≤1, resume treatment at 1 reduced level. 

If not resolved within 4 weeks, permanently discontinue binimetinib.
Grade 3-4

Permanently discontinue binimetinib.


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Hepatotoxicity
Grade 2
AST or ALT increased

Maintain dose level of binimetinib.

If no improvement within 2 weeks, withhold binimetinib until improved to Grade ≤1 or to pretreatment/baseline levels, then resume 
at the same dose.
Grade 3 or 4
AST or ALT increased 

See Other Adverse Reactions.
Rhabdomyolysis or Creatine Phosphokinase (CPK) elevations 
Grade 4 asymptomatic 
CPK elevation or any 
Grade CPK elevation 
with symptoms or with 
renal impairment
Interrupt dosing of binimetinib for up to 4 weeks. 

If resolved to Grade ≤1, resume treatment at 1 reduced dose level. 

If not resolved in ≤4 weeks, permanently discontinue binimetinib. 
Nausea/Vomiting
Grade 1-2
Maintain dose level of binimetinib. Promptly institute antiemetic measures.
Grade 3
Interrupt dosing of binimetinib until resolved to Grade ≤1. 

Then resume treatment at 1 reduced dose level of binimetinib. 

Resume treatment with binimetinib at the current dose if, in the judgment of the Investigator, the toxicity is considered to be 
unrelated to binimetinib, or at 1 reduced dose level.
Note: Interrupt dosing of binimetinib for Grade ≥3 vomiting or Grade 3 nausea only if the vomiting or nausea cannot be controlled with 
optimal antiemetics (as per local practice).


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Grade 4

Permanently discontinue binimetinib.
All Other Adverse Events (Including Hemorrhage)
Recurrent Grade 2 or 
first occurrence of any 
Grade 3
Withhold binimetinib for up to 4 weeks.

If improves to Grade ≤1 or to pretreatment/baseline levels, resume at 1 reduced dose level.

If no improvement, permanently discontinue binimetinib.
First occurrence of any 
Grade 4
Permanently discontinue or interrupt dosing for up to 4 weeks. 

If resolved to Grade ≤1 or baseline then  resume at 1 reduced dose level.

If no improvement, permanently discontinue binimetinib.
Recurrent Grade 3

Consider permanently discontinuing binimetinib.
Recurrent Grade 4

Permanently discontinue binimetinib.
Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; CPK= Creatine Phosphokinase; LLN=lower limit of normal; LVEF=Left Ventricular Ejection 
Fraction


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5.5.7.6. Section C: Treatment Modifications for Avelumab-Related Toxicity
Recommended treatment modifications for avelumab-related toxicity are shown in Table 12.
Recommended treatment modifications in case of avelumab IRRs are shown in Table 13. 
For patients receiving avelumab, any AE suspected to be immune-related (ie, an irAE) 
should be managed according to the guidance for management of irAEs (see Table 14).
Table 12.
Treatment Modification for Avelumab Drug-Related Toxicity
NCI CTCAE 
Severity Grade
Avelumab Treatment Modification
Drug-related adverse reactions
(excluding infusion-related 
reaction/hypersensitivity and 
immune-related AE)
Grade 1
Continue as per schedule.
Grade 2
Continue as per schedule.
Grade 3
Withhold until recovery to Grade 1 or baseline.
Permanently discontinue if toxicities do not 
resolve to Grade 1 or baseline within 12 weeks of 
last administration or if the same Grade 3 toxicity 
recurs. 
Exceptions are:
Laboratory abnormalities that do not have any 
clinical correlate.
Grade 4
Permanently discontinue 
Exceptions are:
Laboratory abnormalities that do not have any 
clinical correlate.  


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Table 13.
Treatment Modification for Symptoms of IRRs Associated with Avelumab
NCI CTCAE Severity Grade
Treatment Modification
Grade 1 – mild
Mild transient reaction; infusion interruption not 
indicated; intervention not indicated.
Decrease the avelumab infusion rate by 50% and 
monitor closely for any worsening.
Grade 2 – moderate
Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment (for 
example, antihistamines, NSAIDs, narcotics, IV 
fluids; prophylactic medications indicated for 
24 hours.
Temporarily discontinue avelumab infusion.
Resume avelumab infusion at 50% of previous rate once 
infusion-related reaction has resolved or decreased to at 
least Grade 1 in severity, and monitor closely for any 
worsening. 
Grade 3 or Grade 4 – severe or life-threatening
Grade 3: Prolonged (for example, not rapidly 
responsive to symptomatic medication and/or brief 
interruption of infusion); recurrence of symptoms 
following initial improvement; hospitalization 
indicated for clinical sequelae.
Grade 4: Life-threatening consequences; urgent 
intervention indicated.
Stop the avelumab infusion immediately and disconnect 
infusion tubing from the patient.
Patients have to be withdrawn immediately from 
avelumab treatment and must not receive any further 
avelumab treatment.
If avelumab infusion rate has been decreased by 50% due to an infusion reaction, it must remain decreased for 
the next scheduled infusion.  If no infusion reaction is observed at the next scheduled infusion, the infusion 
rate may be returned to baseline at subsequent infusions.
Abbreviations: NCI-CTCAE=National Cancer Institute-Common Terminology Criteria for Adverse Event; 
NSAIDs=nonsteroidal anti-inflammatory drugs; IV=intravenous.
If, in the event of a Grade 2 infusion-related reaction that does not improve or worsens after 
implementation of the modifications indicated above (including reducing the infusion rate by 
50%), the Investigator may consider treatment with corticosteroids, and the infusion should 
not be resumed.  At the next dose, the Investigator may consider the addition of H2 blocker 
antihistamines (eg, famotidine or ranitidine), meperidine, or ibuprofen to the mandatory 
premedication.  Prophylactic corticosteroids are not permitted.


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Table 14.
Management of Immune-Related Adverse Events
Gastrointestinal irAEs
Severity of Diarrhea/Colitis
(NCI-CTCAE v4)
Initial Management
Follow-up Management
Grade 1
Diarrhea: <4 stools/day over 
Baseline.
Colitis: asymptomatic 
Continue avelumab therapy.
Symptomatic treatment (eg,
loperamide).
Close monitoring for worsening 
symptoms.
Educate patient to report worsening 
immediately.
If worsens:
Treat as Grade 2, 3 or 4. 
Grade 2 
Diarrhea: 4 to 6 stools per day over 
Baseline; IV fluids indicated 
<24 hours; not interfering with ADL
Colitis: abdominal pain; blood in 
stool. 
Withhold avelumab therapy.
Symptomatic treatment.
If improves to Grade ≤1: 
Resume avelumab therapy.
If  persists >5-7 days or recurs:
Treat as Grade 3 or 4.
Grade 3 to 4
Diarrhea (Grade 3): ≥7 stools per 
day over Baseline; incontinence; IV 
fluids ≥24 h; interfering with ADL
Colitis (Grade 3): severe abdominal 
pain, medical intervention indicated, 
peritoneal signs.
Grade 4: life-threatening, 
perforation.
Withhold avelumab for 
Grade 3.
Permanently discontinue 
avelumab for Grade 4 or 
recurrent Grade 3.
1.0 to 2.0 mg/kg/day 
prednisone IV or equivalent.
Add prophylactic antibiotics 
for opportunistic infections.  
Consider lower endoscopy.
If improves: 
Continue steroids until Grade ≤1, then 
taper over at least 1 month; resume 
avelumab therapy following steroids 
taper (for initial Grade 3). 
If worsens, persists >3 to 5 days, or 
recurs after improvement:
Add infliximab 5mg/kg (if no 
contraindication).  Note: infliximab 
should not be used in cases of 
perforation or sepsis. 
Dermatological irAEs
Grade of Rash
(NCI-CTCAE v4)
Initial Management
Follow-up Management
Grade 1 to 2
Covering ≤30% body surface area.
Continue avelumab therapy 
Symptomatic therapy (for 
example, antihistamines, 
topical steroids).
If Grade 2 persists >1 to 2 weeks or 
recurs:
Withhold avelumab therapy.
Consider skin biopsy.
Consider 0.5-1.0 mg/kg/day prednisone 
or equivalent.  Once improving, taper 
steroids over at least 1 month, consider 
prophylactic antibiotics for 
opportunistic infections, and resume 


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Table 14.
Management of Immune-Related Adverse Events
avelumab therapy following steroids 
taper.
If worsens:
Treat as Grade 3 to 4.
Grade 3 to 4
Grade 3: Covering >30% body 
surface area; 
Grade 4: Life threatening 
consequences.
Withhold avelumab for 
Grade 3.
Permanently discontinue for 
Grade 4 or recurrent Grade 3. 
Consider skin biopsy. 
Dermatology consult. 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent.
Add prophylactic antibiotics 
for opportunistic infections. 
If improves to Grade ≤1: 
Taper steroids over at least 1 month; 
resume avelumab therapy following 
steroids taper (for initial Grade 3).
Pulmonary irAEs
Grade of Pneumonitis
(NCI-CTCAE v4)
Initial Management
Follow-up Management
Grade 1
Radiographic changes only. 
Consider withholding 
avelumab therapy. 
Monitor for symptoms every 
2 to 3 days. 
Consider Pulmonary and 
Infectious Disease consults. 
Re-assess at least every 3 weeks.
If worsens: 
Treat as Grade 2 or Grade 3 to 4. 
Grade 2
Mild to moderate new symptoms. 
Withhold avelumab therapy.
Pulmonary and Infectious 
Disease consults.
Monitor symptoms daily; 
consider hospitalization. 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent.
Add prophylactic antibiotics 
for opportunistic infections. 
Consider bronchoscopy, lung
biopsy. 
Re-assess every 1 to 3 days 
If improves: 
When symptoms return to Grade ≤1, 
taper steroids over at least 1 month, and 
then resume avelumab  therapy 
following steroids taper.
If not improving after 2 weeks or 
worsening: 
Treat as Grade 3 to 4. 
Grade 3 to 4
Grade 3: Severe new symptoms; 
New/worsening hypoxia;
Grade 4: Life-threatening.
Permanently discontinue 
avelumab therapy.
Hospitalize.
Pulmonary and Infectious 
Disease consults.
1.0 to 2.0 mg/kg/day  
prednisone or equivalent.
If improves to Grade ≤1: 
Taper steroids over at least 1 month.
If not improving after 48 hours or 
worsening: 
Add additional immunosuppression (for 
example, infliximab, 
cyclophosphamide, IV 


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Table 14.
Management of Immune-Related Adverse Events
Add prophylactic antibiotics 
for opportunistic infections. 
Consider bronchoscopy, lung 
biopsy.
immunoglobulin, or mycophenolate 
mofetil).
Hepatic irAEs
Grade of Liver Test Elevation
(NCI-CTCAE v4)
Initial Management
Follow-up Management
Grade 1
Grade 1 AST or ALT >ULN to 
3.0 x ULN and/or Total bilirubin 
>ULN to 1.5 x ULN. 
Continue avelumab therapy.
Continue liver function monitoring.
If worsens: 
Treat as Grade 2 or 3 to 4. 
Grade 2
AST or ALT >3.0 to ≤5 x ULN 
and/or total bilirubin >1.5 to ≤3 x 
ULN. 
Withhold avelumab therapy.
Increase frequency of 
monitoring to every 3 days.
If returns to Grade ≤1:
Resume routine monitoring; resume 
avelumab therapy.
If elevation persists >5 to 7 days or 
worsens: 
Treat as Grade 3 to 4.
Grade 3 to 4
AST or ALT >5 x ULN and/or total 
bilirubin >3 x ULN. 
Permanently discontinue 
avelumab therapy.  
Increase frequency of 
monitoring to every 1 to 
2 days. 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent.
Add prophylactic antibiotics 
for opportunistic infections.  
Consult gastroenterologist/ 
hepatologist.
Consider obtaining MRI/CT 
scan of liver and liver biopsy 
if clinically warranted. 
If returns to Grade ≤1: 
Taper steroids over at least 1 month. 
If does not improve in >3 to 5 days, 
worsens or rebounds: 
Add mycophenolate mofetil 1 gram (g) 
twice daily. 
If no response within an additional 3 to 
5 days, consider other 
immunosuppressants per local 
guidelines.
Renal irAEs
Grade of Creatinine Increased 
(NCI-CTCAE v4)
Initial Management
Follow-up Management
Grade 1
Creatinine increased >ULN to 1.5 
x ULN.
Continue avelumab therapy.
Continue renal function monitoring.
If worsens:
Treat as Grade 2 to 3 or 4.
Grade 2 to 3
Withhold avelumab therapy.
If returns to  Grade ≤1:


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Table 14.
Management of Immune-Related Adverse Events
Creatinine increased >1.5 and ≤6 x 
ULN.
Increase frequency of 
monitoring to every 3 days.
1.0 to 2.0 mg/kg/day 
prednisone or equivalent.
Add prophylactic antibiotics 
for opportunistic infections.
Consider renal biopsy.
Taper steroids over at least 1 month, 
and resume avelumab therapy following 
steroids taper.
If worsens:
Treat as Grade 4.
Grade 4
Creatinine increased >6 x ULN.
Permanently discontinue 
avelumab therapy.
Monitor creatinine daily.
1.0 to 2.0 mg/kg/day 
prednisone or equivalent.
Add prophylactic antibiotics 
for opportunistic infections.
Consider renal biopsy.
Nephrology consult.
If returns to Grade ≤1:
Taper steroids over at least 1 month.
Cardiac irAEs
Myocarditis
Initial Management
Follow-up Management
New onset of cardiac signs or 
symptoms and / or new laboratory 
cardiac biomarker elevations (eg, 
troponin, CK-MB, BNP) or cardiac 
imaging abnormalities suggestive of 
myocarditis. 
Withhold avelumab therapy.
Hospitalize.
In the presence of life 
threatening cardiac 
decompensation, consider 
transfer to a facility 
experienced in advanced 
heart failure and arrhythmia 
management.
Cardiology consult to 
establish etiology and 
rule-out immune-mediated 
myocarditis. 
Guideline based supportive 
treatment as per cardiology 
consult.*
Consider myocardial biopsy 
if recommended per 
cardiology consult.
If symptoms improve and 
immune-mediated etiology is ruled out, 
re-start avelumab therapy.
If symptoms do not improve/worsen, 
viral myocarditis is excluded, and 
immune-mediated etiology is suspected 
or confirmed following cardiology 
consult, manage as immune-mediated 
myocarditis.
Immune-mediated myocarditis.
Permanently discontinue 
avelumab.
Once improving, taper steroids over at 
least 1 month.


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Table 14.
Management of Immune-Related Adverse Events
Guideline based supportive 
treatment as appropriate as 
per cardiology consult.*
1.0 to 2.0 mg/kg/day 
prednisone or equivalent.
Add prophylactic antibiotics 
for opportunistic infections.
If no improvement or worsening, 
consider additional 
immunosuppressants (eg, azathioprine, 
cyclosporine A).
*Local guidelines, or eg ESC or AHA guidelines 
ESC guidelines website:  https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines
AHA guidelines website: 
http://professional.heart.org/professional/GuidelinesStatements/searchresults.jsp?q=&y=&t=1001
Endocrine irAEs
Endocrine Disorder
Initial Management
Follow-up Management
Grade 1 or Grade 2 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I diabetes 
mellitus).
Continue avelumab therapy.
Endocrinology consult if 
needed.
Start thyroid hormone 
replacement therapy (for 
hypothyroidism), anti-thyroid 
treatment (for 
hyperthyroidism), 
corticosteroids (for adrenal 
insufficiency) or insulin (for 
Type I diabetes mellitus) as 
appropriate.  
Rule-out secondary 
endocrinopathies (ie 
hypopituitarism/
hypophysitis).
Continue hormone 
replacement/suppression and 
monitoring of endocrine function as 
appropriate.
Grade 3 or Grade 4 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I diabetes 
mellitus).
Withhold avelumab therapy.
Consider hospitalization.
Endocrinology consult.
Start thyroid hormone 
replacement therapy (for 
hypothyroidism), anti-thyroid 
treatment (for 
hyperthyroidism), 
corticosteroids (for adrenal 
insufficiency) or insulin (for 
type I diabetes mellitus) as 
appropriate.  
Rule-out secondary 
endocrinopathies (ie,
Resume avelumab once symptoms 
and/or laboratory tests improve to 
Grade ≤1 (with or without hormone 
replacement/suppression).
Continue hormone 
replacement/suppression and 
monitoring of endocrine function as 
appropriate. 


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Table 14.
Management of Immune-Related Adverse Events
hypopituitarism/ 
hypophysitis).
Hypopituitarism/Hypophysitis 
(secondary endocrinopathies).
If secondary thyroid and/or 
adrenal insufficiency is 
confirmed (ie subnormal 
serum FT4 with 
inappropriately low TSH 
and/or low serum cortisol 
with inappropriately low 
ACTH):

Refer to endocrinologist 
for dynamic testing as 
indicated and 
measurement of other 
hormones (FSH, LH, 
GH/IGF-1, PRL, 
testosterone in men, 
estrogens in women).

Hormone 
replacement/suppressive 
therapy as appropriate.

Perform pituitary MRI 
and visual field 
examination as 
indicated.
If hypophysitis confirmed:

Continue avelumab if 
mild symptoms with 
normal MRI.  Repeat the 
MRI in 1 month.

Withhold avelumab if 
moderate, severe or 
life-threatening 
symptoms of 
hypophysitis and/or 
abnormal MRI.  
Consider hospitalization. 
Initiate corticosteroids 
(1 to 2 mg/kg/day 
prednisone or 
equivalent) followed by 
corticosteroids taper 
during at least 1 month.

Add prophylactic 
antibiotics for 
opportunistic infections.
Resume avelumab once symptoms and 
hormone tests improve to Grade ≤1 
(with or without hormone replacement).
In addition, for hypophysitis with 
abnormal MRI, resume avelumab only 
once shrinkage of the pituitary gland on 
MRI/CT scan is documented. 
Continue hormone 
replacement/suppression therapy as 
appropriate.


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Table 14.
Management of Immune-Related Adverse Events
Other irAEs (not described above)
Grade of other irAEs (NCI-
CTCAE v4)
Initial Management
Follow-up Management
Grade 2 or Grade 3 clinical signs 
or symptoms suggestive of a 
potential irAE.
Withhold avelumab therapy 
pending clinical 
investigation.
If irAE is ruled out, manage as 
appropriate according to the diagnosis 
and consider re-starting avelumab 
therapy.
If irAE is confirmed, treat as Grade 2 or 
3 irAE.
Grade 2 irAE or first occurrence 
of Grade 3 irAE.
Withhold avelumab therapy.
1.0 to 2.0 mg/kg/day 
prednisone or equivalent.
Add prophylactic antibiotics 
for opportunistic infections. 
Specialty consult as 
appropriate.
If improves to Grade ≤1: 
Taper steroids over at least 1 month and 
resume avelumab therapy following 
steroids taper.
Recurrence of same Grade 3 
irAEs.
Permanently discontinue 
avelumab therapy.
to 2.0 mg/kg/day.
prednisone or equivalent.
Add prophylactic antibiotics 
for opportunistic infections.
Specialty consult as 
appropriate.
If improves to Grade ≤1: 
Taper steroids over at least 1 month.
Grade 4.
Permanently discontinue 
avelumab therapy.
to 2.0 mg/kg/day.
prednisone or equivalent 
and/or other 
immunosuppressant as 
needed.
Add prophylactic antibiotics 
for opportunistic infections. 
Specialty consult.
If improves to Grade ≤1: 
Taper steroids over at least 1 month.


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Table 14.
Management of Immune-Related Adverse Events
Requirement for 10 mg per day or 
greater prednisone or equivalent 
for more than 12 weeks for 
reasons other than hormonal 
replacement for adrenal 
insufficiency.
Persistent Grade 2 or 3 irAE lasting 
12 weeks or longer.
Permanently discontinue 
avelumab therapy.
Specialty consult.
Abbreviations: ACTH=adrenocorticotropic hormone; ADL=activities of daily living; ALT=alanine 
aminotransferase; AST=aspartate aminotransferase; BNP=B-type natriuretic peptide; CK-MB=creatine kinase 
MB;  CT= computed tomography; FSH=follicle-stimulating hormone; GH=growth hormone; IGF-1=insulin-
like growth factor 1; irAE=immune-related adverse event; IV=intravenous; LH=luteinizing hormone; 
MRI=magnetic resonance imaging; NCI-CTCAE=National Cancer Institute-Common Terminology Criteria 
for Adverse Events; PRL=prolactin;T4=thyroxine; TSH=thyroid-stimulating hormone; ULN=upper limit of 
normal.
5.5.8. Treatment After Initial Evidence of Radiological Disease Progression
Immunotherapeutic agents such as avelumab, may produce antitumor effects by potentiating 
cancer-specific immune responses.  Following immunotherapy, a clinical response may occur 
later than would typically be expected following treatment with a cytotoxic agent.  In 
addition, this response may occur after an initial increase in tumor burden or even after the 
appearance of new lesions. 
If radiologic imaging shows disease progression, after discussion between the Sponsor and 
Investigator, patients may continue to receive investigational products at the investigators 
discretion if the following criteria are met: 

No decline in ECOG performance status; 

Absence of clinical signs and symptoms (including worsening of laboratory values) 
of disease progression; 

Absence of rapid progression of disease by radiographic imaging; 

Absence of progressive tumor at critical anatomical sites (eg, cord compression) 
requiring urgent alternative medical intervention.
Before continuation of treatment after initial PD, the patient must be re-consented via 
informed consent addendum and informed that, by continuing to receive investigational 
products, the patient may be foregoing approved or investigational therapies with possible 
clinical benefit(s).


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If the patient is subsequently found to have further disease progression at a subsequent tumor 
assessment, either radiologically according to RECIST v1.1 or clinically, then treatment with 
investigational products should be permanently discontinued.
5.6. Investigational Product Storage 
The Investigator, or an approved representative, eg, pharmacist, will ensure that all 
investigational products are stored in a secured area with controlled access under required 
storage conditions and in accordance with applicable regulatory requirements. 
Investigational products should be stored in their original containers and in accordance with 
the labels.  Any storage conditions stated in the SRSD, will be superseded by the storage 
conditions stated on the product labels.
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated and/or room temperature products).  This should be 
captured from the time of investigational product receipt throughout the study.  Even for 
continuous monitoring systems, a log or site procedure that ensures active evaluation for 
excursions should be available.  The intent is to ensure that the minimum and maximum 
temperature is checked each business day to confirm that no excursion occurred since the last 
evaluation and to provide the site with the capability to store or view the minimum/maximum 
temperature for all nonworking days upon return to normal operations.  The operation of the 
temperature monitoring device and storage unit (for example, refrigerator), as applicable, 
should be regularly inspected to ensure it is maintained in working order.
Any excursions from the product label storage conditions should be reported to Pfizer upon 
discovery.  The site should actively pursue options for returning the product to the storage 
conditions as described in the labeling, as soon as possible.  Deviations from the storage 
requirements, including any actions taken, must be documented and reported to Pfizer. 
Once an excursion is identified, the investigational product must be quarantined and not used 
until Pfizer provides permission to use the investigational product.  It will not be considered a 
protocol deviation if Pfizer approves the use of the investigational product after the 
temperature excursion.  Use of the investigational product prior to Pfizer approval will be 
considered a protocol deviation. 
Receipt of materials, door opening and closing, and other routine handling operations where 
the investigational products are briefly out of the temperature range described in the labeling 
are not considered excursions.
Specific details regarding information the site should report for each excursion will be 
provided to the site in the Investigational Product Manual.


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5.6.1. Avelumab Storage
Avelumab must be stored in the refrigerator at 2–8C (36–46F).  Do not freeze.  Protect 
from light.  Do not shake vigorously.  See the Investigational Product Manual for storage 
conditions of avelumab once diluted.
5.6.2. Talazoparib Storage
Talazoparib is stored at room temperature (15C–30C; 59F–86F) or per approved local 
label. 
Site staff will instruct patients on the proper storage requirements for take home 
investigational product, as talazoparib will be self-administered at home by patients.
5.6.3. Binimetinib Storage
Binimetinib – do not store above 25oC (77oF). 
Site staff will instruct patients on the proper storage requirements for take home 
investigational product, as binimetinib will be self-administered at home by patients.
5.7. Investigational Product Accountability 
The investigator site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies.  All investigational products will be 
accounted for using a drug accountability form/record. 
All unused binimetinib and talazoparib (where applicable) must be returned to the 
Investigator or designated investigative site personnel by each patient on Day 1 of every 
cycle and at the end of the trial in order to perform and document drug accountability.
5.7.1. Destruction of Investigational Product Supplies 
The Sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site).  If destruction is authorized to take place at the study site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer, and all destruction must be adequately documented.
5.8. Concomitant Medications
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the active treatment period.
If there is a clinical indication for one of these or other medications or vaccinations 
specifically prohibited during the trial, discontinuation from study therapy or 
medication/vaccination may be required.  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 therapy or medication/vaccination schedule requires 
the mutual agreement of the Investigator, the Sponsor, and the patient.


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Concomitant treatment considered necessary for the patient’s well-being may be given at the 
discretion of the treating physician.
Concomitant medications and treatments, including herbal supplements, will be recorded 
from 28 days prior to the start of study treatment(s) and up to 90 days after the last dose of 
study treatment(s).  All concomitant medications should be recorded in the CRF including 
supportive care drugs (eg, antiemetic treatment and prophylaxis), and the drugs used to treat 
adverse events or chronic diseases, as well as non-drug supportive interventions (eg, 
transfusions).
Given that recording of non-serious AEs ends when a patient begins a new anti-cancer 
therapy (Section 8.1.4.2 Recording Non-serious AEs and SAEs on the CRF), recording of 
concomitant medications associated with these non-serious AEs should also end.  However, 
given that SAEs (Section 8.1.4.2) must continue to be recorded up to 90 days after the last 
dose of study treatment(s) even if the patient begins a new anti-cancer therapy, concomitant 
medications associated with these SAEs must also be recorded.  
Concurrent anti-cancer therapy with agents other than study treatments is not allowed.  
Medications intended solely for supportive care (ie, antiemetics, analgesics, megestrol 
acetate for anorexia) are allowed.
Recommended medications to treat IRRs, hypersensitivity reactions, and immune-related 
adverse events are reported in Table 13 and Table 14, respectively.
5.8.1. Supportive Care Guidelines
Patients should receive appropriate supportive care measures as deemed necessary by the 
treating Investigator including but not limited to the items outlined below: 

Diarrhea: All patients who experience diarrhea 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.

Nausea/Vomiting: Nausea and vomiting should be treated aggressively, and 
consideration should be given in subsequent cycles to the administration of 
prophylactic antiemetic therapy according to standard institutional practice.  Patients 
should be strongly encouraged to maintain liberal oral fluid intake. 

Anti infectives: Patients with a documented infectious complication should receive 
oral or IV antibiotics or other anti-infective agents as considered appropriate by the 
treating Investigator for a given infectious condition, according to standard 
institutional practice.  Prophylactic administration should be considered for the cases 
outlined in Table 14 Management of Immune-Related Adverse Events.


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Patients who need to be on anticoagulant therapy during treatment should be treated with low 
molecular weight heparin.  If low molecular weight heparin cannot be administered, 
coumadin or other coumarin derivatives or other anti-coagulants (including direct Xa 
inhibitors) may be allowed; however, appropriate monitoring of prothrombin 
time/international normalized ratio (PT/INR) should be performed.
Primary prophylactic use of granulocyte-colony stimulating factors is not permitted during 
the DLT observation period (eg, Cycle 1).  These factors may be used at any time to treat
treatment-emergent neutropenia as indicated by the current American Society of Clinical 
Oncology (ASCO) guidelines.25
In subsequent cycles, the use of hematopoietic growth factors is at the discretion of the 
treating physician in line with local guidelines.  
Patients who enter the study on stable doses of erythropoietin or darbepoetin may continue 
this treatment, and patients may start either drug during the study at the discretion of the 
treating physician.
5.8.2. Anti-Inflammatory Therapy
Anti-inflammatory or narcotic analgesic may be offered, as needed, assuming the drug is not 
included in the Prohibited Concomitant Medications and Treatments section (Section 5.8.6). 
5.8.3. Corticosteroids
Data indicate that corticosteroids have an adverse effect on T-cell function and that they 
inhibit and damage lymphocytes.26,27  Furthermore, as for all immunotherapies intended to 
augment cell-mediated immunity, there is a risk that concomitant immunosuppressives, such 
as steroids, will counteract the intended benefit of avelumab.  However, studies with anti-
cytotoxic T-lymphocyte associated protein 4 (CTLA-4) compounds indicate that short-term 
use of steroids can be employed without compromising clinical outcomes.27  Therefore, the 
use of steroids during this trial is restricted as follows while on avelumab treatment:  

Therapeutic use: steroids are permitted for the treatment of adverse drug reactions, 
IRRs, and irAEs.

Physiologic use: replacement for adrenal insufficiency at doses equivalent to 10 mg 
prednisone daily is acceptable.

Intranasal, inhaled topical steroids, eye drops, or local steroid injection 
(eg, intra-articular injection) are permitted.  
5.8.4. Concomitant Surgery 
Caution is advised on theoretical grounds for any surgical procedures during the study.  The 
appropriate interval of time between surgery and administration of investigational products
required to minimize the risk of impaired wound healing and bleeding has not been 
determined.  Stopping investigational products temporarily is recommended in case of a 


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surgical procedure.  Postoperatively, the decision to reinitiate treatment with investigational 
products should be based on a clinical assessment of satisfactory wound healing and recovery 
from surgery.
5.8.5. Concomitant Radiotherapy
Palliative radiotherapy to specific sites of disease is permitted if considered medically 
necessary by the treating physician.  If palliative radiotherapy is needed to control bone pain, 
the sites of bone disease should be present at baseline; otherwise, bone pain requiring 
radiotherapy will be considered as a sign of disease progression.  Study treatment should be 
withheld for the entire duration of palliative radiotherapy and can be restarted upon recovery 
from any radiotherapy-related toxicities, but no sooner than 48 hours after radiotherapy 
completion.
5.8.6. Prohibited Concomitant Medications and Therapies
Patients are prohibited from receiving the following therapies during the treatment phase of 
this trial: 

Anti-cancer systemic chemotherapy or biological therapy.

Immunotherapy not specified in this protocol. 

Investigational agents other than investigational products. 

Radiation therapy (with the exception noted above in Section 5.8.5).

Any vaccine therapies for the prevention of infectious disease (eg, human papilloma 
virus vaccine), except for administration of inactivated vaccines. 

Herbal remedies with immunostimulating properties (eg, mistle toe extract) or known 
to potentially interfere with major organ function (eg, hypericin).

Bisphosphonate or denosumab treatment unless it has been initiated more than 
14 days prior to enrollment. 

Strong P-gp inhibitors that result in ≥ 2-fold increase in the exposure of an in vivo 
probe P-gp substrate according to the FDA website 
(https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/
DrugInteractionsLabeling/ucm093664.htm#table5-2) and University of Washington 
Drug-Drug Interaction database (https://www.druginteractioninfo.org/) 
(eg, amiodarone, carvedilol, clarithromycin, cobicistat, dronedarone, erythromycin, 
glecaprevir/pibrentasvir, indinavir, itraconazole, ketoconazole, lapatinib, lopinavir, 
propafenone, quinidine, ranolazine, ritonavir, saquinavir, 
sofosbuvir/velpatasvir/voxilaprevir, telaprevir, tipranavir, valspodar, and verapamil) 
are not recommended while on binimetinib/talazoparib treatment.  


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
Note: local topical treatments (eg, topical erythromycin) are permitted where 
systemic absorption is minimal.

Strong P-gp inducers (eg, avasimibe, carbamazepine, phenytoin, rifampin, and St. 
John’s wort) while on binimetinib treatment.

Participants with a condition requiring systemic treatment with either corticosteroids 
(>10 mg daily prednisone equivalent) or other immunosuppressive medications 
within 14 days of treatment assignment are excluded.  Inhaled or topical steroids, and 
adrenal replacement steroid doses ≤10 mg daily prednisone equivalent, are permitted 
in the absence of active autoimmune disease.
If there is a clinical indication for one of the medications or vaccinations specifically 
prohibited during the trial, discontinuation from study treatment may be required.  The 
Investigator should consult with the Sponsor about individual cases.
There are no prohibited therapies during the Short-Term and Long-Term Follow-up Phases.
5.8.7. Cautionary Use of Other Medication During Treatment With Binimetinib
The following inhibitors and inducers of UGT1A1 are to be used with caution while being 
treated on study with binimetinib:

UGT1A1 inhibitors: eg, Atazanavir, erlotinib, flunitrazepam, gemfibrozil, indinavir, 
ketoconazole, nilotinib, pazopanib, propofol, regorafenib, sorafenib;

UGT1A1 inducers: eg, Carbamazepine, nicotine, rifampicin, testosterone propionate.

P-gp and BCRP inhibitors/inducers: Caution and monitoring for potential increased 
adverse reactions should be used upon concomitant use of P-gp or BCRP transporter 
inhibitors with talazoparib and binimetinib including the following: atorvastatin, 
azithromycin, conivaptan, curcumin, cyclosporine, diltiazem, diosmin, eliglustat, 
elacridar [GF120918], eltrombopag, felodipine, flibanserin, fluvoxamine, piperine, 
quercetin, and schisandra chinensis extract. 

A list inhibitors/inducers can be found according to the FDA website 
(https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/
DrugInteractionsLabeling/ucm093664.htm#table5-2) and University of Washington 
Drug-Drug Interaction database (https://www.druginteractioninfo.org/).


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6. STUDY PROCEDURES 
6.1. Screening
For screening procedures see the SOA and Section 7.  All screening activities must take place 
within 28 days prior to enrollment into the study, unless otherwise noted.
Upon providing written informed consent, the site should contact the IRT system so as to 
register the patient and receive a centrally assigned study identification code.  
6.2. Treatment Period/ End of Treatment
Once screening procedures have been completed, eligible patients may then be assigned to a 
treatment cohort as described in Section 5.1 Allocation to Treatment.
For the treatment period procedures, see the SOA and Section 7.  
For the treatment period, where multiple procedures are scheduled at the same nominal time 
point(s) relative to dosing, the following prioritization of events should be adhered to, where 
possible:

Pharmacokinetic blood specimens – obtain at the scheduled time.

ECGs – obtain as close as possible to the scheduled time, but prior to 
pharmacokinetic blood specimen collection and within 30 minutes of the nominal 
time. (See Section 7.1.6).

Assessments noted in the SOA table for End of Treatment do not need to be repeated 
if completed in the prior 7 days.
6.3. Patient Withdrawal
Patients may withdraw from treatment or the study overall at any time at their own request, 
or they may be withdrawn at the discretion of the Investigator or Sponsor for safety (see also 
Section 8.1.3) or behavioral reasons, or the inability of the patient to comply with the 
protocol-required schedule of study visits or procedures at a given investigator site. 
Reasons for withdrawal of study treatment may include:

Objective disease progression.  However, patients with disease progression who are 
continuing to derive clinical benefit from the study treatment will be eligible to 
continue study treatment, provided that the treating physician has determined that the 
benefit/risk for doing so is favorable (see Section 5.5.8 for details and exceptions); 

Global deterioration of health status requiring discontinuation;

Unacceptable toxicity.  If the unacceptable toxicity is attributed to one of the two 
investigational products, the Investigator may continue treatment with the other 
investigational product;


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
Pregnancy;

Significant protocol violation;

Lost to follow-up;

Patient refused further treatment;

Study terminated by Sponsor;

Death.
Reasons for withdrawal from the study may include:

Study terminated by Sponsor;

Lost to follow-up;

Refused further follow-up;

Death.
If a patient does not return for a scheduled visit, every effort should be made to contact the 
patient.  All attempts to contact the patient and information received during contact attempts 
must be documented in the patient’s medical record.  In any circumstance, every effort 
should be made to document patient outcome, if possible.  The Investigator should inquire 
about the reason for withdrawal, request that the patient return for a final visit, if applicable, 
and follow-up with the patient regarding any unresolved AEs.
If the patient refuses further visits, the patient should continue to be followed for survival 
unless the patient withdraws consent for disclosure of future information or for further 
contact.  In this case, no further study specific evaluations should be performed, and no 
additional data should be collected.  The Sponsor may retain and continue to use any data 
collected before such withdrawal of consent.
6.4. Follow-up and Long-term Follow-up
For follow-up procedures, see the SOA and Section 7.  
In follow-up, all patients should be evaluated for safety and followed for survival through 
90 days (at 30, 60 and 90 days) after the last dose of investigational product(s) or until the 
initiation of a new anti-cancer therapy, whichever occurs first.  Follow-up beyond 30 days 
and up to and including 90 days after last dose of investigational product(s) may be 
performed either via a clinic visit or by remote contact (eg, telephone), with subsequent 
in-clinic visits requested if any concerns are noted during the telephone call.


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Following early discontinuation or completion of the initial 90 day Follow-up period, all 
patients will continue to be followed in Long-term Follow-up for survival and for subsequent 
anti-cancer treatments every 12 weeks (±14 days) until death, end of the study, or patient 
withdrawal of consent, whichever comes first.  These visits may be conducted in-clinic or by 
remote contact. 
Patients whose disease has not progressed at the time of the End of Treatment visit will 
continue to undergo disease assessments every 8 weeks for 52 weeks from the start of study 
treatment and then every 16 weeks thereafter until documented disease progression 
regardless of initiation of subsequent anti-cancer therapy.
7. ASSESSMENTS
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances, outside of the control of the Investigator that may make it unfeasible to 
perform the test.  In these cases the Investigator will take all steps necessary to ensure the 
safety and well-being of the patient.  When a protocol-required test cannot be performed, the 
Investigator will document the reason for this and any corrective and preventive actions that 
he or she has taken to ensure that normal processes are adhered to as soon as possible.  The 
study team will be informed of these incidents in a timely manner.
For samples being collected and shipped, detailed collection, processing, storage, shipment 
instructions and contact information will be provided to the investigator site prior to initiation 
of the study.
7.1. Safety Assessments
Safety assessments will include, but are not limited to, collection of AEs, SAEs, vital signs, 
physical examination, 12-lead electrocardiogram (ECG), ophthalmology examination, 
echocardiogram (ECHO)/multigated acquisition (MUGA) scan, and laboratory assessments, 
including pregnancy tests, and verification of concomitant treatments.  See the following 
sections regarding the specific safety assessments.
7.1.1. Pregnancy Testing
All pregnancy tests used in this study, either urine or serum, must have a sensitivity of at 
least 25 mIU/mL human chorionic gonadotropin (hCG) and must be performed by a certified 
laboratory.  For female patients of childbearing potential, 2 negative pregnancy tests are 
required before receiving study treatment (1 negative pregnancy test at screening and one at 
the baseline (Cycle 1 Day 1) visit immediately before study treatment administration). 
Following a negative pregnancy test result at screening, appropriate contraception must be 
commenced and the second negative pregnancy result will then be required at the baseline 
(Cycle 1 Day 1) visit before the patient may receive the study treatment.  Pregnancy tests will 
also be repeated on Day 1 of every cycle prior to dosing of either study drug during the active 
treatment period and at the End of Treatment visit- to confirm that the patient has not become 
pregnant during the study.  Pregnancy tests will also be done whenever 1 menstrual cycle is 


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missed and when potential pregnancy is otherwise suspected, and may be repeated if 
requested by institutional review boards (IRBs)/ethics committees (ECs) or if required by 
local regulations.  In the case of a positive confirmed pregnancy, the patient will be 
withdrawn from administration of investigational products but should remain in the study for 
Short-Term and Long-Term Follow-up (see Sections 8.4.3 and 8.4.3.1 for required pregnancy 
follow-up and safety reporting requirements and the SOA for Short-Term and Long-Term 
Follow-Up procedures).
7.1.2. Contraceptive Check
The Investigator or his or her designee will discuss with and confirm that any female patient 
of childbearing potential, who, in the opinion of the investigator, is sexually active and at risk 
for pregnancy is correctly and consistently using contraception (see Lifestyle Guidelines 
section).  This discussion will be documented in the patient’s chart.  These patients must 
continue to use appropriate contraception for 30 days after the last dose of avelumab or 
binimetinib and 7 months after the last talazoparib dose for female patients.  Fertile male 
patients with female partners of reproductive potential or pregnant partners, must agree to use 
a condom (even after vasectomy) during treatment and for at least 30 days after the last dose 
of binimetinib and for 4 months after the last dose of talazoparib.  In addition, the 
investigator or his or her designee will instruct the patient to call immediately if one or both 
selected contraception methods are discontinued, or if pregnancy is known or suspected in 
the patient or the patient’s partner.  See also SOA for timing of contraceptive check.
7.1.3. Adverse Events
Assessment of adverse events will include the type, incidence, severity (graded by NCI 
CTCAE v 4.03), timing, seriousness, and relatedness. 
7.1.4. Laboratory Safety Assessments
Samples for all laboratory assessments will be drawn at the time points indicated in the SOA
and when clinically indicated.  Laboratory tests may be performed up to 3 days prior to the 
scheduled clinic visit.  All safety laboratory analyses will be performed by the local 
laboratory(ies) for each study center.
Prior to study drug administration on Days 1 and 15 of each treatment cycle, hematology (ie, 
hemoglobin, platelets, and white blood cells) and chemistry (ie, ALT, AST, alkaline 
phosphatase, total bilirubin, blood urea nitrogen, creatinine, sodium, potassium, and glucose) 
tests must be performed and results reviewed by the treating physician prior to study drug 
administration.  When applicable, results from pregnancy tests must also be available for 
review prior to dosing.  
The required safety laboratory tests are listed in Table 15.


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Table 15.
Required Safety Laboratory Tests
Hematology
Chemistry
Coagulation
Urinalysis 
(Dipstick is 
acceptable)
Pregnancy Test
Hemoglobin
ALT
INR 
Urine dipstick for 
urine protein: If 
positive collect a 
microscopic 
sample (Reflex 
Testing).
For female patients 
of childbearing 
potential, serum or 
urine with a 
sensitivity of at least 
25 mIU/mL.
Platelets
AST
PTT or 
aPTT
WBC
Alkaline Phosphatase
Absolute Neutrophils
Sodium
Absolute Lymphocytes
Potassium
Magnesium
Urine dipstick for 
urine blood: If 
positive collect a 
microscopic 
sample (Reflex 
Testing).
Chloride
Total Calcium
Total Bilirubina
Thyroid Function 
Tests:
BUN or Urea
TSH, Free T4
Creatinine
Uric Acid
Glucose (fasting not 
required)
Other Tests:
Albumin
ACTH
Phosphorus or Phosphate
HBV surface antigen
Total Protein
Anti-HCV antibody
Amylase
If Anti-HCV antibody 
test positive, then HCV 
RNA
Gamma Glutamyl 
Transferase (GGT)
Creatine Kinase
C-reactive Protein (CRP)


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Table 15.
Required Safety Laboratory Tests
Lactate Dehydrogenase 
(LDH)
Lipase 
CK isozymes (CK-MM, 
CK-MB, CK-BB)b
Other Tests: 
Cardiac Troponin T and/or 
Ic
Myoglobin (blood or 
urine)
Abbreviations: ACTH=adrenocorticotropic hormone, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
BUN=blood urea nitrogen, CRP=C-reactive protein, GGT=gamma-glutamyltransferase, HBV=hepatitis B virus, 
HCV=hepatitis C virus, INR=international normalized ratio, LDH=lactate dehydrogenase, PTT=partial thromboplastin 
time, RNA=ribonucleic acid, TSH=thyroid-stimulating hormone, WBC=white blood cell.
a.
For potential Hy's Law cases, in addition to repeating AST and ALT, laboratory tests should include albumin, 
creatine kinase, total bilirubin, direct and indirect bilirubin, gamma glutamyl transferase, prothrombin time 
(PT)/INR, alkaline phosphatase, total bile acids and acetaminophen drug and/or protein adduct levels.
b.
Measurement of CK-MB is required.  Measurement of CK-MM and CK-BB should also be performed if available 
at the local laboratory.
c.
Measurement of both troponin T and I is preferred where available at the local laboratory; in case where both are 
not available, then the same subunit measured during screening should be measured consistently throughout the 
study for any given patient.
7.1.5. Physical Examinations and Vital Signs
Patients will have physical examinations to include major body systems (including skin), 
vital signs, assessment of ECOG performance status (see Appendix 2), weight and height 
(height will be measured at screening only) at the time points described in the SOA.
Vital signs, to include blood pressure, pulse rate and temperature will be also recorded at the 
time points described in the SOA.  Vital signs should be taken prior to administration of any 
investigational products at the visit.
7.1.6. (12-Lead) Electrocardiograms
Triplicate ECGs will be performed at screening and pre-dose on Day 1 of Cycle 1.  All 
patients require a single ECG measurement on Day 1 of all other Cycles prior to any study 
drug dosing, and at the EOT visit.  See the SOA for the ECG collection time points.  The 
parameters to be recorded are RR, QT, QTc, PR, and QRS.  A standard 12-lead (with a 
10-second rhythm strip) tracing will be used for all ECGs.  It is preferable that the machine 
used has a capacity to calculate the standard intervals automatically.  If, during a single 
measurement, the QTc is prolonged (>500 msec, ie, CTCAE Grade 3), then a triplicate 
ECG will be collected to confirm the original measurement.  Pre-dose ECG results should be 
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Triplicate ECGs
For triplicate measurements, 3 consecutive ECGs will be performed approximately 2 minutes 
apart to determine mean QTc interval.  
If the mean QTc is prolonged (>500 msec, ie, CTCAE Grade 3), then the ECGs should be 
re-evaluated by a qualified person at the site for confirmation as soon as the finding is made, 
including verification that the machine reading is accurate.  If manual reading verifies a QTc 
of >500 msec, immediate correction for reversible causes (including electrolyte 
abnormalities, hypoxia and concomitant medications for drugs with the potential to prolong 
the QTc interval) should be performed, as appropriate.  In addition, repeat ECGs should be 
immediately performed hourly for at least 3 hours until the QTc interval falls below 
500 msec.  If QTc interval reverts to less than 500 msec, and in the judgment of the 
Investigator(s) and Sponsor is determined to be due to cause(s) other than investigational 
products, treatment may be continued with regular ECG monitoring as clinically indicated.  
If in that timeframe the QTc intervals rise above 500 msec the investigational product will be 
held until the QTc interval decreases to 500 msec.  Patients will then restart the 
investigational product at the next lowest dose level or the dose will be withheld as 
appropriate for the specific investigational product.  If the QTc interval has still not 
decreased to <500 msec after 2 weeks, or if at any time a patient has a QTc interval 
>515 msec or becomes symptomatic, the patient will be permanently discontinued from 
study treatment.  Additional triplicate ECGs may be performed as clinically indicated. 
Each episode of prolongation of the QTc interval will be evaluated by a specialist to 
determine if it is due to the investigational product or due to other potential precipitating 
factors (eg, change in patient clinical condition, effect of concurrent medication, electrolyte 
disturbance).
If patient experiences any cardiac AE or neurologic AEs (especially syncope, dizziness, 
seizures, or stroke) an ECG in triplicate should be obtained at time of the event.
Triplicate ECG collections should be started within 30 minutes prior to the PK sampling 
time, except when coinciding with the end of avelumab infusion time, in which case ECG 
collection should be started within up to 10 minutes post infusion.  If the infusion of 
avelumab is interrupted due to a non-cardiac or neurological AE, any ECG scheduled during 
the time the AE is occurring is not required.
7.1.7. Echocardiogram/Multigated Acquisition Scan 
LVEF will be assessed by transthoracic ECHO or MUGA performed as indicated in the 
SOA.
Whichever modality was used at baseline should be used consistently throughout the study.  
The assessment may be performed up to 7 days prior to the clinic visit to enable results to be 
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7.1.8. Ophthalmic Assessments
A full ophthalmic examination will be performed at the time points described in the SOA, 
and will include best corrected visual acuity for distance testing, automated visual field 
testing, slit lamp examination, intraocular pressure and dilated fundoscopy with attention to 
retinal abnormalities, especially retinal pigment epithelial detachment (RPED), serous 
detachment of the retina and RVO (or associated symptoms).
OCT and fluorescein angiography will be performed for any non-vascular/vascular 
abnormality, respectively as indicated in the SOA.
All ophthalmology assessments may be conducted up to 7 days prior to the clinic visit to 
enable results to be available for review.
7.1.8.1. Additional Ophthalmology Assessments
Patients with clinical suspicion of retinal abnormalities (ie, RPED, serous detachment of the 
retina, RVO, photopsia, metamorphopsia, impairment of visual acuity, etc.), must complete 
at least one of the following additional assessments: 

For non-vascular abnormalities: OCT of the macula (spectral domain OCT 
recommended); 

For vascular abnormalities: fluorescein angiography of the central 30 degree. 
Images/results of the ophthalmic examinations (at a minimum, OCT and/or fluorescein 
angiography) should be sent to the study site and be maintained in the patient’s source 
document file.  These images/results may be requested to be sent to the Sponsor or designee.
7.2. Pharmacokinetic Assessments
All efforts should be made to obtain the PK samples at the scheduled nominal time relative to 
dosing.  However, the exact time of the sample collection will always be noted on the CRF.  
If a scheduled blood sample collection cannot be completed for any reason, the missed 
sample time may be re-scheduled with agreement of clinical investigators, patient and 
Sponsor.  PK sampling schedule may be modified based on emerging PK data.
PK samples will be analyzed using a validated analytical method in compliance with Pfizer 
standard operating procedures (SOPs).
Details regarding the collection, processing, storage and shipping of the PK blood samples 
will be provided to the investigator site prior to initiation of the trial.  The samples must be 
processed and shipped as indicated to maintain sample integrity.  Any deviations from the 
processing steps (eg, sample collection and processing steps, interim storage or shipping 
conditions), including any actions taken, must be documented and reported to the Sponsor.  
On a case-by-case basis, the Sponsor may make a determination as to whether sample 
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procedure that resulted in compromised sample integrity will be considered a protocol 
deviation.
 
 
7.2.1. Blood for PK Analysis of Avelumab
Blood samples (3.5 mL whole blood at each time point) will be collected for PK analysis of 
avelumab, as outlined in the SOA.  Blood for PK samples will be drawn from the 
contralateral arm of the drug infusion.  Please refer to the Laboratory Manual for instructions 
for specific details on collection tubes, processing and shipping.
7.2.2. Blood for PK Analysis of Binimetinib 
Blood samples (3 mL whole blood at each time point) will be collected for PK analysis of 
binimetinib and the metabolite AR00426032 as outlined in the SOA.  Please refer to the 
Laboratory Manual for instructions for specific details on collection tubes, processing and 
shipping.
7.2.3. Blood for PK analysis of Talazoparib 
Blood samples (3 mL whole blood at each time point) will be collected for PK analysis of 
talazoparib as outlined in the SOA.  Please refer to the Laboratory Manual for instructions for 
specific details on collection tubes, processing and shipping.
7.3. Immunogenicity Assessments
Blood samples (3.5 mL whole blood) will be collected for assessment of avelumab ADAs 
and nAb, as outlined in the SOA.  Please refer to the Laboratory Manual for instructions for 
specific details on collection tubes, processing and shipping. 
For all patients, blood for ADA samples will be drawn from the contralateral arm of the 
avelumab infusion.
Immunogenicity blood samples will be assayed for ADA using a validated assay in 
compliance with Pfizer standard operating procedures.  The sample analysis will follow a 
tiered approach of screening, confirmation, and titer determination.  
Samples tested positive for ADA will be further analyzed for nAb using a validated assay in 
compliance with Pfizer standard operating procedures.  
Additional details regarding the collection, processing, storage, and shipping of the blood 
samples will be provided in the Laboratory Manual to maintain sample integrity. 
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Any deviations from the processing steps (eg, sample collection and processing steps, interim 
storage or shipping conditions), including any actions taken, must be documented and 
reported to the Sponsor.  On a case by case basis, the Sponsor may make a determination as 
to whether sample integrity has been compromised.  Any deviation from the specified sample 
handling procedure that resulted in compromised sample integrity will be considered a 
protocol deviation.
 
7.4. Biomarker and Pharmacodynamic Assessments
A key objective of the biomarker analyses that will be performed in this study is to 
investigate candidate biomarkers in tissue and blood that may have predictive value in 
identifying those patients who are most likely to benefit from treatment with the combination 
of avelumab and binimetinib or avelumab, binimetinib and talazoparib.  In addition, analyses 
of sequentially obtained blood biomarkers will provide an opportunity to investigate 
pharmacodynamic effects.  Samples collected at the EOT visit may help provide some 
understanding on potential acquired mechanisms of resistance to the drug combination.
Information about PD-L1 expression will be collected at Screening, as part of patient’s 
cancer history, for all patients with prior available results. 
7.4.1. Tumor Biospecimens and De Novo Tumor Biopsies
Tumor tissue samples and tissue from biopsies of the primary and/or metastatic lesion(s) 
performed during the study will be used to analyze candidate DNA, RNA, or protein 
markers, or a relevant signature of markers, for their ability to identify those patients who are
most likely to benefit from treatment with the avelumab and binimetinib or avelumab, 
binimetinib and talazoparib combination. 
Candidate markers of interest include, but may not be limited to:
.
!
PD-L1 expression on tumor and infiltrating immune cells measured by 
immunohistochemistry (IHC).
!
Presence of DDR gene alterations.
!
Tumor mutational burden (TMB).
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.
7.4.1.1. Tumor Biospecimens
Tumor biospecimens to be collected for study purposes include:
!
Mandatory Screening De Novo Tumor Biopsy/Recent Tumor Tissue Sample:
A mandatory de novo (ie, fresh) tumor core needle or excisional biopsy (that can 
yield at least 20 unstained slides) from a locally recurrent or metastatic tumor site that 
is not the only RECIST v1.1 target lesion must be performed during the 28 day 
screening period to provide a FFPE tumor tissue block.  For patients with NSCLC
who require prospective testing of RAS mutation status for eligibility determination, 
the biopsy may be performed within 45 days prior to enrollment.
Exception: If an archival tumor tissue sample (that can yield at least 20 unstained 
slides) is available from a biopsy/surgery that was performed within 1 year prior to 
study enrollment and the patient did not receive any subsequent systemic anti-cancer 
treatment, this tumor tissue sample may be submitted without repeating a tumor 
biopsy during the screening period.  
!
Optional On-Treatment Tumor Sample(s):
Optional biopsies are encouraged between Cycle 2 Day 1 and Cycle 3 Day 1.  In 
addition, tumor tissue is requested for study purposes for patients who undergo tumor 
biopsy or resection as part of routine clinical care at any time during the treatment 
period.
!
End of Treatment Tumor Biopsy:
A biopsy at EOT is requested except in instances where the procedure poses 
unacceptable risks per Investigator documentation.  The EOT tumor biopsy should be 
performed before initiation of subsequent anti-cancer therapy and preferably no later 
than ±14 days after the End of Treatment visit.
For any sample of tumor tissue, one FFPE tissue block should be provided if available and 
permitted by local laws and policies.  If one or more blocks cannot be provided for these 
reasons, then sections must be freshly cut (ie, cut no more than 30 days prior to shipment to 
the central laboratory), 4-5 μm thick and mounted on positively-charged microscope slides 
(SuperFrost Plus glass slides are recommended).  A minimum of 20 slides should be 
provided per timepoint.  
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A minimum 18 gauge core needle (or per institutional practice) should be used in biopsies in 
order to maximize the quality and value of obtained tissue; a minimum of 3 separate cores is 
requested for each biopsy procedure.  Tumor tissue from cytologic sampling (eg, fine needle 
aspiration, including FFPE cell pellet material) is not adequate and should not be submitted. 
Guidance for Selection of Biopsy Site: Where possible, the biopsied lesion must be distinct 
from the target lesion(s) being followed for measurable disease.  Most importantly, the 
biopsied lesion must be one that can be accessed safely.  In cases where only a primary lesion 
is present or accessible, a biopsy should only be collected following determination that the 
procedure will not confound subsequent disease assessments.  Biopsies from bone lesions 
should not be submitted. 
See the Laboratory Manual for additional details on the handling of these samples including 
processing, storage, and shipment.
7.4.2. Peripheral Blood Samples
As described in the SOA, the following blood samples and subsequent analyses will be 
conducted: 
 
!
Blood sample (20 mL whole blood) will be collected as outlined in the SOA for 
processing to circulating tumor DNA (ctDNA) 
 
 
 
 
 
 
  
 
 
 
 
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7.6. Tumor Response Assessment
The decision for body areas to be scanned will depend on the disease under study and the 
extent of disease.  Tumor assessments must include all known or suspected disease sites.  
The minimum recommended body areas to be scanned depending upon malignancy are 
detailed in the Imaging Manual.  Antitumor activity will be assessed through radiological 
tumor assessments conducted at baseline (within 28 days prior to randomization (for 
randomized cohorts) or start of study treatment (for non-randomized cohorts)), then every 
8 weeks for 52 weeks from Cycle 1 Day 1, and then every 16 weeks thereafter until disease 
progression regardless of initiation of subsequent anti-cancer therapy, as specified in the
Schedule of Activities: Safety and Efficacy Assessments.  In addition, radiological tumor 
assessments will be conducted whenever disease progression is suspected (eg, symptomatic 
deterioration) or when clinically indicated. 
The schedule of tumor assessments should be fixed according to the calendar, starting with 
enrollment/randomization, regardless of treatment schedule or treatment interruptions due to 
toxicity. 
Imaging may include chest, abdomen and pelvis computed tomography (CT) or magnetic 
resonance imaging (MRI) scans and other anatomy such as head or neck, as clinically 
indicated or protocol required.  
Brain CT or MRI scans are required at baseline for all patients with stable brain lesions and 
for those for whom Central Nervous System (CNS) involvement is suspected.  If stable brain 
metastases are present at baseline, brain imaging should be repeated at each tumor 
assessment.  Otherwise, brain imaging will be conducted post-baseline only when clinically 
indicated.
Whole body bone imaging using bone scan (bone scintigraphy) or other methods considered 
standard of care locally such as 18-fluorodeoxyglucose positron emission tomography 
(18F-FDG-PET), 18-F-sodium fluoride-PET (18F-NaF-PET), PET/CT, or MRI is required at 
baseline. Bone lesion(s) identified at baseline by bone scintigraphy, 18F-FDG-PET, 
18F-NaF-PET, or PET/CT will be further assessed at baseline by correlative imaging, such as 
diagnostic CT or MRI and subsequently re-assessed by diagnostic CT or MRI as per the 
tumor assessment schedule (every 8 weeks during the first 52 weeks of study treatment and 
then every 16 weeks thereafter).  Only for those patients with bone lesions present at 
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baseline, whole body bone imaging should be repeated at every other tumor assessment visit 
(ie, every 16 weeks during the first 52 weeks of study treatment and every 24 weeks 
thereafter) and at the time of confirmation of CR.  For all patients, whole body bone imaging 
may be repeated during study as clinically indicated (ie, patient has new or worsening bone 
pain, increasing alkaline phosphatase level, or other signs and symptoms of new/progressing 
bone metastases).
The CT and MRI scans should be performed with contrast agents unless contraindicated for 
medical reasons.  The same imaging technique used to characterize each identified and 
reported lesion at baseline will be employed in the following tumor assessments. 
Assessment of response will be made using RECIST v1.1 (Appendix 3). Measurable or 
evaluable lesions that have been previously irradiated will not be considered target lesions 
unless progression of such lesions has been observed following completion of radiation 
therapy.
In case CR or PR is observed, tumor assessments must be confirmed on repeated imaging at 
least 4 weeks after initial documentation. 
The allowable time window for tumor assessments is 7 days.
All patients’ files and radiologic images must be available for source verification and for 
potential peer review.  All radiographic images will be collected and stored by an 
independent third-party imaging laboratory, according to instructions provided in the 
Imaging Manual.
7.7. Tumor RAS Mutation Status 
For patients enrolled in the Phase 2 ‘tumor agnostic’ cohort, documentation of a positive 
KRAS or NRAS mutation status must have been previously obtained through local 
laboratory testing.  Any Clinical Laboratory Improvement Amendments (CLIA) -approved 
test (or comparable local validation) using either tumor tissue or ctDNA may have been used 
for this analysis.
For NSCLC patients who have not previously been tested locally and/or the status is 
unknown, then the mandatory screening tumor tissue sample (Section 7.4.1.1) may be sent to 
the central laboratory to determine the mutation status.  To allow for adequate turnaround 
time (~14 days), this sample may be submitted prior to the 28 day screening period but after 
informed consent has been obtained.
Enrollment rates will be reviewed on an ongoing basis and if appropriate, KRAS/NRAS 
testing may be extended to other tumor types on a case by case basis.
All patients will have centralized testing performed to confirm the tumor KRAS/NRAS 
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8. ADVERSE EVENT REPORTING
8.1. Requirements
The table below summarizes the requirements for recording safety events on the CRF and for 
reporting safety events on the Clinical Trial (CT) Serious Adverse Event (SAE) Report Form 
to Pfizer Safety.  These requirements are delineated for 3 types of events: (1) SAEs; 
(2) non-serious adverse events (AEs); and (3) exposure to the investigational product under 
study during pregnancy or breastfeeding, and occupational exposure. 
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer Safety 
Within 24 Hours of 
Awareness
SAE
All
All
Non-serious AE
All
None
Exposure to the investigational 
product under study during
pregnancy or breastfeeding, and 
occupational exposure
All (regardless of whether 
associated with an AE), except 
occupational exposure
Exposure during pregnancy, 
exposure via breastfeeding, 
occupational exposure 
(regardless of whether 
associated with an AE)
All observed or volunteered events regardless of suspected causal relationship to the 
investigational product will be reported as described in the following paragraphs.
Events listed in the table above that require reporting to Pfizer Safety on the CT SAE Report 
Form within 24 hours of awareness of the event by the Investigator are to be reported 
regardless of whether the event is determined by the Investigator to be related to an 
investigational product under study.  In particular, if the SAE is fatal or life-threatening, 
notification to Pfizer Safety must be made immediately, irrespective of the extent of available 
event information.  This time frame also applies to additional new (follow-up) information on 
previously forwarded reports.  In the rare situation that the Investigator does not become 
immediately aware of the occurrence of an event, the Investigator must report the event 
within 24 hours after learning of it and document the time of his/her first awareness of the 
event.
For each event, the Investigator must pursue and obtain adequate information both to 
determine the outcome and to assess whether it meets the criteria for classification as an SAE 
(see the Serious Adverse Events section below).  In addition, the Investigator may be 
requested by Pfizer Safety to obtain specific follow-up information in an expedited fashion.  
This information is more detailed than that recorded on the CRF.  In general, this will include 
a description of the event in sufficient detail to allow for a complete medical assessment of 
the case and independent determination of possible causality.  Any information relevant to 
the event, such as concomitant medications and illnesses, must be provided.  In the case of a 
patient death, a summary of available autopsy findings must be submitted as soon as possible 
to Pfizer Safety.  Any pertinent additional information must be reported on the CT SAE 


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Report Form; additional source documents (eg, medical records, CRF, laboratory data) are to 
be sent to Pfizer Safety ONLY upon request.
As part of ongoing safety reviews conducted by the Sponsor, any non-serious AE that is 
determined by the Sponsor to be serious will be reported by the Sponsor as an SAE.  To 
assist in the determination of case seriousness, further information may be requested from the 
Investigator to provide clarity and understanding of the event in the context of the clinical 
study.
8.1.1. Additional Details On Recording Adverse Events on the CRF
All events detailed in the table above will be recorded on the AE page(s) of the CRF.  It 
should be noted that the CT SAE Report Form for reporting of SAE information is not the 
same as the AE page of the CRF.  When the same data are collected, the forms must be 
completed in a consistent manner.  AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE Report 
Form for reporting of SAE information.
8.1.2. Eliciting Adverse Event Information
The Investigator is to record on the CRF all directly observed AEs and all AEs spontaneously 
reported by the study patient.  In addition, each study patient will be questioned about the 
occurrence of AEs in a non-leading manner.
8.1.3. Withdrawal From the Study Due to Adverse Events (see also the Patient 
Withdrawal section)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted below, and recorded on the CRF. 
When a patient withdraws from the study because of an SAE, the SAE must be recorded on 
the CRF and reported, as appropriate, on the CT SAE Report Form, in accordance with the 
Requirements section above.
8.1.4. Time Period for Collecting AE/SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each patient begins from the time the patient provides informed consent, which 
is obtained before the patient’s participation in the study (ie, before undergoing any 
study-related procedure and/or receiving investigational product), through and including a 
minimum of 90 calendar days after the last administration of the investigational product.
For patients who are screen failures, the active collection period ends when screen failure 
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8.1.4.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a patient during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form.
SAEs occurring in a patient after the active collection period has ended are reported to Pfizer 
Safety if the Investigator becomes aware of them; at a minimum, all SAEs that the 
Investigator believes have at least a reasonable possibility of being related to investigational 
product must be reported to Pfizer Safety.
Follow up by the Investigator continues throughout and after the active collection period and 
until the event or its sequelae resolve or stabilize at a level acceptable to the Investigator, and 
Pfizer concurs with that assessment.
If a patient begins a new anti-cancer therapy, SAEs occurring during the above-indicated 
active collection period must still be reported to Pfizer Safety irrespective of any intervening 
treatment.
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF
During the active collection period, both non-serious AEs and SAEs are recorded on the 
CRF.
Follow-up by the Investigator may be required until the event or its sequelae resolve or 
stabilize at a level acceptable to the Investigator, and Pfizer concurs with that assessment.
If a patient begins a new anti-cancer therapy, the recording period for non-serious AEs ends 
at the time the new treatment is started; however, SAEs must continue to be recorded on the 
CRF during the above-indicated active collection period.
8.1.5. Causality Assessment
The Investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the Investigator must record the causal relationship on the CRF, and report such 
an assessment in accordance with the SAE reporting requirements, if applicable.  An 
Investigator’s causality assessment is the determination of whether there exists a reasonable 
possibility that the investigational product caused or contributed to an AE; generally the facts 
(evidence) or arguments to suggest a causal relationship should be provided.  If the 
Investigator does not know whether or not the investigational product caused the event, then 
the event will be handled as “related to investigational product” for reporting purposes, as 
defined by the Sponsor.  If the Investigator's causality assessment is “unknown but not 
related” to investigational product, this should be clearly documented on study records. 
In addition, if the Investigator determines that an SAE is associated with study procedures, 
the Investigator must record this causal relationship in the source documents and CRF, and 
report such an assessment in the dedicated section of the CT SAE Report Form and in 
accordance with the SAE reporting requirements.


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8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.
8.2. Definitions
8.2.1. Adverse Events
An AE is any untoward medical occurrence in a study patient administered a product or 
medical device; the event need not necessarily have a causal relationship with the treatment 
or usage.  Examples of AEs include, but are not limited to: 

Abnormal test findings;

Clinically significant signs and symptoms;

Changes in physical examination findings;

Hypersensitivity;

Drug abuse;

Drug dependency.
Additionally, AEs may include signs and symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure.
Worsening of signs and symptoms of the malignancy under study should be recorded as AEs
in the appropriate section of the CRF.  Disease progression assessed by measurement of 
malignant lesions on radiographs or other methods should not be reported as AEs.


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8.2.2. Abnormal Test Findings
Abnormal objective test findings should be recorded as AEs when any of the following 
conditions are met: 

Test result is associated with accompanying symptoms; and/or

Test result requires additional diagnostic testing or medical/surgical intervention; 
and/or

Test result leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional concomitant 
drug treatment, or other therapy; and/or

Test result is considered to be an AE by the Investigator or Sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
recording as an AE.
8.2.3. Serious Adverse Events
A serious adverse event is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect.
Or that is considered to be:

An important medical event.
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the patient or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.


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Progression of the malignancy under study (including signs and symptoms of progression) 
should not be reported as an SAE unless the outcome is fatal within the active collection 
period.  Hospitalization due to signs and symptoms of disease progression should not be 
reported as an SAE.  If the malignancy has a fatal outcome during the study or within the 
active collection period, then the event leading to death must be recorded as an AE on the 
CRF, and as an SAE with Common Terminology Criteria for Adverse Events (CTCAE) 
Grade 5 (see the Severity Assessment section).
8.2.4. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility, or any prolongation of an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit is assessed for medical importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same-day surgeries (as outpatient/same-day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating clinical 
AE is not in itself an SAE.  Examples include: 

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of a persistent pretreatment laboratory abnormality);

Social admission (eg, patient has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
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
Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual patient;

Admission exclusively for the administration of blood products.
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as SAEs.  However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an SAE.  For example, an acute 
appendicitis that begins during the reporting period should be reported if the SAE 
requirements are met, and the resulting appendectomy should be recorded as treatment of the 
AE.
8.3. Severity Assessment
GRADE
Clinical Description of Severity
1
MILD adverse event
2
MODERATE adverse event
3
SEVERE adverse event
4
LIFE-THREATENING consequences; urgent intervention indicated
5
DEATH RELATED TO adverse event
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
the patient's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.
8.4. Special Situations
8.4.1. Protocol-Specified Serious Adverse Events
There are no protocol-specified SAEs in this study.  All SAEs will be reported to Pfizer 
Safety by the investigator as described in previous sections, and will be handled as SAEs in 
the safety database. 
8.4.2. Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury, but adapt 
are termed “adaptors.”  In some patients, transaminase elevations are a harbinger of a more 
serious potential outcome.  These patients fail to adapt and therefore are "susceptible" to 


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progressive and serious liver injury, commonly referred to as drug-induced liver injury 
(DILI).  Patients who experience a transaminase elevation above 3 times the upper limit of 
normal (× ULN) should be monitored more frequently to determine if they are an “adaptor” 
or are “susceptible.”
In the majority of DILI cases, elevations in AST and/or ALT precede total bilirubin (TBili) 
elevations (>2 × ULN) by several days or weeks.  The increase in TBili typically occurs 
while AST/ALT is/are still elevated above 3 × ULN (ie, AST/ALT and TBili values will be 
elevated within the same lab sample).  In rare instances, by the time TBili elevations are 
detected, AST/ALT values might have decreased.  This occurrence is still regarded as a 
potential DILI.  Therefore, abnormal elevations in either AST OR ALT in addition to TBili 
that meet the criteria outlined below are considered potential DILI (assessed per Hy’s law 
criteria) cases and should always be considered important medical events, even before all 
other possible causes of liver injury have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the patient’s 
individual baseline values and underlying conditions.  Patients who present with the 
following laboratory abnormalities should be evaluated further as potential DILI (Hy’s law) 
cases to definitively determine the etiology of the abnormal laboratory values:

Patients with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available;

For patients with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:

Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values >2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is 
smaller).

Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches 
>3 × ULN (whichever is smaller).
Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the Sponsor.
The patient should return to the Investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment.


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In addition to repeating measurements of AST and ALT and TBili, laboratory tests should 
include albumin, creatine kinase (CK), direct and indirect bilirubin, gamma-glutamyl 
transferase (GGT), prothrombin time (PT)/international normalized ratio (INR), total bile 
acids, alkaline phosphatase and acetaminophen drug and/or protein adduct levels.  
Consideration should also be given to drawing a separate tube of clotted blood and an 
anticoagulated tube of blood for further testing, as needed, for further contemporaneous 
analyses at the time of the recognized initial abnormalities to determine etiology.  A detailed 
history, including relevant information, such as review of ethanol, acetaminophen (either by 
itself or as a coformulated product in prescription or over-the-counter medications), 
recreational drug, supplement (herbal) use and consumption, family history, sexual history, 
travel history, history of contact with a jaundiced person, surgery, blood transfusion, history 
of liver or allergic disease, and potential occupational exposure to chemicals, should be 
collected.  Further testing for acute hepatitis A, B, C, D, and E infection and liver imaging 
(eg, biliary tract) may be warranted.
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the liver function test (LFT) abnormalities has yet been found.  Such 
potential DILI (Hy’s law) cases are to be reported as SAEs, irrespective of availability 
of all the results of the investigations performed to determine etiology of the LFT 
abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.
8.4.3. Exposure to the Investigational Product During Pregnancy or Breastfeeding, and 
Occupational Exposure
Exposure to the investigational product under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of Investigator 
awareness.
8.4.3.1. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an EDP occurs if:

A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product;

An example of environmental exposure would be a case involving direct contact 
with a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant 
and has been exposed to chemotherapeutic products).


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
A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy.
If a patient or patient’s partner becomes or is found to be pregnant during the patient’s 
treatment with the investigational product, the Investigator must report this information to 
Pfizer Safety on the CT SAE Report Form and an EDP supplemental form, regardless of 
whether an SAE has occurred.  In addition, the Investigator must submit information 
regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a patient 
reports that she is pregnant and has been exposed to a cytotoxic product by inhalation or 
spillage) to Pfizer Safety using the EDP supplemental form.  This must be done irrespective 
of whether an AE has occurred and within 24 hours of awareness of the exposure.  The 
information submitted should include the anticipated date of delivery (see below for 
information related to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The Investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP supplemental form.  In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth.  In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
pre-procedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
Investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported to Pfizer Safety as SAEs 
follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the Investigator assesses the infant death as related or possibly related to 
exposure to the investigational product. 
Additional information regarding the EDP may be requested by the Sponsor.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays).  In the case of paternal exposure, the 
Investigator will provide the patient with the Pregnant Partner Release of Information Form 
to deliver to his partner.  The Investigator must document in the source documents that the 
patient was given the Pregnant Partner Release of Information Form to provide to his partner.


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8.4.3.2. Exposure During Breastfeeding
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of 
an associated SAE, to Pfizer Safety within 24 hours of the Investigator’s awareness, using the 
CT SAE Report Form.  An exposure during breastfeeding report is not created when a Pfizer 
drug specifically approved for use in breastfeeding women (eg, vitamins) is administered in 
accord with authorized use.  However, if the infant experiences an SAE associated with such 
a drug’s administration, the SAE is reported together with the exposure during breastfeeding.
8.4.3.3. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to Pfizer Safety within 24 hours of the Investigator’s 
awareness, using the CT SAE Report Form, regardless of whether there is an associated 
SAE.  Since the information does not pertain to a patient enrolled in the study, the 
information is not recorded on a CRF; however, a copy of the completed CT SAE Report 
Form is maintained in the Investigator site file.
8.4.4. Medication Errors
Other exposures to the investigational product under study may occur in clinical trial settings, 
such as medication errors.
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
Medication errors
All (regardless of whether 
associated with an AE)
Only if associated with an 
SAE
Medication errors may result from the administration or consumption of the investigational 
product by the wrong patient, or at the wrong time, or at the wrong dosage strength.
Medication errors include:

Medication errors involving patient exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating patient.

Such medication errors occurring to a study participant are to be captured on the 
medication error page of the CRF, which is a specific version of the AE page.

In the event of medication dosing error, the Sponsor should be notified immediately.


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
Whether or not the medication error is accompanied by an AE, as determined by the 
Investigator, the medication error is recorded on the medication error page of the CRF 
and, if applicable, any associated AE(s), serious and non-serious, are recorded on an 
AE page of the CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a statistical analysis plan (SAP), which will be 
maintained by the sponsor.  The SAP may modify what is outlined in the protocol where 
appropriate; however, any major modifications of the primary endpoint or their analyses will 
also be reflected in a protocol amendment.
This section describes the statistical methodology for the analysis of the pre-specified 
endpoints to address the objectives of the study.
Prior to implementation of Amendment 3, this study examined avelumab and binimetinib 
given twice daily (BID) on a continuous dosing schedule with the objective of identifying an 
RP2D for this doublet combination before proceeding to assess the triplet combination of 
avelumab, binimetinib and talazoparib. However, due to observed DLTs with continuous 
binimetinib dosing, the schedule for binimetinib has been modified (Amendment 3) to an 
intermittent dosing schedule(s) which is anticipated to mitigate these potential toxicities.
9.1. Analysis Sets 
9.1.1. Full Analysis Set
For Phase 1b and the non-randomized cohort in Phase 2, the full analysis set includes all 
enrolled patients who receive at least 1 dose of study treatment.  Patients will be classified 
according to the study treatment actually received.
For the randomized cohort in Phase 2, the full analysis set includes all randomized patients. 
Patients will be classified according to the treatment assigned at randomization.
9.1.2. Safety Analysis Set
The safety analysis set includes all enrolled patients who receive at least 1 dose of study 
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9.1.3. DLT-evaluable Analysis Set
The DLT-evaluable analysis set is a subset of the safety analysis set and includes all enrolled 
patients in Phase 1b who are eligible for the study, receive at least one dose of the 
combination treatment, and either experience DLT during the first cycle (28 days) of 
treatment, or complete the DLT observation period for the first cycle of treatment without 
DLT. 
Patients without DLTs who withdraw from study treatment before receiving at least 75% of 
the planned dose of avelumab, binimetinib or talazoparib (if applicable) in Cycle 1 for 
reasons other than toxicity which are attributable to the investigational products are not 
evaluable for DLT.  Additional patients will be enrolled in the specific cohort to replace 
patients who are not considered DLT-evaluable.
 
 
9.1.5. Pharmacokinetics/Immunogenicity Analysis Set
9.1.5.1. Pharmacokinetics Analysis Set
The PK concentration analysis set is a subset of the safety analysis set and will include 
patients who have at least 1 concentration for avelumab, binimetinib or talazoparib.
The PK parameter analysis set is a subset of the safety analysis set and will include patients 
who have at least 1 of the PK parameters of interest for avelumab, binimetinib or talazoparib.
9.1.5.2. Immunogenicity Analysis Set
The immunogenicity analysis set is a subset of the safety analysis set and will include 
patients who have at least one ADA/nAb sample collected for avelumab.
9.1.5.3. Biomarker Analysis (BA) Set
The biomarker analysis set is a subset of the safety analysis set and will include patients who 
have at least one baseline biomarker assessment.  Analysis sets will be defined separately for 
blood-based and tumor tissue-based biomarkers.
CCI


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9.2. Statistical Methods and Properties
9.2.1. Statistical Methods for Dose Finding: BLRM
Identification of a recommended dose
The dosing decision and estimation of the MTDs of the doublet and the triplet combinations 
will be guided by the estimation of the probability of DLT in Cycle 1.  However, other 
evidence such as safety data beyond DLT, clinical activity, PK, and PD data will play an 
important role in the final decision.  A RP2D below the MTD may be determined based on 
these considerations.
Prior to implementation of Amendment 3, the doublet of avelumab in combination with 
binimetinib was evaluated first to determine the RP2D. Per Amendment 3, the doublet 
combination of binimetinib and talazoparib will be evaluated to determine the RP2D.  Upon 
the completion of the dose finding of the doublet combinations, the triplet combinations will 
then be evaluated to determine the RP2D for this combination.
Bayesian adaptive approach
The dose finding in the Phase 1b of the study will be guided by a Bayesian analysis of 
Cycle 1 DLTs in DLT-evaluable patients.38
a.
Doublet combination model:
Prior to implementation of Amendment 3:
For the doublet combination of avelumab and binimetinib, the Bayesian model38 consists 
of three parts, representing:

Single-agent avelumab toxicity;

Single-agent binimetinib toxicity;

Interaction between avelumab and binimetinib.
Per Amendment 3:
For the doublet combination of talazoparib and binimetinib, the Bayesian model38
consists of three parts, representing:

Single-agent talazoparib toxicity;

Single-agent binimetinib toxicity;

Interaction between talazoparib and binimetinib.
b. Triplet combination model:


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For the triplet combination of avelumab, binimetinib, and talazoparib, the Bayesian 
model38 consists of seven parts, representing:

Single-agent talazoparib toxicity;

Single-agent binimetinib toxicity;

Single-agent avelumab toxicity;

Interaction between binimetinib and talazoparib;

Interaction between talazoparib and avelumab;

Interaction between avelumab and binimetinib;

Triple interaction among talazoparib, binimetinib and avelumab.
Single-agent toxicities are modelled using logistic regression for the probability of a patient 
experiencing a DLT against log-dose.  The odds of a DLT are then calculated under no 
interaction for the two/three single-agent toxicities, and interaction is accounted for by 
adjusting these odds with an additional model parameter (odds multiplier).  Details of the 
model are given in Appendix 5 (prior to implementation of Amendment 3) and Appendix 6
(Amendment 3).
Assessment of patient risk
After each cohort of patients completes the DLT evaluation period, the posterior distribution 
for the risk of DLT for different dose combination doses of interest will be evaluated.  The 
posterior distributions will be summarized to provide the posterior probability that the risk of 
DLT lies within the following intervals: 

Underdosing:
[0, 0.16);

Target toxicity:
[0.16, 0.33);

Excessive toxicity:
[0.33, 1].
The EWOC principle
Dosing decisions are guided by the EWOC principle.35  A combination dose may only be 
used for the next cohort of patients if the risk of excessive toxicity ([0.33, 1]) at that 
combination dose is less than 0.25.


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Prior distributions
A meta-analytic-predictive (MAP) approach was used to derive the prior distribution for the 
single-agent model parameters.  The MAP prior for the logistic model parameters for this 
study is the conditional distribution of the parameters given the historical data.36,37,38  MAP 
priors are derived using Bayesian hierarchical models, which take into account possible 
differences between the studies.
A full description of the application of the MAP approach to derive the prior distributions of 
the single-agent model parameters is given in Appendix 5 (prior to implementation of 
Amendment 3) and Appendix 6 (Amendment 3).  
The prior distribution for the interaction parameters (doublet and triplet combinations) were
based on the prior understanding of possible drug safety interactions.  This prior allows for 
the possibility of either synergistic or antagonistic interaction, and is fully described in 
Appendix 5 (prior to implementation of Amendment 3) and Appendix 6 (Amendment 3).
Starting dose levels
Prior to implementation of Amendment 3, the starting dose for the doublet combination was 
D0 (800 mg avelumab IV Q2W, and 45 mg binimetinib orally twice daily).  For this dose the 
prior risk of excessive toxicity was 0.10, which satisfies the EWOC criterion. 
Per Amendment 3, the starting dose for the doublet combination is 0.75 mg talazoparib orally 
once daily, and 45 mg binimetinib orally twice daily, 7 days on, 7 days off.  For this dose the 
prior risk of excessive toxicity is 0.189, which satisfies the EWOC criterion. 
A full assessment of the prior risk to patients is given in Appendix 5 (prior to implementation 
of Amendment 3) and Appendix 6 (Amendment 3).
The starting dose for the triplet will be determined based on all available data after 
completion of the dose finding for the doublet.  A full assessment of the prior risk to patients 
is given in Appendix 5 (prior to implementation of Amendment 3) and Appendix 6
(Amendment 3).
9.3. Sample Size Determination
During the Phase 1b dose finding, prior to implementation of Amendment 3, it was 
estimated that approximately up to 12 and 15 patients will be enrolled and assigned to 
treatment with either the doublet or the triplet combinations.  Per Amendment 3, it is 
estimated that approximately up to 18 and 12 patients will be enrolled and assigned to 
treatment with either the doublet or the triplet combinations (in addition to the 22 patients 
previously enrolled during Phase 1b prior to implementation of Protocol Amendment 3).  
Each combination will include at least 6 patients treated at the MTD level and at least 
9 patients at the RP2D.  The actual number of patients will depend on the number of DLT 
events, dose levels/cohorts and dosing schedules that are tested.


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In Phase 2, the primary objective is to assess the ORR of the doublet and the triplet 
combinations.   

With 20 treated patients per treatment group (doublet and triplet combinations) for 
mPDAC, ORR can be estimated with a maximum standard error of 0.112.  

With 30 treated patients in the ‘tumor agnostic’ cohort of the triplet combination, 
ORR can be estimated with a maximum standard error of 0.091.  

Further, assuming a beta-binomial distribution for the ORR and a beta (0.5, 0.5) prior.

mPDAC cohort for the doublet combination: if 5 responders (out of 20 patients, ORR 
of 25%) are observed, the posterior probability of a true ORR 15% (considered a 
clinically relevant effect) will be 80% (89.0%). 

mPDAC cohort for the triplet combination: if 7 responders (out of 20 patients, ORR 
of 35%) are observed, the posterior probability of a true response rate 
25% (considered a clinically relevant effect) will be 80% (84.9%). 

‘Tumor agnostic’KRAS- or NRAS-mutant solid tumor cohort for the triplet 
combination: if 12 responders (out of 30 patients, ORR of 40%) are observed, the 
posterior probability of a true ORR 30% (considered a clinically relevant effect) will 
be 80% (88.2%). 
The determination of what constitutes a clinically meaningful response rate was based upon a 
review of historical ORR data for clinical studies in mPDAC, second line NSCLC, and 
CRC.49-58
9.4. Efficacy Analysis
In the sections that follow, ‘start date’ refers to date of randomization for randomized cohorts 
and first dose of study treatment for non-randomized cohorts.  All efficacy analyses will be 
performed based on the full analysis set, separately by treatment combination and:

For Phase 1b: by dose level and for all dose levels combined;

For Phase 2: by cohort and the assessment of efficacy will be based on Phase 2 (not 
Phase 1b unless the triplet combination does not move forward, in which case the 
Phase 1b patients treated at the RP2D will be combined with Phase 2 for the mPDAC 
cohort). 


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9.4.1. Analysis of the Primary Endpoint
The primary endpoint for Phase 2 is confirmed OR.
OR is defined as a CR or PR per RECIST v1.1 from ‘start date’ until the date of first 
documentation of PD or death due to any cause.  Both CR and PR must be confirmed by 
repeat assessments performed no less than 4 weeks after the criteria for response are first 
met.  ORR is defined as the proportion of patients with a confirmed CR or PR based on the 
Investigator’s assessment according to RECIST v1.1.  Confirmed responses are those that 
persist on repeat tumor assessments for at least 4 weeks after initial documentation of 
response.  Otherwise, the patient will be counted as a non-responder in the assessment of 
ORR.  Additionally, patients with inadequate data for tumor assessment (eg, no baseline 
assessment or no follow-up assessments) will be considered as non-responders in the 
assessment of ORR.  Within each cohort and for each combination, ORR will be estimated 
and the two-sided exact 95% CIs for ORR will be calculated.  ORR for Phase 1b will be 
summarized by dose level and for all dose levels combined using simple descriptive 
statistics.  
9.4.2. Analysis of the Secondary Endpoints
PFS is defined as the time from ’start date’ to the date of PD by RECIST v1.1 or death due to 
any cause, whichever occurs first.  PFS data will be censored on the date of the last adequate 
tumor assessment for patients who do not have an event (PD or death), for patients who start 
new anti-cancer treatment prior to an event, or for patients with an event after two or more 
missing tumor assessments.  Patients who do not have an adequate baseline tumor assessment 
or who do not have any adequate post-baseline tumor assessments will be censored on the 
date of first dose of study treatment unless death occurred on or before the time of the second 
planned tumor assessment in which case the death will be considered an event.

TTR is defined, for patients with an OR, as the time from the ‘start date’ to the first 
documentation of objective response (CR or PR) which is subsequently confirmed.

DR is defined, for patients with OR, as the time from the first documentation of 
objective response (CR or PR) to the date of first documentation of PD or death due 
to any cause.

OS is defined as the time from time from the ‘start date’ to the date of death due to
any cause.  Patients without an event (death) will be censored at the date of last 
contact.  

TTR will be summarized using simple descriptive statistics (eg, median and range).  
DR, PFS, and OS will be analyzed using Kaplan-Meier methods.  Point estimates will 
be presented with 95% CIs.  


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9.5. Analysis of Pharmacokinetics and Pharmacodynamics 
9.5.1. Analysis of Pharmacokinetics of Investigational Products
Pharmacokinetic analyses will include pre-dose and post-dose sampling for serum avelumab 
concentrations on Days 1 and 15 of Cycle 1; Days 1 and 15 of Cycle 2; and Day 1 of Cycles 
3, 5, 9, and 12.  An additional single avelumab PK sample will also be obtained at the Cycle 
1 Day 8 visit.  For binimetinib and talazoparib, PK samples will be collected at pre-dose on 
Days 1, 8 and 15 of Cycle 1, and on Day 1 of Cycles 2 and 3.  In addition, PK samples 
collected at 1, 2 and 3 hours post-binimetinib dosing will be collected for binimetinib (and 
metabolites, if analyzed) on Day 1 and Day 8 of Cycle 1.  If indicated, an additional 
unplanned PK sample may also be drawn with agreement between the Investigator and 
Sponsor (eg, to investigate a potential exposure-toxicity relationship for a particular patient).  
PK analyses will include descriptive summary statistics of the post-infusion concentration for 
avelumab and pre-dose/trough (Ctrough) concentrations  for avelumab, binimetinib and 
talazoparib for each planned sampling occasion by dose level in Phase 1b and by cohort in 
Phase 2, as applicable.  
Other PK parameters (eg, Cmax, Tmax) may be determined, as appropriate.  
The summary data will be compared with the historical data of avelumab, binimetinib and 
talazoparib as single-agents and to assess the potential drug-drug interaction effect of 
co-administration of the study drugs.
9.5.2. Population Pharmacokinetic Analysis or Pharmacokinetic/Pharmacodynamic 
(PK/Pharmacodynamic) Modeling
Pharmacokinetic and pharmacodynamic data from this study may be analyzed using 
modeling approaches and may also be pooled with data from other studies investigating 
avelumab, binimetinib or talazoparib to: 1) further assess the effect of binimetinib with or 
without avelumab on the PK of talazoparib, 2) assess the effect of talazoparib with or without 
avelumab on the PK of binimetinib, and 3) assess the effect of talazoparib and/or binimetinib 
on the PK of avelumab, and 4) explore any association between study drug exposure and 
biomarkers, efficacy or significant safety endpoints.  If performed, the details of these 
analyses will be outlined in a separate pharmacometric analysis plan (PMAP).  The results of 
these analyses, if performed, may be reported separately.
9.5.3. Analysis of Immunogenicity Data of Avelumab
ADA/nAb data for avelumab will be listed and summarized for each sampling occasion per 
the schedule of assessments.
The percentage of patients with positive ADA and nAbs will each be summarized by 
treatment group and for all treatment groups combined.  For patients with positive ADA, the 
magnitude (titer), time of onset, and duration of ADA response will also be described, if data 
permit.  The effect of ADA on avelumab concentrations and pharmacokinetics may be 
evaluated, if data permit.  A comparison of safety and efficacy endpoints between avelumab 
ADA and nAb positive vs. negative patients may be performed, if data permit. 


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9.6. Analysis of Biomarker Secondary
For continuous measurement biomarker results, summary statistics (eg, the mean, standard 
deviation, median, percent of coefficient of variation, and minimum/maximum levels) will be 
determined at baseline and on-treatment/end of treatment time points, as appropriate.
Appropriate change from baseline measurements will be provided.  
For discrete measurement biomarkers (eg, tumor marker status), frequencies and percentages 
of categorical biomarker measures will be determined at baseline and 
on-treatment/post-treatment time points.  Shift tables may also be provided.
Data from biomarker assays may be analyzed using graphical methods and descriptive 
statistics such as Fisher’s exact test, Kaplan-Meier estimates, and linear regression as 
appropriate.  The statistical approaches will explore the correlations of biomarker results with 
pharmacokinetic parameters and measures of anti-tumor efficacy, such as tumor response and 
progression free survival.
 
9.7. Safety Analysis
9.7.1. Analysis of the Primary Endpoint in Phase 1b
DLT during the primary DLT evaluation period (Cycle 1) is the primary endpoint for 
Phase 1b. 
Analyses of DLT are based on the DLT-evaluable analysis set.  The occurrence of DLTs and 
AEs constituting DLTs will be summarized and listed for each combination per dose level, 
overall and by dose level for patients enrolled in Phase 1b.
9.7.2. Adverse Events
AEs will be graded by the Investigator according to the CTCAE v4.03 and coded using the 
Medical Dictionary for Regulatory Activities (MedDRA).  The focus of AE summaries will 
be on TEAEs, those with initial onset or increasing in severity after the first dose of study 
treatment.  The number and percentage of patients who experienced any AE, SAE, 
treatment-related AE, and treatment-related SAE will be summarized according to worst 
toxicity grades.
9.7.3. Laboratory Test Abnormalities
The laboratory results will be graded according to the CTCAE v4.03 severity grade whenever 
applicable.  The number and percentage of patients who experienced laboratory test 
abnormalities will be summarized according to worst toxicity grade observed for each 
laboratory test.
For laboratory tests without CTCAE grade definitions, results will be categorized as normal, 
abnormal, or not done.
CCI
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Shift tables will be provided to examine the distribution of laboratory toxicities.
9.7.4. Electrocardiogram
Baseline ECG measurements and changes from baseline will be summarized by cohort and 
visit.  Interval measurements from clinically indicated on treatment ECGs will be included in 
the outlier analysis (categorical analysis) as individual values obtained at unscheduled time 
points.
QT intervals will be corrected for heart rate (QTc) using standard correction factors 
[ie, Fridericia’s (default correction), Bazett’s, and possibly a study specific factor, as 
appropriate].  Data will be summarized and listed for QT, HR, RR, PR, QRS, and QTc.
Descriptive statistics (n, mean, median, standard deviation, minimum, and maximum) will be 
used to summarize the absolute corrected QT interval.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI


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9.9. Interim Analysis
No formal interim analysis will be conducted for this study.  However, as this is an 
open-label phase 1b/2 study, the Sponsor may conduct unblinded reviews of the data during 
the course of the study for the purpose of safety assessment, facilitating dose-finding 
decisions, facilitating PK/Pharmacodynamic modeling, or to support clinical development.
9.10. Data Monitoring Committee 
An external independent Data Safety Monitoring Committee will not be established for the 
study.  For the purpose of this protocol, Pfizer procedures for periodic safety review will be 
applied by an internal safety review team with medical and statistical capabilities to review 
individual and summary data collected in the safety and clinical databases.  Procedures 
include:
!
Surveillance for serious adverse events (SAEs) according to regulatory guidelines;
!
Discussions between the Investigators and the Sponsor of AEs and laboratory tests 
alterations seen at each dose level will be performed in an ongoing manner at regular 
teleconferences and/or meetings to determine the safety profile and risk/benefit ratio 
and decide if further enrollment is appropriate.
10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits during study conduct to ensure that 
the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs are accurate.  The 
Investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification.  This 
verification may also occur after study completion.
During study conduct and/or after study completion, the Investigator site may be subject to 
review by the IRB/EC, and/or to quality assurance audits performed by Pfizer, or companies 
working with or on behalf of Pfizer, and/or to inspection by appropriate regulatory 
authorities.
The Investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study.  Furthermore, the Investigator will cooperate with Pfizer 
or its agents to prepare the Investigator site for the inspection and will allow Pfizer or its 
agent, whenever feasible, to be present during the inspection.  The Investigator site and 
Investigator will promptly resolve any discrepancies that are identified between the study 
data and the patient's medical records.  The Investigator will promptly provide copies of the 
inspection findings to Pfizer or its agent.  Before response submission to the regulatory 
authorities, the Investigator will provide Pfizer or its agents with an opportunity to review 
and comment on responses to any such findings.
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It is important that the Investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included patient.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.  The investigator shall ensure that the 
CRFs are securely stored at the study site in encrypted electronic and/or paper form and will 
be password protected or secured in a locked room to prevent access by unauthorized third 
parties.
The Investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required.  The 
CRFs must be signed by the Investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true.  Any corrections to entries made in the CRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry.
In most cases, the source documents are the hospital or the physician's chart.  In these cases, 
data collected on the CRFs must match those charts. 
In some cases, the CRF may also serve as the source document.  In these cases, a document 
should be available at the Investigator site and at Pfizer that clearly identifies those data that 
will be recorded on the CRF, and for which the CRF will stand as the source document.
11.2. Record Retention
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, the 
investigator agrees to keep records, including the identity of all participating patients 
(sufficient information to link records, eg, CRFs and hospital records), all original signed 
informed consent documents, copies of all CRFs, safety reporting forms, source documents, 
detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, and telephone call reports).  The records should 
be retained by the investigator according to the ICH guidelines, according to local 
regulations, or as specified in the clinical study agreement (CSA), whichever is longer.  The 
investigator must ensure that the records continue to be stored securely for so long as they are 
retained.


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If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer. 
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations. 
The Investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board/Ethics Committee 
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, eg, 
recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the 
IRB/EC should be retained in the investigator file.  Copies of IRB/EC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the patients.  In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, legal and regulatory 
requirements, and the general principles set forth in the International Ethical Guidelines for 
Biomedical Research Involving Human Subjects (Council for International Organizations of 
Medical Sciences 2002), ICH Guideline for Good Clinical Practice, and the Declaration of 
Helsinki. 
12.3. Patient Information and Consent
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of subject personal data.  Such 
measures will include omitting subject names or other directly identifiable data in any 
reports, publications, or other disclosures, except where required by applicable laws. 
The personal data will be stored at the study site in encrypted electronic and/or paper form 
and will be password protected or secured in a locked room to ensure that only authorized 
study staff have access.  The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster.  In the event of a potential personal data breach, the study site shall be responsible 
for determining whether a personal data breach has in fact occurred and, if so, providing 
breach notifications as required by law.


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To protect the rights and freedoms of natural persons with regard to the processing of 
personal data, when study data are compiled for transfer to Pfizer and other authorized 
parties, subject names will be removed and will be replaced by a single, specific, numerical 
code, based on a numbering system defined by Pfizer.  All other identifiable data transferred 
to Pfizer or other authorized parties will be identified by this single, subject-specific code.  
The investigator site will maintain a confidential list of subjects who participated in the 
study, linking each subject’s numerical code to his or her actual identity.  In case of data 
transfer, Pfizer will maintain high standards of confidentiality and protection of subjects’ 
personal data consistent with the Clinical Study Agreement and applicable privacy laws.
The informed consent documents and any subject recruitment materials must be in 
compliance with ICH GCP, local regulatory requirements, and legal requirements, including 
applicable privacy laws.
The informed consent documents used during the informed consent process and any subject 
recruitment materials must be reviewed and approved by Pfizer, approved by the IRB/EC 
before use, and available for inspection.
The investigator must ensure that each study subject, or his or her legally acceptable 
representative,  is fully informed about the nature and objectives of the study, the sharing of 
data relating to the study and possible risks associated with participation, including the risks 
associated with the processing of the subject’s personal data.  The investigator further must 
ensure that each study subject, or his or her legally acceptable representative, is fully 
informed about his or her right to access and correct his or her personal data and to withdraw 
consent for the processing of his or her personal data.
Whenever consent is obtained from a subject’s legally acceptable representative, the 
subject’s assent (affirmative agreement) must subsequently be obtained when the subject has 
the capacity to provide assent, as determined by the IRB/EC.  If the investigator determines 
that a subject’s decisional capacity is so limited that he or she cannot reasonably be 
consulted, then, as permitted by the IRB/EC and consistent with local regulatory and legal 
requirements, the subject’s assent may be waived with source documentation of the reason 
assent was not obtained.  If the study subject does not provide his or her own consent, the 
source documents must record why the subject did not provide consent (eg, decisionally 
impaired adult), how the investigator determined that the person signing the consent was the 
subject’s legally acceptable representative, the consent signer’s relationship to the study
subject (eg, spouse), and that the subject’s assent was obtained or waived.  If assent is 
obtained verbally, it must be documented in the source documents.
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately. 


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In addition, the Investigator will inform Pfizer immediately of any urgent safety measures 
taken by the Investigator to protect the study patients against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
13.1. End of Trial in a Member State
End of trial in a Member State of the European Union (EU) is defined as the time at which it 
is deemed that a sufficient number of patients have been recruited and completed the study as 
stated in the regulatory application (ie, clinical trial application (CTA) and ethics application 
in the Member State.  Poor recruitment (recruiting less than the anticipated number in the 
CTA) by a Member State is not a reason for premature termination but is considered a 
normal conclusion to the study in that Member State.
13.2. End of Trial in All Other Participating Countries
End of trial in all other participating countries is defined as last subject last visit (LSLV).
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, or investigational product safety problems, or at the 
discretion of Pfizer.  In addition, Pfizer retains the right to discontinue development of 
avelumab and/or talazoparib at any time.
If a study is prematurely terminated, Pfizer will promptly notify the investigator.  After 
notification, the investigator must contact all participating patients and the hospital pharmacy 
(if applicable) within 1 month.  As directed by Pfizer, all study materials must be collected 
and all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations. 
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies (conducted in patients) that evaluate the safety and/or efficacy of a 
Pfizer product, regardless of the geographical location in which the study is conducted.  US 
Basic Results are submitted for posting within 1 year of the primary completion date (PCD) 


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for studies in adult populations or within 6 months of the PCD for studies in pediatric 
populations.
PCD is defined as the date that the final patient was examined or received an intervention for 
the purposes of final collection of data for the primary outcome, whether the clinical study 
concluded according to the prespecified protocol or was terminated.
EudraCT
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-sponsored 
interventional studies that are in scope of EU requirements.  EU Basic Results are submitted 
for posting within 1 year of the PCD for studies in adult populations or within 6 months of 
the PCD for studies in pediatric populations.
www.pfizer.com
Pfizer posts Public Disclosure Synopses (CSR synopses in which any data that could be used 
to identify individual patients has been removed) on www.pfizer.com for Pfizer-sponsored 
interventional studies at the same time the US Basic Results document is posted to 
www.clinicaltrials.gov.
15.2. Publications by Investigators
Pfizer supports the exercise of academic freedom and has no objection to publication by the 
Principal Investigator (PI) of the results of the study based on information collected or 
generated by the PI, whether or not the results are favorable to the Pfizer product.  However, 
to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, the Investigator will provide Pfizer an opportunity to review any proposed 
publication or other type of disclosure of the results of the study (collectively, “publication”) 
before it is submitted or otherwise disclosed.
The Investigator will provide any publication to Pfizer at least 30 days before it is submitted 
for publication or otherwise disclosed.  If any patent action is required to protect intellectual 
property rights, the Investigator agrees to delay the disclosure for a period not to exceed an 
additional 60 days.
The Investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results.
If the study is part of a multicenter study, the Investigator agrees that the first publication is 
to be a joint publication covering all investigator sites, and that any subsequent publications 
by the PI will reference that primary publication.  However, if a joint manuscript has not 
been submitted for publication within 12 months of completion or termination of the study at 
all participating sites, the Investigator is free to publish separately, subject to the other 
requirements of this section.


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For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the CSA between Pfizer and the 
institution.  In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the CSA.
If there is any conflict between the CSA and any attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study patients, and the CSA will control as to all other 
issues.


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Appendix 1. Abbreviations and Definitions of Terms
The following is a list of abbreviations that are used in the protocol.
ACTH
Adrenocorticotropic Hormone
ADA
Anti-Drug Antibody
ADME
Absorption, Distribution, Metabolism, and Excretion
ADP
Adenosine Diphosphate
AE
Adverse Event
AIDS 
Acquired Immune Deficiency Syndrome
ALK
Anaplastic Lymphoma Kinase
ALT 
Alanine Aminotransferase
AML
Acute Myeloid Leukemia
ANC
Absolute Neutrophil Count
aPTT
activated Partial Thromboplastin Time
ASCO
American Society of Clinical Oncology
AST
Aspartate Aminotransferase
ATM
Ataxia-Telangiectasia Mutated
ATR
Ataxia-Telangiectasia and Rad3-Related
AUC
Area Under the Curve
BA
Biomarker Analysis
BID
Twice daily
BLRM
Bayesian Logistic Regression Model
BCRP
Breast Cancer Resistance Protein
BNP
B-type natriuretic peptide
BOR
Best Overall Response
BP
Blood Pressure
BT0
Starting dose level for binimetinib and talazoparib
BRAF
B-Raf proto-oncogene serine/threonine-protein kinase
BRCA
Breast Cancer Susceptibility Gene
BUN
Blood Urea Nitrogen
C1D1
Cycle 1 Day 1
CAP
College of American Pathologists
CDK
Cyclin-Dependent Kinase
CI
Confidence Interval
CK
Creatine Kinase
CL
Clearance
CLCR
Creatinine Clearance
CL/F
Apparent Oral Clearance
CLIA
Clinical Laboratory Improvement Amendments
Cmax
Maximum Plasma Concentration
CRPC
Castration Resistant Prostate Cancer
CRC
Colorectal Cancer
CPK
Creatine Phosphokinase
Ctrough
Lowest Mean Plasma Trough Concentration 
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CR
Complete Response
CRF
Case Report Form
CRP
C-Reactive Protein
CSA
Clinical Study Agreement
CSR
Clinical Study Report
CT
Clinical Trial
CT
Computed Tomography
CTA
Clinical Trial Application
CTC
Circulating Tumor Cell
CTCAE 
Common Terminology Criteria for Adverse Events
ctDNA
Circulating Tumor DNA
CTLA-4
Cytotoxic T-Lymphocyte Associated Protein 4
CV
Coefficient of Variation
CYP450
Cytochrome P450
D
Dose
DDI
Drug-Drug Interaction
DDR
DNA Damage Repair
DILI
Drug-Induced Liver Injury
DLT
Dose-Limiting Toxicity
DNA
Deoxyribonucleic Acid
DR
Duration of Response
DU
Dispensable Unit
E
Escalation/ Re-Escalation
EC
Ethics Committee 
ECG 
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
EDP
Exposure During Pregnancy
EDTA
Ethylene Diamene Tetra-acetic Acid
EGFR
Epidermal Growth Factor Receptor
eGFR
Estimated Glomerular Filtration Rate
EOT
End of Treatment
ER
Estrogen Receptor
ERK
Extracellular regulated signal kinase
EWOC
Escalation With Overdose Control
EU
European Union
EudraCT
European Union Drug Regulating Authorities Clinical Trials
FANC
Fanconi Anemia Complementation
FDA
Food and Drug Administration
FDG
Fluorodeoxyglucose
FFPE
Formalin-Fixed Paraffin-Embedded 
FSFV
First Subject First Visit
FSH
Follicle Stimulating Hormone
gBRCA
germline Breast Cancer Susceptibility gene
CCI
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GCP 
Good Clinical Practice
GGT
Gamma-Glutamyl Transferase
GITR
Glucocorticoid Induced TNF Receptor
GnRH
Gonadotropin-Releasing Hormone
GMP
Good Manufacturing Practice
GVHD
Graft Versus Host Disease
HBV
Hepatitis B Virus
hCG
Human Chorionic Gonadotropin
HCV
Hepatitis C Virus
HER2
Human Epidermal Growth Factor Receptor 2
HFSR
Hand Foot Skin Reaction
HIV 
Human Immunodeficiency Virus
IB
Investigator’s Brochure
IC50
Half Maximal Inhibitory Concentrations
ICH
International Council for Harmonisation
ICOSL
Inducible Costimulator Ligand
ID
Identification
IDO
Indoleamine 2,3-Dioxygenase
IEC 
Independent Ethics Committee
IERC
Independent Endpoint Review Committee
IFN
Interferon
Ig
Immunoglobulin
IgF
Immunoglobulin F
IgG1
Immunoglobulin G1
IHC
Immunohistochemistry
IL-2
Interleukin-2
IND
Investigational New Drug
INR
International Normalized Ratio
IP
Investigational Product
irAE
Immune-Related Adverse Event
IRB
Institutional Review Board
IRR
Infusion-Related Reaction
IRT
Interactive Response Technology
IUD
Intra-Uterine Device
IUS
Intra-Uterine System
IV
Intravenous
K2EDTA
Dipotassium Ethylenediaminetetraacetic Acid
KRAS
Kirsten Rat Sarcoma Viral Oncogene Homolog
LDH
Lactate Dehydrogenase
LFT
Liver Function Test
LLN
Lower Limit of Normal
LLQ
Lower Limit of Quantitation
LOH
Loss of Heterozygosity
LSLV
Last Subject Last Visit
LVEF
Left Ventricular Ejection Fraction
mAb
Monoclonal Antibody


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MAD
Maximum Administered Dose
MAP
Meta-Analytic-Predictive
MCC
Merkel Cell Carcinoma
MCMC
Markov Chain Monte Carlo
M-CSF
Macrophage-Colony Stimulating Factor
MDS
Myelodysplastic Syndrome
MedDRA
Medical Dictionary for Regulatory Activities
MEK 
Mitogen-activated protein kinase kinase
MEKi
MEK Inhibitor
MHC
Major Histocompatibility Complex
mPDAC
Metastatic Pancreatic Ductal Adenocarcinoma
MRI 
Magnetic Resonance Imaging
MTD
Maximum Tolerated Dose
mTOR
Mammalian Target of Rapamycin
MUGA
Multigated Acquisition
NA
North America
N/A
Not Applicable
Nab
Neutralizing Antibody
NCI 
National Cancer Institute
 
NDA
New Drug Application
NE
Not Estimable
NEMO
NF-κB essential modulator
NK
Natural Killer
NKG2DL
Natural Killer Group 2 Member D Ligand
NRAS
NRAS proto-oncogene, GTPase
NSAIDs
Nonsteroidal Anti-inflammatory Drugs
NSCLC
Non-Small Cell Lung Cancer
OCT
Optical Coherence Tomography
OR
Objective Response
ORR
Objective Response Rate
OS 
Overall Survival
PARP
Poly (ADP-Ribose) Polymerase
PBMC
Peripheral Blood Mononuclear Cell
PCD
Primary Completion Date
PD
Pharmacodynamic
PD
Progressive Disease 
PDAC
Pancreatic Ductal Adeno Carcinoma
PD-1
Programmed Death-1
PD-L1
Programmed Death-Ligand 1
PD-L2
Programmed Death-Ligand 2
PET
Positron Emission Tomography
PFS
Progression-Free Survival
P-gp
P-glycoprotein
PI
Principal Investigator
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PI3K
Phosphatidylinositol-3 kinase
PK
Pharmacokinetics
PKC
Protein Kinase C
PMAP
Pharmacometric analysis plan
PO
Orally
PR
Partial Response
PS
Performance Status
PT
Prothrombin Time
PTEN
Phosphatase and Tensin Homolog Gene
PTT
Partial Thromboplastin Time
Q2W
Every 2 Weeks
Q3W
Every 3 Weeks
QD
Once Daily
QLQ
Quality of Life Questionnaire
RCC
Renal Cell Carcinoma
RE
Re-escalation
RECIST v1.1
Response Evaluation Criteria in Solid Tumors, version 1.1
RNA
Ribonucleic Acid
RPED
Retinal Pigment Epithelial Detachment
RP2D
Recommended Phase 2 Dose
RVO
Retinal Vein Occlusion
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SCLC
Small Cell Lung Cancer
SD
Standard Deviation
SD
Stable Disease
SE
Standard Error
SOA
Schedule of Assessments
SOPs
Standard Operating Procedures
SRSD
Single Reference Safety Document
STING
Stimulation of Interferon Genes
t1/2
Terminal Half-Life
TBili
Total Bilirubin
TCR
T-cell Receptor
TEAE
Treatment Emergent Adverse Event
Tmax
Time to Maximum Plasma Concentration
TMB
Tumor Mutational Burden
TNM
Tumor, Node, Metastasis
TNBC
Triple-Negative Breast Cancer
TO
Target Occupancy
TPS
Tumor Proportion Score
TSH
Thyroid Stimulating Hormone
TTR
Time-to-Tumor Response
UC
Urothelial Cancer
UGT
Uridine Diphosphate Glucuronosyl Transferase
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ULN 
Upper Limit of Normal
UPM
Unit Probability Mass
US
United States
VEGF
Vascular Endothelial Growth Factor
V/F
Apparent Volume of Distribution
Vss/F
Apparent Steady-State Volume of Distribution
WBC
White Blood Cell
WHO
World Health Organization
WOCBP
Woman of Childbearing Potential
5d/2d
5 days on/2 days off
7d/7d
7 days on/7 days off


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Appendix 2. ECOG Performance Status
Score
Definition
0
Fully active, able to carry on all pre-disease activities without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature, eg, light house work or office work
2
Ambulatory and capable of all selfcare but unable to carry out any work 
activities.  Up and about more than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours
4
Completely disabled.  Cannot carry on any selfcare.  Totally confined to bed 
or chair
5
Dead
From: Oken MM, Creech RH, Tormey DC et al.  Toxicity and response criteria of the Eastern Cooperative 
Oncology Group.  Am J Clin Oncol. 1982; 5: 649–655.28


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Appendix 3. Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1 Guidelines
Adapted from E.A. Eisenhauer, et al.  New response evaluation criteria in solid tumours: 
Revised RECIST guideline (version 1.1). European Journal of Cancer 45 (2009) 228-247.29  
CATEGORIZING LESIONS AT BASELINE
Measurable Lesions

Lesions that can be accurately measured in at least one dimension.

Lesions with longest diameter twice the slice thickness and at least 10 mm or greater 
when assessed by CT or MRI (slice thickness 5-8 mm).

Lesions with longest diameter at least 20 mm when assessed by Chest X-ray. 

Superficial lesions with longest diameter 10 mm or greater when assessed by caliper. 

Malignant lymph nodes with the short axis 15 mm or greater when assessed by CT.
NOTE: The shortest axis is used as the diameter for malignant lymph nodes, longest 
axis for all other measurable lesions. 
Non-measurable disease
Non-measurable disease includes lesions too small to be considered measurable (including 
nodes with short axis between 10 and <15 mm) and truly non-measurable disease such as
pleural or pericardial effusions, ascites, inflammatory breast disease, leptomeningeal disease, 
lymphangitic involvement of skin or lung, clinical lesions that cannot be accurately measured 
with calipers, abdominal masses identified by physical exam that are not measurable by 
reproducible imaging techniques.

Bone disease: Bone disease is non-measurable with the exception of soft tissue 
components that can be evaluated by CT or MRI and meet the definition of 
measurability at baseline. 

Previous local treatment: A previously irradiated lesion (or lesion subjected to other 
local treatment) is non-measurable unless it has progressed since completion of 
treatment.


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Normal sites

Cystic lesions: Simple cysts should not be considered as malignant lesions and should 
not be recorded either as target or non-target disease.  Cystic lesions thought to 
represent cystic metastases can be measurable lesions, if they meet the specific 
definition above.  If non-cystic lesions are also present, these are preferred as target 
lesions.

Normal nodes: Nodes with short axis <10 mm are considered normal and should not 
be recorded or followed either as measurable or non-measurable disease.
RECORDING TUMOR ASSESSMENTS 
All sites of disease must be assessed at baseline.  Baseline assessments should be done as 
close as possible prior to study start.  For an adequate baseline assessment, all required scans 
must be done within 28 days prior to randomization (for randomized cohorts) or start of 
study treatment (for non-randomized cohorts) and all disease must be documented 
appropriately.  If baseline assessment is inadequate, subsequent statuses generally should be 
indeterminate. 
Target Lesions
All measurable lesions up to a maximum of 2 lesions per organ, 5 lesions in total, 
representative of all involved organs, should be identified as target lesions at baseline.  
Target lesions should be selected on the basis of size (longest lesions) and suitability for 
accurate repeated measurements.  Record the longest diameter for each lesion, except in the 
case of pathological lymph nodes for which the short axis should be recorded.  The sum of 
the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions 
at baseline will be the basis for comparison to assessments performed post-baseline. 

If two target lesions coalesce the measurement of the coalesced mass is used.  If a 
large target lesion splits, the sum of the parts is used.

Measurements for target lesions that become small should continue to be recorded.  If 
the lesion is considered to have disappeared, 0 mm should be recorded; otherwise if a 
lesion is determined to be present but too small to measure, the lesion status will 
indicate “too small to measure and judged to be less than 10 mm” and 5 mm will be 
used in the calculation of the sum of the diameters.
NOTE: When nodal lesions decrease to <10 mm (normal), the actual measurement 
should still be recorded.


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Non-target Disease 

All non-measurable disease is non-target.  All measurable lesions not identified as 
target lesions are also included as non-target disease.  Measurements are not required 
but rather assessments will be expressed as ABSENT, INDETERMINATE (ie, Not 
Evaluable), PRESENT/NOT INCREASED, INCREASED.  Multiple non-target 
lesions in one organ may be recorded as a single item on the case report form 
(eg, ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver metastases’).
OBJECTIVE RESPONSE STATUS AT EACH EVALUATION
Disease sites must be assessed using the same technique as baseline, including consistent 
administration of contrast and timing of scanning.  If a change needs to be made the case 
should be discussed with the radiologist and the Sponsor to determine if substitution is 
possible.  If not, subsequent objective statuses are not evaluable. 
Target Disease

Complete Response (CR): Complete disappearance of all target lesions with the 
exception of nodal disease.  All target nodes must decrease to normal size (short axis 
<10 mm).  All target lesions must be assessed.

Partial Response (PR): Greater than or equal to 30% decrease under baseline of the 
sum of diameters of all target measurable lesions.  All target lesions must be assessed. 

Stable Disease (SD): Does not qualify for CR, PR or Progression.  All target lesions 
must be assessed.  Stable can follow PR only in the rare case that the sum increases 
by less than 20% from the nadir (smallest sum of diameters consider baseline and all 
assessments prior to the time point under evaluation), but enough that a previously 
documented 30% decrease no longer holds. 

Objective Progression (PD): 20% increase in the sum of diameters of target 
measurable lesions above the smallest sum observed (over baseline if no decrease in 
the sum is observed during therapy), with a minimum absolute increase of 5 mm. 

Not evaluable (NE): Progression has not been documented, and 

one or more target lesions have not been assessed; or

assessment methods used were inconsistent with those used at baseline; or

one or more target lesions cannot be measured accurately (eg, poorly visible 
unless due to being too small to measure); or

one or more target lesions were excised or irradiated and have not reappeared or 
increased. 


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Non-target Disease

CR: Disappearance of all non-target lesions and normalization of tumor marker levels 
(if being followed).  All lymph nodes must be ‘normal’ in size (<10 mm short axis).

Non-CR/Non-PD: Persistence of any non-target lesions and/or tumor marker level (if 
being followed) above the normal limits. 

PD: Unequivocal progression of pre-existing lesions.  Generally the overall tumor 
burden must increase sufficiently to merit discontinuation of therapy.  In the presence 
of SD or PR in target disease, progression due to unequivocal increase in non-target 
disease should be rare. 

Not evaluable (NE): Progression has not been determined and one or more non-target 
lesion sites have not been assessed or assessment methods used were inconsistent 
with those used at baseline or one or more non-target lesions cannot be assessed 
(eg, poorly visible or unclear images) or one or more non-target lesions were excised 
or irradiated and have not reappeared or increased. 
New Lesions 
The appearance of any new unequivocal malignant lesion indicates PD.  If a new lesion is 
equivocal, for example due to its small size, continued assessment will clarify the etiology.  
If repeat assessments confirm the lesion, then progression should be recorded on the date of 
the initial assessment.  A lesion identified in an area not previously scanned will be 
considered a new lesion.
Supplemental Investigations

If CR determination depends on a residual lesion that decreased in size but did not 
disappear completely, it is recommended the residual lesion be investigated with 
biopsy or fine needle aspirate.  If no disease is identified, objective status is CR.

If progression determination depends on a lesion with an increase possibly due to 
necrosis, the lesion may be investigated with biopsy or fine needle aspirate to clarify 
status. 
Subjective Progression
Patients requiring discontinuation of treatment without objective evidence of disease 
progression should not be reported as PD on tumor assessment CRFs.  This should be 
indicated on the end of treatment CRF as off treatment due to Global Deterioration of Health 
Status.  Every effort should be made to document PD even after discontinuation of study 
treatment. 


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Determination of Tumor Response by RECIST
When both target and non-target lesions are present, individual assessments will be recorded 
separately.  New lesions will also be recorded separately.  Determination of tumor response 
at each assessment based on target, non-target and new lesions is summarized in the 
following table.
Table 16.
Objective Response Status at Each Assessment for Patients with Measurable 
Disease at Baseline
Target Lesions
Non-target Lesions
New Lesions
Objective status
CR
CR
No
CR
CR
Non-CR/Non-PD or not all 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
*Non-PD includes CR and Non-CR/Non-PD
** New lesions must be unequivocal 
Determination of Best Overall Response
The best overall response is the best response recorded from randomization (for randomized 
cohorts) or the start of the treatment (for non-randomized cohorts) until disease 
progression/recurrence (taking as reference for progressive disease the smallest sum on 
study).  For CR and PR, the patient’s best response assignment will depend on the 
achievement of both measurement and confirmation criteria.  CR and PR must be confirmed 
by 2 measurements at least 4 weeks apart.  In the case of SD, follow up measurements must 
have met the SD criteria at least once after start of the treatment at a minimum interval of 
6 weeks.


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Appendix 4. Cockroft-Gault Formula
[(140-Age) * Mass (in kg)]/[72 * Serum creatinine (in mg/dL)].
If the patient is female, multiply the above by 0.85.


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Appendix 5. Detailed Dose Escalation/De-escalation Scheme for BLRM Design – prior 
to implementation of Amendment 3
This appendix provides the details of the statistical model, the derivation of prior 
distributions from historical data, the results of the Bayesian analyses and respective dosing 
decisions for some hypothetical data scenarios, and a simulation study of the operating 
characteristics of the model.  In this appendix, no data from study B9991025 for the 
combination of avelumab and talazoparib is considered.  However, prior to the initiation of 
the dose finding for the triplet combination (avelumab, binimetinib and talazoparib), all 
applicable DLT data from study B9991025 and the doublet combination of study B9991033 
will be incorporated into the BLRM to guide the starting dose and dose finding of the triplet 
combination.
In this appendix, the reported avelumab dose is 10 mg/kg.  Note that the fixed dose of 
800 mg to be investigated in this study is expected to be equivalent to the 10 mg/kg dose 
(see Section 1.2.6.1).
A.5.1. Statistical Model
The statistical model for triplet combination dose-DLT data comprises single-agent toxicity 
parts, which allow the incorporation of single-agent toxicity data, and interaction parts.
A.5.1.1. Single Agent Parts 
Let () be the risk of DLT for avelumab given as a single agent at dose ; 	(	) be the 
risk of DLT for binimetinib given as a single agent at dose 	; and 
(
) be the risk of 
DLT for talazoparib given as a single agent at dose 
.  These single agent dose-DLT models 
are logistic:
avelumab:
logit() = log() +  log( 
∗
⁄
)
binimetinib:
logit	(	) = log(	) + 	 log(	 	
∗
⁄
)
talazoparib:
logit
(
) = log(
) + 
 log(
 
∗
⁄
)
where 
∗=10 mg/kg, 	
∗=45 mg, and 
∗= 1.0 mg are used to scale the doses of avelumab, 
binimetinib, and talazoparib, respectively.  Hence, , 	 , and 
 (all >0) are the single-
agent odds of a DLT at 
∗mg/kg, 	
∗mg, and 
∗mg, respectively; and  , 	, and 
(>0) 
are the increase in the log-odds of a DLT by a unit increase in log-dose.
A.5.1.2. Interaction Parts
Under an assumption that there is no interaction, the risk of a DLT at dose  of avelumab, 
dose 	 of binimetinib, and dose 
 of talazoparib is:
	
 (, 	, 
) = 1 −1 −()1 −	(	)1 −
(
)


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To model the interaction between avelumab, binimetinib, and talazoparib, the following four 
odds multipliers are introduced.

	: Two-way interaction between avelumab and binimetinib.


: Two-way interaction between avelumab and talazoparib.

	
: Two-way interaction between binimetinib and talazoparib.

	
: Three-way interaction between avelumab, binimetinib and talazoparib.
The risk of DLT for combination dose (, 	, 
) is then given by:
odds	
(, 	, 
) =  (	, 
, 	
, 	
) × odds	
 (, 	, 
)
 (	, 
, 	
, 	
) = exp(	 ×  
∗
⁄
× 	 	
∗
⁄
)
                                                                × exp( 
 ×  
∗
⁄
× 
 
∗)
⁄
                                                                × exp(	
 × 	 	
∗
⁄
× 
 
∗)
⁄
                                                              × exp(	
 ×  
∗
⁄
× 	 	
∗
⁄
× 
 
∗
⁄
)
where odds() =  (1 −)
⁄
; %& is the log-odds ratio between the interaction and no 
interaction model at the reference doses of drug i and j and a zero dose of the third drug.  For 
example, 	 is the log-odds ratio between the interaction and no interaction model at 
avelumab = 10 mg/kg, binimetinib= 45 mg, and talazoparib=0 mg.  Therefore, 	 + 
 +
	
 + 	
 is the log-odds ratio between the interaction and no interaction model at the 
reference doses for all three drugs.  Here  = 0 corresponds to no interaction, with  > 0 and 
 < 0 representing synergistic and antagonistic toxicity respectively.
The dose-DLT data of the doublet combination of avelumab and binimetinib will be modeled 
using the same model by setting the talazoparib dose 
 = 0 mg.  The model will contain 
parameters related to single agent effects of avelumab (log(), log()), binimetinib 
(log(	), log(	)), and two-way interaction between avelumab and binimetinib (	).
A.5.2. Prior Specifications
The Bayesian approach requires the specification of prior distributions for all model 
parameters, which include the single agent parameters log(), log() for avelumab, 
log(	), log(	) for binimetinib, log(
), log(
) for talazoparib, and the interaction 
parameters  = (	, 
, 	
, 	
).  A meta-analytic-predictive (MAP) approach was used 
to derive the prior distribution for the single-agent model parameters. 


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A.5.2.1. Prior Distribution for the Logistic Parameters for Single Agent
This section illustrates the derivation of prior distributions for single agent model parameters 
(log()), log()))’s using the available single agent dose-DLT information via a MAP 
approach.  
A.5.2.1.1. Description of the Meta-Analytic-Predictive Approach
The aim of the MAP approach is to derive a prior distribution for the logistic parameters 
log(∗), log(∗) of the new trial using DLT data from historical studies.  Let *+) and ,+)
be the number of patients with a DLT, and the total number of patients at dose  in historical 
trial - (- = 1, … , 〈0〉).  The corresponding probability of a DLT is +).  The model 
specifications are as follows:
*+) | +) ~ Bin(+), ,+))
logit(+)) = log()) + ) log(/∗)
56 ()), 56 ()) 7 8, 9:()) ~ BVN8, 9:()),
s = 1, … , 〈0〉
56 (∗), 56 (∗) 7 8, 9: (∗) ~ BVN8, 9: (∗)
The historical trials are partitioned into 〈?〉exchangeability groups, with the exchangeability 
group membership of historical trial - being represented by  (-).  The new trial is assigned 
to exchangeability group  (∗).  The parameter 8 = (8, 8	)  is the mean for the logistic 
parameters, and 9: is the between-trial covariance matrix for exchangeability 
group  = 1, … , 〈?〉.  Covariance matrix 9: is defined by the standard deviations (:, :	), 
and correlation (a common value for is used across all groups).  The parameters : and 
:	 quantify the degree of between trial heterogeneity for exchangeability group  .  With 
different prior distributions for the parameter sets :, :	 it is possible to allow for 
differential discounting for the historical strata.  In this way the quality and relevance of 
historical data can be accounted for in the meta-analysis.  The following priors will be used 
for these parameters:  

normal priors for 8 and 8	, 

log-normal priors for : and :	, and 

a uniform prior for .
The MAP prior for single-agent model parameters in the new trial, 56 (∗), 56 (∗), is the 
predictive distribution 
56 (∗), 56 (∗) 7 (*+), ,+) ∶- = 1, … , 〈0〉)


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Since the predictive distribution is not available analytically, the Markov chain Monte Carlo
(MCMC) method is used to simulate values from this distribution.  This is implemented 
using JAGS version 4.0.
A.5.2.1.2. Single Agent Avelumab
Dose-DLT data in the avelumab IB4 (Section 5.3.1.1.1.7) from study EMR100070-001 as 
presented in Table 17 are used to derive the prior of the single agent logistic parameters for 
avelumab.  Based on clinical review, the population of the current study is moderately similar 
to study EMR100070-001.  
Table 17.
Historical Dose Limiting Toxicity Data from Study EMR100070-001
Avelumab 
dose (mg/kg 
Q2W)
Number of 
patients
Number of patient with 
DLTs
1
4
0
3
3
0
10
6
0
20
6
1
Abbreviations: mg=milligram: DLT=dose limiting toxicity; Q2W=every 2 weeks.
Weakly informative normal priors are assumed for 8A and 8	A, with means corresponding to 
a 50% chance of DLT at avelumab=10 mg/kg, and a doubling in dose leading to a doubling 
in the odds of the risk of a DLT, respectively.  Priors for A and 	A are assigned such that 
(1) their medians correspond to moderate between trial heterogeneity, and (2) their 
uncertainty (95% prior interval) cover plausible between-trial standard deviations 
(Neuenschwander 2014).38  
The prior distributions for the model used for deriving the MAP priors are specified in
Table 18 below.  
Table 18.
Prior Distributions for the Parameters of the MAP Model Used to Derive 
the Prior for the Single-Agent Avelumab Model Parameters
Parameter
Prior distribution
8A
N(mean = 0, sd = 2)
8	A
N(mean = 0, sd=1)
A
log-normal(mean = log(0.25), sd = log(2)/1.96)
	A
log-normal(mean = log(0.125), sd = log(2)/1.96)
A
uniform(-1,1)


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A.5.2.1.3.
Single Agent Binimetinib
Dose-DLT data in the binimetinib IB30 (section 5.2.3.1.1) from studies ARRAY-162-111 and 
CMEK162X11 as presented in Table 19 are used to derive the prior of the single agent 
logistic parameters for binimetinib.
Table 19.
Historical Dose Limiting Toxicity Data from Studies ARRAY-162-111 and 
CMEK162X1101
Study ARRAY-162-111*
Study CMEK162X1101*
Binimetinib 
dose (mg BID)
Number of 
patients
Number of patients 
with DLTs
Number of patients
Number of 
patients with 
DLTs
30
4
0
6
0
45
44
2
15
2
60
41
2
80
4
2
Abbreviations: BID=twice a day; DLT=dose limiting toxicity.
Weakly informative normal priors are assumed for 8B and 8	B, with means corresponding to 
a 50% chance of DLT at avelumab=45 mg, and a doubling in dose leading to a doubling in 
the odds of the risk of a DLT, respectively.  The priors for between-trial heterogeneity 
parameters are set in the following way: 

Priors for B and 	B (ARRAY-162-111) are assigned such that (1) their medians 
correspond to moderate between-trial heterogeneity, and (2) their uncertainty 
(95% prior interval) cover plausible between-trial standard deviations.  

Priors for 	B and 		B (CMEK162X1101) are assigned such that (1) their medians 
correspond to large between-trial heterogeneity, and (2) their uncertainty (95% prior 
interval) cover plausible between-trial standard deviations. 
Study ARRAY-162-111 is a phase 1 study conducted in advanced or metastatic cancer 
patients the United States.  Study CMEK162X1101 is a study in Japanese patients with 
advanced solid tumors whose disease has progressed despite standard therapy or for whom 
no standard therapy exists.  The patient population in study CMEK162X1101 is less similar 
to study B9991033 and hence large between trial heterogeneity is assumed.
The prior distributions for the model used for deriving the MAP priors are specified in
Table 20 below.  


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Table 20.
Prior Distributions for the Parameters of the MAP Model Used to Derive 
the Prior for the Single-Agent Binimetinib Model Parameters
Parameter
Prior distribution
8B
N(mean = 0, sd =2)
8	B
N(mean = 0, sd=1)
B
log-normal(mean = log(0.25), sd = log(2)/1.96)
	B
log-normal(mean = log(0.125), sd = log(2)/1.96)
	B
log-normal(mean = log(1), sd = log(2)/1.96)
		B
log-normal(mean = log(0.5), sd = log(2)/1.96)
B
uniform(-1,1)
(B, 	B) = the degree of between trial heterogeneity for Study ARRAY-162-111; (	B, 		B) = the degree of 
between-trial heterogeneity for Study CMEK162X1101.
A.5.2.1.4 Single Agent Talazoparib
Dose-DLT data from study PRP-001 (C3441007) (de Bono et al. 2017)59 presented in
Table 21 are used to derive the prior of the single agent logistic parameters for talazoparib.
Table 21.
Historical Dose Limiting Toxicity data from study NCT01286987
Talazoparib dose 
(mg QD)
Number of patients
Number of patients with DLTs
0.025
3
0
0.05
3
0
0.1
3
0
0.2
3
0
0.4
3
0
0.6
6
0
0.9
6
1
1.0
6
0
1.1
6
2
Abbreviations: DLT=dose limiting toxicity; QD=once daily.
Weakly informative normal priors are assumed for 8C and 8	C, with means corresponding to 
a 50% chance of DLT at talazoparib=1.0 mg, and a doubling in dose leading to a doubling in 
the odds of the risk of a DLT, respectively.  Priors for C and 	C are assigned such that 
(1) their medians correspond to moderate between trial heterogeneity, and (2) their 
uncertainty (95% prior interval) cover plausible between-trial standard deviations.  


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Table 22.
Prior Distributions for the Parameters of the MAP Model Used to Derive 
the Prior for the Single-Agent Talazoparib Model Parameters
Parameter
Prior distribution
8C
N(mean = 0, sd = 2)
8	C
N(mean = 0, sd=1)
C
log-normal(mean = log(0.25), sd = log(2)/1.96)
	C
log-normal(mean = log(0.125), sd = log(2)/1.96)
C
uniform(-1,1)
A.5.2.2. Prior Distribution for the Interaction Parameters
Based on pharmacometrics assessment, no two-way or three-way drug-drug interaction is 
expected, although uncertainty remains.  Based upon this, normal priors for the log-odds 
multipliers 	, 
, 	
, 	
 are used.  All priors are centered on an assumption of no
drug-drug interaction, but with appropriate uncertainty that allows for both synergistic and 
antagonistic toxicity.  The prior for 	, 
, 	
, 	
 are specified as percentiles of increase 
in the odds of DLT due to possible interaction in combination therapy at reference doses;
	 is normally distributed, with mean 0 and sd 0.639 (corresponds to no increase in 
DLT odds at median and 3.5 fold increase in DLTs at 97.5th percentile).
	
 is normally distributed, with mean 0 and sd 0.207 (corresponds to no increase in 
DLT odds at median and 1.5 fold increase in DLTs at 97.5th percentile).

 is normally distributed, with mean 0 and sd 0.207 (corresponds to no increase in 
DLT odds at median and 1.5 fold increase in DLTs at 97.5th percentile).
	
 is normally distributed, with mean 0 and sd 0.025 (corresponds to no increase in 
DLT odds at median and 1.05 fold increase in DLTs at 97.5th percentile).
A.5.2.3. Summary of Prior Distributions 
The prior distributions of the model parameters are provided in Table 23.  Table 24 and 
Table 25 illustrates the resulting prior distribution of DLT rate derived from the prior given 
in Table 23 for the doublet combination and the triplet combination, respectively.  Based on 
the available information the starting dose avelumab= 10 mg/kg and binimetinib= 45 mg for 
the doublet satisfies the EWOC criteria. 


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Table 23.
Prior Distribution for the Model Parameters
Parameter
Mean
Standard deviations
Correlation
Avelumab single agent parameters: BVN MAP Prior 
log(), log()
-2.665,-0.056
0.961, 0.825
-0.234
Binimetinib single agent parameters: BVN MAP Prior
log(	), log(	)
-2.795,  0.313 
0.578,  0.854 
-0.313
Talazoparib single agent parameters: BVN MAP Prior
log(
), log(
)
-1.757, 0.657  
0.727, 0.888
0.191
Interaction parameters: Normal prior
	
0
0.639

0
0.207
	
0
0.207
	
0
0.0249
	: Two-way interaction between avelumab and binimetinib;

: Two-way interaction between avelumab and talazoparib;
	
: Two-way interaction between binimetinib and talazoparib;
	
: Three-way interaction between avelumab, binimetinib and talazoparib.
Table 24.
Summary of Prior Distribution of Dose Limiting Toxicity Rates for the 
Doublet Combination of Avelumab in Combination with Binimetinib
Binimetinib 
dose (mg 
BID)
Prior probabilities that DLT rate 
is in the interval :
Mean
SD
Quantiles
[0, 0.16)
[0.16, 0.33)
[0.33,1]
2.5%
50%
97.5%
In combination with Avelumab = 10 mg/kg, Talazoparib = 0 mg
30
0.716
0.234
0.050
0.132
0.098
0.022
0.106
0.397
45
0.598
0.302
0.100
0.165
0.120
0.028
0.133
0.486
Abbreviations: BID=twice a day; DLT=dose limiting toxicity; SD=Standard Deviation.
From Table 25: in absence of doublet combination data, avelumab= 10mg/kg, 
binimetinib= 30 mg and talazoparib= 0.75 mg is an acceptable starting dose.  However, the 
final starting dose for the triplet will be determined after the dose-DLT data for the doublet is 
available.  Some hypothetical examples for the starting dose of the triplet are shown in Table 
27. 


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Table 25.
Summary of Prior Distribution of DLT Rates for the Triplet Combination of 
Avelumab in Combination with Binimetinib and Talazoparib
Bini 
dose 
(mg 
BID)
Tala 
dose 
(mg 
QD)
Prior probabilities that DLT rate 
is in the interval :
Mean
SD
Quantiles
[0, 0.16)
[0.16, 0.33)
[0.33,1]
2.5%
50%
97.5%
30
0.5
0.522
0.374
0.104
0.180
0.113
0.036
0.154
0.465
30
0.75
0.383
0.447
0.170
0.217
0.123
0.050
0.193
0.521
30
1.0
0.212
0.464
0.324
0.282
0.142
0.074
0.258
0.614
45
0.5
0.438
0.385
0.177
0.211
0.137
0.038
0.180
0.557
45
0.75
0.334
0.412
0.254
0.248
0.149
0.048
0.217
0.610
45
1.0
0.208
0.395
0.397
0.309
0.169
0.066
0.281
0.694
Avelumab dose fixed at 10 mg/kg every 2 weeks. 
Abbreviations: BID=twice a day; Bini=Binimetinib; QD=once daily; SD=Standard Deviation; Tala=Talazoparib.
A.5.3 Hypothetical on-Study Data Scenarios
To illustrate the performance of the Bayesian model used to guide dose finding, hypothetical 
dose finding scenarios following the provisional dose levels specified in the protocol are 
displayed.  In each case, the possible recommended dose that can be used in the next cohort 
of patients is shown.  These recommended doses are determined using the model-based 
assessment of the risk of DLT in future patients, EWOC criteria and maximum amount of 
escalation allows (100% of current dose).  In practice, the dose recommended by the adaptive 
Bayesian logistic model may be regarded as guidance.  The final recommendation will be 
based on overall safety profile and PK data.
Table 26 shows some hypothetical dose escalation data scenarios for the doublet combination 
and the corresponding recommendations for the next dose.  For example, in Scenario 1, if no 
DLT is observed among 3 DLT-evaluable patients at the starting dose, the recommendation 
is to remain at the same dose level with probability of overdosing of 0.03.  Note that the 
starting dose is already the maximum possible dose for the doublet combination.  In 
Scenario 3, if 2 patients experience a DLT out of 3 DLT-evaluable patients at the starting 
dose, the recommendation is to de-escalate the dose of binimetinib to 30 mg with avelumab 
remaining at 10 mg/kg; this lower dose combination has a probability of overdosing of 0.21.  
Scenarios 2, 4, 5 and 6 show clinically plausible next dose recommendations.


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Table 26.
Doublet Combination: Data Scenarios, Next Dose Recommendation, and the 
Interval Probability of Target Toxicity and Overdosing at Next Dose.
Dose Evaluated
D/N*
Next Dose (ND)
Pr(TT) 
at ND
Pr(OD) 
at ND
Scenarios
Ave 
(mg/kg 
Q2W)
Bini
(mg 
BID)
Tala
mg 
(QD)
Ave 
(mg/kg 
Q2W)
Bini
(mg 
BID)
Tala
(mg 
QD)
1
(10)
45
-
0/3
(10)
45
-
0.231
0.031
2
(10)
45
-
1/3
(10)
45
-
0.422
0.133
3
(10)
45
-
2/3
(10)
30
-
0.465
0.212
4
(10)
45
-
2/6
(10)
45
-
0.507
0.170
5
(10)
45
-
3/6
(10)
30
-
0.528
0.198
6
(10)
45
-
3/6
(10)
30
-
0.580
0.225
(10)
30
-
1/3
Abbreviations: Ave=avelumab; BID=twice a day; Bini=Binimetinib; *D=number of patients with DLT, N=number of 
DLT-evaluable patients; ND=next dose; Pr(TT)=probability of target toxicity; Pr(OD)=probability of overdosing; 
Tala=Talazoparib; QD=once daily; Q2W=every 2 weeks.
Table 27 shows the plausible starting dose level(s) for the triplet combinations given 
hypothetical data from the doublet combination.  If the dose-DLT profile of the doublet is 
safe at avelumab= 10mg/kg, binimetinib= 45mg (Scenarios 1 and 2), triplet dose escalation 
can begin at avelumab= 10mg/kg, binimetinib= 45mg and talazoparib= 0.75mg.  If 
2-3 patients with DLT observed out of 12 DLT-evaluable patients at avelumab= 10mg/kg, 
binimetinib= 45mg, the starting dose will be avelumab= 10mg/kg, binimetinib= 30mg and 
talazoparib= 0.75mg (Scenarios 3 and 4).
Table 27.
Triplet Combination: Clinically Meaningful Starting Dose Given 
Hypothetical Data from the Doublet Combination, and the Interval 
Probability of Target Toxicity and Overdosing at Starting Dose.
Doublet Dose 
D/N*
Triplet starting dose (SD) 
Pr(TT) at 
SD
Pr(OD) 
at SD
Scenarios
Ave 
(mg/kg 
Q2W)
Bini 
(mg 
BID)
Tala
(mg 
QD)
Ave 
(mg/kg 
Q2W)
Bini 
(mg 
BID)
Tala
(mg 
QD)
1
(10)
45
-
0/9
(10)
45
0.75
0.354
0.070
2
(10)
45
-
1/12
(10)
45
0.75
0.449
0.113
3
(10)
45
-
2/12
(10)
30
0.75
0.544
0.125
4
(10)
45
-
3/12
(10)
30
0.75
0.586
0.217
Abbreviations: Ave=avelumab;  BID=twice a day; Bini=Binimetinib; *D=number of patients with DLT, N=number of 
DLT-evaluable patients; ND=next dose; Pr(TT)=probability of target toxicity; Pr(OD)=probability of overdosing; Tala= 
Talazoparib; QD=once daily; Q2W=every 2 weeks.


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Table 28 shows data scenarios for the triplet combination and the corresponding 
recommendations for the next dose.
Table 28.
Triplet Combination: Data Scenarios (Given Hypothetical Doublet Data), 
Next Dose Recommendation, and the Interval Probability of Target Toxicity 
and Overdosing at Next Dose.
Dose evaluated 
D/N*
Next Dose (ND)
Pr(TT) 
at ND
Pr(OD) 
at ND
Scenarios
Ave 
(mg/kg 
Q2W)
Bini
(mg 
BID)
Tala
(mg 
QD)
Ave 
(mg/kg 
Q2W)
Bini
(mg 
BID)
Tala
(mg 
QD)
1
(10)
45
-
0/9
(10)
45
1.0
0.408
0.103
(10)
45
0.75
0/3
2
(10)
45
-
0/9
(10)
45
0.75
0.463
0.099
(10)
45
0.75
1/3
3
(10)
45
-
0/9
(10)
30
0.75
0.572
0.172
(10)
45
0.75
2/3
4
(10)
45
-
0/9
(10)
30
0.5 
0.566
0.170
(10)
45
0.75
3/3
5
(10)
45
-
3/12
(10)
45
0.75
0.571
0.225
(10)
30
0.75
0/3
6
(10)
45
-
3/12
(10)
30
0.75 
0.617
0.239
(10)
30
0.75
1/3
7
(10)
45
-
3/12
(10)
30
0.5 
0.624
0.249
(10)
30
0.75
2/3
Abbreviations: Ave=avelumab; BID=twice a day; Bini=Binimetinib; *D=number of patients with DLT; N=number of 
DLT-evaluable patients; ND=next dose Pr(TT)=probability of target toxicity; Pr(OD)=probability of overdosing; QD=once 
daily; Q2W=every 2 weeks; Tala=Talazoparib. 
Based on Table 26 and Table 28, the recommended next dose is adequate for all considered 
scenarios. 


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A.5.4. Operating Characteristics 
A simulation study is used to illustrate the properties of the dose finding model guided by 
BLRM.  Several example scenarios were investigated (A.5.4.1) and in each scenario 
1000 trials were simulated, with results summarized in A.5.4.3.
A.5.4.1. Simulation Scenarios 
Several scenarios are considered for doublet and triplet combinations.  Scenario 1 represents 
the case when the distribution of DLT coincides with prior, ie, the true DLT probability 
equals to mean of prior DLT.  Scenarios 2-3 of the doublet combination and scenarios 2-3 of 
the triplet combination represent an increased DLT rate compared to Scenario 1.  The true 
DLT rates under different scenarios for doublet and triplet combinations are shown in Table 
29 and Table 30, respectively.  Scenario 4 in Table 30 represents a true toxicity profile with 
dose combinations in both under-dose and over-dose regions.
Table 29.
Doublet Combination: Dose Limiting Toxicity Rate Scenarios (Fixed 
Avelumab Dose 10mg/kg Every 2 Weeks)
Scenarios 
Binimetinib (mg BID)
30
45
1.  Prior means
0.132
0.165
2.  50% more toxic
0.199
0.248
3.  Higher dose is overly toxic
0.200
0.400
Abbreviations: BID=twice a day; mg=milligramme.
Table 30.
Triplet Combination: Dose Limiting Toxicity Rate Scenarios (Fixed 
Avelumab Dose 10mg/kg Every 2 Weeks)
Binimetinib (mg 
BID)
Talazoparib (mg QD)
0.5
0.75
1.0
0.5
0.75
1.0
Scenario 1. prior means
Scenario 2. 25% more toxic
30
0.180
0.217
0.282
0.225
0.272
0.352
45
0.211
0.248
0.309
0.264
0.310
0.387
Scenario 3. 50% more toxic
Scenario 4. With underdose and 
overdose
30
0.270
0.326
0.423
0.05
0.15
0.35
45
0.317
0.372
0.464
0.10
0.25
0.50
Abbreviations: BID=twice a day; QD=once daily; Q2W=every 2 weeks.


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A.5.4.2. Simulation Details 
Simulations were performed using R version 3.3.2 (The R-project for Statistical Computing.  
https://www.r-project.org/), and JAGS 4.0 to perform the MCMC analyses. 
For each scenario, data for 1000 trials were generated, with a cohort size of 3.  At any time 
during the course of dose finding, escalation to doses where the risk of overdose exceeds 
25% is not permitted.  The ‘next dose recommendation’ is the dose with maximum 
probability of overdose among all dose levels that meet the EWOC criteria.
For the doublet combination, the starting dose was avelumab 10 mg/kg (fixed) and 
binimetinib 45 mg.  The maximum number of patients per trial was set to 30.  The trial was 
stopped when the following criteria were met:
At least 6 patients have been treated at the recommended MTD D.
The dose D satisfies one of the following conditions:

The probability of target toxicity at dose D exceeds 50%, 
ie, Pr(0.16 ≤+E <0.33)≥50%; 

A minimum of 9 patients have been treated in the trial.
A simulation of the triplet combination is performed using the starting dose of avelumab 
10 mg/kg (fixed), binimetinib 30mg, and talazoparib 0.5mg.  No doublet combination data is 
considered in this exercise.  The maximum number of patients per trial was set to 60.  Each 
trial was stopped when the following criteria were met:
At least 6 patients have been treated at the recommended MTD D.
The dose D satisfies one of the following conditions:

The probability of target toxicity at dose D exceeds 50%, 
ie, Pr(0.16 ≤+E <0.33)≥50%;

A minimum of 15 patients have been treated in the trial.
The following metrics were assessed in the simulations:
Percentage of patients receiving dose combination(s) in the target toxicity interval; 
Percentage of patients receiving an overdose;
Percentage of patients receiving an underdose;
Probability that recommended MTD at the end of the trial is in the target toxicity 
interval;


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Probability that recommended MTD is an overdose;
Probability that recommended MTD is an underdose;
Percentage of trials stopped without MTD declaration;
Average sample size.
A.5.4.3. Simulation Results
Operating characteristics for the doublet and the triplet combinations are presented in
Table 31 and Table 32, respectively.  The percentage of trials with a correctly identified 
MTD ranges from 67.4% to 99%.  Furthermore the percentage of patients treated at overly 
toxic doses is well controlled.The average sample size for the doublet combination is 
between 9 and 11 patients, and the average sample size for the triplet combination is between 
9 to 17 patients.
Table 31.
Doublet Combination: Operating Characteristics
Scenarios
Patient allocation (%)
Pr (declare MTD)
% stop (no 
MTD)
Average 
sample size
TT
OD
UD
TT
OD
UD
1.  Prior means
95.7
0
4.3
0.927
0
0
7.3
9
2.  50% more toxic
100
0
0
0.857
0
00
14.3
9
3.  Higher dose level is 
overly toxic
48.6
51.4
0
0.674
0
00
32.6
11
Abbreviations: MTD=maximum tolerated dose: OD=overdose; TT=target toxicity; UD=underdose.
Table 32.
Triplet Combination: Operating Characteristics
Scenarios 
Patient allocation 
(%)
Pr (declare MTD)
% stop 
(no MTD)
Average 
sample 
size
TT
OD
UD
TT
OD
UD
1.  Prior means
100
0
0
0.922
0
0
7.8
14
2.  25% more toxic
83.6
16.4
0
0.877
0
0
12.3
13
3.  50% more toxic
89.6
10.4
0
0.831
0
0
16.9
9
4.  With underdose and 
overdose
35.0
28.9
36.0
0.990
0
0
1.0
17
Abbreviations: MTD=maximum tolerated dose; OD=overdose; TT=target toxicity; UD=underdose.


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Appendix 6. Detailed Dose Escalation/De-escalation Scheme for BLRM Design 
- Amendment 3 
This appendix provides the details of the statistical model, the derivation of prior 
distributions using historical data, analyses and respective dosing decisions for some 
hypothetical data scenarios, and a simulation study to evaluate the long-run operating 
characteristics for the model based dose-escalation of the binimetinib (7 days on/7 days off, 
7d/7d) + talazoparib doublet and the avelumab + binimetinib (7d/7d) + talazoparib triplet 
combinations.  If the binimetinib 5 days on/2 days off (5d/2d) dosing schedule is explored 
upon the completion of the binimetinib (7d/7d) + talazoparib doublet, the prior distributions 
of the model parameters for the binimetinib 5d/2d dosing schedule will be adjusted 
appropriately to account for new information prior to the initiation.  
Note that the fixed dose of 800 mg to be investigated in this study is expected to be 
equivalent to the 10 mg/kg dose (see Section 1.2.6.1).
A.6.1. Statistical Model
The statistical model comprises single-agent toxicity parts, which allow the incorporation of 
single-agent toxicity data, and interaction parts.
A.6.1.1. Single Agent Parts 
Let () be the risk of DLT for talazoparib given as a single agent at dose ; 	(	) be 
the risk of DLT for binimetinib given as a single agent at dose 	; and 
(
) be the risk of 
DLT for avelumab given as a single agent at dose 
.  These single agent dose-DLT models 
are logistic:
talazoparib:
logit() = log() +  log( 
∗
⁄
);
binimetinib:
logit	(	) = log(	) + 	 log(	 	
∗
⁄
);
avelumab:
logit
(
) = log(
) + 
 log(
 
∗
⁄
).
where 
∗=1.0 mg , 	
∗=45 mg, and 
∗= 10 mg/kg are used to scale the doses of 
talazoparib, binimetinib, and avelumab, respectively.  Hence, , 	 , and 
 (all >0) are the 
single-agent odds of a DLT at 
∗mg, 	
∗mg, and 
∗mg/kg, respectively; and  ,
	, and 
(>0) are the increase in the log-odds of a DLT by a unit increase in log-dose.
A.6.1.2. Interaction Parts
Under an assumption that there is no interaction, the risk of a DLT at dose  of talazoparib, 
dose 	 of binimetinib, and dose 
 of avelumab is:
	
 (, 	, 
) = 1 −1 −()1 −	(	)1 −
(
)


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To model the interaction between talazoparib, binimetinib, and avelumab, the following four 
odds multipliers are introduced.

	: two-way interaction between talazoparib and binimetinib.


: two-way interaction between talazoparib and avelumab.

	
: two-way interaction between binimetinib and avelumab.

	
: three-way interaction among talazoparib, binimetinib and avelumab.
The risk of DLT for combination dose (, 	, 
) is then given by:
odds	
(, 	, 
) =  (	, 
, 	
, 	
) × odds	
 (, 	, 
)
 (	, 
, 	
, 	
) = exp(	 ×  
∗
⁄
× 	 	
∗
⁄
)
                                                                × exp( 
 ×  
∗
⁄
× 
 
∗)
⁄
                                                                × exp(	
 × 	 	
∗
⁄
× 
 
∗)
⁄
                                                              × exp(	
 ×  
∗
⁄
× 	 	
∗
⁄
× 
 
∗
⁄
)
where odds() =  (1 −)
⁄
; %& is the log-odds ratio between the interaction and no 
interaction model at the reference doses of  drug i and j and a zero dose of the third drug.  For 
example, 	 is the log-odds ratio between the interaction and no interaction model at 
talazoparib=1.0mg, binimetinib= 45 mg, and avelumab=0 mg.  Therefore, 	 + 
 + 	
 +
	
 is the log-odds ratio between the interaction and no interaction model at the reference 
doses for all three drugs.  Here  = 0 corresponds to no interaction, with
 > 0 and  < 0 representing synergistic and antagonistic toxicity respectively.
The dose-DLT data of the doublet of talazoparib and binimetinib combination (7d/7d) will be 
modeled using the same model by setting the avelumab dose 
 = 0 mg/kg.  The model will 
contain parameters related to single agent effects of talazoparib (log(), log()), 
binimetinib (log(	), log(	)), and the interaction between talazoparib and binimetinib 
(	).
A.6.2. Prior Specifications
The Bayesian approach requires the specification of prior distributions for all model 
parameters, which include the single agent parameters log(), log() for talazoparib, 
log(	), log(	) for binimetinib, log(
), log(
) for avelumab, and the interaction 
parameters  = (	, 
, 	
, 	
).  A meta-analytic-predictive (MAP) approach was used 
to derive the prior distribution for the single-agent model parameters. 


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A.6.2.1. Prior Distribution for the Logistic Parameters for Single Agent
This section illustrates the derivation of prior distributions for single agent model parameters 
(log()), log()))’s using the available single agent dose-DLT information via a MAP 
approach.  
A.6.2.1.1. Description of the Meta-Analytic-Predictive Approach
The aim of the MAP approach is to derive a prior distribution for the logistic parameters 
log(∗), log(∗) of the new trial using DLT data from historical studies.  Let *+) and ,+)
be the number of patients with a DLT, and the total number of patients at dose  in historical 
trial - (- = 1, … , 〈0〉).  The corresponding probability of a DLT is +).  The model 
specifications are as follows:
*+) | +) ~ Bin(+), ,+))
logit(+)) = log()) + ) log(/∗)
56 ()), 56 ()) 7 8, 9:()) ~ BVN8, 9:()),
s = 1, … , 〈0〉
56 (∗), 56 (∗) 7 8, 9: (∗) ~ BVN8, 9: (∗)
The historical trials are partitioned into 〈?〉exchangeability groups, with the exchangeability 
group membership of historical trial - being represented by  (-).  The new trial is assigned 
to exchangeability group  (∗).  The parameter 8 = (8, 8	)  is the mean for the logistic 
parameters, and 9: is the between-trial covariance matrix for exchangeability group
 = 1, … , 〈?〉.  Covariance matrix 9: is defined by the standard deviations (:, :	), and 
correlation (a common value for is used across all groups).  The parameters : and :	
quantify the degree of between trial heterogeneity for exchangeability group  .  With 
different prior distributions for the parameter sets :, :	 it is possible to allow for 
differential discounting for the historical strata.  In this way the quality and relevance of 
historical data can be accounted for in the meta-analysis.  The following priors will be used 
for these parameters:  

normal priors for 8 and 8	;

log-normal priors for : and :	, and 

a uniform prior for .
The MAP prior for single-agent model parameters in the new trial, 56 (∗), 56 (∗), is the 
predictive distribution 
56 (∗), 56 (∗) 7 (*+), ,+) ∶- = 1, … , 〈0〉)


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Since the predictive distribution is not available analytically, the Markov chain Monte Carlo
(MCMC) method is used to simulate values from this distribution.  This is implemented 
using JAGS version 4.0.
A.6.2.1.2. Single Agent Talazoparib
Dose-DLT data from study PRP-001 (C3441007) (de Bono et al. 2017)59 presented in Table
33 are used to derive the prior of the single agent logistic parameters for talazoparib.
Table 33.
Historical Dose Limiting Toxicity data from study NCT01286987
Talazoparib dose 
(mg QD)
Number of patients
Number of patients with DLTs
0.025
3
0
0.05
3
0
0.1
3
0
0.2
3
0
0.4
3
0
0.6
6
0
0.9
6
1
1.0
6
0
1.1
6
2
Abbreviations: DLT=dose-limiting toxicity; QD=once daily; mg=milligram.
Weakly informative normal priors are assumed for 8C and 8	C, with means corresponding to 
a 50% chance of DLT at talazoparib=1.0 mg, and a doubling in dose leading to a doubling in 
the odds of the risk of a DLT, respectively.  Priors for C and 	C are assigned such that (1) 
their medians correspond to moderate between trial heterogeneity, and (2) their uncertainty 
(95% prior interval) cover plausible between-trial standard deviations.  The prior 
distributions for the model used for deriving the MAP priors for talazoparib are specified in 
Table 34 below.  
Table 34.
Prior Distributions for the Parameters of the MAP Model Used to Derive 
the Prior for the Single-Agent Talazoparib Model Parameters
Parameter
Prior distribution
8C
N(mean = 0, sd = 2)
8	C
N(mean = 0, sd=1)
C
log-normal(mean = log(0.25), sd = log(2)/1.96)
	C
log-normal(mean = log(0.125), sd = log(2)/1.96)
C
uniform(-1,1)


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A.6.2.1.3. Single Agent Binimetinib 
A.6.2.1.3.1. Single Agent Binimetinib (Intermittent Dosing)
No prior Dose-DLT data are available for an intermittent binimetinib dosing schedule. 
Therefore, a mixture of bivariate normal prior is used for (log(α	), log(β	).  The 
components are 
Meta-analysis predictive prior using continuous regimen data for binimetinib
Weakly informative prior considering higher toxicity that has been observed in the 
continuous regimen
A.6.2.1.3.1. Single Agent Binimetinib (Continuous Dosing)
Dose-DLT data in the binimetinib IB30 from studies ARRAY-162-111 and CMEK162X11 
(continuous dosing schedule) as presented in Table 35 are used to derive the MAP priors of 
the single agent logistic parameters for continuous binimetinib.
Table 35.
Historical Dose Limiting Toxicity Data from Studies ARRAY-162-111 and 
CMEK162X1101
Study ARRAY-162-111*
Study CMEK162X1101*
Binimetinib 
dose (mg BID)
Number of 
patients
Number of patients 
with DLTs
Number of patients
Number of 
patients with 
DLTs
30
4
0
6
0
45
44
2
15
2
60
41
2
80
4
2
Abbreviations: BID=twice a day; DLT=dose-limiting toxicity; mg=milligram.
Weakly informative normal priors are assumed for 8B and 8	B, with means corresponding to 
a 50% chance of DLT at binimetinib=45 mg, and a doubling in dose leading to a doubling in 
the odds of the risk of a DLT, respectively.  The priors for between-trial heterogeneity 
parameters are set in the following way:  

Priors for B and 	B (ARRAY-162-111) are assigned such that (1) their medians 
correspond to moderate between-trial heterogeneity, and (2) their uncertainty 
(95% prior interval) cover plausible between-trial standard deviations.  

Priors for 	B and 		B (CMEK162X1101) are assigned such that (1) their medians 
correspond to large between-trial heterogeneity, and (2) their uncertainty (95% prior 
interval) cover plausible between-trial standard deviations. 


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Study ARRAY-162-111 is a phase 1 study conducted in advanced or metastatic cancer 
patients the United States.  Study CMEK162X1101 is a study in Japanese patients with 
advanced solid tumors whose disease has progressed despite standard therapy or for whom 
no standard therapy exists.  The patient population in study CMEK162X1101 is less similar 
to study B9991033 and hence large between trial heterogeneity is assumed.
The prior distributions for the model used for deriving the MAP priors for binimetinib are 
specified in Table 36 below.
Table 36.
Prior Distributions for the Parameters of the MAP Model Used to Derive 
the Prior for the Single-Agent Binimetinib Model Parameters
Parameter
Prior distribution
8B
N(mean = 0, sd =2)
8	B
N(mean = 0, sd=1)
B
log-normal(mean = log(0.25), sd = log(2)/1.96)
	B
log-normal(mean = log(0.125), sd = log(2)/1.96)
	B
log-normal(mean = log(1), sd = log(2)/1.96)
		B
log-normal(mean = log(0.5), sd = log(2)/1.96)
B
uniform(-1,1)
(B, 	B) = the degree of between trial heterogeneity for Study ARRAY-162-111; (	B, 		B) = the degree of between-
trial heterogeneity for Study CMEK162X1101.
A.6.2.1.3.2. Weakly Informative Prior for Binimetinib (7d/7d) Regimen
Higher DLT rates were observed in the avelumab + binimetinib doublet combination than 
that observed in historical binimetinib studies. To account for uncertainty, mixture priors of 
the MAP prior and a weakly informative prior were used for the binimetinib 7d/7d regimen 
single agent model parameters. The default weakly informative multivariate normal (MVN) 
prior of (log(α) and log(β)) is used where (mean1, mean2, standard deviation1, standard 
deviation2, correlation) = (logit(p*), 0, 2, 1, 0).  Where p* is the anticipated DLT rate at the 
scaling dose 45 mg.  Based on historical continuous binimetinib data, the apriori probability 
of DLT at the reference dose 45 mg is exp(-2.795)/(1+exp(-2.795)) ~= 6%.  We used a prior 
of doubling the DLT rate (12%) at the reference dose, ie. (mean1, mean2, standard deviation1, 
standard deviation2, correlation) =(logit(0.12), 0, 2, 1, 0) = (-1.992, 0, 2, 1, 0).
Apriori 50% weights are assigned to MAP prior and weakly informative priors respectively.
A.6.2.1.4. Single Agent Avelumab
Dose-DLT data in the avelumab IB4 from study EMR100070-001 as presented in Table 37
are used to derive the prior of the single agent logistic parameters for avelumab.  Based on 
clinical review, the population of the current study is moderately similar to study 
EMR100070-001.  


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Table 37.
Historical Dose Limiting Toxicity Data from Study EMR100070-001
Avelumab dose 
(mg/kg Q2W)
Number of patients
Number of patient with DLTs
1
4
0
3
3
0
10
6
0
20
6
1
Abbreviations: mg=milligram: DLT=dose-limiting toxicity; Q2W=every 2 weeks.
Weakly informative normal priors are assumed for 8A and 8	A, with means corresponding to 
a 50% chance of DLT at avelumab=10 mg/kg, and a doubling in dose leading to a doubling 
in the odds of the risk of a DLT, respectively.  Priors for A and 	A are assigned such that 
(1) their medians correspond to moderate between trial heterogeneity, and (2) their 
uncertainty (95% prior interval) cover plausible between-trial standard deviations 
(Neuenschwander 2014).38  
The prior distributions for the model used for deriving the MAP priors are specified in
Table 38 below.  
Table 38.
Prior Distributions for the Parameters of the MAP Model Used to Derive 
the Prior for the Single-Agent Avelumab Model Parameters
Parameter
Prior distribution
8A
N(mean = 0, sd = 2)
8	A
N(mean = 0, sd=1)
A
log-normal(mean = log(0.25), sd = log(2)/1.96)
	A
log-normal(mean = log(0.125), sd = log(2)/1.96)
A
uniform(-1,1)
A.6.2.2. Prior Distribution for the Interaction Parameters
Normal priors for the log-odds multipliers 	, 
, 	
, 	
  are used.  Based on 
pharmacometrics assessment, no drug-drug interaction between avelumab and talazoparib 
and between binimetinib and talazoparib, or three-way drug-drug interaction is expected, 
although uncertainty remains.  The priors for these interactions are centered on an 
assumption of no drug-drug interaction, but with appropriate uncertainty that allows for both 
synergistic and antagonistic toxicity.  Based on the data from continuous binimetinib and 
avelumab doublet combination in B9991033, synergistic interaction between these two drugs 
is expected. The prior for 	, 
, 	
, 	
 are specified as percentiles of increase in the 
odds of DLT due to possible interaction in combination therapy at reference doses;


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	 is normally distributed, with mean 0 and sd 0.207 (corresponds to no increase in DLT 
odds at median and 1.5 fold increase in DLTs at 97.5th percentile).

 is normally distributed, with mean 0 and sd 0.207 (corresponds to no increase in DLT 
odds at median and 1.5 fold increase in DLTs at 97.5th percentile).
	
 is normally distributed, with mean 0.140 and sd 0.636 (corresponds to 15% increase in 
DLT odds at median and 4-fold increase in DLTs at 97.5th percentile)	
 is normally 
distributed, with mean 0 and sd 0.025 (corresponds to no increase in DLT odds at median and 
1.05 fold increase in DLTs at 97.5th percentile).
	: Two-way interaction between talazoparib and binimetinib;

: Two-way interaction between talazoparib and avelumab;
	
: Two-way interaction between binimetinib and avelumab;
	
: Three-way interaction among talazoparib, binimetinib and avelumab.
A.6.2.3.  Use of Dose-DLT Data from B9991025 Study
In this appendix, data from study B9991025 for the combination of avelumab and talazoparib 
was incorporated in the prior distribution of the DLT, feasible starting dose assessment, data 
scenarios and simulations for the avelumab + binimetinib (7d/7d) + talazoparib triplet. 
Based on the preliminary data from the Phase 1b portion of study B9991025, a total of 
12 patients were enrolled at the starting dose level of 800 mg avelumab Q2W in combination 
with talazoparib at 1.0 mg once daily. All 12 patients were DLT-evaluable with a DLT rate 
of 3/12. This information was incorporated using a direct down-weighting approach. The 
weight is calculated using the formula below: 
O =

P QRQ
SQ T
  
where N=12 (total number of patients enrolled in the Phase 1b of study B9991025)
        σ =2 (population standard deviation)
        τ = 0.25 (moderate heterogeneity between populations in the Phase 1b of study 
B9991025 and the triplet of this study in terms of DLT).
A.6.2.3. Summary of Prior Distributions 
The prior distributions of the model parameters are provided in Table 39.  


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Table 39.
Prior Distribution for the Model Parameters
Parameter
Mean
Standard deviations
Correlation
Talazoparib single agent parameters: BVN MAP  Prior 
log(), log()
-1.757, 0.657  
0.727, 0.888
0.191
Binimetinib single agent parameters: BVN MAP Prior
log(	), log(	)
-2.795,  0.313 
0.578,  0.854 
-0.313
Binimetinib single agent parameters: Weakly Informative Prior
log(	), log(	)
-1.992, 0
2, 1
0
Avelumab single agent parameters*: BVN MAP Prior
log(
), log(
)
-2.665,-0.056
0.961, 0.825
-0.234 
Interaction parameters: Normal prior
	
0
0.207

0
0.207
	
0.140
0.636
	
0
0.0249
	: Two-way interaction between talazoparib and binimetinib;

: Two-way interaction between talazoparib and avelumab;
	
: Two-way interaction between binimetinib and avelumab;
	
: Three-way interaction between avelumab, binimetinib and talazoparib.
Abbreviations: BVN=bivariate normal; MAP=meta-analytic-predictive.
Table 40 and Table 41 illustrate the resulting prior distribution of DLT rate derived from the 
prior given in Table 39 for the doublet and the triplet combinations, respectively.  The 
probability of overdosing for the proposed starting dose level for the doublet with 
binimetinib 45 mg (7d/7d) and talazoparib 0.75 mg is 0.189, which satisfies the EWOC 
criteria.
Table 40.
Summary of Prior Distribution of Dose Limiting Toxicity Rates for the 
Binimetinib (7d/7d) + Talazoparib Doublet
Bini 
dose 
(mg 
BID)
Tala 
dose 
(mg 
QD)
Prior probabilities that DLT rate is in 
the interval:
Mean
SD
Quantiles
[0, 0.16)
[0.16, 0.33)
[0.33,1]
2.5%
50%
97.5%
30
0.5
0.719
0.171
0.11
0.153
0.17
0.011
0.096
0.717
30
0.75
0.581
0.283
0.137
0.191
0.168
0.029
0.139
0.732
30
1.0
0.323
0.443
0.234
0.257
0.169
0.064
0.211
0.756
45
0.5
0.625
0.219
0.156
0.193
0.193
0.023
0.124
0.805
45
0.75
0.475
0.336
0.189
0.23
0.19
0.042
0.167
0.815
45
1.0
0.243
0.457
0.3
0.293
0.188
0.076
0.24
0.833
Abbreviations: Bini=binimetinib; mg=milligram; tala=talazoparib; BID=twice daily; OD=once daily; 
DLT=dose-limiting toxicity; SD=standard deviation.


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From Table 41, in absence of the binimetinib (7d/7d) doublet combination data, avelumab= 
10mg/kg, binimetinib= 30 mg (7d/7d) and talazoparib= 0.5 mg is an acceptable starting dose 
for the triplet.  However, the final starting dose for the triplet will be determined after the 
dose-DLT data for the binimetinib (7d/7d) + talazoparib doublet is available.  Some 
hypothetical examples for the starting dose of the triplet are shown in Table 43. 
Table 41.
Summary of Prior Distribution of DLT Rates for the Avelumab 
+ Binimetinib + Talazoparib Triplet
Bini 
dose 
(mg 
BID)
Tala 
dose 
(mg 
QD)
Prior probabilities that DLT rate is in the 
interval:
Mean
SD
Quantiles
[0, 0.16)
[0.16, 0.33)
[0.33,1]
2.5%
50%
97.5%
30
0.5
0.379
0.394
0.227
0.246
0.178
0.044
0.198
0.766
30
0.75
0.257
0.447
0.296
0.283
0.176
0.064
0.24
0.778
30
1.0
0.114
0.431
0.454
0.345
0.175
0.101
0.311
0.801
45
0.5
0.301
0.361
0.338
0.298
0.21
0.046
0.241
0.858
45
0.75
0.217
0.371
0.412
0.333
0.209
0.061
0.283
0.867
45
1.0
0.118
0.335
0.547
0.391
0.208
0.088
0.355
0.883
Avelumab dose fixed at 10 mg/kg every 2 weeks. 
Abbreviation: Bini=binimetinib; mg=milligram; tala=talazoparib; BID=twice daily; OD=once daily; 
DLT=dose-limiting toxicity; SD=standard deviation.
A.6.3. Hypothetical on-Study Data Scenarios
To illustrate the performance of the Bayesian model used to guide dose finding, hypothetical 
dose finding scenarios following the provisional dose levels specified in the protocol are 
displayed.  In each case, the possible recommended dose that can be used in the next cohort 
of patients is shown.  These recommended doses are determined using the model-based 
assessment of the risk of DLT in future patients, EWOC criteria and maximum amount of 
escalation allows (100% of current dose).  In practice, the dose recommended by the adaptive 
Bayesian logistic model may be regarded as guidance.  The final recommendation will be 
based on overall safety profile and PK data.
Table 42 shows some hypothetical dose escalation data scenarios for the binimetinib (7d/7d) 
+ talazoparib doublet combination and the corresponding recommendations for the next dose.  


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Table 42.
Binimetinib (7d/7d) + Talazoparib Doublet: Data Scenarios, Next Dose 
Recommendation, and the Interval Probability of Target Toxicity and 
Overdosing at Next Dose.
Scenarios
Dose Evaluated
D/N*
Next Dose (ND)
Pr(TT) at 
ND
Pr(OD) at 
ND
Ave (mg/kg 
Q2W)
Bini
(mg BID)
Tala
(mg QD)
Ave (mg/kg 
Q2W)
Bini
(mg BID)
Tala
(mg 
QD)
1
0
45
0.75
1/5
0
45
1
0.548
0.224
2
0
45
0.75
1/6
0
45
1
0.561
0.186
3
0
45
0.75
2/6
0
45
0.75
0.513
0.202
4
0
45
0.75
3/6
0
30
0.5
0.380
0.245
5
0
0
45
45
0.75
1
1/6
2/12
0
45
1
0.639
0.058
6
0
0
45
45
0.75
1
1/6
3/12
0
45
1
0.705
0.131
7
0
0
45
45
0.75
0.75
2/6
1/6
0
0
45
30
0.75
1.0
0.574
0.594
0.099
0.191
8
0
0
45
45
0.75
0.75
2/6
2/6
0
45
0.75
0.599
0.243
9
0
0
45
45
0.75
0.5
3/6
1/5
0
0
30
30
0.75
0.5
0.576
0.476
0.247
0.150
Abbreviations: Ave=avelumab; BID=twice a day; Bini=Binimetinib; mg=milligrams; mg/kg=milligrams per 
kilogram;*D=number of patients with DLT, N=number of DLT-evaluable patients; ND=next dose.
Table 43 shows the plausible starting dose level(s) for the avelumab + binimetinib (7d/7d) + 
talazoparib triplet given hypothetical data from the binimetinib (7d/7d) + talazoparib doublet.
Table 43.
Avelumab + Binimetinib (7d/7d) + Talazoparib Triplet: Clinically 
Meaningful Starting Dose Given Hypothetical Data from the Doublet, and 
the Interval Probability of Target Toxicity and Overdosing at Starting Dose.
Scenarios
Doublet Dose
D/N*
Triplet starting dose (SD)
Pr(TT) at 
SD
Pr(OD) 
at SD
Ave 
(mg/kg 
Q2W)
Bini 
(mg 
BID)
Tala
(mg 
QD)
Ave 
(mg/kg 
Q2W)
Bini 
(mg 
BID)
Tala
(mg 
QD)
1
0
0
45
45
0.75
1.0
1/6
2/12
(10)
(10)
30
45
0.75
0.5
0.525
0.424
0.168
0.215
2
0
0
45
45
0.75
1.0
1/6
3/12
(10)
(10)
30
45
0.75
0.5
0.530
0.424
0.204
0.245
3
0
0
45
45
0.75
1.0
0/6
1/12
(10)
(10)
30
45
1.0
0.75
0.548
0.381
0.209
0.198
4
0
45
0.75
3/12
(10)
30
0.5
0.486
0.180
5
0
45
0.75
4/12
No feasible starting dose for the triplet
6
0
0
45
30
0.75
0.5
3/6
3/12
No feasible starting dose for the triplet
7
0
45
0.75
3/6
No feasible starting dose for the triplet


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Scenarios
Doublet Dose
D/N*
Triplet starting dose (SD)
Pr(TT) at 
SD
Pr(OD) 
at SD
Ave 
(mg/kg 
Q2W)
Bini 
(mg 
BID)
Tala
(mg 
QD)
Ave 
(mg/kg 
Q2W)
Bini 
(mg 
BID)
Tala
(mg 
QD)
0
0
30
30
0.5
0.75
1/5
3/12
8
0
0
45
45
0.75
1.0
0/6
0/12
(10)
(10)
30
45
1.0
0.75
0.526
0.409
0.164
0.173
9
0
0
0
45
30
45
0.75
0.5
0.5
3/6
0/4
3/12
No feasible starting dose for the triplet
Abbreviations: Ave=avelumab; BID=twice a day; Bini=Binimetinib; mg=milligrams; mg/kg=milligrams per 
kilogram;*D=number of patients with DLT, N=number of DLT-evaluable patients; ND=next dose; 
Pr(TT)=probability of target toxicity; Pr(OD)=probability of overdosing; Tala=Talazoparib; QD=once daily; 
Q2W=every 2 weeks.
Table 44 shows data scenarios for the triplet and the corresponding recommendations for the 
next dose.
Table 44.
Avelumab + Binimetinib (7d/7d) + Talazoparib Triplet: Data Scenarios 
(Given Hypothetical Doublet Data), Next Dose Recommendation, and the 
Interval Probability of Target Toxicity and Overdosing at Next Dose.
Scenarios
Dose evaluated 
D/N*
Next Dose (ND)
Pr(TT) 
at ND
Pr(OD) at 
ND
Ave 
(mg/kg 
Q2W)
Bini
(mg 
BID)
Tala
(mg 
QD)
Ave 
(mg/kg 
Q2W)
Bini
(mg 
BID)
Tala
(mg 
QD)
1
0
0
(10)
45
45
45
0.75
1.0
0.5
1/6
2/12
0/6
(10)
45
1.0
0.510
0.175
2
0
0
(10)
45
45
45
0.75
1.0
0.5
1/6
2/12
1/6
(10)
45
0.75
0.544
0.186
3
0
0
(10)
45
45
45
0.75
1.0
0.5
1/6
2/12
2/6
(10)
30
0.75
0.641
0.207
4
0
0
(10)
45
45
45
0.75
1.0
0.5
1/6
2/12
3/6
Stop (all doses are overdosing)
5
0
0
(10)
45
45
45
0.75
1.0
0.5
1/6
3/12
0/6
(10)
45
1.0
0.517
0.229
6
0
0
(10)
45
45
45
0.75
1.0
0.5
1/6
3/12
1/6
(10)
45
0.75
0.548
0.215
7
0
0
(10)
45
45
45
0.75
1.0
0.5
1/6
3/12
2/6
(10)
30
0.75
0.633
0.240
8
0
0
(10)
45
45
45
0.75
1.0
0.5
1/6
3/12
3/6
Stop (all doses are overdosing)


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Scenarios
Dose evaluated 
D/N*
Next Dose (ND)
Pr(TT) 
at ND
Pr(OD) at 
ND
Ave 
(mg/kg 
Q2W)
Bini
(mg 
BID)
Tala
(mg 
QD)
Ave 
(mg/kg 
Q2W)
Bini
(mg 
BID)
Tala
(mg 
QD)
9
0
0
(10)
45
45
30
0.75
1.0
0.75
1/6
2/12
0/6
(10)
45
1.0
0.498
0.210
10
0
0
(10)
45
45
30
0.75
1.0
0.75
1/6
2/12
1/6
(10)
30
45
1.0
0.75
0.614
0.512
0.239
0.209
11
0
0
(10)
45
45
30
0.75
1.0
0.75
1/6
2/12
2/6
(10)
30
0.75
0.620
0.215
12
0
0
(10)
45
45
30
0.75
1.0
0.75
1/6
2/12
3/6
Stop (all doses are overdosing)
13
0
0
(10)
45
45
30
0.75
1.0
0.75
1/6
3/12
0/6
(10)
30
45
1.0
0.75
0.609
0.445
0.167
0.113
14
0
0
(10)
45
45
30
0.75
1.0
0.75
1/6
3/12
1/6
(10)
30
45
0.75
0.75
0.590
0.513
0.111
0.237
15
0
0
(10)
45
45
30
0.75
1.0
0.75
1/6
3/12
2/6
(10)
(10)
30
30
0.75
0.5
0.614
0.565
0.248
0.144
16
0
0
(10)
45
45
30
0.75
1.0
0.75
1/6
3/12
3/6
Stop (all doses are overdosing)
Abbreviations: Ave=avelumab; BID=twice a day; Bini=Binimetinib; mg=milligrams; mg/kg=milligrams per 
kilogram;*D=number of patients with DLT, N=number of DLT-evaluable patients; ND=next dose; 
Pr(TT)=probability of target toxicity; Pr(OD)=probability of overdosing; Tala=Talazoparib; QD=once daily; Q2W=every 
2 weeks.
A.6.4. Operating Characteristics 
A simulation study is used to illustrate the properties of the dose finding model guided by 
BLRM.  Several example scenarios were investigated (A.6.4.1) and in each scenario 
1000 trials were simulated, with results summarized in A.6.4.3.
A.6.4.1. Simulation Scenarios 
The true DLT rates under different scenarios for doublet and triplet combinations are shown 
in Table 45 and Table 46, respectively.  Several scenarios are considered: Scenario 1 
represents the case when the distribution of DLT coincides with prior, ie, the true DLT 
probability equals to mean of prior DLT.  Scenarios 2-3 represent a proportionally 
increased/decreased DLT rate compared to Scenario 1.  Scenario 4 in Table 45 represents a 
true toxicity profile with dose combinations in both under-dose and over-dose regions.


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Table 45.
Binimetinib (7d/7d) + Talazoparib Doublet: True Dose Limiting Toxicity 
Rate Scenarios
Binimetinib (mg 
BID)
Talazoparib (mg QD)
0.5
0.75
1.0
0.5
0.75
1.0
Scenario 1. prior means of DLT rate
Scenario 2. 25% more toxic than prior 
means
30
0.153
0.191
0.257
0.192
0.239
0.321
45
0.193
0.23
0.293
0.242
0.287
0.366
Scenario 3. 40% more toxic than prior 
means
Scenario 4. With underdose and 
overdose
30
0.215
0.268
0.360
0.100
0.200
0.300
45
0.271
0.322
0.410
0.150
0.250
0.450
Abbreviations: BID=twice a day; DLT=dose-limiting toxicity; QD=once daily; mg=milligram.
Table 46.
Avelumab + Binimetinib (7d/7d) + Talazoparib Triplet: True Dose Limiting 
Toxicity Rate Scenarios
Binimetinib (mg 
BID)
Talazoparib (mg QD)
0.5
0.75
1.0
0.5
0.75
1.0
Scenario 1. prior means of DLT rate
Scenario 2. 10% more toxic than prior 
means
30
0.246
0.283
0.345
0.271
0.311
0.379
45
0.298
0.333
0.391
0.328
0.366
0.430
Scenario 3. 10% less toxic than prior 
means
Scenario 4. With underdose and 
overdose
30
0.222
0.254
0.310
0.100
0.250
0.350
45
0.269
0.300
0.352
0.200
0.300
0.450
Avelumab dose fixed at 10 mg/kg every 2 weeks; Abbreviations: BID=twice a day; DLT=dose-limiting toxicity;
mg=milligram; QD=once daily.
A.6.4.2. Simulation Details 
Simulations were performed using R version 3.3.5 (The R-project for Statistical Computing.  
https://www.r-project.org/), and JAGS 4.8 to perform the MCMC analyses. 
For each scenario, data for 1000 trials were generated, with a cohort size of 3.  At any time 
during the course of dose finding, escalation to doses where the risk of overdose exceeds 
0.25 is not permitted.  The ‘next dose recommendation’ is the dose with maximum 
probability of overdose among all dose levels that meet the EWOC criteria.


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For the doublet, the starting dose was binimetinib 45 mg and talazoparib 0.75 mg.  For the 
triplet, the starting dose is the lowest dose of avelumab 10 mg/kg, binimetinib 30 mg, and 
talazoparib 0.5 mg.  No on-trial binimetinib + talazoparib doublet combination data is 
considered in this exercise.  The maximum number of patients per trial was set to 60.  The 
trial was stopped when the following criteria were met:
At least 6 patients have been treated at the recommended MTD D.
The dose D satisfies one of the following conditions:

The probability of target toxicity at dose D exceeds 50%, 
ie, Pr(0.16 ≤+E <0.33)≥50%;

A minimum of 15 patients have been treated in the trial.
The following metrics were assessed in the simulations:
Percentage of patients receiving dose combination(s) in the target toxicity interval; 
Percentage of patients receiving an overdose;
Percentage of patients receiving an underdose;
Probability that recommended MTD at the end of the trial is in the target toxicity 
interval;
Probability that recommended MTD is an overdose;
Probability that recommended MTD is an underdose;
Percentage of trials stopped without MTD declaration;
Average sample size.
A.6.4.3. Simulation Results
Operating characteristics for the doublet and the triplet combinations are presented in
Table 47 and Table 48 respectively.  The percentage of trials with a correctly identified MTD 
ranges from 67.4% to 99% is reasonable and the percentage of patients treated at overly toxic 
doses is well controlled for most of the scenarios.  The average sample size for the doublet 
combination is between 10 and 11 patients, and the average sample size for the triplet is 
between 9 to 15 patients.


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Table 47.
Binimetinib + Talazoparib (7d/7d) Doublet Combination: Operating 
Characteristics
True DLT Scenarios 
% Patient allocation
% declare MTD
% stop 
(no MTD)
Average 
sample 
size
TT
OD
UD
TT
OD
UD
1.  Prior means
97.2
0
2.8
85.2
0
0
14.8
10
2.  25% more toxic 
than prior means 
88.8
11.2
0
77.3
0
0
22.7
10
3.  40% more toxic 
than prior means
82.5
17.5 
0
59.0
0
00
41.0
11
4.  With underdose and 
overdose
83.9
12.9
3.2
88.0
0
00
12.0
10
Abbreviations: DLT=dose-limiting toxicity; MTD=maximum tolerated dose: OD=overdose; TT=target toxicity; 
UD=underdose.
Table 48.
Avelumab + Binimetinib (7d/7d) + Talazoparib Triplet: Operating 
Characteristics
True DLT Scenarios 
% Patient 
allocation
%declare MTD
% stop 
(no MTD)
Average 
sample 
size
TT
OD
UD
TT
OD
UD
Prior means
90.5
9.5
0
60.8
0
0
39.2
11
10% more toxic than 
prior means
91.6
8.4
0
56.4
0
0
43.6
9
10% less toxic than 
prior means
100
0
0
65.4
0
0
34.6
12
With underdose and 
overdose
53.0
3.8
43.2
68.4
0
17.1
14.5
15
Abbreviations: DLT=dose-limiting toxicity; MTD=maximum tolerated dose; OD=overdose; TT=target toxicity; 
UD=underdose.


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SAP_001.pdf: 
Avelumab 
B9991033 (MSB0010718C, MDV3800, BMN 673, MEK162) Statistical Analysis Plan     
 
PFIZER CONFIDENTIAL 
Page 1 
 
A PHASE 1B/2 STUDY TO EVALUATE SAFETY AND CLINICAL ACTIVITY OF 
COMBINATIONS OF AVELUMAB, BINIMETINIB AND TALAZOPARIB IN 
PATIENTS WITH LOCALLY ADVANCED OR METASTATIC RAS-MUTANT 
SOLID TUMORS 
 
 
STATISTICAL ANALYSIS PLAN – B9991033 
 
Compounds:  
MSB0010718C 
MDV3800, BMN 673 
MEK162 
Compound Name: 
Avelumab 
Talazoparib  
Binimetinib  
Version: 
3.0 
Date: 
13-Nov-2019 
 
 
 
 
 
 
 
 
This document contains confidential information belonging to Pfizer.  Except as otherwise agreed to in 
writing, by accepting or reviewing this document, you agree to hold this information in confidence and not 
copy or disclose it to others (except where required by applicable law) or use it for unauthorized purposes.  
In the event of any actual or suspected breach of this obligation, Pfizer must be promptly notified. 
 
 


A v el u ma b  
B9 9 9 1 0 3 3  ( M S B0 0 1 0 7 1 8 C , M D V3 8 0 0,  B M N  6 7 3 , M E K 1 6 2)  St atis tic al A n al ysis Pla n     
 
P FI Z E R C O N FI D E N TI A L  
Pa g e 2 
T A B L E O F C O N T E N T S  
LI S T O F T A B L E S .............................................................................................................. 6 
A P P E N DI C E S .................................................................................................................... 8 
1. V E R SI O N HI S T O R Y  ..................................................................................................... 9 
2. I N T R O D U C TI O N  ........................................................................................................ 1 0  
2. 1. St u d y O bje cti ves  ............................................................................................... 1 0  
2. 2. St u d y D es ig n  .................................................................................................... 1 1  
3. E N D P OI N T S A N D  B A S E LI N E V A RI A B L E S:  D E FI NI TI O N S A N D 
C O N V E N TI O N S  ......................................................................................................... 1 2  
3. 1. Pri mar y E n d p oi nt(s)  .......................................................................................... 1 2  
3. 2. Se c o n dar y E n d p oi nts  ......................................................................................... 1 6  
3. 2. 1. Safet y e n d p oi nts  .................................................................................... 1 6  
3. 2. 2. Effic a c y e n d p oints  ................................................................................. 1 6  
3. 2. 3. P har ma c o ki netic e n d p oints  .................................................................... 1 7  
3. 2. 4. I m m u n o ge nic it y e n d p oi nts ..................................................................... 1 8  
3. 2. 5. Bio mar ker e n d p oi nts  ............................................................................. 1 8  
3. 3. E x pl orat or y E n d p oints  ....................................................................................... 1 8  
3. 4. Bas eline V aria bles ............................................................................................. 1 9  
3. 4. 1. St u d y dr u g, st u d y tre at me nt a n d bas eli ne definiti o ns  ............................... 1 9  
3. 4. 2. Bas eline c hara cteristics .......................................................................... 2 1  
3. 5. Safet y E n d p oi nts  ............................................................................................... 2 1  
3. 5. 1. A d vers e e ve nts  ...................................................................................... 2 1  
4. A N A L Y SI S S E T S  ........................................................................................................ 2 1  
4. 1. F ull A nal ys is Set  ............................................................................................... 2 1  
4. 2. Safet y A nal ys is Set  ........................................................................................... 2 1  
4. 3. Ot her A nal ys is Set  ............................................................................................ 2 2  
4. 3. 1. D L T -e valua ble s et  ................................................................................. 2 2  
4. 3. 2. P er -pr ot oc ol a na l ys is s et f or O R ............................................................. 2 2  
4. 3. 3. P K a nalys is s ets ..................................................................................... 2 2  
4. 3. 4. Bio mar ker a nal ys is s et ........................................................................... 2 3  
4. 3. 5. I m m u n o ge nic it y a nal ys is s et  .................................................................. 2 3  
 ...................................................................... 2 3  
5. GE N E R A L M E T H O D O L O G Y A N D C O N V E N TI O N S  ................................................ 2 3  
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Avelumab 
B9991033 (MSB0010718C, MDV3800, BMN 673, MEK162) Statistical Analysis Plan     
 
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Page 3 
5.1. Hypotheses and Decision Rules ......................................................................... 23 
5.1.1. Hypotheses and sample size determination ............................................. 23 
5.1.2. Decision rules ....................................................................................... 24 
5.2. General Methods ............................................................................................... 27 
5.2.1. Data handling after the cut-off date ........................................................ 30 
5.2.2. Pooling of centers.................................................................................. 30 
5.2.3. Presentation of continuous and qualitative variables ............................... 30 
5.2.4. Definition of study day .......................................................................... 30 
5.2.5. Definition of start of new anti-cancer drug therapy ................................. 30 
5.2.6. Definition of start of new anti-cancer therapy ......................................... 31 
5.2.7. Definition of on-treatment period ........................................................... 31 
5.2.8. Standard derivations and reporting conventions ...................................... 31 
5.2.9. Unscheduled visits................................................................................. 32 
5.2.10. Adequate baseline tumor assessment .................................................... 32 
5.2.11. Adequate post-baseline tumor assessment............................................. 32 
5.3. Methods to Manage Missing Data ...................................................................... 32 
5.3.1. Missing data.......................................................................................... 32 
5.3.1.1. Pharmacokinetic concentrations............................................. 33 
5.3.1.2. Pharmacokinetic parameters .................................................. 33 
5.3.2. Handling of incomplete dates................................................................. 34 
5.3.2.1. Disease history...................................................................... 34 
5.3.2.2. Adverse events...................................................................... 34 
5.3.2.3. Prior and concomitant medications ........................................ 34 
5.3.2.4. Exposure............................................................................... 35 
5.3.3. Imputation rules for date of last contact and efficacy assessments ........... 35 
5.3.3.1. Date of last contact................................................................ 35 
5.3.3.2. Death date............................................................................. 36 
5.3.3.3. Tumor assessments ............................................................... 36 
5.3.3.4. Date of start of new anti-cancer therapy ................................. 36 
6. ANALYSES AND SUMMARIES................................................................................. 38 
6.1. Primary Endpoints............................................................................................. 38 
6.1.1. DLT for Phase 1b .................................................................................. 38 
6.1.1.1. Primary analysis.................................................................... 38 


A v el u ma b  
B9 9 9 1 0 3 3  ( M S B0 0 1 0 7 1 8 C , M D V3 8 0 0,  B M N  6 7 3 , M E K 1 6 2)  St atis tic al A n al ysis Pla n     
 
P FI Z E R C O N FI D E N TI A L  
Pa g e 4 
6. 1. 2. O bje ctive res p o ns e as ass esse d b y t he I n vesti gat or per R E CI S T  v 1. 1 ....... 3 9  
6. 1. 2. 1. Pri mar y a na lys is .................................................................... 3 9  
6. 1. 2. 2. Se ns iti vit y a na lys is f or O R R .................................................. 4 0  
6. 2. Se c o n dar y E n d p oi nts  ......................................................................................... 4 0  
6. 2. 1. Safet y e n d p oi nts  .................................................................................... 4 0  
6. 2. 2. Effic a c y e n d p oints  ................................................................................. 4 0  
6. 2. 2. 1. T u m or s hrin ka ge fr o m bas eli ne .............................................. 4 1  
6. 2. 2. 2. D urati o n of res p o ns e  ............................................................. 4 1  
6. 2. 2. 3. Ti me t o res p o ns e  ................................................................... 4 3  
6. 2. 2. 4.  Pr o gress io n -fre e s ur vival ....................................................... 4 3  
6. 2. 2. 5. O vera ll S ur viva l  .................................................................... 4 5  
6. 2. 3. P har ma c o ki netic e n d p oints  .................................................................... 4 6  
6. 2. 4. P o p ulati o n p har ma c o ki netic e n d p oints  ................................................... 4 7  
6. 2. 5. Bio mar ker e n d p oi nts  ............................................................................. 4 7  
6. 2. 6. E n d p oints f or i m m u n o ge nic it y data of a vel u ma b  .................................... 4 8  
6. 2. 6. 1. Ti me t o a n d D urati o n  of A D A a n d n A b res p o ns e  ................... 5 0  
6. 2. 6. 2. A D A titer .............................................................................. 5 1  
6. 2. 6. 3. A na lys is  of P K  a n d s afet y b y i m m u n o ge nic it y stat us  .............. 5 1  
 ................................................................................................ 5 3  
 ...................................................................... 5 3  
........................................................................................ 5 3  
 ........................................................... 5 4  
6. 4. S u bs et A nal ys es  ................................................................................................ 5 4  
6. 5. Bas eline a n d Ot her S u m maries a n d A na lys es  ..................................................... 5 4  
6. 5. 1. Bas eline s u m maries  ............................................................................... 5 4  
6. 5. 1. 1. D e m o gr a p hic c hara cteristics  .................................................. 5 4  
6. 5. 1. 2. Me dic a l hist or y  ..................................................................... 5 6  
6. 5. 1. 3.  Dis e as e c haracteristics ........................................................... 5 6  
6. 5. 1. 4. Pri or a nti-c a nc er t hera pies  ..................................................... 5 6  
6. 5. 2. St u d y c o n d uct a n d patie nt dis p os iti o n ..................................................... 5 7  
6. 5. 2. 1. P atie nt  dis p os iti o n  ................................................................. 5 7  
6. 5. 2. 2. Pr ot oc ol  de viati o ns ................................................................ 5 8  
6. 5. 3. St u d y tre at me nt c o m plia nc e a n d e x p os ure  .............................................. 5 9  
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6.5.3.1. Exposure to avelumab ........................................................... 60 
6.5.3.2. Exposure to binimetinib ........................................................ 60 
6.5.3.3. Exposure to talazoparib ......................................................... 61 
6.5.3.4. Dose reductions .................................................................... 62 
6.5.3.5. Dose interruptions ................................................................. 62 
6.5.3.6. Dose delays .......................................................................... 62 
6.5.3.7. Infusion rate reductions ......................................................... 63 
6.5.3.8. Infusion interruptions ............................................................ 63 
6.5.4. Concomitant medications and non-drug treatments ................................. 63 
6.5.5. Subsequent anti-cancer therapies............................................................ 64 
6.6. Safety Summaries and Analyses ........................................................................ 64 
6.6.1. Adverse events ...................................................................................... 65 
6.6.1.1. All adverse events ................................................................. 66 
6.6.1.2. Adverse events leading to dose reduction ............................... 67 
6.6.1.3. Adverse events leading to interruption of study treatment ....... 67 
6.6.1.4. Adverse events leading to discontinuation of study 
treatment ...................................................................................... 68 
6.6.2. Deaths................................................................................................... 69 
6.6.3. Serious adverse events ........................................................................... 69 
6.6.4. Other significant adverse events ............................................................. 69 
6.6.5. Laboratory data ..................................................................................... 70 
6.6.5.1. Hematology and chemistry parameters................................... 70 
6.6.5.2. Other laboratory parameters .................................................. 73 
6.6.6. Vital signs ............................................................................................. 74 
6.6.7. Electrocardiogram ................................................................................. 74 
6.6.8. MUGA/ECHO ...................................................................................... 75 
6.6.9. Ophthalmic Examination ....................................................................... 76 
6.6.10. ECOG performance status.................................................................... 76 
7. INTERIM ANALYSES ................................................................................................ 76 
7.1. Introduction ...................................................................................................... 76 
7.2. Interim Analyses and Summaries ....................................................................... 76 
8. REFERENCES ............................................................................................................. 77 
9. APPENDICES .............................................................................................................. 78 


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B9991033 (MSB0010718C, MDV3800, BMN 673, MEK162) Statistical Analysis Plan     
 
PFIZER CONFIDENTIAL 
Page 6 
 
LIST OF TABLES 
Table 1. 
Summary of Major Changes in SAP Amendments ............................................. 9 
Table 2. 
PK Parameters to be Determined for Avelumab, talazoparib, and/or 
binimetinib (as applicable) .............................................................................. 17 
Table 3. 
Biomarker Definition and Determination ......................................................... 18 
Table 4.  
Treatment Groups ........................................................................................... 19 
Table 5. 
Study Summaries and Tabulations ................................................................... 28 
Table 6. 
Outcome and Event Dates for DR Analyses ..................................................... 42 
Table 7. 
DR Censoring Reasons and Hierarchy ............................................................. 43 
Table 8. 
Outcome and Event Dates for PFS Analyses .................................................... 44 
Table 9. 
PFS Censoring Reasons and Hierarchy ............................................................ 45 
Table 10. 
OS Censoring Reasons and Hierarchy.............................................................. 46 
Table 11.  Patients Characterized Based on Anti-Drug Antibody Results (ADA 
Status) ............................................................................................................ 49 
Table 12.  Patients Characterized Based on Neutralizing Antibody Results (nAb 
Status) ............................................................................................................ 50 
Table 13. 
Case Definition for irAEs................................................................................ 78 
Table 14. 
Case Definition for IRRs – IV Study Drugs Administered Alone Or In 
Combination With Non-IV Study Drugs .......................................................... 80 
Table 15. 
Historical Dose Limiting Toxicity Data from Study EMR100070-001 .............. 84 
Table 16. 
Prior Distributions for the Parameters of the MAP Model Used to Derive 
the Prior for the Single-Agent Avelumab Model Parameters............................. 84 
Table 17. 
Historical Dose Limiting Toxicity Data from Studies ARRAY-162-111 and 
CMEK162X1101............................................................................................ 85 
Table 18. 
Prior Distributions for the Parameters of the MAP Model Used to Derive 
the Prior for the Single-Agent Binimetinib Model Parameters .......................... 85 
Table 19. 
Historical Dose Limiting Toxicity data from study NCT01286987 ................... 86 
Table 20. 
Prior Distributions for the Parameters of the MAP Model Used to Derive 
the Prior for the Single-Agent Talazoparib Model Parameters .......................... 86 
Table 21. 
Prior Distribution for the Model Parameters..................................................... 87 
Table 22. 
Summary of Prior Distribution of Dose Limiting Toxicity Rates for the 
Doublet Combination of Avelumab in Combination with Binimetinib .............. 87 
Table 23. 
Summary of Prior Distribution of DLT Rates for the Triplet Combination 
of Avelumab in Combination with Binimetinib and Talazoparib....................... 88 


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B9991033 (MSB0010718C, MDV3800, BMN 673, MEK162) Statistical Analysis Plan     
 
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Table 24. 
Doublet Combination: Data Scenarios, Next Dose Recommendation, and 
the Interval Probability of Target Toxicity and Overdosing at Next Dose. ......... 89 
Table 25. 
Triplet Combination: Clinically Meaningful Starting Dose Given 
Hypothetical Data from the Doublet Combination, and the Interval 
Probability of Target Toxicity and Overdosing at Starting Dose. ...................... 89 
Table 26. 
Triplet Combination: Data Scenarios (Given Hypothetical Doublet Data), 
Next Dose Recommendation, and the Interval Probability of Target 
Toxicity and Overdosing at Next Dose. ........................................................... 90 
Table 27. 
Doublet Combination: Dose Limiting Toxicity Rate Scenarios (Fixed 
Avelumab Dose 10mg/kg Every 2 Weeks)....................................................... 91 
Table 28. 
Triplet Combination: Dose Limiting Toxicity Rate Scenarios (Fixed 
Avelumab Dose 10mg/kg Every 2 Weeks)....................................................... 91 
Table 29. 
Doublet Combination: Operating Characteristics.............................................. 92 
Table 30. 
Triplet Combination: Operating Characteristics ............................................... 93 
Table 31. 
Historical Dose Limiting Toxicity data from study NCT01286987 ................... 97 
Table 32. 
Prior Distributions for the Parameters of the MAP Model Used to Derive 
the Prior for the Single-Agent Talazoparib Model Parameters .......................... 97 
Table 33. 
Historical Dose Limiting Toxicity Data from Studies ARRAY-162-111 and 
CMEK162X1101............................................................................................ 98 
Table 34. 
Prior Distributions for the Parameters of the MAP Model Used to Derive 
the Prior for the Single-Agent Binimetinib Model Parameters .......................... 99 
Table 35. 
Historical Dose Limiting Toxicity Data from Study EMR100070-001 ............ 100 
Table 36. 
Prior Distributions for the Parameters of the MAP Model Used to Derive 
the Prior for the Single-Agent Avelumab Model Parameters........................... 100 
Table 37. 
Prior Distribution for the Model Parameters................................................... 102 
Table 38. 
Summary of Prior Distribution of Dose Limiting Toxicity Rates for the 
Binimetinib (7d/7d) + Talazoparib Doublet Combination ............................... 103 
Table 39. 
Summary of Prior Distribution of DLT Rates for the Avelumab + 
Binimetinib + Talazoparib Triplet Combination ............................................. 103 
Table 40. 
Binimetinib (7d/7d) + Talazoparib Doublet Combination: Data Scenarios, 
Next Dose Recommendation, and the Interval Probability of Target 
Toxicity and Overdosing at Next Dose. ......................................................... 104 
Table 41. 
Avelumab + Binimetinib (7d/7d) + Talazoparib Triplet Combination: 
Clinically Meaningful Starting Dose Given Hypothetical Data from the 
Doublet, and the Interval Probability of Target Toxicity and Overdosing at 
Starting Dose. ............................................................................................... 104 


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B9991033 (MSB0010718C, MDV3800, BMN 673, MEK162) Statistical Analysis Plan     
 
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Table 42. 
Avelumab + Binimetinib (7d/7d) + Talazoparib Triplet Combination: Data 
Scenarios (Given Hypothetical Doublet Data), Next Dose 
Recommendation, and the Interval Probability of Target Toxicity and 
Overdosing at Next Dose. ............................................................................. 105 
Table 43. 
Binimetinib (7d/7d) + Talazoparib Doublet Combination: True Dose 
Limiting Toxicity Rate Scenarios .................................................................. 107 
Table 44. 
Avelumab + Binimetinib (7d/7d) + Talazoparib Triplet Combination: True 
Dose Limiting Toxicity Rate Scenarios.......................................................... 107 
Table 45. 
Binimetinib + Talazoparib (7d/7d) Doublet Combination: Operating 
Characteristics .............................................................................................. 109 
Table 46. 
Avelumab + Binimetinib (7d/7d) + Talazoparib Triplet Combination: 
Operating Characteristics .............................................................................. 109 
 
APPENDICES 
Appendix 1. Immune-Related Adverse Events ................................................................... 78 
Appendix 2. Infusion Related Reactions ............................................................................ 80 
Appendix 3. Detailed Dose Escalation/De-escalation Scheme for BLRM Design prior 
to implementation of Protocol Amendment 3. .................................................. 81 
Appendix 4. Detailed Dose Escalation/De-escalation Scheme for BLRM Design -per 
implementation of Protocol Amendment 3. ...................................................... 94 


A v el u ma b  
B9 9 9 1 0 3 3  ( M S B0 0 1 0 7 1 8 C , M D V3 8 0 0,  B M N  6 7 3 , M E K 1 6 2)  St atis tic al A n al ysis Pla n 
 
P FI Z E R C O N FI D E N TI A L  
Pa g e 9 
1.  V E R SI O N HI S T O R Y  
T his  Sta tistic a l  A na l ysis  Pla n ( S A P) f or st u d y  B 9 9 91 0 3 3  is  bas e d o n t he P r ot oc ol 
A me n d me nt 3 date d 2 4 -Se p -2 0 1 9 .    
T a ble  1. 
S u m m ar y  of M ajo r  C h a n g e s  i n S A P A me n d me nts  
Ve rsi on  Ve rs i o n D ate  S u m mar y of C h a n g es  
3. 0  
1 3 -N o v -2 0 1 9  
U p d at es were ma d e t o t h e title of t h e  S A P a n d t he f oll o wi n g Se cti o ns of t h e 
S A P, as p er Pr ot o c ol A me n d me nt 3 . 
Se cti o n 2. 1  “ St u d y O bje cti ves”, Se cti o n 2. 2  “ St u d y Desi g n”, Se cti o n 3. 2. 3  
“ P h ar ma c o ki n etic e n d p oi n ts”, Se cti o n 3. 3  “ Expl orat or y En d p oi nts”, Se cti o n 3. 4  
“ Bas eli n e v aria bles” – tre at me nt gr o u p d efi niti o ns, Se cti o n 4. 3  “ Ot h er A n al ysis 
Set ”, Se cti o n 5. 1  “ H y p ot heses a n d De cisi o n Rules”, Se cti o n 5. 2  “ Ge n eral 
M et h o ds” – d escr i pti o n of s u m mar y a n d t a b ulati o ns,  Se cti o n 6. 2. 3  
“ P h ar ma c o ki n etic e n d p oi nts”, S e cti o n 6. 2. 4  “ P o p ulati o n p har ma c o kin etic 
e n d p oi nts
 
 Se cti o n 6. 4  “ S u bset A n al yses”,  Se cti o n 6. 5. 3  “ St u d y tre at me nt 
c o mplia n c e a n d e xp os ure ”  – d eri v ati o ns f or bi ni meti ni b , A p pen di x  4 “Det aile d 
D os e Es c alati o n/ De -escalati o n Sc h e me f or B L R M Desi g n -p er i mple me nt ati o n 
of Pr ot o c ol A me n d me nt 3 ”. 
I n a d diti o n, t he f oll o wi n g c h an g es were i mpleme nt e d.  
Se cti o n 2  “I ntr o d ucti o n”  – c h a n ge d t h e pri mar y a n al ysis c ut -off d at e fr o m 1 8 
mo nt hs t o 1 2 mo nt hs aft er t h e last p atie nt is ra n d o mize d (f or ra n d o mize d 
c o h orts) or re c ei v es t he first d ose of st u d y tre at me nt (f or n o n -ra n d o mize d 
c o h orts).  A 1 2 -mo nt h mi ni mu m f oll o w -u p is d e e me d a d e q u at e f or t h e pri mar y 
as s ess me nt of t h e safet y a n d effic a c y of  t h e e xp eri me nt al tre at me nts f or t h e 
t ar g et p o p ulati o n i n t his st u d y. 
Se cti o n 3. 1  “ Pri mar y e n d p oi nt(s)” – a d de d t h e d efi niti o n of d ose li miti n g 
t o xicit y b ef ore a n d aft er i mple me nt ati o n of Pr ot o col A me n d me nt 3 . 
Se cti o n 6. 5. 3  “St u d y tre at me nt c o mplia nc e a n d e xp os ure ” - re mo v e d su m ma rie s  
b y c y cle f or a v el u ma b . 
Se cti o n 6. 6. 1  “ A d verse e vents” – re mo v ed s u m ma r y  o f ‘ T E A Es  Excl u d i n g S A Es, 
wit h fre q u e n c y ≥ 5 % i n a n y tre at me nt gr o u p b y S O C a n d P T ’. 
Se cti o n 6. 6. 7  “ Ele ctr o c ar di o gra m” – re mo v e d t h e d eri v ati o n of Q Tc P  as t he 
n u mb er of p atie nts i n e a c h of t h e d o u blet a n d tri plet c o mbi nati o ns is t o o  s mall t o 
e n a ble t h e d eri v ati o n. 
A p p e n di x 1 “I m mu n e-Relat e d A d verse Ev e nts ” – pr o vi d ed a d diti o nal 
s p e cific ati o ns f or t h e pr o gra m matic s ele cti o n of ir A Es pri or t o a dj u dic ati o n. 
Mi n or e dit orial a n d c o nsiste ncy c h an g es t hr o u g h o ut t h e d oc u me nt.  
2. 0  
0 9 -M a y -2 0 1 9  
Se cti o n  2. 1  “ St u d y O bje cti ves”,
 
 
Se cti o n  3. 5. 1  “ A d v erse e v ents” – u p dat ed t he d efi niti o n of tre at me nt -e mer g e nt 
a d v ers e e v e nts . 
Se cti o n 5. 1. 2  “ De cisi o n r ules” - clarifie d  t h at all a v aila ble d at a i n cl u di n g i n -trial 
d o u blet d at a a n d D L T -d ose d at a fr o m s t u d y B9 9 9 1 0 2 5 , will  b e i n c or p orate d i n 
t h e d et er mi n ati o n of t h e starti n g d ose f or t he tri plet;  
Se cti o n 5. 2  “Ge n eral M et h o d s” - Ta ble 6  u p d at e d a n d re mo v e d s o me p o ole d 
a n d b y tre at me nt gr o u p s u m maries.  
Se cti o n 6. 2. 2. 2  “ D urati o n of res p o nse ” – a d d ed d et ails re g ar di n g c e ns ori n g f or 
d urati o n of res p o nse si n ce “ n o a d e q uate b aseli n e assess me nt”  w hic h is use d i n 
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censoring for PFS analyses is not applicable to analyses of duration of response 
for patients with objective response. 
Section 6.2.6 “Endpoints for immunogenicity data of avelumab” the analysis of 
efficacy by immunogenicity status was removed. 
Section 6.5.1.1 “Demographic characteristics”: added ‘multiracial’ to the 
summary of race. 
Section 6.5.3.5 “Dose interruptions” - the counting of the number of dose 
interruption for oral drugs was updated since reasons for dose adjustment are 
not collected in the eCRF. Section 6.6 “Safety Summaries and Analyses” - 
subsection “Physical examination” was removed. 
Section 6.6.5.1 “Hematology and chemistry parameters” - added summary for 
patients with newly occurring or worsening laboratory abnormalities.  
Section 6.6.5.2 “Other laboratory parameters” - coagulation parameter 
prothrombin time (PT) was removed. 
Section 8 “References” – updated. 
Appendix 3 “Detailed Dose Escalation/De-escalation Scheme for BLRM 
Design” preliminary safety data for the Phase 1b portion of the B9991025 study 
was added.  It was also clarified that the information from B9991025 study will 
be incorporated into the BLRM to guide the starting dose and dose finding for 
the triplet combination using direct down-weighting approach. 
Minor editorial and consistency changes throughout the document. 
1.0 
15-Jun-2018 
Not applicable (N/A) 
 
2. INTRODUCTION 
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in study B9991033.  This document may modify the plans outlined in the protocol; 
however, any major modifications of the primary endpoint definition or its analysis will also 
be reflected in a protocol amendment. 
Statistical analyses will be performed using cleaned eCRF data as well as non-CRF data (ie, 
pharmacokinetics [PK], immunogenicity, and biomarker data). The primary analysis will 
include all data up to a cut-off date corresponding to 12 months after the last patient is 
randomized (for randomized cohorts) or receives the first dose of study treatment (for non-
randomized cohorts).  The final analysis of the data will be performed after last patient last 
visit (LPLV).  
Additional analyses of the data may be performed for publication or regulatory reporting 
purposes. 
Throughout this document ‘start date’ refers to date of randomization for randomized cohorts 
and first dose of study treatment for non-randomized cohorts.  
2.1. Study Objectives 
Primary Objective(s) 
• Phase 1b: To assess the dose-limiting toxicity (DLT) rate of the doublet and triplet 
combinations in patients with mPDAC in order to determine the recommended Phase 2 
dose (RP2D) for the combinations;  


A v el u ma b  
B9 9 9 1 0 3 3  ( M S B0 0 1 0 7 1 8 C , M D V3 8 0 0,  B M N  6 7 3 , M E K 1 6 2)  St atis tic al A n al ysis Pla n 
 
P FI Z E R C O N FI D E N TI A L  
Pa g e 1 1  
•  P has e  2:  T o  ass ess t he o bje ctive  res p o ns e rate ( O R R) of t he d o u blet  a n d triplet 
c o m binatio ns  bas e d o n  t he I n vestigat or  ass ess me nt per Res p o ns e E valuatio n  Crite ria  in 
S olid  T u m ors,  versio n  1. 1 ( R E CI S T  v 1. 1)  in  patie nts  wit h  m P D A C, a n d ot her  K R A S - or 
N R A S -m uta nt  a d va nc e d  s olid  t u m ors . 
Se c o n d ar y O bje cti v e s  
•  T o ass ess t he o verall  s afet y a n d t olera bilit y  of t he d o u blet  a n d triplet  c o m binatio ns ;  
•  T o c har a cterize  t he P K of a velu ma b,  bini metini b  a n d tala z o parib  w he n give n  in 
c o m binatio n; 
•  T o e valuate  t he i m m u n o ge nic it y  of  a velu ma b  w he n give n  in  c o m binatio n  wit h  t he  ot her 
st u d y  dr u gs; 
•  T o ass ess t he a nti -t u m or  a ctivit y  of t he d o u blet  a n d triplet  c o m binatio ns; 
•  T o ass e ss t he c orrelatio n  of a nti-t u m or  a ctivit y  of t he d o u blet  a n d triplet  c o m binatio ns 
wit h  P D -L 1 e x pressio n,  D N A D a ma ge Re pair ( D D R) ge ne alteratio ns,  a n d t u m or 
m utatio nal  b ur de n  ( T M B)  in  bas eline  t u m or  tiss ue.  
E x pl o r at o r y O bje cti v e s  
 
 
 
 
 
 
 
 
 
 
. 
2. 2.  St u d y  D e s i g n  
T his  is  a  P has e 1 b/ 2,  o pe n  l a be l,  m ulti-c e nter  st u d y  of c o m binatio ns of a velu ma b, bini me ti n ib  
a n d tala z o parib  in e ligib le a d ult  patie nts  wit h  m P D A C  (re gar dless of K R A S stat us),  a n d  ot her 
loc ally  a d va nc e d or metastatic K R A S - or N R A S -m uta nt  s olid  t u m ors.  
I nitially,  t his  st u d y  e xa mine d a velu ma b give n  I V Q 2 W a n d bini meti nib  give n  t wic e daily 
( BI D) o n a c o ntin u o us  d osin g  s c he d ule  wit h  t he o bje ctive  of ide ntif yin g  a n R P 2 D f or t his 
d o u blet  c o m binatio n bef ore  pr oc e e din g  t o ass ess t he triplet  c o m binatio n  of a velu ma b, 
bini me tin i b o n  a c o ntin u o u s  d osin g  s c he d ule a n d tala z o parib.  D ue t o o bs er ve d  D L Ts wit h 
c o ntin u o us  bini metini b  d osin g,  t he d osin g  s c he d ule  f or bini meti nib  has be e n m o difie d 
(Pr ot oc ol  A me n d me nt  3) t o a n inter mitte nt  d osin g  s c he d ule(s) w hic h  is e x pe cte d t o mitigate 
t hes e p ote ntial  t oxic itie s .    
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Per Protocol Amendment 3, the study will include a sequential dose-finding phase (Phase 1b) 
for binimetinib in combination with talazoparib (doublet) and avelumab in combination with 
binimetinib and talazoparib (triplet) followed by Phase 2.   
Approximately 122 patients will be enrolled into the study, including 52 patients in Phase 1b 
(inclusive of the 22 patients enrolled prior to implementation of Protocol Amendment 3) and 
70 patients in Phase 2. The actual number of patients will depend on the number of DLT 
events, dose levels/cohorts and dosing schedules that are tested during Phase 1b. 
Once Phase 1b is completed and the RP2Ds for the doublet and triplet combinations have 
been determined, Phase 2 will be initiated to evaluate the safety and anti-tumor activity of the 
RP2D for each combination.  Up to 40 patients within mPDAC will be randomized in a 1:1 
ratio to the doublet and the triplet combinations (ie, 20 patients per combination) to reduce 
potential treatment selection bias.  In the case that an RP2D is determined for the doublet 
combination using more than 1 binimetinib dosing schedule (ie, Schedules 7d/7d and 5d/2d), 
only one will be chosen to be evaluated in Phase 2 on the basis of all available safety, PK and 
anti-tumor activity data.    
In addition to the above mPDAC tumor cohorts, 30 patients with other locally advanced or 
metastatic KRAS- or NRAS-mutant solid tumors (such as NSCLC, CRC, melanoma and 
endometrial cancer) will be enrolled in a ‘tumor agnostic’ cohort to receive the triplet 
combination as this may provide clinical benefit to a broader population of patients than 
primarily planned for this study (ie, mPDAC).   
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS 
3.1. Primary Endpoint(s) 
• Phase 1b: DLT during the primary DLT evaluation period (Cycle 1). 
Prior to implementation of protocol amendment 3, in Phase 1b, any of the following AEs 
occurring in the first cycle of treatment (28 days) which are attributable to any or all 
study drugs administered in the combination will be classified as DLTs: 
• 
Hematologic:  
o Grade 4 neutropenia (absolute neutrophil count [ANC] <500/mm3 or <0.5 x 
109/L) lasting >5 days. 
o Febrile neutropenia, defined as ANC <1000/mm3 with a single temperature of 
>38.3°C (>101°F) or a sustained temperature of ≥38°C (100.4°F) for more than 
1 hour. 
o Neutropenic infection (ANC <1,000/mm3 or <1.0 x 109/L, and Grade >3 
infection). 
o Grade ≥3 thrombocytopenia (platelet count <50,000 mm3 or <50.0 × 109/L) with 
bleeding. 
o Grade 4 thrombocytopenia (platelet count <25,000/mm3 or <25.0 x 109/L). 


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o Grade 4 anemia (life-threatening consequences; urgent intervention indicated). 
• Non-Hematologic: 
o Grade ≥3 toxicities of any duration except: 
- Grade 3 nausea, vomiting, or diarrhea and Grade 4 vomiting or diarrhea in 
the absence of maximal medical therapy that resolves in 72 hours; 
- Grade 3 fatigue lasting <5 days; 
- Grade 3 hypertension that can be controlled with medical therapy; 
- Grade 3 serum lipase and/or serum amylase ≤7 consecutive days without 
clinical signs or symptoms of pancreatitis; 
- Grade ≥3 laboratory abnormalities without a clinical correlate and that do 
not require medical intervention; 
- Grade ≥3 laboratory abnormalities that do not represent a clinically 
relevant shift from baseline; 
- Grade 3 endocrinopathies controlled with hormonal therapy. 
o CK elevation Grade ≥3 associated with an increase in creatinine ≥1.5 × the 
patient’s baseline creatinine.  
o Grade 3 troponin increase associated with any sign of cardiac toxicity (as 
determined by a cardiac evaluation). 
o Potential Hy’s Law cases defined as: ALT or AST >3 x upper limit of normal 
(ULN) if normal at baseline OR >3 x ULN and doubling the baseline (if >ULN at 
baseline) associated with total bilirubin >2 x ULN and an alkaline phosphatase <2 
x ULN. 
• Eye Disorders: 
o Retinopathy or retinal detachment Grade ≥3, confirmed by ophthalmic 
examination. 
o Retinal vascular disorder including RVO, confirmed by ophthalmic examination. 
o Any Grade 2 immune-related uveitis or eye pain or blurred vision or decreased 
visual acuity that does not improve to Grade 1 despite topical therapy OR requires 
systemic treatment. 
o Any other eye disorder Grade ≥3 for >21 consecutive days. 
o Any other eye disorder Grade 4 confirmed by ophthalmic examination. 
• Cardiac Disorders 
o Absolute decrease of left ventricular ejection fraction (LVEF) >10% compared to 
baseline and the LVEF is below the institution’s lower limit of normal (LLN). 
o Symptomatic left ventricular systolic dysfunction Grade ≥3. 
o Other cardiac disorders Grade ≥3. 


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• Respiratory Disorders: 
o Interstitial lung disease/pneumonitis Grade ≥2. 
o Bronchospasm Grade 3. 
• Skin and Subcutaneous Tissue Disorders: 
o Rash, hand foot skin reaction (HFSR), or photosensitivity CTCAE Grade 3 for 
>14 consecutive days despite maximal skin toxicity treatment (as per local 
practice). 
o Grade 3 rash that does not improve to Grade 1 within 14 days, limits self-care, or 
which is associated with infection. 
o Rash, HFSR, or photosensitivity CTCAE Grade 4. 
• Non-Adherence to Treatment Schedule: 
o Failure to deliver at least 75% of the planned doses of any study drug during the 
first cycle of treatment due to treatment-related toxicities. 
• Dose Reductions: 
o Any AE that results in a dose reduction of talazoparib or binimetinib during the 
first cycle of treatment. 
 
Per protocol amendment 3, in Phase 1b, any of the following AEs occurring in the first 
cycle of treatment (28 days) which are attributable to any or all study drugs administered 
in the combination will be classified as DLTs: 
• Hematologic 
o Grade 4 neutropenia (absolute neutrophil count [ANC] <500/mm3 or <0.5 x 
109/L) lasting >5 days. 
o Febrile neutropenia, defined as ANC <1000/mm3 with a single temperature of 
>38.3°C (>101°F) or a sustained temperature of ≥38°C (100.4°F) for more than 
1 hour. 
o Neutropenic infection (ANC <1,000/mm3 or <1.0 x 109/L, and Grade >3 
infection). 
o Grade ≥3 thrombocytopenia (platelet count <50,000 mm3 or <50.0 × 109/L) with 
bleeding. 
o Grade 4 thrombocytopenia (platelet count <25,000/mm3 or <25.0 x 109/L). 
o Grade 4 anemia (life-threatening consequences; urgent intervention indicated). 
• Non-Hematologic 
o Grade ≥3 toxicities of any duration except: 
- Grade 3 nausea, vomiting, or diarrhea and Grade 4 vomiting or diarrhea in 
the absence of maximal medical therapy that resolves in 72 hours; 


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- Grade 3 fatigue lasting <5 days; 
- Grade 3 hypertension that can be controlled to Grade ≤2 within ≤14 days 
with or without ongoing medical therapy; 
- Grade 3 serum lipase and/or serum amylase without clinical signs or 
symptoms of pancreatitis; 
- Grade ≥3 laboratory abnormalities without a clinical correlate and that do 
not require medical intervention; 
- Grade ≥3 laboratory abnormalities that do not represent a clinically 
relevant shift from baseline; 
- Grade 3 endocrinopathies controlled with hormonal therapy. 
o CK elevation Grade ≥3 associated with an increase in creatinine ≥1.5 × the 
patient’s baseline creatinine.  
o Grade 3 troponin increase associated with any sign of cardiac toxicity (as 
determined by a cardiac evaluation). 
o Potential Hy’s Law cases defined as: ALT or AST >3 x upper limit of normal 
(ULN) if normal at baseline OR >3 x ULN and doubling the baseline (if >ULN at 
baseline) associated with total bilirubin >2 x ULN and an alkaline phosphatase 
<2 x ULN. 
• Eye Disorders 
o Retinopathy or retinal detachment Grade ≥3, confirmed by ophthalmic 
examination. 
o Retinal vascular disorder including RVO, confirmed by ophthalmic examination. 
o Any Grade ≥3 uveitis, blurred vision, flashing lights, or floaters. 
o Any other eye disorder Grade ≥3 for >21 consecutive days. 
o Any other eye disorder Grade 4 confirmed by ophthalmic examination. 
• Cardiac Disorders 
o Absolute decrease of left ventricular ejection fraction (LVEF) >10% compared to 
baseline and the LVEF is below the institution’s lower limit of normal (LLN). 
o Symptomatic left ventricular systolic dysfunction Grade ≥3. 
o Other cardiac disorders Grade ≥3. 
• Respiratory Disorders 
o Interstitial lung disease/pneumonitis Grade ≥2. 
o Bronchospasm Grade 3. 
• Skin and Subcutaneous Tissue Disorders 


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o Rash, hand foot skin reaction (HFSR), or photosensitivity CTCAE Grade 3 for 
>14 consecutive days despite maximal skin toxicity treatment (as per local 
practice). 
o Rash, HFSR, or photosensitivity CTCAE Grade 4. 
• Non-Adherence to Treatment Schedule 
o Failure to deliver at least 75% of the planned doses of any study drug during the 
first cycle of treatment due to treatment-related toxicities. 
• Dose Reductions 
o Any AE that results in a dose reduction of talazoparib or binimetinib during the 
first cycle of treatment. 
While the rules for adjudicating DLTs in the context of Phase 1b are specified above, an 
AE not listed above, or an AE meeting the DLT criteria above but occurring outside of 
the DLT observation period may be defined as a DLT following assessment, based on the 
emerging safety profile for the combinations. 
• Phase 2: Confirmed objective response (OR) based on Investigator assessment per 
RECIST v1.1. 
OR is defined as complete response (CR) or partial response (PR) according to RECIST 
v1.1 from the ‘start date’ until the date of the first documentation of progressive disease 
(PD). Both CR and PR must be confirmed by repeat assessments performed no less than 
4 weeks after the criteria for response are first met.  
3.2. Secondary Endpoints 
3.2.1. Safety endpoints 
• Adverse Events (AEs) as characterized by type, severity (as graded by National Cancer 
Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] v4.03), 
timing, seriousness, and relationship to study treatment; 
AEs will be graded by the investigator according to the Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.03 and coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) 
• Laboratory abnormalities as characterized by type, severity (as graded by NCI CTCAE 
v4.03) and timing. 
3.2.2. Efficacy endpoints 
• Phase 1b: Confirmed OR based on Investigator assessment per RECIST v1.1; 
• Time to tumor response (TTR), duration of response (DR), and PFS based on Investigator 
assessment per RECIST v1.1, and overall survival (OS); 
DR is defined, for patients with OR, as the time from the first documentation of objective 
response (CR or PR) to the date of first documentation of PD or death due to any cause.   


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TTR is defined, for patients with an OR, as the time from the ‘start date’ to the first 
documentation of objective response (CR or PR) which is subsequently confirmed.  
PFS is defined as the time from the ‘start date’ to the date of the first documentation of 
PD or death due to any cause, whichever occurs first. 
OS is defined as the time from the ‘start date’ to the date of death due to any cause. 
3.2.3. Pharmacokinetic endpoints 
• PK parameters, ie, concentration at the end of the dosing interval (Ctrough) for avelumab, 
binimetinib and talazoparib, and maximum plasma concentration (Cmax) for avelumab and 
binimetinib, at various cycles.  
Pharmacokinetic parameters Cmax and Ctrough for avelumab and binimetinib, and Ctrough for 
talazoparib will be reported at steady state.  Other parameters will be evaluated include 
Tmax for avelumab and binimetinib may include dose normalized parameters (Cmax and/or 
Ctrough) for binimetinib and talazoparib.  
For avelumab, the difference of actual time of end of infusion (EOI) captured in the eCRF 
relative to start of the infusion (TEOI), the difference of actual PK sampling time relative to 
the start of infusion (Tmax) will be reported.  
For avelumab, talazoparib and binimetinib, the post-dose concentration value and its actual 
time relative to the last dose prior to the sampling (Ttrough) will also be reported.  
Table 2. 
PK Parameters to be Determined for Avelumab, talazoparib, and/or 
binimetinib (as applicable) 
Parameter 
Definition 
Method of Determination 
Cmax for avelumab and 
binimetinib   
Maximum observed plasma concentration  Observed directly from data 
Tmax for avelumab and 
binimetinib 
Time for Cmax  
Observed directly from data as 
time of first occurrence 
TEOI for avelumab 
Time difference between actual end of 
infusion and the start of infusion  
Observed directly from data  
Ctrough for avelumab, 
binimetinib, and talazoparib 
Pre-dose concentration during multiple 
dosing 
Observed directly from data 
Ttrough for avelumab, 
binimetinib and talazoparib 
Time difference between PK sampling 
time and dosing time of last dose prior to 
the sampling 
Observed directly from data 
Cmax (dn) for binimetinib  
Dose normalized Cmax  
Cmax / Dose 
Ctrough (dn) for binimetinib 
and/or talazoparib 
Dose normalized Ctrough  
Ctrough / Dose 
  


A v el u ma b  
B9 9 9 1 0 3 3  ( M S B0 0 1 0 7 1 8 C , M D V3 8 0 0,  B M N  6 7 3 , M E K 1 6 2)  St atis tic al A n al ysis Pla n 
 
P FI Z E R C O N FI D E N TI A L  
Pa g e 1 8  
3. 2.4.  I m m u n o g e nicit y e n d p oi nts  
•  A velu ma b  a nti -dr u g  a ntib o d y  ( A D A) le vels  a n d  ne utralizin g  a ntib o dies  ( n A b)  a gainst 
a velu ma b. 
3. 2.5.  Bi o m ar k e r e n d p oi nts  
•  P D -L 1 e x pressio n  le vel, D N A D a ma ge Re pair (D D R ) ge ne alteratio ns,  a n d  t u m or  
m utatio nal  b ur de n ( T M B) in  bas eline  t u m or  tiss ue.  
T a ble  3. 
Bi o m ar k e r D e fi niti o n a n d D e te r mi n ati o n  
P ar a mete r  
Defi niti o n  
Met h o d  of Dete r mi n ati o n  
P D -L1 e xpres si o n le vel 
i n b as eli n e t u mor 
tis s u e 
T h e n u mb er of P D -L1  p os iti v e c ells  a n d / or 
q u alit ati v e assess me nt of P D -L1 st ai ni n g o n  
t u mor a n d i nfla m mat or y c ells i n re gi o ns of 
i nt erest 
Pat h ol o gis t, as sist ed b y 
i ma g e 
a n al ys is. 
Ge n o mic s c arri n g a n d  
t h e pres e nc e of d efe cts  
i n s ele ct g e nes, 
c o nsi d ere d critic al t o  
effe cti v e D D R, i n  
b as eli n e t u mo r t is s ue  
Q u a ntit ati o n of g e n o mic s c arri n g i n t h e f or m  
of l os s of h et er o zy g osit y;  
T h e n u mb er of  s o matic a n d g er mli n e 
mut ati o ns prese nt i n a p a n el of  
g e n es ass ociate d wit h D D R  i n b as eli n e t u mor 
d eri v e d n u cleic a ci d, i n g er mli n e n u cleic a cid 
a n d i n circ ulat i n g t u mor D N A. 
Ne xt g e n erati o n s e q ue nci n g  
f oll o we d b y c o mp ut ati o n al 
a n al ys is. 
T u mor mut ati o nal 
b ur d e n  
Det er mi n ati o n/ esti mati o n of t h e fre q ue nc y of 
mut ati o ns (t ot al a n d n o n -s y n o n y mo us) 
pres e nt i n b as eli n e t u mor d eri v ed n ucleic 
a ci d s a mples  a n d i n b aseli n e circ ulati n g 
t u mor D N A 
W h ole e xo me or g e n o me 
s e q u en ci n g a n d/ or R N As eq 
 
3. 3.  E x pl o r at o r y  E n d p oi nts  
 
 
 
 
 
 
 
 
 
 
 
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3.4. Baseline Variables 
3.4.1. Study drug, study treatment and baseline definitions 
In this study, ‘study drug’ refers to avelumab or talazoparib or binimetinib and ‘study 
treatment’ (or ‘treatment group’) refers to one of the treatments in Table 4. 
Table 4.  
Treatment Groups  
Phase  
Treatment groups         
(Dose Level) 
Avelumab  
(mg Q2W IV) 
Binimetinib 
(mg BID PO) 
Talazoparib 
(mg QD PO) 
1b 
D0 
800 
45 (continuous) 
N/A 
1b 
D-1 
800 
30 (continuous) 
N/A 
1b 
BT1 
N/A 
45 (7d/7d) 
1.0 
1b 
BT0 
N/A 
45 (7d/7d) 
0.75 
1b 
BT-1 
N/A 
45 (7d/7d) 
0.5 
1b 
BT-2 
N/A 
30 (7d/7d) 
1.0 
1b 
BT-3 
N/A 
30 (7d/7d) 
0.75 
1b 
BT-4 
N/A 
30 (7d/7d) 
0.5 
1b 
BT2-1   
N/A 
30 (5d/2d) 
0.5 
1b 
BT2-2   
N/A 
30 (5d/2d) 
0.75 
1b 
BT2-3  
N/A 
30 (5d/2d) 
1.0 
1b 
BT2-4  
N/A 
45 (5d/2d) 
0.5 
1b 
BT2-5   
N/A 
45 (5d/2d) 
0.75 
1b 
BT2-6   
N/A 
45 (5d/2d) 
1.0 
1b 
ABT1 
800 
30 (7d/7d) 
0.5 
1b 
ABT2 
800 
30 (7d/7d) 
0.75 
1b 
ABT3 
800 
30 (7d/7d) 
1.0 
1b 
ABT4 
800 
45 (7d/7d) 
0.5 
1b 
ABT5 
800 
45 (7d/7d) 
0.75 
1b 
ABT6 
800 
45 (7d/7d) 
1.0 
2 
BT:mPADC 
N/A 
RP2D (for doublet)  
RP2D (for doublet) 
2 
ABT:mPADC 
800 
RP2D (for triplet)  
RP2D (for triplet) 
2 
ABT:tumor agnostic 
800 
RP2D (for triplet)  
RP2D (for triplet) 
7d/7d=7 days on/7 days off; 5d/2d=5 days on/2 days off. 
N/A = not applicable. 
 
Start and end dates of study treatment: 
The date/time of first dose of study treatment in a combination group is the earliest date/time 
of the first non-zero dose date/time for the study drugs in the combination.  
The date/time of last dose of study treatment in a combination group is the latest date/time of 
the last non-zero dose date/time for the study drugs in the combination. 


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Definition of baseline:  
Definition of baseline for efficacy analyses in randomized cohorts 
The last measurement prior to randomization will serve as the baseline measurement for 
efficacy analyses. If such a value is missing, the last measurement prior to the first dose of 
study treatment will be used as the baseline measurement except for analyses of tumor 
assessments data where the baseline assessment would be considered as missing.  
Definition of baseline for immunogenicity analyses 
The last available assessment prior to the start of treatment with avelumab is defined as 
‘baseline’ result or ‘baseline’ assessment.  If an assessment is planned to be performed prior 
to the first dose of avelumab in the protocol and the assessment is performed on the same day 
as the first dose of avelumab, it will be assumed that it was performed prior to avelumab 
administration, if assessment time point is not collected or is missing. 
Definition of baseline for efficacy analyses in non-randomized cohorts and for safety 
analyses 
The last available assessment prior to the start of study treatment is defined as ‘baseline’ 
value or ‘baseline’ assessment for safety and efficacy (for non-randomized cohorts) analyses.  
If an assessment is planned to be performed prior to the first dose of study treatment in the 
protocol and the assessment is performed on the same day as the first dose of study 
treatment, it will be assumed that it was performed prior to study treatment administration, if 
assessment time point is not collected or is missing. If assessment time points are collected, 
the observed time point will be used to determine pre-dose on study day 1 for baseline 
calculation. Unscheduled assessments will be used in the determination of baseline. 
However, if time is missing, an unscheduled assessment on study day 1 will be considered to 
have been obtained after study treatment administration. 
Patients who start treatment and discontinue from the study on the same day may have two 
different sets of data collected on study day 1 (one during study and one in the End of 
Treatment (EOT) visit. Data reported at the EOT visit are not eligible for baseline selection.  
If a scheduled pre-dose measurement actually occurred post-dose, then the corresponding 
measurement will be treated and analyzed similar to an unscheduled post-dose measurement. 
Baseline for RR and QT/QTc interval assessments will be derived from the visit where both 
RR and QT are not missing. Triplicate ECGs (at screening and pre-dose Cycle 1 Day 1) and 
Single ECGs (following start of study drug) are collected in the study.  The baseline for each 
ECG measurement is the average of the pre-dose replicate measurements on the baseline day. 
Unscheduled assessments will not be included in the calculation of the average. QTcB and 
QTcF will be derived based on RR and QT.  In the case of triplicate ECGs, the average of the 
replicate measurements will be determined after the derivation of the individual parameter at 
each time point. 


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3.4.2. Baseline characteristics 
Baseline characteristics (including demographics, physical measurements, disease history 
and prior anti-cancer therapies) are described in Section 6.5.1.  These baseline characteristics 
are not planned to be included as stratification variables or covariates in statistical models 
unless otherwise specified in Section 6.   
3.5. Safety Endpoints 
3.5.1. Adverse events 
Treatment-Emergent Adverse Events 
Treatment-emergent adverse events (TEAEs) are those events with onset dates occurring 
during the on-treatment period.  
On-treatment period is defined as the time from the first dose of study treatment through 
minimum (30 days + last dose of study treatment, start day of new anti-cancer drug therapy – 
1 day). The start day of new anti-cancer drug therapy after the first dose of study treatment is 
derived as outlined in Section 5.2.5. 
Adverse Events of Special Interest (AESIs) 
AESIs are immune-related adverse events (irAE) and infusion-related reactions (IRRs).  The 
criteria for classification of an AE as an irAE or IRR are described in Appendix 1 and 
Appendix 2, respectively. 
4. ANALYSIS SETS 
Data for all patients will be assessed to determine if patients meet the criteria for inclusion in 
each analysis population prior to releasing the database and classifications will be 
documented per Pfizer’s standard operating procedures. 
Only patients who signed informed consent will be included in the analysis sets below. 
4.1. Full Analysis Set 
For the Phase 1b cohorts and the non-randomized cohort in Phase 2: The FAS will include all 
patients who receive at least one dose of study drug.  Patients will be classified according to 
the study treatment actually received.  If a patient receives more than one treatment the 
patient will be classified according to the first study treatment received.  
For the randomized cohorts in Phase 2: The full analysis set (FAS) will include all 
randomized patients.  Patients will be classified according to the study treatment assigned at 
randomization.  
4.2. Safety Analysis Set 
For the Phase 1b cohorts and the non-randomized cohort in Phase 2: The safety analysis set 
will include all patients who receive at least one dose of study drug.  Patients will be 


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classified according to the study treatment actually received.  If a patient receives more than 
one study treatment, the patient will be classified according to the first study treatment 
received.  For these non-randomized cohorts of the study, the FAS and the safety analysis set 
are identical. 
For the randomized cohorts in Phase 2: The safety analysis set will include all patients who 
receive at least one dose of study drug. Patients will be classified according to the study 
treatment assigned at randomization unless the incorrect treatment(s) was/were received 
throughout the dosing period in which case patients will be classified according to the first 
study treatment received.  
4.3. Other Analysis Set 
4.3.1. DLT-evaluable set 
The DLT-evaluable analysis set is a subset of the safety analysis set and includes all enrolled 
patients in Phase 1b who are eligible for the study, receive at least one dose of the 
combination treatment, and either experience DLT during the first cycle (28 days) of 
treatment, or complete the DLT observation period for the first cycle of treatment without 
DLT.  
Patients without DLTs who withdraw from study treatment before receiving at least 75% of 
the planned dose of avelumab, binimetinib or talazoparib (if applicable) in Cycle 1 for 
reasons other than toxicity which are attributable to the investigational products are not 
evaluable for DLT.   
4.3.2. Per-protocol analysis set for OR 
Applicable to Phase 2 only.  Per-protocol (PP) analysis set is a subset of the FAS and will 
include patients who do not meet any of the following criteria that could impact the primary 
objective of the Phase 2 of the study.  Patients who meet any of the following criteria will be 
excluded from the PP analysis set: 
• Patient did not receive at least one dose of the assigned study treatment. 
• Patient without a tumor assessment >7 weeks after ‘start date’ (unless PD or death is 
observed before that time in which case the patient will not be excluded from the PP 
analysis set).  
• Patient without measurable disease at baseline by Investigator. 
• Baseline ECOG status ≥ 2. 
• Patients did not meet inclusion criteria 1, 2, or 3.   
4.3.3. PK analysis sets 
The PK concentration analysis set is a subset of the safety analysis set and will include 
patients who have at least one concentration measurement for avelumab, talazoparib or 
binimetinib.  


A v el u ma b  
B9 9 9 1 0 3 3  ( M S B0 0 1 0 7 1 8 C , M D V3 8 0 0,  B M N  6 7 3 , M E K 1 6 2)  St atis tic al A n al ysis Pla n 
 
P FI Z E R C O N FI D E N TI A L  
Pa g e 2 3  
T he P K para meter a nalysis  s et is a s u bs et of t he s afet y a nalysis  s et a n d will  inclu de  patie nts 
w h o ha ve at le ast o ne of t he P K para meters of interest f or a velu ma b ,  tala z o parib or 
bini me tin i b . 
4. 3.4.  Bi o m ar k e r a n al ys is  s e t  
T he bio mar ker  a nalysis  s et is  a s u bs et of t he safet y a nalysis  s et a n d will  inclu de  patie nts    
w h o  ha ve at le ast o ne  bas eline  bio mar ker  ass ess me nt.   
A nalysis  s ets will  be define d  s e parately  f or blo o d -bas e d  a n d t u m or  tiss ue -bas e d  bio mar kers.  
4. 3.5.  I m m u n o g e nicit y a n al ys is  s e t  
T he i m m u n o ge nic i t y  a na lysis  s e t is a s u bs et of t he s afet y a nalysis  s et a n d  will  inclu de 
patie nts  w h o  ha ve at le ast o ne A D A/ n A b ass ess me nt f or a velu ma b. 
 
 
 
5.  G E N E R A L M E T H O D O L O G Y A N D C O N V E N TI O N S  
5. 1.  H y p ot he s es a n d D e cis i o n R ule s  
5. 1.1.  H y p ot he s es a n d s a m ple  s ize  de te r mi n ati o n  
T here is n o  f or mal  h y p ot hesis  testin g  in  t his  st u d y . 
D ur i n g  t he  P h as e  1 b d os e  fi n di n g, prior  t o i m ple me ntati o n  of Pr ot oc ol  A me n d me nt  3,  it 
w as esti mate d  t hat  a p pr o xi mately  u p  t o 1 2 a n d 1 5 patie nts  wo uld  be e nr olle d  a n d  assig ne d  t o 
tre at me nt wit h  t he d o u blet a n d t he triple t c o m binatio ns ,  res pe ctively.   P er Pr ot oc ol  
A me n d me nt  3,  it  is  esti mate d  t hat a p pr o xi mately  u p t o  1 8  a n d 1 2  patie nts  will  be e nr olle d 
a n d assig ne d  t o tre at me nt  wit h  t he d o u blet a n d t he triplet  c o m binatio ns,  res pe ctively (in 
a d ditio n  t o t he 2 2  patie nts  pre vio usly  e nr olle d  d urin g  P has e 1 b  prior  t o  i m ple me ntati o n  of 
Pr ot oc ol  A me n d me nt  3).  Ea c h c o m binatio n  will  inclu de  at le ast 6 patie nts tre ate d at t he 
M T D as des cribe d  in Se ctio n  2. 2  a n d  at le ast 9  patie nts  at t he R P 2 D.  T he a ct ual n u m ber  of 
patie nts  will  de pe n d  o n t he n u m ber  of D L T e ve nts a n d  d os e le vels/c o h orts  a n d d osin g 
s c he d ules t hat are teste d. 
I n P h as e  2, t he pri mar y  o bje ctive  is  t o ass ess t he O R R of the d o u blet  a n d t he triplet 
c o m binatio ns . 
F or  patie nts  wit h m P D A C ,  wit h  2 0  tre ate d patie nts  per tre at me nt gr o u p ( d ou blet  a n d  triplet 
c o m binatio ns) ,  O R R c a n be esti mate d  wit h  a ma xi m u m  sta n dar d  err or of  0. 1 1 2.   F or patie nts 
in  t he ‘t u m or  a g n ostic’  c o h ort  of t he triplet  c o m binatio n,  O RR c a n be esti mate d  wit h a 
ma xi m u m  sta n dar d err or of 0. 0 9 1  wit h  3 0  tre ate d patie nts.  
F u rt her,  ass u min g  a beta-bin o mia l  distrib utio n  f or  t he O R R a n d  a beta ( 0. 5,  0. 5)  prior,  
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• mPDAC cohort treated with the doublet combination at the RP2D: if 5 responders (out of 
20 patients, ORR of 25%) are observed, the posterior probability of a true ORR ≥15% 
(considered a clinically relevant effect) will be ≥80% (89.0%).  
• mPDAC cohort treated with the triplet combination at the RP2D: if 7 responders (out of 
20 patients, ORR of 35%) are observed, the posterior probability of a true response rate 
≥25% (considered a clinically relevant effect) will be ≥80% (84.9%).  
• ‘Tumor agnostic’ KRAS- or NRAS -mutant solid tumor cohort treated with the triplet 
combination at the RP2D: if 12 responders (out of 30 patients, ORR of 40%) are 
observed, the posterior probability of a true ORR ≥30% (considered a clinically relevant 
effect) will be ≥80% (88.2%).  
The determination of what constitutes a clinically meaningful response rate was based upon a 
review of historical ORR data for clinical studies in mPDAC, second line NSCLC, and 
CRC5,11. 
5.1.2. Decision rules 
Identification of a recommended Phase 2 dose 
The dosing decision and estimation of the MTDs of the doublet and the triplet combinations 
will be guided by the estimation of the probability of DLT in Cycle 1.  However, other 
evidence such as safety data beyond DLT, clinical activity, PK, and PD data will play an 
important role in the final decision.  A RP2D below the MTD may be determined based on 
these considerations. 
Prior to implementation of Protocol Amendment 3, the doublet of avelumab in combination 
with binimetinib on continuous dose schedule was evaluated to determine the RP2D.   
Per Protocol Amendment 3, the doublet combination of binimetinib on intermittent 7d/7d 
dosing schedule and talazoparib will be evaluated to determine the RP2D. Upon the 
completion of the dose finding for the doublet combination, the triplet combination will then 
be evaluated to determine the triplet RP2D. 
Bayesian adaptive approach 
The dose finding in the Phase 1b of the study will be guided by a Bayesian analysis of Cycle 
1 DLTs in DLT-evaluable patients (Neuenschwander et al. 2014)13.  
A. Doublet combination model: 
Prior to implementation of Protocol Amendment 3, the Bayesian model for the doublet 
combination of avelumab and binimetinib consists of three parts, representing: 
• Single-agent avelumab toxicity 
• Single-agent binimetinib toxicity 
• Interaction between avelumab and binimetinib 


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Per Protocol Amendment 3, the Bayesian model for the doublet combination of talazoparib 
and binimetinib consists of three parts, representing: 
• Single-agent talazoparib toxicity; 
• Single-agent binimetinib toxicity; 
• Interaction between talazoparib and binimetinib. 
B. Triplet combination model: 
For the triplet combination of avelumab, binimetinib, and talazoparib, the Bayesian model 
consists of seven parts, representing: 
• Single-agent talazoparib toxicity 
• Single-agent binimetinib toxicity 
• Single-agent avelumab toxicity 
• Interaction between binimetinib and talazoparib 
• Interaction between talazoparib and avelumab 
• Interaction between binimetinib and avelumab 
• Triple interaction among binimetinib, talazoparib, and avelumab 
Single-agent toxicities are modelled using logistic regression for the probability of a patient 
experiencing a DLT against log-dose.  The odds of a DLT are then calculated under no 
interaction for the two/three single-agent toxicities, and interaction is accounted for by 
adjusting these odds with an additional model parameter (odds multiplier).  Details of the 
model are given in Appendix 3 (prior to implementation of Protocol Amendment 3) and 
Appendix 4 (per Protocol Amendment 3). 
Assessment of patient risk 
After each cohort of patients completes the DLT evaluation period, the posterior distribution 
for the risk of DLT for different dose combination doses of interest will be evaluated.  The 
posterior distributions will be summarized to provide the posterior probability that the risk of 
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• Underdosing: 
 
[0, 0.16) 
• Target toxicity: 
 
[0.16, 0.33) 
• Excessive toxicity: 
[0.33, 1] 
The EWOC principle 
Dosing decisions are guided by the EWOC principle (Babb et al. 1998)1. A combination dose 
may only be used for the next cohort of patients if the risk of excessive toxicity ([0.33, 1]) at 
that combination dose is less than 0.25. 
Prior distributions 
A meta-analytic-predictive (MAP) approach was used to derive the prior distribution for the 
single-agent model parameters.  The MAP prior for the logistic model parameters for this 
study is the conditional distribution of the parameters given the historical data 
(Neuenschwander et al. 201012; Neuenschwander et al. 201413; Spiegelhalter et al. 200414). 
MAP priors are derived using Bayesian hierarchical models, which take into account possible 
differences between the studies. 
A full description of the application of the MAP approach to derive the prior distributions of 
the single-agent model parameters is given in Appendix 3 (prior to implementation of 
Protocol Amendment 3) and Appendix 4 (per Protocol Amendment 3).   
The prior distribution for the interaction parameters (doublet and triplet combinations) were 
based on the prior understanding of possible drug safety interactions.  This prior allows for 
the possibility of either synergistic or antagonistic interaction and is fully described in 
Appendix 3 (prior to implementation of Protocol Amendment 3) and Appendix 4 (per 
Protocol Amendment 3). 
Starting dose levels 
Prior to implementation of Protocol Amendment 3, the starting dose for the doublet 
combination was D0 (800 mg avelumab IV Q2W and 45 mg binimetinib orally twice daily 
continuous dosing).  For this dose the prior risk of excessive toxicity was 0.1, which satisfied 
the EWOC criterion.   
Per Protocol Amendment 3, the starting dose for the doublet combination is 0.75 mg 
talazoparib orally once daily, and 45 mg binimetinib orally twice daily, 7 days on, 7 days off 
(Schedule 7d/7d).  For this dose the prior risk of excessive toxicity is 0.189, which satisfies 
the EWOC criterion.  
The starting dose for the triplet combination will be determined after completion of the dose 
finding for the doublet combination.  
A full assessment of the prior risk to patients is given in Appendix 3 (prior to implementation 
of Protocol Amendment 3) and Appendix 4 (per Protocol Amendment 3). 


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5.2. General Methods 
The definition of ‘treatment group’ in this study is provided in Table 4. 
Table 5 provides an overview of the summaries and the tabulations for this study. 
 


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Table 5. 
Study Summaries and Tabulations  
Summaries  
Analysis Sets 
Phase 1b 
Phase 2 
Phase 1b and Phase 2 combined 
Baseline 
characteristics  
FAS 
- by treatment group 
- pooled: D0+D-1  
- pooled: BT doublet (7d/7d)   
- pooled: BT doublet (5d/2d) 
- pooled: ABT triplet 
- pooled: all patients in 
avelumab containing treatment 
groups 
- by treatment group  
- pooled ABT:mPADC and 
ABT:tumor agnostic 
  
- pooled: all doublet at the RP2D  
- pooled: all triplet at the RP2D 
-pooled: all patients in avelumab 
containing treatment groups 
  
Disposition 
FAS 
- by treatment group 
- pooled: D0+D-1  
- pooled: BT doublet (7d/7d)   
- pooled: BT doublet (5d/2d) 
- pooled: ABT triplet  
- by treatment group  
- ABT:mPADC and ABT:tumor 
agnostic 
 
Not Done 
DLTs 
DLT-evaluable set 
- by treatment group 
- pooled: D0+D-1  
- pooled: BT doublet (7d/7d)   
- pooled: BT doublet (5d/2d) 
- pooled: ABT triplet  
Not Done 
Not Done 
Efficacy data 
FAS, Per-protocol 
analysis set a 
- by treatment group 
- pooled: D0+D-1  
- pooled: BT doublet (7d/7d)   
- pooled: BT doublet (5d/2d) 
- pooled: ABT triple 
- by treatment group 
 
Not Done 
Other safety data, 
exposure data, 
concomitant 
medications, non-
drug treatment 
Safety analysis set 
- by treatment group 
- pooled: D0+D-1  
- pooled: BT doublet (7d/7d)   
- pooled: BT doublet (5d/2d) 
- pooled: ABT triplet 
- by treatment group 
- ABT:mPADC and ABT:tumor 
agnostic 
  
- pooled: all doublet at the RP2D  
- pooled: all triplet at the RP2D  
 


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PK data for 
avelumab 
PK analysis set 
- by treatment group (for 
avelumab containing treatment 
groups only) 
- pooled: D0+D-1  
- pooled: ABT triplet   
- pooled: all patients in 
avelumab containing treatment 
groups b 
 
- by treatment group 
- ABT:mPADC and ABT:tumor 
agnostic 
 
 -pooled: all patients in avelumab 
containing treatment groups b  
PK data for 
talazoparib 
PK analysis set 
- by treatment group (for 
talazoparib containing 
treatment groups only) 
- by treatment group (for 
talazoparib containing treatment 
groups) 
- ABT:mPADC and ABT:tumor 
agnostic 
- pooled: all doublet at the RP2D  
- pooled: all triplet at the RP2D  
 
PK data for 
binimetinib 
PK analysis set 
- by treatment group 
- by treatment group 
- ABT:mPADC and ABT:tumor 
agnostic 
 
- pooled: all doublet at the RP2D  
- pooled: all triplet at the RP2D  
 
Biomarker data 
Biomarker analysis 
set 
Not Done 
- by treatment group  
 
Not Done 
Immunogenicity 
data 
Immunogenicity 
analysis set 
- by treatment group (for 
avelumab containing treatment 
groups only) 
- pooled: D0+D-1  
- pooled: ABT triplet     
- pooled: all patients in 
avelumab containing treatment 
groups  
- by treatment group (for avelumab 
containing treatment groups only) 
- ABT:mPADC and ABT:tumor 
agnostic 
 
-pooled: all patients in avelumab 
containing treatment groups  
a Per-protocol analysis set is used only for the analysis of OR in Phase 2; 
b Pool all patients only if no evidence of impact of binimetinib or talazoparib on avelumab exposure; RP2D=recommended phase 2 dose 
  
 


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5.2.1. Data handling after the cut-off date 
 Data after the cut-off date may not undergo the cleaning process and will not be displayed in 
any listings or used for summary statistics, statistical analyses or imputations. 
5.2.2. Pooling of centers 
In order to provide overall estimates of treatment effects, data will be pooled across centers.  
The ‘center’ factor will not be considered in statistical models or for subgroup analyses due 
to the high number of participating centers in contrast to the anticipated small number of 
patients treated at each center. 
5.2.3. Presentation of continuous and qualitative variables 
Continuous variables will be summarized using descriptive statistics ie, number of non-
missing values and number of missing values [ie, n (missing)], mean, median, standard 
deviation (SD), minimum, maximum and first and third quartile (Q1 and Q3).  
Qualitative variables will be summarized by frequency counts and percentages. Unless 
otherwise specified, the calculation of proportions will include the missing category. 
Therefore, counts of missing observations will be included in the denominator and presented 
as a separate category. 
In case the analysis refers only to certain visits, percentages will be based on the number of 
patients still present in the study at that visit, unless otherwise specified. 
5.2.4. Definition of study day 
Start day of study treatment is the day of the first dose of study treatment. 
The study day for assessments occurring on or after the start of study treatment (eg, adverse 
event onset, tumor measurement) will be calculated as: 
Study day = Date of the assessment/event - start of study treatment + 1.  
The study day for assessments occurring prior to the first dose of study treatment (eg, 
baseline characteristics, medical history) will be negative and calculated as: 
Study day = Date of the assessment/event - start of study treatment. 
The study day will be displayed in all relevant data listings. 
5.2.5. Definition of start of new anti-cancer drug therapy 
Start date of new anti-cancer drug therapy is used to determine the end of the on-treatment 
period (see Section 5.2.7). 
The start date of new anti-cancer drug therapy is the earliest start date of anti-cancer drug 
therapy recorded in the ‘Follow-up Cancer Therapy’ eCRF pages that is after the first dose of 
study treatment. When start date of anti-cancer drug therapy is missing or partially missing, 


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the imputation rules described in Section 5.3.3.4 should be applied using only data from the 
‘Follow-up Cancer Therapy’ eCRF pages. 
5.2.6. Definition of start of new anti-cancer therapy 
Start date of new anti-cancer therapy (drug, radiation, surgery) is used for censoring in 
efficacy analyses (see Section 6.1.2 and Section 6.2.2). 
The start date of new anti-cancer therapy is the earliest date after the first dose of study 
treatment for non-randomized cohorts or after the date of randomization for randomized 
cohorts amongst the following: 
• Start date of anti-cancer drug therapy recorded in the ‘Follow-up Cancer Therapy’ eCRF 
pages 
• Start date of radiation therapy recorded in ‘Concomitant Radiation Therapy’, and 
‘Follow-up Radiation Therapy’ eCRF pages with ‘Treatment Intent’ = ‘Curative in 
intent’  
• Surgery date recorded in ‘On-Study Anti-Cancer Surgery’, and ‘Follow-up Anti-Cancer 
Surgery’ eCRF pages when ‘Surgery Outcome’ = ‘Resected’ or ‘Partially Resected’.   
When start date of anti-cancer therapy is missing or partially missing, the imputation rules 
described in Section 5.3.3.4 should be applied using ‘Follow-up Cancer Therapy’, 
‘Concomitant Radiation Therapy’, ‘Follow-up Radiation Therapy’, ‘On-Study Anti-Cancer 
Surgery’, and ‘Follow-up Anti-Cancer Surgery’ eCRF pages. 
5.2.7. Definition of on-treatment period 
Safety endpoints will be summarized based on the on-treatment period unless otherwise 
specified. 
On-treatment period is defined as the time from the first dose of study treatment through 
minimum (30 days + last dose of study treatment, start day of new anti-cancer drug therapy – 
1 day). 
Safety data collected outside the on-treatment period as described above will be listed and 
flagged in listings but not summarized. 
5.2.8. Standard derivations and reporting conventions 
The following conversion factors will be used to convert days into weeks, months or years:   
1 week = 7 days, 1 month = 30.4375 days, 1 year = 365.25 days. 
Demographics and physical measurements: 
• Age [years]:  
- (date of given informed consent - date of birth + 1) / 365.25 
- In case of missing day, day only: Age [years]: (year/month of given informed consent 
– year/month of birth) 


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- In case only year of birth is given: Age [years]: (year of given informed consent - 
year of birth) 
The integer part of the calculated age will be used for reporting purposes.  
• BMI (kg/m2) = weight (kg)/[height (m)]2 
For reporting conventions, mean and median should generally be displayed one more 
decimal place than the raw data and standard deviation should be displayed to two more 
decimal places than the raw data. Percentages will be reported to one decimal place. The 
rounding will be performed to closest integer / first decimal using the common mid-point 
between the two consecutive values. Eg, 5.1 to 5.4 will be rounded to an integer of 5, and 5.5 
to 5.9 will be rounded to an integer of 6. 
5.2.9. Unscheduled visits 
Generally, data collected at unscheduled visits will be included and analyzed for both safety 
and efficacy analyses in the same fashion as the data collected at scheduled visits except 
where otherwise noted in the sections that follow. Descriptive statistics (mean, SD, median, 
minimum, maximum, quartiles) by nominal visit or time point for safety endpoints such as 
laboratory measurements, ECGs and vital signs will include only data from scheduled visits. 
5.2.10. Adequate baseline tumor assessment 
Adequate baseline is defined using the following criteria: 
• All baseline assessments must be within 28 days prior to and including enrollment date. 
In this study, the date of treatment assignment will be considered the “date of 
enrollment”, Investigational product administration should begin within 3 days after 
enrollment. 
• All documented lesions must have non-missing assessments (ie, non-missing 
measurements for target lesions and non-missing lesions assessment status at baseline for 
non-target lesions). 
5.2.11. Adequate post-baseline tumor assessment 
An adequate post-baseline assessment is defined as an assessment where a response of CR, 
PR, SD, non-CR/non-PD, or PD can be determined (see Section 6.1.2.1).  Time points where 
the response is not evaluable (NE) or no assessment was performed will not be used for 
determining the censoring date. 
5.3. Methods to Manage Missing Data 
5.3.1. Missing data 
Unless otherwise specified, all data will be evaluated as observed, and no imputation method 
for missing values will be used. 
In all patient data listings imputed values will be presented.  In all listings imputed 
information will be flagged. 


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Missing statistics, eg when they cannot be calculated, should be presented as ‘ND’ or ‘NA’.  
For example, if N=1, the measure of variability (SD) cannot be computed and should be 
presented as ‘ND’ or ‘NA’.  
5.3.1.1. Pharmacokinetic concentrations 
Concentrations Below the Limit of Quantification 
For all calculations, figures and estimation of individual pharmacokinetic parameters, all 
concentrations assayed as below the level of quantification (BLQ) will be set to zero. In log-
linear plots these values will not be represented.  The BLQ values will be excluded from 
calculations of geometric means and their CIs. A statement similar to ‘All values reported as 
BLQ have been replaced with zero’ should be included as a footnote to the appropriate tables 
and figures. 
Deviations, Missing Concentrations and Anomalous Values 
In summary tables and plots of median profiles, concentrations will be set to missing if one 
of the following cases is true: 
1. A concentration has been reported as ND (ie, not done) or NS (ie, no sample); 
2. A deviation in sampling time is of sufficient concern or a concentration has been 
flagged as anomalous by the clinical pharmacologist. 
Summary statistics may not be presented at a particular time point if more than 50% of the 
data are missing.  For analysis of pharmacokinetic concentrations, no values will be imputed 
for missing data. 
5.3.1.2. Pharmacokinetic parameters 
Whether actual or nominal PK sampling time will be used for the derivation of PK 
parameters will be determined by the results of interim PK analyses.  If a PK parameter is 
missing, the parameter will be coded as NC (ie, not calculated).  NC values will not be 
generated beyond the day that a patient discontinues. 
In summary tables, statistics will be calculated by setting NC values to missing. Statistics 
will not be presented for a particular treatment if more than 50% of the data are NC.  For 
statistical analyses (ie, analysis of variance), PK parameters coded as NC will also be set to 
missing. 
If an individual patient has a known biased estimate of a PK parameter (due for example to a 
deviation from the assigned dose level), this will be footnoted in summary tables and will not 
be included in the calculation of summary statistics or statistical analyses. 


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5.3.2. Handling of incomplete dates 
5.3.2.1. Disease history 
Incomplete dates for disease history (eg, initial diagnosis date, date of documented, locally 
advanced, inoperable or metastatic disease diagnosis, date of response or progression in prior 
treatment) will be imputed as follows: 
• If the day is missing, it will be imputed to the 15th day of the month.  
• If both day and month are missing and the year is prior to the year of the first study 
treatment, the month and day will be imputed as July 1st. 
• If both day and month are missing and the year is same as the year of the first study 
treatment, the month and day will be imputed as January 1st.  
• If the date is completely missing, no imputation will be performed. 
5.3.2.2. Adverse events 
Incomplete AE-related dates will be imputed as follows: 
• If the AE onset date is missing completely, then the onset date will be replaced by the 
start of study treatment. 
• If only the day part of the AE onset date is missing, but the month and year are equal to 
the start of study treatment, then the AE onset date will be replaced by the start of study 
treatment. For example, if the AE onset date is --/JAN/2015, and study treatment start 
date is 15/JAN/2015, then the imputed AE onset date will be 15/JAN/2015. 
• If both the day and month of the AE onset date are missing but the onset year is equal to 
the start of study treatment, then the onset date will be replaced by the start of study 
treatment. For example, if AE onset date is --/---/2014, and study treatment start date is 
19/NOV/2014, then the imputed AE onset date will be 19/NOV/2014. 
• In all other cases the missing onset day or missing onset month will be replaced by 1. 
• Incomplete stop date will be replaced by the last day of the month (if day is missing 
only), if not resulting in a date later than the date of patient's death. In the latter case the 
date of death will be used to impute the incomplete stop date.  
• In all other cases the incomplete stop date will not be imputed.  If stop date of AE is after 
the date of cut-off outcome of AE is ongoing at cut-off.  
5.3.2.3. Prior and concomitant medications 
Incomplete prior/concomitant medication dates will be imputed as follows: 
• If the medication date is missing completely, then the medication date will be replaced by 
the start of study treatment. 
• If the day of medication date is missing, but the month and year are equal to the start of 
study treatment, then the medication date will be replaced by the start of study treatment. 
For example, if the medication start date is --/JAN/2015, and study treatment start date is 
15/JAN/2015, then the imputed medication start date will be 15/JAN/2015.  


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• If both the day and month of medication start date are missing but the start year is equal 
to the start of study treatment, then the medication date will be replaced by the start of 
study treatment. For example, if the medication start date is --/---/2014, and study 
treatment start date is 19/NOV/2014, then the imputed medication start date will be 
19/NOV/2014. 
• In all other cases the missing medication day or missing medication month will be 
replaced by 1. 
• Incomplete stop date will be replaced by the last day of the month (if day is missing 
only), if not resulting in a date later than the date of patient's death. In the latter case the 
date of death will be used to impute the incomplete stop date.  
• In all other cases the incomplete medication stop date will not be imputed.  
5.3.2.4. Exposure 
No imputation will be done for first dose date.  Date of last dose of study drug, if unknown or 
partially unknown, will be imputed as follows: 
• If the last date of study drug is completely missing and there is no End of Treatment 
eCRF page and no death date, the patient should be considered to be ongoing and use the 
cut-off date for the analysis as the last dosing date 
• If the last date of study drug is completely or partially missing and there is EITHER an 
End of Treatment eCRF page OR a death date available (within the cut-off date), then 
imputed last dose date is: 
= 31DECYYYY, if only Year is available and Year < Year of min (EOT date, death date)  
= Last day of the month, if both Year and Month are available and Year = Year of min 
(EOT date, death date) and Month < the month of min (EOT date, death date) 
= min (EOT date, death date), for all other cases. 
5.3.3. Imputation rules for date of last contact and efficacy assessments 
5.3.3.1. Date of last contact 
The date of last contact will be derived for patients not known to have died at the analysis 
cut-off using the latest complete date among the following: 
• All patient assessment dates (blood draws (laboratory, PK), vital signs, performance 
status, ECG, tumor assessments) 
• Start and end dates of anti-cancer therapies administered after study treatment 
discontinuation 
• AE start and end dates 
• Last date of contact collected on the ‘Survival Follow-up’ eCRF (do not use date of 
survival follow-up assessment unless status is ‘alive’) 
• Study drug start and end dates 
• Randomization date 


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• Withdrawal of consent date 
• Date of discontinuation on disposition eCRF pages (do not use if reason for 
discontinuation is lost to follow-up). 
Only dates associated with actual examinations of the patient will be used in the derivation.  
Dates associated with a technical operation unrelated to patient status such as the date a 
blood sample was processed will not be used. Assessment dates after the cut-off date will not 
be applied to derive the last contact date. 
5.3.3.2. Death date 
Missing or partial death dates will be imputed based on the last contact date: 
• If the date is missing it will be imputed as the day after the date of last contact  
• If the day or both day and month is missing, death will be imputed to the maximum of the 
full (non-imputed) day after the date of last contact and the following: 
- Missing day:  
 
1st day of the month and year of death 
- Missing day and month: 
January 1st of the year of death 
5.3.3.3. Tumor assessments 
All investigation dates (eg, X-ray, CT scan) must be completed with day, month and year. 
If there are multiple scan dates associated with an evaluation, ie, radiological assessments 
occur over a series of days rather than the same day, the choice of date of assessment could 
impact the date of progression and/or date of response.  If there are multiple scan dates 
associated with an evaluation, the earliest of the scan dates associated with the evaluation 
will be used as the date of assessment. 
If one or more investigation dates for an evaluation are incomplete but other investigation 
dates are available, the incomplete date(s) are not considered for calculation of the 
assessment date and assessment date is calculated as the earliest of all investigation dates (eg, 
X-ray, CT-scan).   
If all measurement dates for an evaluation have no day recorded, the 1st of the month is used.  
If the month is not completed, for any of the investigations for an evaluation, the respective 
assessment will be considered to be at the date which is exactly between the previous and the 
following assessment.  If both a previous and following assessments are not available, this 
assessment will not be used for any calculations. 
5.3.3.4. Date of start of new anti-cancer therapy 
Incomplete dates for start date of new anti-cancer therapy (drug therapy, radiation, surgery) 
will be imputed as follows and will be used for determining censoring dates for efficacy 
analyses and in the derivation of the end of on-treatment period.  PD date below refers to PD 
date by investigator assessment. If the imputation results in an end date prior to the imputed 
start date then the imputed start date should be set to the end date. 


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• The end date of new anti-cancer therapy will be included in the imputations for start date 
of new anti-cancer therapy.  If the end date of new anti-cancer therapy is 
o completely missing then it will be ignored in the imputations below 
o partially missing with only year (YYYY) available then the imputations below will 
consider 31DECYYYY as the end date of the new anti-cancer therapy 
o partially missing with only month and year available then the imputations below will 
consider the last day of the month for MMMYYYY as the end date of the new anti-
cancer therapy 
• For patients who have not discontinued study treatment at the analysis cut-off date, last 
dose of study treatment is set to the analysis cut-off date in the imputations below.  
• If the start date of new anti-cancer therapy is completely or partially missing, then the 
imputed start date of new anti-cancer therapy is derived as follows: 
o Start date of new anti-cancer therapy is completely missing 
Imputed start date = min [max (PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy] 
o Only year (YYYY) for start of anti-cancer therapy is available 
IF YYYY < Year of min [max (PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy] THEN imputed start date = 31DECYYYY;  
ELSE IF YYYY = Year of min [max (PD date + 1, last dose of study treatment + 1), 
end date of new anti-cancer therapy]  
THEN imputed start date = min [max (PD date + 1, last dose of study treatment + 1), 
end date of new anti-cancer therapy] 
ELSE IF YYYY > Year of min [max (PD date + 1, last dose of study treatment + 1), 
end date of new anti-cancer therapy]  
THEN imputed start date = 01JANYYYY 
o Both Year (YYYY) and Month (MMM) for start of anti-cancer therapy are available 
IF 
YYYY = Year of min [max (PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy], AND 
MMM < Month of min [max (PD date + 1 day, last dose of study treatment + 1 
day), end date of new anti-cancer therapy]  
THEN  
imputed start date = DAY (Last day of MMM) MMM YYYY; 
ELSE IF 
YYYY = Year of min [max (PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy], AND 


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MMM = Month of min [max (PD date + 1 day, last dose of study treatment + 1 
day), end date of new anti-cancer therapy]  
THEN  
imputed start date = min [max (PD date + 1 day, last dose of study treatment + 1 
day), end date of new anti-cancer therapy]); 
ELSE IF 
YYYY = Year of min [max (PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy], AND 
MMM > Month of min [max (PD date + 1 day, last dose of study treatment + 1 
day), end date of new anti-cancer therapy]  
THEN  
imputed start date = 01 MMM YYYY; 
ELSE IF 
YYYY < Year of min [max (PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy] 
THEN  
imputed start date = DAY (Last day of MMM) MMM YYYY; 
ELSE IF 
YYYY > Year of min [max (PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy] 
THEN  
imputed start date = 01 MMM YYYY. 
6. ANALYSES AND SUMMARIES 
Refer to Section 4 for definitions of analysis sets and Section 5.2 for general methodology.  
6.1. Primary Endpoints  
6.1.1. DLT for Phase 1b 
6.1.1.1. Primary analysis 
The following analyses will be based on the DLT-evaluable set for patients in the Phase 1b.  
DLTs will be listed and summarized as shown in Table 5. 
The posterior distribution of DLT rate (posterior probabilities that DLT rate is in the intervals 
of underdosing (<0.16), target toxicity (≥0.16 and <0.33) and overdosing (≥0.33) at the end 
of Phase 1b will be provided as shown in Table 5. 


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6.1.2. Objective response as assessed by the Investigator per RECIST v1.1  
6.1.2.1. Primary analysis 
The following analyses will be based on the FAS as shown in Table 5.  Assessment of 
response will be made using RECIST v1.1 based on investigator assessment. 
Best overall response (BOR) will be assessed based on reported overall lesion responses at 
different evaluation time points from the ‘start date’ until the first documentation of PD, 
according to the following rules. Only tumor assessments performed on or before the start 
date of any further anti-cancer therapies will be considered in the assessment of BOR.  
Clinical deterioration will not be considered as documentation of disease progression.  
BOR Based on Confirmed Responses:  
• CR = at least two determinations of CR at least 4 weeks apart and before first 
documentation of PD  
• PR = at least two determinations of PR or better (PR followed by PR or PR followed by 
CR) at least 4 weeks apart and before first documentation of PD (and not qualifying for a 
CR)  
• SD (applicable only to patients with measurable disease at baseline) = at least one SD 
assessment (or better) ≥ 6 weeks after the ‘start date’ and before first documentation of 
PD (and not qualifying for CR or PR).  
• Non-CR/non-PD (applicable only to patients with non-measurable disease at baseline) = 
at least one non-CR/non-PD assessment (or better) ≥ 6 weeks after the ‘start date’ and 
before first documentation of PD (and not qualifying for CR or PR). 
• PD = first documentation of PD ≤ 12 weeks after the ‘start date’ (and not qualifying for 
CR, PR, SD or non-CR/non-PD).   
• NE: all other cases. 
An objective status of PR or SD cannot follow one of CR.  SD can follow PR only in the rare 
case that tumor increases by less than 20% from the nadir, but enough that a previously 
documented 30% decrease from baseline no longer holds.  If this occurs, the sequence PR-
SD-PR is considered a confirmed PR.  A sequence of PR – SD – SD – PD would be a best 
response of SD if the window for SD definition has been met. 
Objective Response (OR) is defined as confirmed BOR of CR or PR according to RECIST 
v1.1. 
Patients who do not have a post-baseline radiographic tumor assessment due to early 
progression, who receive anti-cancer therapies other than the study treatments prior to 
reaching a CR or PR, or who die, progress, or drop out for any reason prior to reaching a CR 
or PR will be counted as non-responders in the assessment of OR. Each patient will have an 
objective response status (0: no OR; 1: OR).  OR rate (ORR) is the proportion of patients 
with OR in the analysis set. 


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ORR will also be calculated along with the 2-sided 95% CI using the Clopper-Pearson 
method (exact CI for a binomial proportion as computed by default by the FREQ procedure 
using the EXACT option).  
In addition, the frequency (number and percentage) of patients with a confirmed BOR of CR, 
PR, SD, non-CR/non-PD (applicable only to patients with non-measurable disease at 
baseline), PD, and NE will be tabulated. Patients with confirmed BOR of NE will be 
summarized by reason for having NE status. The following reasons will be used: 
• No baseline assessment  
• No post-baseline assessments due to death  
• No post-baseline assessments due to other reasons 
• All post-baseline assessments have overall response NE 
• New anti-cancer therapy started before first post-baseline assessment 
• SD of insufficient duration (<6 weeks after the ‘start date’ without further evaluable 
tumor assessments) 
• PD too late (>12 weeks after the ‘start date’) 
Special and rare cases where BOR is NE due to both SD of insufficient duration and late PD 
will be classified as ‘SD too early’ (ie, SD of insufficient duration). 
6.1.2.2. Sensitivity analysis for ORR 
Sensitivity analysis for ORR (Phase 2 only) will be performed using the methodology 
described in Section 6.1.2.1 based on the per-protocol analysis set.  
6.2. Secondary Endpoints 
6.2.1. Safety endpoints 
Refer to Section 6.6. 
6.2.2. Efficacy endpoints 
The OR for Phase 1b will be summarized using the methodology described in Section 
6.1.2.1, as shown in Table 5.   
The following analyses will be based on the FAS as shown in Table 5. 
Assessment of response will be made using RECIST v1.1.  Tumor-related endpoints will be 
analyzed based on investigator assessment.   


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6.2.2.1. Tumor shrinkage from baseline 
Tumor shrinkage will be summarized as the percent change from baseline in target lesions 
(sum of longest diameter for non-nodal lesion and short axis for nodal lesion) per time point. 
It will be derived as: 
• ((Sum of target lesions at week XX – sum of target lesions at baseline)/sum of target 
lesions at baseline) × 100 
The maximum reduction in target lesions from baseline will be derived across all the post-
baseline assessments until documented disease progression, excluding assessments after start 
of subsequent anti-cancer therapy, as: 
• Minimum of ((sum of target lesions at week XX – sum of target lesions at baseline)/sum 
of target lesions at baseline) × 100 
A waterfall plot of maximum percent reduction in the sum of longest diameter for non-nodal 
lesions and short axis for nodal lesions from baseline will be created. These plots will display 
the best percentage change from baseline in the sum of the diameter of all target lesions for 
each patient with measurable disease at baseline and at least one post-baseline assessment. 
6.2.2.2. Duration of response 
Duration of Response (DR) is defined, for patients with OR, as the time from the first 
documentation of objective response (CR or PR) to the date of first documentation of PD or 
death due to any cause.  If a patient has not had an event (PD or death), DR is censored at the 
date of last adequate tumor assessment. The censoring rules for DR are described in Table 6. 
 
DR (months) = [date of event or censoring– first date of OR +1]/30.4375 


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Table 6. 
Outcome and Event Dates for DR Analyses 
Scenario 
Date of event/censoring 
Outcome 
PD or death  
- 
After at most one missing or inadequate 
post-baseline tumor assessment, OR 
- 
≤ 16 weeks after the ‘start date’ 
Date of PD or death 
Event 
 
PD or death  
- 
After 2 or more missing or inadequate 
post-baseline tumor assessments 
Date of last adequate tumor 
assessment a documenting no PD 
before new anti-cancer therapy is 
given or missed tumor assessments  
Censored 
 
No PD and no death 
Date of last adequate tumor 
assessment a documenting no PD 
before new anti-cancer therapy is 
given or missed tumor assessments  
Censored 
 
Treatment discontinuation due to ‘Disease 
progression’ without documented progression 
Not applicable 
 
Information is ignored. 
Outcome is derived 
based on documented 
progression only. 
New anti-cancer therapy given  
Date of last adequate tumor 
assessment a documenting no PD 
before new anti-cancer therapy is 
given or missed tumor assessments 
Censored 
 
a  If there are no adequate post-baseline assessments prior to PD or death, then the time without adequate 
assessment should be measured from the ’start date’; if the criteria were met the censoring will be on the ’start 
date’. 
 
Kaplan-Meier estimates (product-limit estimates) will be presented together with a summary 
of associated statistics including the median DR time with 2-sided 95% CIs.  In particular, 
the DR rates at 2, 4, 6, 8, 10, and 12 months will be estimated with corresponding 2-sided 
95% CIs.  The CIs for the median will be calculated according to Brookmeyer and Crowley 
(1982)3 and the CIs for the survival function estimates at the time points defined above will 
be derived using the log-log transformation according to Kalbfleisch and Prentice (2002)9 
(conftype=loglog default option in SAS Proc LIFETEST) with back transformation to a CI 
on the untransformed scale. The estimate of the standard error will be computed using 
Greenwood’s formula. 
DR will be displayed graphically and analyzed using Kaplan-Meier methodology. If the 
number of patients with OR is small, the Kaplan-Meier method may not provide reliable 
estimates.  In this case, only descriptive statistics or listings will be provided. 
Frequency (number and percentage) of patients with each event type (PD or death) and 
censoring reasons will be presented by treatment group. Reasons for censoring will be 
summarized according to the categories in Table 7 following the hierarchy shown. 


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Table 7. 
DR Censoring Reasons and Hierarchy 
Hierarchy 
Condition 
Censoring Reason 
1 
Start of new anti-cancer therapy    
Start of new anti-cancer therapy 
2  
Event after 2 or more missing or inadequate post-baseline 
tumor assessments/’start date’ 
Event after 2 or more missing 
assessments a 
3 
No event and [withdrawal of consent date ≥ date of 
randomization OR End of study (EOS) = Patient refused 
further follow-up]  
Withdrawal of consent 
4 
No event and lost to follow-up in any disposition page  
Lost to follow-up 
5  
No event and none of the conditions in the prior hierarchy 
are met  
Ongoing without an event 
a 2 or more missing or inadequate post-baseline tumor assessments 
 
The DR time or censoring time and the reasons for censoring will also be presented in a 
patient listing. 
6.2.2.3. Time to response 
Time to response (TTR) is defined, for patients with OR, as the time from the ‘start date’ to 
the first documentation of objective response (CR or PR) which is subsequently confirmed.  
 
TTR (in months) = [first date of OR – ‘start date’ +1]/30.4375 
TTR will be summarized using simple descriptive statistics (mean, SD, median, min, max. 
Q1, Q3). 
6.2.2.4. Progression-free survival 
Progression-Free Survival (PFS) is defined as the time from the ‘start date’ to the date of the 
first documentation of PD or death due to any cause, whichever occurs first.    
PFS data will be censored on the date of the last adequate tumor assessment for patients who 
do not have an event (PD or death), for patients who start a new anti-cancer therapy prior to 
an event (see Section 5.2.6) or for patients with an event after 2 or more missing tumor 
assessments.   Patients who do not have an adequate baseline tumor assessment or who do 
not have an adequate post-baseline tumor assessment will be censored on the ‘start date’ 
unless death occurred on or before the time of the second planned tumor assessment (ie ≤ 16 
weeks after the ‘start date’) in which case the death will be considered an event.  
In this study antitumor activity will be assessed through radiological tumor assessments 
conducted at screening and every 8 weeks (± 7 days) for 52 weeks from the ‘start date’, and 
then every 16 weeks (± 7 days) thereafter until PD regardless of initiation of subsequent anti-
cancer therapy.    
The censoring and event date options to be considered for the PFS analysis are presented in 
Table 8.   


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PFS (months) = [date of event or censoring– ‘start date’ +1]/30.4375 
 Table 8. 
Outcome and Event Dates for PFS Analyses 
Scenario 
Date of event/censoring 
Outcome 
No adequate baseline assessment 
‘Start date’ a 
Censored a 
PD or death  
- 
After at most one missing or 
inadequate post-baseline tumor 
assessment, OR 
- 
≤ 16 weeks after the ‘start date’ 
Date of PD or death 
Event 
 
PD or death  
- 
After 2 or more missing or 
inadequate post-baseline tumor 
assessments  
Date of last adequate tumor 
assessment b documenting no PD 
before new anti-cancer therapy is 
given or missed tumor assessments 
Censored 
 
No PD and no death 
Date of last adequate tumor 
assessment b documenting no PD 
before new anti-cancer therapy is 
given or missed tumor assessments 
Censored 
 
Treatment discontinuation due to ‘Disease 
progression’ without documented progression 
Not applicable 
 
Information is ignored. 
Outcome is derived 
based on documented 
progression only. 
New anti-cancer therapy given  
Date of last adequate tumor 
assessment b documenting no PD 
before new anti-cancer therapy is 
given or missed tumor assessments 
Censored 
 
a However if the patient dies ≤16 weeks after the ‘start date’ and did not initiate new anti-cancer therapy, the death is an event 
with date on death date 
b  If there are no adequate post-baseline assessments prior to PD or death, then the time without adequate assessment should 
be measured from the ‘start date’; if the criteria were met the censoring will be on the ‘start date’ 
 
Kaplan-Meier estimates (product-limit estimates) will be presented together with a summary 
of associated statistics including the median PFS time with 2-sided 95% CIs.  In particular, 
the PFS rates at 2, 4, 6, 8, 10, 12, 16, and 20 months will be estimated with corresponding 2-
sided 95% CIs.  The CIs for the median will be calculated according to Brookmeyer and 
Crowley (1982)3 and the CIs for the survival function estimates at the time points defined 
above will be derived using the log-log transformation according to Kalbfleisch and Prentice 
(2002)9 (conftype=loglog default option in SAS Proc LIFETEST) with back transformation 
to a CI on the untransformed scale. The estimate of the standard error will be computed using 
Greenwood’s formula.   
Frequency (number and percentage) of patients with each event type (PD or death) and 
censoring reasons will be presented. Reasons for censoring will be summarized according to 
the categories in Table 9 following the hierarchy shown. 


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Table 9. 
PFS Censoring Reasons and Hierarchy 
Hierarchy 
Condition 
Censoring Reason 
1 
No adequate baseline assessment 
No adequate baseline assessment 
2 
Start of new anti-cancer therapy  
Start of new anti-cancer therapy 
3  
Event after 2 or more missing or inadequate post-baseline 
tumor assessments/’start date’ 
Event after missing assessments a 
4 
No event and [withdrawal of consent date ≥ ‘start date’ OR 
End of study (EOS) = Patient refused further follow-up]  
Withdrawal of consent 
5 
No event and lost to follow-up in any disposition page  
Lost to follow-up 
6 
No event and [EOS present OR disposition page for any 
epoch after screening says patient will not continue into 
any subsequent phase of the study] and no adequate post-
baseline tumor assessment  
No adequate post-baseline tumor 
assessment 
7  
No event and none of the conditions in the prior hierarchy 
are met  
Ongoing without an event 
a 2 or more missing or inadequate post-baseline tumor assessments.  
 
The PFS time or censoring time and the reasons for censoring will also be presented in a 
patient listing. 
Time of Follow-Up for PFS 
A plot will be generated to compare planned and actual relative day of tumor assessments. A 
Kaplan-Meier plot for PFS follow-up duration will also be generated to assess the follow-up 
time in the treatment groups reversing the PFS censoring and event indicators.  Kaplan-Meier 
estimates (product-limit estimates) will be presented together with a summary of associated 
statistics including the median time of follow-up for PFS with 2-sided 95% CIs.   In 
particular, the rates at 2, 4, 6, 8, 10, 12, 16, and 20 months will be estimated with 
corresponding 2-sided 95% CIs. 
6.2.2.5. Overall Survival 
Overall survival (OS) is defined as the time from the ‘start date’ to the date of death due to 
any cause. Patients last known to be alive will be censored at date of last contact. 
 
OS (months) = [date of death or censoring– ‘start date’ +1]/30.4375 
Kaplan-Meier estimates (product-limit estimates) will be presented together with a summary 
of associated statistics including the median OS time with 2-sided 95% CIs.  In particular, the 
OS rates at 2, 4, 6, 8, 10, 12, 16, 20, and 24 months will be estimated with corresponding 2-
sided 95% CIs.  The CIs for the median will be calculated according to Brookmeyer and 
Crowley (1982)3 and the CIs for the survival function estimates at the time points defined 
above will be derived using the log-log transformation according to Kalbfleisch and Prentice 
(2002)9 (conftype=loglog default option in SAS Proc LIFETEST) with back transformation 
to a CI on the untransformed scale. The estimate of the standard error will be computed using 
Greenwood’s formula.   


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Frequency (number and percentage) of patients with an event (death) and censoring reasons 
will be presented. Reasons for censoring will be summarized according to the categories in 
Table 10 following the hierarchy shown. 
Table 10. OS Censoring Reasons and Hierarchy 
Hierarchy 
Condition 
Censoring Reason 
1 
No event and [withdrawal of consent date ≥ ‘start date’ OR 
End of study (EOS) = Patient refused further follow-up]  
Withdrawal of consent 
2 
No event and [lost to follow-up in any disposition page OR 
data cut-off date – last contact date > 14 weeks]   
Lost to follow-up 
3 
No event and none of the conditions in the prior hierarchy 
are met  
Alive 
 
The OS time or censoring time and the reasons for censoring will also be presented in a 
patient listing. 
Time of Follow-Up for OS 
A Kaplan-Meier plot for OS follow-up duration will also be generated to assess the follow-up 
time in the treatment groups reversing the OS censoring and event indicators.  Kaplan-Meier 
estimates (product-limit estimates) will be presented together with a summary of associated 
statistics including the median time of follow-up for OS with 2-sided 95% CIs.  In particular, 
the rates at 2, 4, 6, 8, 10, 12, 16, 20, and 24 months will be estimated with corresponding 2-
sided 95% CIs. 
6.2.3. Pharmacokinetic endpoints 
The following pharmacokinetic analyses will be based on the PK analyses set as shown in 
Table 5. 
Ctrough, Cmax, Tmax, defined in Section 3.2.3 for avelumab and binimetinib, TEOI for avelumab, 
Ctrough and the time relative to the previous dosing time (Ttrough) for avelumab, binimetinib and 
talazoparib will be reported. Dose normalized parameter Ctrough(dn) for binimetinib and 
talazoparib will be reported as appropriate.  
Pharmacokinetic parameters for avelumab, binimetinib and talazoparib will be taken from 
observed values.  
Presentation of pharmacokinetic data will include: 
• Pharmacokinetic parameters will be listed and summarized by cycle and study day using 
descriptive statistics (n, mean, SD, %CV, median, minimum, maximum, geometric mean 
and its associated %CV, and 95% CI). For Tmax, the range (min, max) will also be 
provided. PK parameters with zero values will be excluded from the calculation of 
geometric means and its associated %CV. For talazoparib and binimetinib, if an intra-
patient dose escalation or reduction occurs, dose-dependent PK parameter Ctrough for that 


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patient may be dose-normalized or may only be included in descriptive statistics and 
summary plots up to the time of the dose change. 
• Box plots for Ctrough and Cmax for avelumab and binimetinib (Cmax is not available for D0 
and D-1), Ctrough for talazoparib will be generated by dose, cycle, and study day and may 
be separated by treatment group or combination.  Individual data points, the geometric 
mean and the median of the parameter in each treatment will be overlaid on the box plots. 
If a treatment group has limited evaluable PK data (n<4), matchstick plots showing 
changes in Cmax for avelumab and Ctrough for each drug in individual patients will then be 
generated.   
• For Ctrough of binimetinib and talazoparib in Phase 2, an arithmetic mean of the Ctrough 
across all PK samples collected at different cycles and days within each patient may be 
calculated (only 1 value per patient) and the descriptive statistics (n, mean, SD, %CV, 
median, minimum, maximum, geometric mean and associated CV% and 95% CI) of the 
individual arithmetic mean would be summarized as shown in Table 5 and/or presented 
in box plot accordingly.   
• 
PK parameters of avelumab, binimetinib, and talazoparib from this study may be compared 
with the historical PK parameters when avelumab, binimetinib or talazoparib were 
administered as single agents.  
6.2.4. Population pharmacokinetic endpoints 
Pharmacokinetic and pharmacodynamic data from this study may be analyzed using 
modeling approaches and may also be pooled with data from other studies investigating 
avelumab, binimetinib or talazoparib to : 1) further assess the effect of binimetinib with or 
without avelumab on the PK of talazoparib, 2) assess the effect of talazoparib with or without 
avelumab on the PK of binimetinib, and 3) assess the effect of talazoparib and/or binimetinib 
on the PK of avelumab, and 4) explore any association between avelumab, binimetinib and/or 
talazoparib exposure and biomarkers or significant safety/efficacy endpoints.  If performed, 
the details of these analyses will be outlined in a separate pharmacometrics analysis plan 
(PMAP).  The results of these analyses, if performed, may be reported separately. 
6.2.5. Biomarker endpoints 
Secondary biomarker endpoints include PD-L1 expression level, DDR gene alterations, and 
TMB in baseline tumor tissue. 
Biomarker data will be analyzed based on the biomarker analysis sets as defined in Section 
4.3.4.  Data will be summarized as shown in Table 5. 
Biomarkers values at screening will be listed and summarized. 
For PD-L1 expression, patients will be classified as positive or negative according to scoring 
algorithms and cut-offs established from internal or external sources.  For continuous 
measurement biomarker results, summary statistics (eg, the mean, standard deviation, 
median, percent of coefficient of variation, and minimum/maximum levels) will be 
determined at baseline and on-treatment/end of treatment time points, as appropriate. 


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Change from baseline measurements will be provided, as appropriate. 
For discrete measurement biomarker results (eg, tumor marker status), frequencies and 
percentages of categorical biomarker measures will be determined at baseline and on-
treatment/end of treatment time points.  Shift tables may also be provided. 
For genomic scarring, as measured by loss of heterozygosity score, for the total number of 
DDR gene mutations and for the number of mutations in DDR genes, patients may be 
classified as positive, negative, or some other category according to scoring algorithms and 
cut-offs established from external sources.  If no external standards exist, patients may be 
stratified using the median, quartiles and tertiles.  For example, patients will be classified as 
positive if they have a mutation in any one of the assessed DDR genes and will otherwise be 
classified as negative.  The number and percentage of patients in each category will be 
tabulated. 
BOR will be summarized and for each category following the methodology outlined in 
Section 6.1.2.1.  The number of responders (patients with BOR of CR or PR) will be 
tabulated relative to biomarker classifications using a contingency table. 
6.2.6. Endpoints for immunogenicity data of avelumab  
All analyses described below are performed as shown in Table 5. 
Blood samples for avelumab immunogenicity testing will be collected pre-dose on Day 1 and 
Day 15 of Cycle 1 and Cycle 2; on Day 1 of Cycles 3, 5, 9, and 12. 
Samples positive for ADA will be analyzed for titer and may be analyzed for nAb.  The 
analyses of nAb data described in the following sections will only be conducted contingent 
upon data availability at the time of reporting.  
Patients will be characterized into different ADA categories based on the criteria defined in 
Table 11. 


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Table 11.  Patients Characterized Based on Anti-Drug Antibody Results (ADA Status) 
Category 
Definition 
Patients at Risk (Denominator for 
Incidence) 
ADA never-positive  No positive ADA results at any time point; 
ADA-negative patients (titer < cutpoint) 
Number of patients with at least one 
valid ADA result at any time point 
ADA ever-positive  
At least one positive ADA result at any time 
point; ADA-positive patients (titer ≥ cutpoint) 
Number of patients with at least one 
valid ADA result at any time point 
Baseline ADA 
positive 
A positive ADA result at baseline 
Number of patients with valid baseline 
ADA result 
Treatment-boosted 
ADA 
A positive ADA result at baseline and the titer 
≥ 8×baseline titer at least once after treatment 
with avelumab 
Number of patients with valid baseline 
ADA results and at least one valid 
post-baseline ADA result 
Treatment-induced 
ADA 
Patient is ADA-negative at baseline and has at 
least one positive post-baseline ADA result; or 
if patient does not have a baseline sample, the 
patient has at least one positive post-baseline 
ADA result 
Number of patients with at least one 
valid post-baseline ADA result and 
without positive baseline ADA result 
(including missing, NR) 
Transient ADA 
response 
If patients with treatment-induced ADA have (a 
single positive ADA result or duration between 
first and last positive result <16 weeks) and 
ADA result at the last assessment is not 
positive. 
Number of patients with at least one 
valid post-baseline ADA result and 
without positive baseline ADA result 
(including missing, NR) 
Persistent ADA 
response 
If patients with treatment-induced ADA have 
duration between first and last positive ADA 
result ≥16 weeks or a positive ADA result at 
the last assessment 
Number of patients with at least one 
valid post-baseline ADA result and 
without positive baseline ADA result 
(including missing, NR) 
ADA: anti-drug antibody, NR = not reportable. 
 
Patients will be characterized into different nAb categories based on the criteria in Table 12.  
For nAb, treatment-boosted is not applicable since no titer result is available. 


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Table 12.  Patients Characterized Based on Neutralizing Antibody Results (nAb 
Status) 
Category 
Definition 
Patients at Risk (Denominator for 
Incidence) 
nAb never-positive  
No positive nAb results at any time point 
Number of patients with at least one 
valid ADA result at any time point 
nAb ever-positive  
At least one positive nAb result at any time 
point 
Number of patients with at least one 
valid ADA result at any time point 
Baseline nAb 
positive 
A positive nAb result at baseline 
Number of patients with valid baseline 
ADA result 
Treatment-induced 
nAb 
Patient is not nAb positive at baseline and has 
at least one positive post-baseline nAb result; 
or if patient does not have a baseline sample, 
the patient has at least one positive post-
baseline ADA result 
Number of patients with at least one 
valid post-baseline ADA result and 
without positive baseline nAb result 
(including missing, NR) 
Transient nAb 
response 
If patients with treatment-induced nAb have (a 
single positive nAb result or duration between 
first and last positive result <16 weeks) and 
nAb result at the last assessment is not 
positive. 
Number of patients with at least one 
ADA valid post-baseline result and 
without positive baseline nAb result 
(including missing, NR) 
Persistent nAb 
response 
If patients with treatment-induced nAb have 
duration between first and last positive nAb 
result ≥16 weeks or a positive nAb result at 
the last assessment 
Number of patients with at least one 
valid post-baseline ADA result and 
without positive baseline nAb result 
(including missing, NR) 
ADA = antidrug antibody, nAb = neutralizing antibody, NR = no result. 
 
The number and percentage of patients in each ADA and nAb category will be summarized.  
6.2.6.1. Time to and Duration of ADA and nAb response  
The ADA and nAb analyses described below will include patients with treatment-induced 
ADA or nAb, respectively. 
Time (weeks) to ADA response is defined as: 
(Date of first positive ADA result – date of first dose of avelumab + 1)/7.  
Time to ADA response will be summarized using simple descriptive statistics (mean, SD, 
median, min, max. Q1, Q3).   
Duration (weeks) of ADA response is defined as: 
(Date of last positive ADA result – date of first positive ADA result + 1)/7.  
Duration of ADA response will be censored if:  
• the last ADA assessment is positive AND patient is ongoing treatment with avelumab, or 


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• the last ADA assessment is positive AND patient discontinued treatment with avelumab 
AND the last planned ADA assessment (day 30 follow-up visit) is after the cut-off date. 
Time to nAb response and duration of nAb response are defined similarly based on first and 
last positive nAb result.  
Kaplan-Meier estimates (product-limit estimates) will be presented together with a summary 
of associated statistics including the median ADA response time with 2-sided 95% CIs.  
ADA response rates at different timepoints will be estimated with corresponding 2-sided 
95% CIs.  The CIs for the median will be calculated according to Brookmeyer and Crowley 
(1982)3 and the CIs for the survival function estimates will be derived using the log-log 
transformation according to Kalbfleisch and Prentice (2002)9 (conftype=loglog default option 
in SAS Proc LIFETEST) with back transformation to a CI on the untransformed scale. The 
estimate of the standard error will be computed using Greenwood’s formula. 
Duration of ADA response will be displayed graphically and analyzed using Kaplan-Meier 
methodology. If the number of patients with ADA response is small, the Kaplan-Meier 
method may not provide reliable estimates.  In this case, only descriptive statistics or listings 
will be provided 
As data permit, the analyses described above will be repeated for patients with treatment-
induced nAb.  
6.2.6.2. ADA titer 
For patients who are ADA ever positive, the maximum observed ADA titer for a patient will 
be summarized, overall and by ADA subcategories (baseline ADA positive, treatment-
boosted ADA, treatment-induced ADA, transient ADA response, persistent ADA response) 
of patients having each discrete maximum titer value will be tabulated.  The denominator to 
calculate the percentages will be the total number of patients in the associated ADA 
subcategory.  
For patients with treatment-induced ADA, a cross tabulation of duration of ADA response 
and maximum ADA titer will be provided.  The following categories for duration of ADA 
response will be used: ≤1, >1 to ≤3, >3 to ≤5, >5 to ≤7, >7 to ≤13, >13 to ≤16, >16 to ≤25, 
>25 weeks.  In this categorization, the censoring in duration of ADA response is ignored.  
6.2.6.3. Analysis of PK and safety by immunogenicity status 
The following ADA and nAb status will be used for the analyses described below. 
ADA  
• ADA ever-positive versus ADA never-positive 
• ADA: treatment-induced ADA versus ADA never-positive or baseline ADA positive 


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nAb 
• nAb ever-positive versus nAb never-positive 
• nAb: treatment-induced nAb versus nAb never-positive or baseline nAb positive 
Data listings will include immunogenicity data together with relevant PK, and safety data. 
PK parameters and immunogenicity status 
The following analyses will include patients in both the immunogenicity analysis set and in 
the PK parameter analysis set.  The PK endpoints pertinent to the immunogenicity analyses 
are Ctrough and Cmax for avelumab.   
Blood samples for avelumab PK will be collected at pre-dose (within 1 hour prior to taking 
binimetinib/talazoparib dose) and at the end of infusion (within 10 minutes after the 
avelumab infusion ends) on Day 1, Day 7 and Day 15 of Cycle 1; Day 1 and Day 15 of Cycle 
2; and Day 1 of Cycles 3, 5, 9 and 12. 
Ctrough and Cmax for avelumab will be summarized descriptively (n, mean, SD, CV, median, 
minimum, maximum, geometric mean, its associated CV, and 95% CI) and ADA status and 
presented via box plot.  
Among patients with treatment-induced ADA, analyses will be conducted to assess whether 
Ctrough and Cmax have any changes before and after the first positive ADA assessment.  To be 
included in this analysis, patients must have the same PK parameter available both before 
and after the first positive ADA assessment.  Relative PK day will be calculated as: 
(PK assessment nominal day) – (first positive ADA assessment nominal day). 
Nominal day is the protocol scheduled timing for an assessment. For example, if Ctrough is 
collected on Day 1 of Cycle 2 and the first positive ADA result is observed on Day 1 of 
Cycle 3, then the relative PK day for this Ctrough is -28.  Plots of mean and median for Ctrough 
and Cmax over relative PK day will be presented.  
As data permit, the analyses described above will be repeated for nAb. 
Safety and immunogenicity status 
The following analyses will include patients in the immunogenicity analysis set. 
The frequency (number and percentage) of patients with each of the following will be 
presented by ADA status. 
• TEAEs, by SOC and PT  
• TEAEs leading to dose reduction of avelumab, by SOC and PT 


A v el u ma b  
B9 9 9 1 0 3 3  ( M S B0 0 1 0 7 1 8 C , M D V3 8 0 0,  B M N  6 7 3 , M E K 1 6 2)  St atis tic al A n al ysis Pla n 
 
P FI Z E R C O N FI D E N TI A L  
Pa g e 5 3  
•  T E A E s le a din g  t o dis c o ntin uatio n  of a velu ma b , b y S O C a n d  P T  
•  T E A E s le a din g  t o dis c o ntin uatio n  of st u d y  tre at me nt b y  S O C a n d P T  
•  Gra de ≥ 3 T E A Es , b y  S O C a n d P T   
•  S A Es , b y S O C a n d  P T  
•  I R Rs, b y P T 
F or  patie nts  w h o  ha d at le ast o ne I R R a n d ha ve tre at me nt -in d uc e d  A D A, ti me  relate d t o  first 
o ns et of  a n I R R (inf usio n  1,  inf usio n  2,  inf usio n  3,  inf usio n  4 or later)  will  be s u m marize d 
ta kin g int o  a c c o u nt  w het her t he I R R oc c urre d o n  or after t he first  A D A p ositive  ass ess me nt 
or w het her t he I R R oc c urre d bef ore t he first  A D A p ositive  ass ess me nt.   
As data per mit,  t he a nalys es des cribe d  a b o ve will  be re pe ate d f or n A b.  
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
    
 
 
    
 
 
 
 
C CI


A v el u ma b  
B9 9 9 1 0 3 3  ( M S B0 0 1 0 7 1 8 C , M D V3 8 0 0,  B M N  6 7 3 , M E K 1 6 2)  St atis tic al A n al ysis Pla n 
 
P FI Z E R C O N FI D E N TI A L  
Pa g e 5 4  
 
 
    
 
 
 
 
 
 
 
  
6. 4.  S u bs e t A n al ys e s  
A p plic a ble  t o P has e 2 o nly.   O R a n d  D R (if  me a nin gf ul)  will  be s u m marize d  in  t he f ollo win g 
s u bs ets: 
•  Se parately f or c o h o rts B T: m P A D C , A B T: m P A D C ,  a n d A B T:t u m or  a g n ostic     
o  
E C O G  perf or ma nc e stat us  at bas eline :  0 vs ≥1 
o  
N u m ber  of prior  a nti -c a nc er dr u g  t hera p y re gi me ns  f or a d va nc e d  dis e as e: ≤1 vs ≥2 
•  Se parately f or  C o h ort s B T: m P A D C  a n d A B T: m P A D C  
o  Prior  a nti -c a nc er platin u m-bas e d  re gi me n:  Y es vs  N o  
•  F or  c o h ort A B T:t u m or  a g n ostic    
o  B y t u m or  t y pe  
6. 5.  B as e li ne a n d Ot he r S u m m arie s  a n d  A n al ys e s  
6. 5.1.  B as e li ne s u m m arie s  
T he f ollo win g  a nalys es  will  be bas e d o n t he F A S  as s h o w n  in Ta ble 5 . 
6. 5.1.1.  D e  m o g r a p hic c h ar acte ris tics  
D e m o gra p hic  c hara cteristics a n d p h ysic al  me as ure me nts will  be s u m marize d  usin g  t he 
f ollo win g  inf or matio n  fr o m  t he ‘ Scre e nin g/ Bas eline  Visit’ e C R F pa ges.  
•  D e m o gra p h ic  c hara cteristics  
-  Ge n der:  Male, Fe male  
-  Ra c e: W hite,  Bla c k  or Afric a n  A meric a n,  Asia n,  A meric a n  I n dia n  or Alas ka  N ative, 
N ative H a w aiia n or O t her P a cific Isla n der, M ultira c ia l,  N ot Re p orte d  
C CI


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- Ethnic origin:  
 Hispanic or Latino  
 Not Hispanic or Latino 
 Not Reported 
- Age (years): summary statistics  
- Age categories:  
 < 65 years, ≥ 65 years  
 < 65, 65-<75, 75-<85, ≥ 85 years 
- Pooled Geographical Region (as applicable):  
 North America  
 Europe 
 Asia 
 Rest of the World (Australasia, Latin America, Africa and/or Middle East will be 
included as additional pooled geographical regions if including > 10% of the overall 
randomized/treated population) 
- Geographic Region (as applicable): 
 North America 
 Latin America 
 Western Europe 
 Eastern Europe 
 Middle East 
 Australasia 
 Asia 
 Africa 
- Eastern Cooperative Oncology Group (ECOG) Performance Status: 0, 1, 2, 3, and 4  
• Physical measurements 
- Height (cm) 
- Weight (kg) 
- Body Mass Index (BMI) (kg/m2) 
Center codes will be used for the determination of the patient’s geographic region. 
The listing of demographics and baseline characteristics will include the following 
information: patient identifier, treatment group, age, sex, race, ethnicity, height (cm), weight 
(kg), BMI (kg/m2), and ECOG performance status. 


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6.5.1.2.  Medical history 
Medical history will be coded using the most current available version of Medical Dictionary 
for Regulatory Activities (MedDRA) and will be summarized from the ‘Medical History’ 
eCRF page.  Medical history will be summarized as the numbers and percentages of patients 
by MedDRA preferred term (PT) as event category and MedDRA primary system organ 
class (SOC) as summary category.  Each patient will be counted only once within each PT or 
SOC. 
Medical history will be displayed in terms of frequency tables: ordered by primary SOC and 
PT in alphabetical order. 
6.5.1.3.  Disease characteristics 
Information on disease characteristics collected on ‘Primary Diagnosis’, ‘Substance Use’ and 
RECIST eCRF pages will be summarized for the following. 
From the ‘Primary Diagnosis’ eCRF page: 
• Site of primary tumor 
• Primary diagnosis (summarize all categories collected in the ‘Primary Diagnosis’ eCRF 
page) 
• Time since initial diagnosis to ‘start date’ (months), defined as (‘start date’ – date of initial 
diagnosis)/30.4375 
From the RECIST eCRF page: 
• Measurable disease (lesions) at baseline (Yes, No, No disease) 
• Involved tumor sites at baseline 
From the ‘Substance Use’ eCRF page: 
• Smoking history: Never smoker vs current vs former smoker  
Listing of disease history will be provided with all relevant data (as collected on the ‘Primary 
Diagnosis’ and ‘Substance Use’ eCRF pages) and derived variables as above. 
6.5.1.4.  Prior anti-cancer therapies 
The prior anti-cancer therapies are collected under the ‘Prior Cancer Therapy’, ‘Prior 
Radiation Therapy’ and ‘Prior Anti-Cancer Surgery’ eCRF pages. 
The number and percentage of patients in each of the following anti-cancer therapy 
categories will be tabulated: 
• Patients with at least one type of prior anti-cancer therapy 
• Patients with at least one prior anti-cancer drug therapy 
• Patients with at least one prior anti-cancer radiotherapy 
• Patients with at least one prior anti-cancer surgery 


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Prior anti-cancer drug therapy will be summarized as follows based on the number and 
percentage of patients with the following: 
• At least one prior anti-cancer drug therapy 
• Number of prior anti-cancer drug therapy regimens: missing, 1, 2, 3, ≥4 
• Prior anti-cancer immune therapy (including PD-1, PD-L1, anti-CTLA4, others) 
• Intent of Drug Therapy: Neo-Adjuvant, Adjuvant, Advanced – Metastatic, Local regional 
Disease-Recurrence 
• Best response: CR, PR, SD, PD, Unknown, Not applicable. Best response is derived from 
the last treatment regimen. 
The prior anti-cancer drugs will also be summarized based on the number and percentage of 
patients by the drug class and preferred term.  A patient will be counted only once within a 
given drug class and within a given drug name, even if he/she received the same medication 
at different times.  The summary will be sorted on decreasing frequency of drug class and 
decreasing frequency of drug name in a given drug class.  In case of equal frequency 
regarding drug class (respectively drug name), alphabetical order will be used. 
Prior anti-cancer therapies will be included in the listings that follow with a flag to identify 
prior therapies. These will include the patient identification number, and all the relevant 
collected data-fields on the corresponding eCRF pages. 
• Listing of anti-cancer drug therapies  
• Listing of anti-cancer radiotherapy  
• Listing of anti-cancer surgeries 
6.5.2. Study conduct and patient disposition 
The following analyses will be based on the FAS as shown in Table 5. 
6.5.2.1. Patient disposition 
The percentages below will be calculated based on the number of patients in the FAS as 
applicable. 
For randomized cohorts  
• Total number of patients screened overall 
• Number of patients who discontinued from the study prior to ‘start date’ overall and by the 
main reason for discontinuation 
• Number and percentage of randomized patients in each of the analysis sets defined in 
Section 4 
• Number and percentage of randomized patients with study drug ongoing (separately for 
each study drug administered in combination) 


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• Number and percentage of randomized patients who discontinued study drug overall and 
by the main reason for discontinuation of study drug (separately for each study drug 
administered in combination) 
• Number and percentage of patients who entered follow-up 
• Number and percentage of patients who discontinued follow-up overall and by the main 
reason for discontinuation 
The results of the randomization algorithm (according to IRT) will be summarized as 
follows: 
• Number and percentage of randomized patients overall, by region (Europe, North America, 
Latin America, Middle East, Asia, Australasia, Africa), by country within region  
• Number and percentage of randomized patients by center 
• Cross tabulation: 
patients randomized 
(doublet/triplet/none) 
vs. patients treated 
(doublet/triplet/none)  
For non-randomized cohorts  
• Total number of patients screened overall 
• Number of patients who discontinued from the study prior to treatment with study drug  
overall and by the main reason for discontinuation 
• Number and percentage of treated patients in each of the analysis sets defined in Section 4 
• Number and percentage of patients with study drug ongoing (separately for each study drug 
administered in combination) 
• Number and percentage of patients who discontinued study drug overall and by the main 
reason for discontinuation of study drug (separately for each study drug administered in 
combination) 
• Number and percentage of patients who entered follow-up 
• Number and percentage of patients who discontinued follow-up overall and by the main 
reason for discontinuation 
In addition, the following will be summarized: 
• Number and percentage of treated patients overall, by region (Europe, North America, 
Latin America, Middle East, Asia, Australasia, Africa), by country within region  
• Number and percentage of treated patients by center 
6.5.2.2. Protocol deviations 
All protocol violations that impact the safety of the patients and/or the conduct of the study 
and/or its evaluation will be reported.  These include: 
• Patients who are dosed on the study despite not satisfying the inclusion criteria or meeting 
exclusion criteria. 


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• Patients who develop withdrawal criteria whilst on the study but are not withdrawn 
• Patients who receive the wrong treatment or an incorrect dose 
• Patients who receive an excluded concomitant medication 
• Deviations from GCP. 
The identification of these and other CSR-reportable deviations will be based on the 
inclusion/exclusion criteria or other criteria presented in the protocol. 
6.5.3. Study treatment compliance and exposure 
The following analyses will be based on the safety analysis set as shown in Table 5. 
Cycle definitions for study drugs that are administered in combination apply to all the study 
drugs in the combination.  Ie, cycle is patient-dependent, rather than study-drug-dependent 
when study drugs are administered in combination. 
For Cycle X, actual cycle start date for each patient is 
• the earliest start date of dosing in the Cycle X day 1 visit eCRF exposure page, if the patient 
received study treatment on that visit (ie, any study drug with dose>0 at that visit) 
• the first day of assessments in the Cycle X day 1 visit, if the patient did not receive study 
treatment on that visit (ie, all study drugs had dose=0 at that visit).  Use start date in the 
exposure page if available; if start date is not available then use date of collection of vital 
signs on Cycle X day 1 visit. 
Actual cycle end date for each patient is,  
• for all cycles X except the last cycle, actual cycle end date = actual cycle (X+1) start date 
– 1 day; 
• for the last cycle, actual cycle end date = actual cycle start date + 28 (in days) – 1 day 
Cycle duration (weeks) = (actual cycle end date – actual cycle start date + 1)/7  
When summarizing exposure for each study drug, only cycles from first dose of study 
treatment until the last cycle with non-zero dose of at least one of the study drugs should be 
included.   
Exposure may be summarized as dose received (cumulative dose, actual dose intensity) and 
as dose received relative to intended dose (relative dose intensity [RDI]).   
The information that will be summarized depends on how the study drug is dosed (eg, 
infusion cyclical, oral daily).   
The formulae below should be applied to each study drug separately even when study drugs 
are administered in combination. 


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The derivations below are provided for the following study drugs (administered alone or in 
combination): 
• Avelumab administered as a 1-hour IV infusion at a dose of 800 mg Q2W.  
• Binimetinib: administered orally BID at a dose of 30 mg or 45 mg 
- 
Patients enrolled prior to implementation of Protocol Amendment 3 (treatment groups 
D0 and D-1): on continuous dosing schedule;  
- 
Per Protocol Amendment 3 (treatment groups other than D0 and D-1): administered on 
intermittent dosing schedule in accordance with the assigned intermittent dosing 
schedule (ie, Schedule 7d/7d or 5d/2d). 
• Talazoparib administered orally QD at a dose of 0.5 mg, 0.75 mg, or 1 mg. 
6.5.3.1. Exposure to avelumab  
The dose level for avelumab is calculated as actual dose administered (mg).  
Intended duration of treatment with avelumab (weeks) =  
(end date–date of first dose of study drug +1)/7,  
where end date = start date of last cycle with non-zero dose of study drug + 28 – 1 
Duration of exposure to avelumab (weeks) =  
(last dose date of avelumab – first dose date of avelumab + 14)/7   
Cumulative dose is the sum of the actual doses of avelumab received.   
Actual Dose Intensity (DI)  
• Overall actual DI (mg /4-week cycle) = [overall cumulative dose (mg)] / [intended 
duration of treatment with avelumab (weeks)/4].   
Relative Dose Intensity (RDI)   
• Intended DI (mg /4-week cycle) = [intended cumulative dose per cycle] / [intended 
number of 4-weeks in a cycle] = [1600 (mg)] / [1 (4-week cycle)] = 1600 (mg /4-week 
cycle) 
• 
  Overall RDI (%) = 100 × [overall actual DI] / [intended DI]                                                                
= 100 × [overall actual DI] / [1600 (mg /4-week cycle)]  
6.5.3.2. Exposure to binimetinib  
The dose level is calculated as actual dose administered (mg/day).   
Intended duration of treatment with binimetinib (weeks)= (end date – date of first dose of 
binimetinib +1)/7,  
where end date = date of last dose of binimetinib. 


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Duration of exposure to binimetinib (weeks) =  
(last dose date of binimetinib – first dose date of binimetinib + 1)/7 
Cumulative dose is the sum of the actual doses of binimetinib received in the study. 
Actual Dose Intensity (DI) 
• Overall actual DI (mg/week) = [overall cumulative dose (mg)] / [intended treatment 
duration (weeks)] 
Relative Dose Intensity (RDI) 
• RDI (%) = 100 × [overall cumulative dose] / [intended cumulative dose per week × 
number of weeks from first dose of binimetinib to last dose of binimetinib] 
 = 100 × [overall cumulative dose] / [7 ×2 × d × f × duration of exposure to binimetinib in 
weeks]  
where d=30 or 45 mg and 
- f=1 if treatment group is D0 or D-1 (patients enrolled prior to implementation of 
Protocol Amendment 3) 
- f=1/2 if binimetinib is administered on the 7d/7d dosing schedule 
- f=5/7 if binimetinib is administered on the 5d/2d dosing schedule 
6.5.3.3. Exposure to talazoparib 
The dose level is calculated as actual dose administered (mg/day). 
Intended duration of treatment with talazoparib (weeks)= (end date – date of first dose of 
talazoparib +1)/7,  
where end date = date of last dose of talazoparib. 
Duration of exposure to talazoparib (weeks) =  
(last dose date of talazoparib – first dose date of talazoparib + 1)/7   
Cumulative dose is the sum of the actual doses of talazoparib received in the study.   
Actual Dose Intensity (DI)  
• Overall actual DI (mg/week) = [overall cumulative dose (mg)] / [intended treatment 
duration (weeks)]    
Relative Dose Intensity (RDI) 
• RDI (%) = 100 × [overall cumulative dose] / [intended cumulative dose per week × 
number of weeks from first dose of study drug to last dose of study drug]  


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 = 100 × [overall cumulative dose] / [7 × d × duration of exposure to talazoparib in 
weeks]  
where d=0.5 mg, 0.75mg, or 1.0 mg. 
6.5.3.4. Dose reductions  
Applicable to avelumab.  Dose reduction is defined as actual non-zero dose < 90% of the 
planned dose.  
Applicable to binimetinib and talazoparib.  Dose reduction is defined as a change to a non-
zero dose level lower than that planned in the protocol. 
The number and percentage of patients with at least one dose reduction as well as a 
breakdown of the number of dose reductions (1, 2, 3, ≥4) will be summarized.  
6.5.3.5. Dose interruptions 
Applicable to binimetinib and talazoparib.  
An interruption is defined a 0 mg total daily dose of binimetinib within the dosing periods or 
talazoparib administered on one or more days.  What follows defines how dose interruptions 
will be counted, for each of binimetinib and talazoparib separately, in the case of multiple 
dose interruptions.  In what follows, d is a value > 0. 
• If an interruption occurs consecutively for at least two days, then it will be counted only 
once (example: If the actual total daily dose on days 1-3 is d mg and actual dose on days 
4-5 is 0 mg , then the total number of dose interruptions is 1). 
• If an interruption occurs for more than one day, but the days are not consecutive, ie there 
is at least one dosing day in between, then each dose interruption will be counted as a 
different occurrence (example: If the actual dose on days 1, 3 and 5, is d mg and actual 
dose on days 2 and 4 is 0 mg, the total number of dose interruptions is 2).  
A dose interruption is not considered a dose reduction. 
The number and percentage of patients with dose interruptions will be summarized. 
6.5.3.6. Dose delays  
Applicable to avelumab only. 
Dose Delay is the difference between the actual time between two consecutive non-zero 
doses and the planned time between the same two consecutive non-zero doses.  
For Cycle 1 Dose 1: 
Dose Delay (days) = day of the first day of study drug -1 
After Cycle 1 Dose 1: 


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Dose Delay for Dose x (days) = Date of Dose x – Date of Dose (x-1) – Planned days 
between two consecutive doses = Date of Dose x – Date of Dose (x-1) – 14.  
Dose delays will be grouped into the following categories:  
• No delay  
• 1-2 days delay  
• 3-6 days delay 
• 7 or more days delay 
For example, for avelumab, administered on a 2-week schedule, if one patient receives 
avelumab on Day 1, then the next avelumab administration date will be on Day 15; however, 
if the patient receives avelumab at Day 16 or 17, this is considered as 1-2 days delay.   
No delay and 1-2 days delay will also be summarized together.  
The number and percentage of patients with delayed study drug administration and maximum 
length of delay, ie, the worst case of delay if patients have multiple dose delays will be 
summarized.  
6.5.3.7. Infusion rate reductions 
Applicable to avelumab only. 
The number and percentage of patients with at least one infusion rate reduction of ≥50% 
compared to the first infusion rate reported in the eCRF as well as the frequency of patients 
with 1, 2, 3 or ≥4 infusion rate reductions of ≥50% will be summarized. 
6.5.3.8. Infusion interruptions 
Applicable to avelumab only. 
An infusion interruption is defined as an infusion that is stopped and re-started on the same 
day (ie, for a visit more than one infusion start time and infusion end time are recorded). 
The number and percentage of patients with at least one infusion interruption as well as the 
frequency of patients with 1, 2, 3, or ≥4 infusion interruptions will be summarized. 
6.5.4. Concomitant medications and non-drug treatments 
The following analyses will be based on the safety analysis set as shown in Table 5. 
Concomitant medications are medications, other than study drugs, which started prior to 
first dose date of study treatment and continued during the on-treatment period as well as 
those started during the on-treatment period.  Prior medications are medications, other than 
study drugs and pre-medications for study drug, which are started before the first dose of 
study treatment.  


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Prior and concomitant medications will be summarized from the ‘Concomitant Medications’ 
eCRF page.  Pre-medications for study drug will also be summarized separately from the 
‘Pre-Medication Treatment’ eCRF page.  
Summary of prior medications, summary of concomitant medications and summary of pre-
medications will include the number and percentage of patients by Anatomical Therapeutic 
Chemical (ATC) Classification level 2 and preferred term.  A patient will be counted only 
once within a given drug class and within a given drug name, even if he/she received the 
same medication at different times.  If any prior or concomitant medication is classified into 
multiple ATC classes, the medication will be summarized separately under each of these 
ATC classes.  The summary tables will be sorted on decreasing frequency of drug class and 
decreasing frequency of drug name in a given drug class.  In case of equal frequency 
regarding drug class (respectively drug name), alphabetical order will be used. In case any 
specific medication does not have ATC classification level 2 coded term, it will be 
summarized under ‘Unavailable ATC classification’ category.  
A listing of prior medications and a listing of concomitant medications will be created with 
the relevant information collected on the ‘General Concomitant Medications’ eCRF page.  A 
listing of pre-medications will be created with the relevant information collected on the ‘Pre-
Medication Treatment’ eCRF page. 
All concurrent procedures, which were undertaken any time during the on-treatment period, 
will be listed according to the eCRF page ‘General Non-drug Treatments’.  
A listing of concurrent procedures will be created with the relevant information collected on 
the ‘General Non-drug Treatments’ eCRF page. 
6.5.5. Subsequent anti-cancer therapies 
The following analyses will be based on the FAS as shown in Table 5.  
Anti-cancer treatment will be provided in a data listing with data retrieved from ‘Follow-up 
Cancer Therapy’, ‘Concomitant Radiation Therapy’, ‘Follow-up Radiation Therapy’, ‘On-
study Anti-Cancer Surgery’, and ‘Follow-up Surgery’ eCRF pages.  
Number and percentage of patients with any anti-cancer therapy after discontinuation will be 
tabulated overall and by type of therapy based on the data collected from the ‘Follow-up 
Cancer Therapy’, ‘Follow-up Radiation Therapy’ and ‘Follow-up Anti-Cancer Surgery’ 
eCRF pages.  
6.6. Safety Summaries and Analyses 
The Safety Analysis Set will be the primary population for safety evaluations.  
Summaries of AEs and other safety parameters will be based on the safety analysis set as 
shown in Table 5. 


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6.6.1. Adverse events 
Treatment-emergent adverse events (TEAEs) are those events with onset dates occurring 
during the on-treatment period as defined in Section 3.5.1. 
All analyses described will be based on TEAEs if not otherwise specified. The AE listings 
will include all AEs (whether treatment-emergent or not). AEs outside the on-treatment 
period will be flagged in the listings. 
• Related Adverse Events: adverse events with relationship to study treatment (as recorded 
on the AE eCRF page, Relationship with study treatment = Related) reported by the 
investigator and those of unknown relationship (ie, no answer to the question ‘Relationship 
with study treatment’).  Related AEs are those related to any study drug (ie, at least one of 
the study drugs).  
• Serious Adverse Events (SAE): serious adverse events (as recorded on the AE eCRF 
page, Serious Adverse Event = Yes). 
• Adverse Events Leading to Dose Reduction: adverse events leading to dose reduction of 
study treatment (as recorded on the AE eCRF page, Action taken with study treatment = 
Dose reduced). 
• Adverse Events Leading to Interruption of Study Treatment: adverse events leading 
to interruption of study treatment (as recorded on the AE eCRF page, Action taken with 
study treatment = Drug interrupted).  The eCRF does not allow for a clear separation 
between interruption of an infusion and delays of administration for a parenteral drug as 
both are recorded using the same term on the eCRF (“Drug interrupted”).  IRRs will be 
excluded in the analysis of AEs leading to Drug Interruption in case they only led to an 
interruption of the infusion. 
• Adverse Events Leading to Permanent Treatment Discontinuation: adverse events 
leading to permanent discontinuation of study treatment (as recorded on the AE eCRF 
page, Action taken with study treatment = Drug withdrawn).   
• Adverse Events Leading to Death: adverse event leading to death (as recorded on the AE 
eCRF page, Outcome = Fatal, as well as AEs of Grade 5). 
• Immune-related Adverse Events (irAE): irAEs (as identified according to the 
methodology outlined in Appendix 1 for a pre-specified search list of MedDRA PTs, 
documented in the Safety Review Plan [SRP] and finalized for analysis of the current study 
data prior to DB lock) 
• Infusion-related Reactions (IRR): IRRs (as identified according to the methodology 
outlined in Appendix 2 for a pre-specified search list of MedDRA PTs documented in the 
SRP and finalized for analysis of the current study data prior to DB lock. 
Unless otherwise specified, AEs will be summarized by number and percentage of patients 
with the AE in the category of interest as described above, by primary SOC and PT in 
decreasing frequency.  


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Each patient will be counted only once within each SOC or PT.  If a patient experiences more 
than one AE within a SOC or PT for the same summary period, only the AE with the 
strongest relationship or the worst severity, as appropriate, will be included in the summaries 
of relationship and severity. 
6.6.1.1. All adverse events 
Adverse events will be summarized by worst severity (according to NCI-CTCAE version 
4.03) per patient, using the latest version of MedDRA preferred term (PT) as event category 
and MedDRA primary system organ class (SOC) body term as Body System category.  
In case a patient has events with missing and non-missing grades, the maximum of the non-
missing grades will be displayed. No imputation of missing grades will be performed.  
The following tables will be created:  
• The overall summary of AEs table will include the frequency (number and percentage) of 
patients with each of the following: 
- TEAEs 
- TEAEs, Grade ≥ 3 
- Related TEAEs 
- Related TEAEs, Grade ≥ 3 
- TEAEs leading to dose reduction of avelumab  
- TEAEs leading to dose reduction of binimetinib 
- TEAEs leading to dose reduction of talazoparib   
- TEAEs leading to interruption of avelumab 
- TEAES leading to interruption of binimetinib 
- TEAES leading to interruption of talazoparib 
- TEAEs leading to discontinuation of avelumab 
- TEAEs leading to discontinuation of binimetinib 
- TEAEs leading to discontinuation of talazoparib 
- TEAEs leading to discontinuation of any study drug 
- TEAEs leading to discontinuation of all study drugs 
- Related TEAEs leading to discontinuation of avelumab 
- Related TEAEs leading to discontinuation of binimetinib 
- Related TEAEs leading to discontinuation of talazoparib 
- Related TEAEs leading to discontinuation of any study drug 


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- Related TEAEs leading to discontinuation of all study drugs 
- Serious TEAEs 
- Related Serious TEAEs  
- TEAEs leading to death 
- Related TEAEs leading to death 
- irAEs 
- IRRs  
• TEAEs by SOC and PT and worst grade 
• TEAEs related to avelumab by SOC and PT and worst grade 
• TEAEs related to binimetinib by SOC and PT and worst grade 
• TEAEs related to talazoparib by SOC and PT and worst grade 
• TEAEs related to any study drug by SOC and PT and worst grade  
• TEAEs leading to death by SOC and PT 
• Related TEAEs leading to death by SOC and PT 
6.6.1.2. Adverse events leading to dose reduction 
The frequency (number and percentage) of patients with each of the following will be 
presented for TEAEs leading to dose reduction of each study drug: 
• TEAEs leading to dose reduction of avelumab by SOC and PT 
• TEAEs leading to dose reduction of binimetinib by SOC and PT 
• TEAEs leading to dose reduction of talazoparib by SOC and PT 
The listing of all AEs leading to dose reduction will also be provided with the relevant 
information.  
6.6.1.3. Adverse events leading to interruption of study treatment 
The eCRF does not allow for a clear separation between interruption of an infusion and 
delays of administration for a parenteral drug as both are recorded using the same term on the 
eCRF (“Drug interrupted”).  IRRs will be excluded in the analysis of AEs leading to Drug 
Interruption in case they only led to an interruption of the infusion (ie, did not lead to a dose 
reduction or a dose delay).  
As such, AEs leading to interruption will be defined as AEs identified in the AE eCRF page 
with an action taken with study treatment of ‘drug interrupted’ excluding  
• IRRs that occurred on the day of infusion with ≥90% of the planned dose given (ie IRRs 
that did not lead to a dose reduction) and subsequent administration of study drug had no 
delay (as defined in Section 6.5.3.6).  These IRRs will be considered as IRRs leading to 
interruption of infusion. 


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• IRRs occurring on the day after infusion and subsequent dose administration had no delay 
(as defined in Section 6.5.3.6). 
The frequency (number and percentage) of patients with each of the following will be 
presented for TEAEs leading to interruption of each study drug: 
• TEAEs leading to interruption of avelumab by SOC and PT 
• TEAEs leading to interruption of binimetinib by SOC and PT 
• TEAEs leading to interruption of talazoparib by SOC and PT 
The listing of all AEs leading to interruption of study treatment will also be provided with the 
relevant information. 
In addition, the frequency (number and percentage) of patients with each of the following 
will be presented for TEAEs leading to both interruption and dose reduction of each study 
drug: 
• TEAEs leading to both interruption and dose reduction of avelumab by SOC and PT 
• TEAEs leading to both interruption and dose reduction of binimetinib by SOC and PT 
• TEAEs leading to both interruption and dose reduction of talazoparib by SOC and PT 
This summary will take into account PTs with both actions as defined in Section 6.6.1, even 
though the actions may be captured for different PT records (ie, different onset for the PT 
with action “drug interrupted” and the PT with action “dose reduced”.   
6.6.1.4. Adverse events leading to discontinuation of study treatment 
The frequency (number and percentage) of patients with each of the following will be 
presented for TEAEs leading to permanent discontinuation of each study drug and study 
treatment: 
• TEAEs leading to discontinuation of avelumab by SOC and PT 
• Related TEAEs leading to discontinuation of avelumab by SOC and PT 
• TEAEs leading to discontinuation of binimetinib by SOC and PT 
• Related TEAEs leading to discontinuation of binimetinib by SOC and PT 
• TEAEs leading to discontinuation of talazoparib by SOC and PT 
• Related TEAEs leading to discontinuation of talazoparib by SOC and PT 
• TEAEs leading to discontinuation of any study drug by SOC and PT 
• Related TEAEs leading to discontinuation of any study drug by SOC and PT 
• TEAEs leading to discontinuation of all study drugs by SOC and PT 
• Related TEAEs leading to discontinuation of all study drugs by SOC and PT 


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The listing of all AEs leading to treatment discontinuation will also be provided with the 
relevant information.  
6.6.2. Deaths 
The frequency (number and percentage) of patients in the safety analysis set who died and 
who died within 30 days after last dose of study treatment as well as the reason for death, 
will be tabulated based on information from the ‘Notice of Death’ and ‘Survival Follow-Up’ 
eCRFs.   
• All deaths  
• Deaths within 30 days after last dose of study treatment 
• Reason for Death  
- Disease progression 
- Study treatment toxicity 
- AE not related to study treatment 
- Unknown 
- Other. 
In addition, date and cause of death will be provided in individual patient data listing together 
with selected dosing information (study treatment received, date of first / last administration, 
dose) and will include the following information: 
• AEs with fatal outcome (list preferred terms of AEs with outcome=Fatal, as well as AEs 
of Grade 5),  
• Flag for death within 30 days of last dose of study treatment.  
6.6.3. Serious adverse events 
The frequency (number and percentage) of patients with each of the following will be 
presented for treatment-emergent SAEs: 
• SAEs by SOC and PT 
•  Related SAEs by SOC and PT 
The listings of all SAEs will also be provided with the relevant information with a flag for 
SAEs with onset outside of the on-treatment period. 
6.6.4. Other significant adverse events 
The frequency (number and percentage) of patients with each of the following will be 
presented for irAEs: 
• irAEs leading to death, by Cluster and PT  
• irAEs, by Cluster and PT 
• irAEs, Grade ≥ 3, by Cluster and PT 


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• irAEs leading to discontinuation of avelumab, by Cluster and PT  
• irAEs leading to discontinuation of binimetinib, by Cluster and PT  
• irAEs leading to discontinuation of talazoparib, by Cluster and PT  
• irAEs leading to discontinuation of any study drug, by Cluster and PT 
• irAEs leading to discontinuation of all study drugs, by Cluster and PT 
• Serious irAEs, by Cluster and PT  
The listing of all irAEs will also be provided with the relevant information with a flag for 
irAEs with onset outside of the on-treatment period.  
The frequency (number and percentage) of patients with each of the following will be 
presented for IRRs: 
• IRRs leading to death, by PT  
• IRRs, by PT 
• IRRs, Grade ≥ 3, by PT 
• IRRs leading to discontinuation of avelumab, by PT  
• IRRs leading to discontinuation of any study drug, by PT  
• IRRs leading to discontinuation of all study drugs, by PT 
• Serious IRRs, by PT 
• Time related to first onset of an IRR (infusion 1, infusion 2, infusion 3, infusion 4 or later). 
The listing of all IRRs will also be provided with the relevant information with a flag for 
IRRs with onset outside of the on-treatment period. 
6.6.5. Laboratory data 
6.6.5.1. Hematology and chemistry parameters 
Laboratory results will be classified according to the NCI-CTCAE criteria version 4.03.  
Non-numerical qualifiers (with the exception of fasting flags) will not be taken into 
consideration in the derivation of CTCAE criteria (eg, hypokalemia Grade 1 and Grade 2 are 
only distinguished by a non-numerical qualifier and therefore Grade 2 will not be derived).  
Additional laboratory results that are not part of NCI-CTCAE will be presented according to 
the categories: below normal limit, within normal limits and above normal limit (according to 
the laboratory normal ranges).  
Quantitative data will be summarized using simple descriptive statistics (mean, SD, median, 
Q1, Q3, minimum, and maximum) of actual values and changes from baseline for each 
nominal visit over time (unscheduled measurements would therefore not be included in these 
summaries as described in Section 5.2.9).  End of Treatment visit laboratory results will be 
summarized separately.  The changes computed will be the differences from baseline. 
Qualitative data based on reference ranges will be described according to the categories (ie, 
Low, Normal, High).  


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Abnormalities classified according to NCI-CTCAE toxicity grading v.4.03 will be described 
using the worst grade. For those parameters which are graded with two toxicities such as 
potassium (hypokalemia/hyperkalemia), the toxicities will be summarized separately.  Low 
direction toxicity (eg, hypokalemia) grades at baseline and post baseline will be set to 0 when 
the variables are derived for summarizing high direction toxicity (eg, hyperkalemia), and vice 
versa. 
For WBC differential counts (total neutrophil [including bands], lymphocyte, monocyte, 
eosinophil, and basophil counts), the absolute value will be used when reported.  When only 
percentages are available (this is mainly important for neutrophils and lymphocytes, because 
the CTCAE grading is based on the absolute counts), the absolute value is derived as follows:  
Derived differential absolute count = (WBC count) × (Differential %value / 100) 
If the range for the differential absolute count is not available (only range for value in % is 
available) then Grade 1 will be attributed to as follows:  
• Lymphocyte count decreased:   
- derived absolute count does not meet Grade 2-4 criteria, and 
- % value < % LLN value, and 
- derived absolute count  ≥ 800/mm3 
• Neutrophil count decreased  
- derived absolute count does not meet Grade 2-4 criteria, and 
- % value < % LLN value, and 
- derived absolute count  ≥ 1500/mm3 
For calcium, CTCAE grading is based on Corrected Calcium and Ionized Calcium 
(CALCIO). Corrected Calcium is calculated from Albumin and Calcium as follows 
  
Corrected calcium (mmol/L) = measured total Calcium (mmol/L) + 0.02 (40 - serum 
albumin [g/L]) 
Liver function tests: Alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
and total bilirubin (TBILI) are used to assess possible drug induced liver toxicity.  The ratios 
of test result over upper limit of normal (ULN) will be calculated and classified for these 
three parameters during the on-treatment period.  
Summary of liver function tests will include the following categories.  The number and 
percentage of patients with each of the following during the on-treatment period will be 
summarized: 
• ALT ≥ 3×ULN, ALT ≥ 5×ULN, ALT ≥ 10×ULN, ALT ≥ 20×ULN 
• AST ≥ 3×ULN, AST ≥ 5×ULN, AST ≥ 10×ULN, AST ≥ 20×ULN 
• (ALT or AST) ≥ 3×ULN, (ALT or AST) ≥ 5×ULN, (ALT or AST) ≥ 10×ULN, (ALT or 
AST) ≥ 20×ULN 


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• TBILI ≥ 2×ULN 
• Concurrent  ALT ≥ 3×ULN and TBILI ≥ 2×ULN 
• Concurrent AST ≥ 3×ULN and TBILI ≥ 2×ULN 
• Concurrent (ALT or AST) ≥ 3×ULN and TBILI ≥ 2×ULN  
• Concurrent (ALT or AST) ≥ 3×ULN and TBILI ≥ 2×ULN and ALP > 2×ULN 
• Concurrent (ALT or AST) ≥ 3×ULN and TBILI ≥ 2×ULN and (ALP ≤ 2×ULN or missing) 
Concurrent measurements are those occurring on the same date. 
Categories will be cumulative, ie, a patient with an elevation of AST ≥10×ULN will also 
appear in the categories ≥5×ULN and ≥3×ULN. Liver function elevation and possible Hy’s 
Law cases will be summarized using frequency counts and percentages.  
An evaluation of Drug-Induced Serious Hepatotoxicity (eDISH) plot will also be created, 
with different symbols for different treatment groups, by graphically displaying 
• peak serum ALT(/ULN) vs peak total bilirubin (/ULN) including reference lines at 
ALT=3×ULN and total bilirubin =2×ULN.  
• peak serum AST(/ULN) vs peak total bilirubin (/ULN) including reference lines at 
AST=3×ULN and total bilirubin =2×ULN .  
In addition, a listing of all TBILI, ALT, AST and ALP values for patients with a post-
baseline TBILI ≥ 2×ULN, ALT≥ 3×ULN or AST ≥ 3×ULN will be provided. 
Parameters with NCI-CTC grades available:  
The laboratory toxicities will be tabulated using descriptive statistics (number of patients and 
percentages) during the on-treatment period.  The denominator to calculate percentages for 
each laboratory parameter is the number of patients evaluable for CTCAE grading (ie those 
patients for whom a Grade 0, 1, 2, 3 or 4 can be derived). 
• The summary of laboratory parameters by CTCAE grade table will include number and 
percentage of patients with Grade 1, 2, 3, 4, Grade 3/4 and any grade (Grades 1-4), 
laboratory abnormalities during the on-treatment period. 
• The shift table will summarize baseline CTCAE grade versus the worst on-treatment 
CTCAE grade. The highest CTCAE grade during the on-treatment period is considered as 
the worst grade for the summary.  
• The number and percentage of patients with newly occurring or worsening laboratory 
abnormalities during the on-treatment period will be summarized by worst grade on-
treatment (Grade 1, 2, 3, 4, Grade 3/4 and any grade (Grades 1-4)). 
 


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The above analyses apply to hematology and chemistry evaluations which can be graded per 
CTCAE, ie: 
• Hematology:  
Hemoglobin (HB), Leukocytes (white blood cell decreased), Lymphocytes (lymphocyte 
count increased/decreased), Neutrophils / Absolute Neutrophils Count (ANC) (neutrophil 
count decreased), Platelet Count (PLT) (platelet count decreased). 
•  Serum Chemistry: 
Albumin (hypoalbuminemia), Alkaline Phosphatase (alkaline phosphatase increased), 
Alanine Aminotransferase (ALT) (ALT increased), Amylase (serum amylase increased), 
Aspartate Aminotransferase (AST) (AST increased), Total Bilirubin (blood bilirubin 
increased), Creatinine (creatinine increased), Creatine Kinase (CPK increased), Potassium 
(hypokalemia/ hyperkalemia), Sodium (hyponatremia/ hypernatremia), Magnesium 
(hypomagnesemia/hypermagnesemia), Calcium (hypocalcemia/ hypercalcemia), Glucose 
(hypoglycemia/hyperglycemia), Gamma Glutamyl Transferase (GGT) (GGT increased), 
Lipase (lipase increased), Phosphates (hypophosphatemia). 
Parameters with NCI-CTC grades not available: 
Hematology and chemistry evaluations which cannot be graded per CTCAE criteria will be 
summarized as frequency (number and percentage) of patients with:  
• shifts from baseline normal to at least one result above normal during on-treatment period  
• shifts from baseline normal to at least one result below normal during on-treatment period 
In this study, these apply to the following parameters:  
Serum Chemistry: Chloride, 
Uric Acid, Total Protein, C-Reactive Protein, Lactate 
Dehydrogenase (LDH), CK isoenzymes (CK-MB, CK-MM and CK-BB), Cardiac Troponin I 
and/or T. 
6.6.5.2. Other laboratory parameters 
The listings of laboratory results will be provided for all laboratory parameters. The listings 
will be sorted by parameters and assessment dates or visits for each patient. Laboratory 
values that are outside the normal range will also be flagged in the data listings, along with 
corresponding normal ranges.  A listing of CTCAE grading will also be generated for those 
laboratory tests.  
In addition, listings of abnormal values will be provided for hematology, chemistry, 
urinalysis, coagulation parameters. If there is at least one abnormal assessment for any 
parameter, all the data for that laboratory parameter will be included into the listing.  
For all tests not mentioned above but present in the clinical data, a listing of patients with at 
least one result for the relevant test will be provided. 


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6.6.6. Vital signs 
Weight will be recorded at screening and within 2 days pre-dose Day 1 of each cycle and at 
End of Treatment.  Height will be measured at screening only. 
Vital sign summaries will include all vital sign assessments from the on-treatment period.  
All vital sign assessments will be listed, and those collected outside the on-treatment period 
will be flagged in the listing.  
All vital sign parameters will be summarized using descriptive statistics (mean, SD, median, 
Q1, Q3, minimum, and maximum) of actual values and changes from baseline for each visit 
over time. End of Treatment visit will be summarized separately. The changes computed will 
be the differences from baseline.  
6.6.7. Electrocardiogram 
ECG summaries will include all ECG assessments from the on-treatment period.  All ECG 
assessments will be listed, and those collected outside the on-treatment period will be flagged 
in the listing.  QTcB and QTcF will be derived based on RR and QT (see below).  In the case 
of triplicate ECG (at screening and pre-dose Cycle 1 Day 1), the average of the replicate 
measurements should be determined after the derivation of the individual parameter at each 
time point. 
Selecting Primary QT Correction for Heart Rate 
The analysis of QT data is complicated by the fact that the QT interval is highly correlated 
with heart rate.  Because of this correlation, formulas are routinely used to obtain a corrected 
value, denoted QTc, which is independent of heart rate. This QTc interval is intended to 
represent the QT interval at a standardized heart rate. Several correction formulas have been 
proposed in the literature. For this analysis we will use some of those methods of correction, 
as described below. The QT interval corrected for heart rate by the Bazett’s formula, QTcB, 
is defined as  
RR
QT
QTcB =
, 
the QT interval corrected for heart rate by the Fridericia’s formula, QTcF, is defined as  
3 RR
QT
QTcF =
 , 
where RR represents the RR interval of the ECG, in seconds, and can be estimated as 
60/Heart Rate.   
Although Bazett’s correction is the historical standard, it does not perform well when heart 
rate fluctuates. Fridericia’s formula may perform better under these conditions.   
ECG Summaries 
The following analyses will be performed for each applicable ECG parameters (RR, PR, 
QRS, QT, ventricular rate -denoted as HR in what follows-, and QTc), during the on-


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treatment period. The denominator to calculate percentages for each category is the number 
of patients evaluable for the category. 
• Pearson correlation between QT and HR, QTc (QTcB, QTcF) and HR using individua l 
(non-averaged) baseline assessments  
• For each of the ECG parameters (HR, and QT, QTc, QRS, PR intervals), descriptive 
statistics at baseline, at each post-baseline time point and changes from baseline at each 
post-baseline time point  
• Frequency (number and percentage) of patients with notable ECG values according to the 
following categories:            
- 
QT/QTc increase from baseline >30 ms, >60 ms 
- 
QT/QTc > 450 ms, > 480 ms, > 500 ms 
- 
HR ≤ 50 bpm and decrease from baseline ≥ 20 bpm 
- 
HR ≥ 120 bpm and increase from baseline ≥ 20 bpm 
- 
PR ≥ 220 ms and increase from baseline ≥ 20 ms 
- 
QRS ≥ 120 ms  
Patients with notable ECG interval values and qualitative ECG abnormalities will be listed 
for each patient and time point and the corresponding notable values and abnormality 
findings will be included in the listings. 
Unscheduled ECG measurements will not be used in computing the descriptive statistics for 
change from baseline at each post-baseline time point.  However, they will be used in the 
analysis of notable ECG changes and the shift table analysis of notable QT parameters. 
6.6.8. MUGA/ECHO 
LVEF% will be summarized using simple descriptive statistics (mean, SD, median, Q1, Q3, 
minimum, and maximum) of actual values and changes from baseline for each nominal visit 
over time.  In addition, LVEF% will be summarized as frequency (number and percentage) 
of patients with:  
• a shift from baseline normal to at least one result below the institutional lower limit of 
normal during the on-treatment period 
• ≥10-point decrease from baseline in LVEF% during the on-treatment period 
• ≥10-point decrease from baseline in LVEF% to a post-baseline value < LLN during the on-
treatment period 
• ≥15-point decrease from baseline in LVEF% during the on-treatment period 
• ≥15-point decrease from baseline in LVEF% to a post-baseline value < LLN during the on-
treatment period 
Clinically significant findings will be listed. 


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6.6.9. Ophthalmic Examination 
Abnormal findings in ophthalmic examination are recorded in the Medical history (at 
screening) or the Adverse Event eCRF pages. No separate analysis will be performed for 
ophthalmic examination findings.  A listing of ophthalmic examination findings will be 
provided. 
6.6.10. ECOG performance status 
The ECOG shift from baseline to highest score during the on-treatment period will be 
summarized. ECOG performance status with shift from ECOG=0 or 1 to ECOG 2 or higher 
will also be presented in a data listing. 
7. INTERIM ANALYSES 
There is no formal interim analysis planned for this study. 
7.1. Introduction 
Not applicable. 
7.2. Interim Analyses and Summaries 
Not applicable. 


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8. REFERENCES 
1. 
Babb J, Rogatko A, Zacks S. Cancer Phase I clinical trials: efficient dose escalation 
with overdose control. Statistics in Medicine. 1998;17(10):1103-20. 
2. 
Binimetinib Investigator Brochure, 11 March 2019. 
3. 
Brookmeyer R, Crowley JJ. A confidence interval for the median survival time. 
Biometrics. 38: 29-41, 1982. 
4. 
Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case 
of the binomial.  Biometrika; 26, 404-413. 1934. 
5. 
Desai J, Hong, YS, Kim JE, et al. Efficacy and safety of cobimetinib (cobi) and 
atezolizumab (atezo) in an expanded phase 1b study of microsatellite-stable (MSS) 
metastatic colorectal cancer. Annals of Oncology (2016) 27 (6): 149-206. 
6. 
de Bono J, Ramanathan RK, Mina L. Phase I, Dose-Escalation, Two-Part Trial of the 
PARP Inhibitor Talazoparib in Patients with Advanced Germline BRCA1/2 Mutations 
and Selected Sporadic Cancers. Cancer Discov. 2017;7(6):620-9. 
7. 
Investigator’s Brochure of talazoparib (MDV3800, BMN673), dated August 2018. 
8. 
Investigator’s Brochure of avelumab (MSB0010718C), dated May 2018. 
9. 
Kalbfleisch JD, Prentice RL. Statistical Analysis of Failure Time Data, 2nd Edition. 
Hoboken, Wiley Interscience. 2002.  
10. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am 
Stat Assoc. 53: 457-81, 1958. 
11. Merck KGaA, Darmstadt, Germany, and Pfizer provide update on Phase III JAVELIN 
Lung 200 trial of avelumab monotherapy in previously treated patients with advanced 
non-small cell lung cancer. Press release; https://investors.pfizer.com/investor-
news/press-release-details/2018/Merck-KGaA-Darmstadt-Germany-and-Pfizer-Provide-
Update-on-Phase-III-JAVELIN-Lung-200-Trial-of-Avelumab-Monotherapy-in-
Previously-Treated-Patients-with-Advanced--Non-Small-Cell-Lung-
Cancer/default.aspx. 
12. Neuenschwander B, Capkun-Niggli G, Branson M, and Spiegelhalter DJ. Summarizing 
Historical Information on Controls in Clinical Trials. Clinical Trials 2010; 7:5-18. 
13. Neuenschwander B, Matano A, Tang Z, et al. A Bayesian Industry Approach to Phase I 
Combination Trials in Oncology.  In Statistical Methods in Drug Combination Studies.  
Zhao W and Yang H (eds); Chapman & Hall/CRC; 2014. 
14. Spiegelhalter DJ, Abrams KR, Myles JP. Bayesian Approaches to Clinical Trials and 
Health-Care Evaluation. John Wiley & Sons; New York; 2004. 


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9. APPENDICES 
Appendix 1. Immune-Related Adverse Events 
The MedDRA PTs and clusters for irAEs are defined in the Safety Review Plan (SRP) for 
avelumab. 
Immune-related AEs (irAEs) will be programmatically identified as outlined in Table 13.   
This case definition is hierarchical, ie, each step is only checked for patients and events that 
have already met the prior step except for Steps 3 and 4 which will be checked in parallel.  
Step 5 will be checked for patients who meet the criteria in Step 4 (irrespective of whether 
Step 3 criteria are met).  
Table 13. Case Definition for irAEs 
Step 
Selection Criteria 
Additional Notes 
1 
Event selected based on a list of pre-
specified MedDRA PTs within clusters.  
These are included in the SRP as Tier1 
events (Immune-mediated xxxx).  If AE 
matches the list then it is in for the next step 
 
2 
AE onset during 1st study drug 
administration or anytime thereafter through 
90 days after last dose of study treatment. 
This is regardless of start of new anti-cancer drug 
therapy and regardless of TEAE classifications 
3 
Answer in the AE eCRF page to ‘Was 
another treatment given because of the 
occurrence of the event’ is ‘YES’ 
 
4 
AE treated with corticosteroids or other 
immunosuppressant therapy.   
For endocrinopathies only: AE required 
hormone replacement 
Look in the conmed pages for AE identifiers that 
match the AEs from Step 3.  For each of such AEs 
if A) OR B) OR C) below are met then the AE is in 
for the next step 
A) conmed ATC code is in (H02A, H02B, D07, 
A01AC, S01BA, S01BB, L04AA, L04AB,  
L04AC, L04AD,  L04AX, A07EA) and AE PT 
is in any of the irAE clusters. 
B) conmed ATC code is in (H03A, H03B) and AE 
PT is in one of the irAE clusters associated 
with “Immune-mediated endocrinopathies” 
C) conmed ATC code is A10A and AE PT is in 
the irAE cluster associated with “Immune-
mediated endocrinopathies: Type I Diabetes 
Mellitus” 


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5 
A) No clear etiology (other than immune 
mediated etiology) 
 
 
 
 
 
 
 
 
B) Histopathology / biopsy consistent with 
immune-mediated event 
 
 
 
 
 
 
 
 
 
Event is in if  
[Answer to 5B1 and 5B2 is YES  
(regardless of answer to 5A)] 
OR 
[Answer to 5B1 is YES AND answer to 
5B2 is NO AND answer to 5A is NO]  
OR 
[Answer to 5B1 is NO AND answer to 5A 
is NO] 
A) From the AE eCRF page. 
Is the AE clearly related to an etiology other 
than immune-mediated etiology?    Yes / No 
If answer is Yes, check all that apply: 
• Underlying malignancy / progressive disease. 
• Other medical conditions.  
• Prior or concomitant medications / 
procedures.   
• Other.  Specify. 
 
B) From the AE eCRF page. 
B1) Was there a pathology /histology 
evaluation performed to investigate the AE?  
Y/N 
B2) If answer to the above is Yes, does the 
pathology/histology evaluation confirms an 
immune mediated mechanism for the AE?  Y/N 
B3) If pathology / histology evaluation 
performed to investigate the AE, provide 
summary of relevant findings of the pathology 
/histology report.  (Free Text) 
 
The data set associated with irAEs may be refined based on medical review.  The final data 
set including any changes based on medical review (eg, addition of cases that are not selected 
by the programmatic algorithm) will be the basis of the irAE analyses. 
 


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Appendix 2. Infusion Related Reactions 
For defining an AE as IRR the onset of the event in relation to the infusion of study drug and 
time to resolution of the event will be considered.  
• All AEs identified by the MedDRA PT query describing signs and symptoms will be 
considered potential IRRs when onset is on the day of study drug infusion (during or after 
infusion) and the event resolved with end date within 2 days after onset.  
• All AEs identified by the MedDRA PTs of Infusion related reaction, Drug 
hypersensitivity, Anaphylactic reaction, Hypersensitivity, Type 1 hypersensitivity, will be 
considered potential IRRs when onset is on the day of study drug infusion (during or after 
the infusion) or the day after the study drug infusion (irrespective of resolution date). 
The list of MedDRA PTs for ‘IRRs SIGNS and SYMPTOMS’ and PTs ‘IRRs CORE’ are 
defined in the SRP for avelumab.  
Infusion-related reactions (IRRs) will be programmatically identified as outlined in  Table 14 
will be identified for IV drugs only.      
Table 14. Case Definition for IRRs – IV Study Drugs Administered Alone Or In 
Combination With Non-IV Study Drugs 
Condition 
Selection criterion 
If AE meets [1 AND 2] OR [3 AND (4A OR 4B)] then AE is classified as an IRR 
1 
PT is included in the ‘IRRs SIGNS and SYMPTOMS’ list  
2 
• AE onset date = date of infusion of study drug AND  
• AE timing related to study drug (‘DURING’, ‘AFTER’) AND  
• AE outcome in (‘RECOVERED/RESOLVED’, ‘RECOVERED/RESOLVED WITH 
SEQUELAE’, ‘RECOVERING/RESOLVING’) AND  
• AE end date – AE onset date <=2  
3 
PT is included in the ‘IRRs CORE’ list  
4A 
• AE onset date = date of infusion of study drug AND  
• AE timing related to study drug in (‘DURING’, ‘AFTER’) 
4B 
AE onset on the day after infusion 
 


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Appendix 3. Detailed Dose Escalation/De-escalation Scheme for BLRM Design prior to 
implementation of Protocol Amendment 3. 
This appendix provides the details of the statistical model, the derivation of prior 
distributions from historical data, the results of the Bayesian analyses and respective dosing 
decisions for some hypothetical data scenarios, and a simulation study of the operating 
characteristics of the model.   
In this appendix, no data from study B9991025 for the combination of avelumab and 
talazoparib is considered.  However, prior to the initiation of the dose finding for the triplet 
combination (avelumab, binimetinib and talazoparib), all applicable DLT data from study 
B9991025 and the doublet combination of study B9991033 will be incorporated into the 
BLRM to guide the starting dose and dose finding of the triplet combination.  
As of protocol amendment 2 (05-Nov-2018), preliminary safety data became available for 
the Phase 1b portion of study B9991025.  A total of 12 patients were enrolled at the starting 
dose level of 800 mg avelumab Q2W in combination with talazoparib at 1.0 mg once daily. 
All 12 patients were DLT-evaluable with a DLT rate of 3/12. This information from study 
B9991025 will be incorporated using direct down-weighting approach. The weight will be 
calculated using the formula below;  
𝑤𝑤=  
1
1+ 2𝜏𝜏2
𝜎𝜎2  𝑁𝑁
   
where N= Total number of patients enrolled in the Phase 1b of study B9991025 (12) 
        σ = population standard deviation (σ = 2) 
        τ = heterogeneity between populations in the Phase 1b of study B9991025 and the triplet 
in terms of DLT (τ =0.25). 
In this appendix, the reported avelumab dose is 10 mg/kg.  Note that the fixed dose of 
800 mg to be investigated in this study is expected to be equivalent to the 10 mg/kg dose. 
A.3.1. Statistical Model 
The statistical model for triplet combination dose-DLT data comprises single-agent toxicity 
parts, which allow the incorporation of single-agent toxicity data, and interaction parts. 
A.3.1.1. Single Agent Parts  
Let 𝜋𝜋1(𝑑𝑑1) be the risk of DLT for avelumab given as a single agent at dose 𝑑𝑑1; 𝜋𝜋2(𝑑𝑑2) be the 
risk of DLT for binimetinib given as a single agent at dose 𝑑𝑑2; and 𝜋𝜋3(𝑑𝑑3) be the risk of 
DLT for talazoparib given as a single agent at dose 𝑑𝑑3.  These single agent dose-DLT models 
are logistic: 
avelumab: 
logit൫𝜋𝜋1(𝑑𝑑1)൯ =  log(𝛼𝛼1) + 𝛽𝛽1 log(𝑑𝑑1 𝑑𝑑1
∗
⁄
) 
binimetinib: 
logit൫𝜋𝜋2(𝑑𝑑2)൯ =  log(𝛼𝛼2) + 𝛽𝛽2 log(𝑑𝑑2 𝑑𝑑2
∗
⁄
) 


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talazoparib: 
logit൫𝜋𝜋3(𝑑𝑑3)൯ =  log(𝛼𝛼3) + 𝛽𝛽3 log(𝑑𝑑3 𝑑𝑑3
∗
⁄
) 
where 𝑑𝑑1
∗=10 mg/kg, 𝑑𝑑2
∗ =45 mg, and 𝑑𝑑3
∗=1.0 mg are used to scale the doses of avelumab, 
binimetinib, and talazoparib, respectively.  Hence, 𝛼𝛼1,  𝛼𝛼2 , and 𝛼𝛼3 (all >0) are the single-
agent odds of a DLT at 𝑑𝑑1
∗ mg/kg, 𝑑𝑑2
∗ mg, and 𝑑𝑑3
∗ mg, respectively; and  𝛽𝛽1, 𝛽𝛽2, and 𝛽𝛽3(all >0) 
are the increase in the log-odds of a DLT by a unit increase in log-dose. 
A.3.1.2. Interaction Parts 
Under an assumption that there is no interaction, the risk of a DLT at dose 𝑑𝑑1 of avelumab, 
dose 𝑑𝑑2 of binimetinib, and dose 𝑑𝑑3 of talazoparib is: 
𝜋𝜋123
0 (𝑑𝑑1,𝑑𝑑2,𝑑𝑑3) = 1 − ൫1 −𝜋𝜋1(𝑑𝑑1)൯൫1 −𝜋𝜋2(𝑑𝑑2)൯൫1 −𝜋𝜋3(𝑑𝑑3)൯ 
To model the interaction between avelumab, binimetinib, and talazoparib, the following four 
odds multipliers are introduced. 
• 𝜂𝜂12: Two-way interaction between avelumab and binimetinib 
• 𝜂𝜂13: Two-way interaction between avelumab and talazoparib 
• 𝜂𝜂23: Two-way interaction between binimetinib and talazoparib 
• 𝜂𝜂123: Three-way interaction between avelumab, binimetinib and talazoparib 
The risk of DLT for combination dose (𝑑𝑑1, 𝑑𝑑2,𝑑𝑑3) is then given by: 
odds൫𝜋𝜋123(𝑑𝑑1,𝑑𝑑2,𝑑𝑑3)൯= 𝑔𝑔(𝜂𝜂12, 𝜂𝜂13,𝜂𝜂23,𝜂𝜂123) × odds൫𝜋𝜋123
0 (𝑑𝑑1,𝑑𝑑2,𝑑𝑑3)൯ 
𝑔𝑔(𝜂𝜂12,𝜂𝜂13,𝜂𝜂23, 𝜂𝜂123) =   exp(𝜂𝜂12 × 𝑑𝑑1 𝑑𝑑1
∗
⁄
× 𝑑𝑑2 𝑑𝑑2
∗
⁄
) 
                                                                × exp ( 𝜂𝜂13 × 𝑑𝑑1 𝑑𝑑1
∗
⁄
× 𝑑𝑑3 𝑑𝑑3
∗)
⁄
 
                                                                × exp (𝜂𝜂23 × 𝑑𝑑2 𝑑𝑑2
∗
⁄
× 𝑑𝑑3 𝑑𝑑3
∗)
⁄
 
                                                              × exp (𝜂𝜂123 × 𝑑𝑑1 𝑑𝑑1
∗
⁄
× 𝑑𝑑2 𝑑𝑑2
∗
⁄
× 𝑑𝑑3 𝑑𝑑3
∗
⁄
) 
where odds(𝜋𝜋) = 𝜋𝜋(1 −𝜋𝜋)
⁄
; 𝜂𝜂𝑖𝑖𝑖𝑖 is the log-odds ratio between the interaction and no 
interaction model at the reference doses of drug i and j and a zero dose of the third drug.  For 
example, 𝜂𝜂12 is the log-odds ratio between the interaction and no interaction model at 
avelumab = 10 mg/kg, binimetinib= 45 mg, and talazoparib=0 mg.  Therefore, 𝜂𝜂12 + 𝜂𝜂13 +
𝜂𝜂23 + 𝜂𝜂123 is the log-odds ratio between the interaction and no interaction model at the 
reference doses for all three drugs.  Here 𝜂𝜂= 0 corresponds to no interaction, with 𝜂𝜂> 0 and 
𝜂𝜂< 0 representing synergistic and antagonistic toxicity respectively. 
The dose-DLT data of the doublet combination of avelumab and binimetinib will be modeled 
using the same model by setting the talazoparib dose 𝑑𝑑3 = 0 mg.  The model will contain 
parameters related to single agent effects of avelumab (log(𝛼𝛼1), log(𝛽𝛽1)), binimetinib 
(log(𝛼𝛼2), log(𝛽𝛽2)), and two-way interaction between avelumab and binimetinib (𝜂𝜂12). 
A.3.2. Prior Specifications 


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The Bayesian approach requires the specification of prior distributions for all model 
parameters, which include the single agent parameters log(𝛼𝛼1), log(𝛽𝛽1) for avelumab, 
log(𝛼𝛼2), log(𝛽𝛽2) for binimetinib, log(𝛼𝛼3), log(𝛽𝛽3) for talazoparib, and the interaction 
parameters 𝜂𝜂= (𝜂𝜂12, 𝜂𝜂13, 𝜂𝜂23,𝜂𝜂123).  A meta-analytic-predictive (MAP) approach was used 
to derive the prior distribution for the single-agent model parameters.  
A.3.2.1. Prior Distribution for the Logistic Parameters for Single Agent 
This section illustrates the derivation of prior distributions for single agent model parameters 
(log(𝛼𝛼𝑠𝑠), log(𝛽𝛽𝑠𝑠))’s using the available single agent dose-DLT information via a MAP 
approach.   
A.3.2.1.1. Description of the Meta-Analytic-Predictive Approach 
The aim of the MAP approach is to derive a prior distribution for the logistic parameters 
൫log(𝛼𝛼∗),  log(𝛽𝛽∗)൯ of the new trial using DLT data from historical studies.  Let 𝑟𝑟𝑑𝑑𝑑𝑑 and 𝑛𝑛𝑑𝑑𝑑𝑑 
be the number of patients with a DLT, and the total number of patients at dose 𝑑𝑑 in historical 
trial 𝑠𝑠 (𝑠𝑠= 1, …, 〈𝑆𝑆〉).  The corresponding probability of a DLT is 𝜋𝜋𝑑𝑑𝑑𝑑.  The model 
specifications are as follows: 
𝑟𝑟𝑑𝑑𝑑𝑑 | 𝜋𝜋𝑑𝑑𝑑𝑑 ~ Bin(𝜋𝜋𝑑𝑑𝑑𝑑,𝑛𝑛𝑑𝑑𝑑𝑑) 
logit(𝜋𝜋𝑑𝑑𝑑𝑑) = log(𝛼𝛼𝑠𝑠) + 𝛽𝛽𝑠𝑠 log(𝑑𝑑/𝑑𝑑∗) 
 ൫𝑙𝑙𝑙𝑙𝑙𝑙(𝛼𝛼𝑠𝑠), 𝑙𝑙𝑙𝑙𝑙𝑙(𝛽𝛽𝑠𝑠)൯ ห 𝜇𝜇, 𝜓𝜓𝑔𝑔(𝑠𝑠) ~ BVN൫𝜇𝜇, 𝜓𝜓𝑔𝑔(𝑠𝑠)൯,
s = 1,… , 〈𝑆𝑆〉 
൫𝑙𝑙𝑙𝑙𝑙𝑙(𝛼𝛼∗), 𝑙𝑙𝑙𝑙𝑙𝑙(𝛽𝛽∗)൯ ห 𝜇𝜇, 𝜓𝜓𝑔𝑔 (∗) ~ BVN൫𝜇𝜇, 𝜓𝜓𝑔𝑔 (∗)൯ 
The historical trials are partitioned into 〈𝐺𝐺〉 exchangeability groups, with the exchangeability 
group membership of historical trial 𝑠𝑠 being represented by 𝑔𝑔(𝑠𝑠).  The new trial is assigned 
to exchangeability group 𝑔𝑔(∗).  The parameter 𝜇𝜇 = (𝜇𝜇1,𝜇𝜇2)  is the mean for the logistic 
parameters, and 𝜓𝜓𝑔𝑔 is the between-trial covariance matrix for exchangeability group 𝑔𝑔=
1, … ,〈𝐺𝐺〉.  Covariance matrix 𝜓𝜓𝑔𝑔 is defined by the standard deviations (τ𝑔𝑔1, τ𝑔𝑔2), and 
correlation ρ (a common value for ρ is used across all groups).  The parameters τ𝑔𝑔1 and τ𝑔𝑔2 
quantify the degree of between trial heterogeneity for exchangeability group 𝑔𝑔.  With 
different prior distributions for the parameter sets ൫τ𝑔𝑔1,τ𝑔𝑔2൯ it is possible to allow for 
differential discounting for the historical strata.  In this way the quality and relevance of 
historical data can be accounted for in the meta-analysis.  The following priors will be used 
for these parameters:   
• normal priors for 𝜇𝜇1 and 𝜇𝜇2,  
• log-normal priors for τ𝑔𝑔1 and τ𝑔𝑔2, and  
• a uniform prior for ρ. 
The MAP prior for single-agent model parameters in the new trial, ൫𝑙𝑙𝑙𝑙𝑙𝑙(𝛼𝛼∗), 𝑙𝑙𝑙𝑙𝑙𝑙(𝛽𝛽∗)൯, is the 
predictive distribution  
൫𝑙𝑙𝑙𝑙𝑙𝑙(𝛼𝛼∗), 𝑙𝑙𝑙𝑙𝑙𝑙(𝛽𝛽∗)൯ ห (𝑟𝑟𝑑𝑑𝑑𝑑, 𝑛𝑛𝑑𝑑𝑑𝑑∶𝑠𝑠= 1, …, 〈𝑆𝑆〉) 


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Since the predictive distribution is not available analytically, the Markov chain Monte Carlo 
(MCMC) method is used to simulate values from this distribution.  This is implemented 
using JAGS version 4.0. 
A.3.2.1.2. Single Agent Avelumab 
Dose-DLT data in the avelumab IB8 from study EMR100070-001 as presented in Table 15 
are used to derive the prior of the single agent logistic parameters for avelumab.  Based on 
clinical review, the population of the current study is moderately similar to study 
EMR100070-001.    
Table 15. Historical Dose Limiting Toxicity Data from Study EMR100070-001 
Avelumab dose 
(mg/kg Q2W) 
Number of patients 
Number of patients with DLTs 
1 
4 
0 
3 
3 
0 
10 
6 
0 
20 
6 
1 
Abbreviations: mg=milligram: DLT=dose limiting toxicity; Q2W=every 2 weeks. 
Weakly informative normal priors are assumed for 𝜇𝜇1𝑎𝑎 and 𝜇𝜇2𝑎𝑎, with means corresponding to 
a 50% chance of DLT at avelumab=10 mg/kg, and a doubling in dose leading to a doubling 
in the odds of the risk of a DLT, respectively.  Priors for τ1𝑎𝑎 and τ2𝑎𝑎 are assigned such that 
(1) their medians correspond to moderate between trial heterogeneity, and (2) their 
uncertainty (95% prior interval) cover plausible between-trial standard deviations 
(Neuenschwander 201413).  
The prior distributions for the model used for deriving the MAP priors are specified in Table 
16 below.   
Table 16. Prior Distributions for the Parameters of the MAP Model Used to Derive 
the Prior for the Single-Agent Avelumab Model Parameters 
Parameter 
Prior distribution 
𝜇𝜇1𝑎𝑎 
N(mean = 0, sd = 2) 
𝜇𝜇2𝑎𝑎 
N(mean = 0, sd=1) 
τ1𝑎𝑎 
log-normal(mean = log(0.25), sd = log(2)/1.96) 
τ2𝑎𝑎 
log-normal(mean = log(0.125), sd = log(2)/1.96) 
ρ𝑎𝑎 
uniform(-1,1) 
A.3.2.1.3. Single Agent Binimetinib 
Dose-DLT data in the binimetinib IB2 from studies ARRAY-162-111 and CMEK162X11 as 
presented in Table 17 are used to derive the prior of the single agent logistic parameters for 
binimetinib. 


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Table 17. Historical Dose Limiting Toxicity Data from Studies ARRAY-162-111 and 
CMEK162X1101 
 
Study ARRAY-162-111* 
Study CMEK162X1101* 
Binimetinib dose 
(mg BID) 
Number of 
patients 
Number of patients 
with DLTs 
Number of patients 
Number of 
patients with 
DLTs 
30 
4 
0 
6 
0 
45 
44 
2 
15 
2 
60 
41 
2 
 
 
80 
4 
2 
 
 
Abbreviations: BID=twice a day; DLT=dose limiting toxicity. 
Weakly informative normal priors are assumed for 𝜇𝜇1𝑏𝑏 and 𝜇𝜇2𝑏𝑏, with means corresponding to 
a 50% chance of DLT at avelumab=45 mg, and a doubling in dose leading to a doubling in 
the odds of the risk of a DLT, respectively.  The priors for between-trial heterogeneity 
parameters are set in the following way:   
• Priors for τ11𝑏𝑏 and τ12𝑏𝑏 (ARRAY-162-111) are assigned such that (1) their medians 
correspond to moderate between-trial heterogeneity, and (2) their uncertainty 
(95% prior interval) cover plausible between-trial standard deviations.   
• Priors for τ21𝑏𝑏 and τ22𝑏𝑏 (CMEK162X1101) are assigned such that (1) their medians 
correspond to large between-trial heterogeneity, and (2) their uncertainty (95% prior 
interval) cover plausible between-trial standard deviations.  
Study ARRAY-162-111 is a phase 1 study conducted in advanced or metastatic cancer 
patients the United States.  Study CMEK162X1101 is a study in Japanese patients with 
advanced solid tumors whose disease has progressed despite standard therapy or for whom 
no standard therapy exists.  The patient population in study CMEK162X1101 is less similar 
to study B9991033 and hence large between trial heterogeneity is assumed. 
The prior distributions for the model used for deriving the MAP priors are specified in Table 
18 below.   
Table 18. Prior Distributions for the Parameters of the MAP Model Used to Derive 
the Prior for the Single-Agent Binimetinib Model Parameters 
Parameter 
Prior distribution 
𝜇𝜇1𝑏𝑏 
N(mean = 0, sd =2) 
𝜇𝜇2𝑏𝑏 
N(mean = 0, sd=1) 
τ11𝑏𝑏 
log-normal(mean = log(0.25), sd = log(2)/1.96) 
τ12𝑏𝑏 
log-normal(mean = log(0.125), sd = log(2)/1.96) 
τ21𝑏𝑏 
log-normal(mean = log(1), sd = log(2)/1.96) 
τ22𝑏𝑏 
log-normal(mean = log(0.5), sd = log(2)/1.96) 
ρ𝑏𝑏 
uniform(-1,1) 
(τ11𝑏𝑏,τ12𝑏𝑏) = the degree of between trial heterogeneity for Study ARRAY-162-111; (τ21𝑏𝑏, τ22𝑏𝑏) = the degree of between-
trial heterogeneity for Study CMEK162X1101. 


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A.3.2.1.4. Single Agent Talazoparib 
Dose-DLT data from study PRP-001 (C3441007) (de Bono et al. 2017)6 presented in Table 
19 are used to derive the prior of the single agent logistic parameters for talazoparib. 
Table 19. Historical Dose Limiting Toxicity data from study NCT01286987 
Talazoparib 
dose (mg QD) 
Number of patients 
Number of patients with DLTs 
0.025 
3 
0 
0.05 
3 
0 
0.1 
3 
0 
0.2 
3 
0 
0.4 
3 
0 
0.6 
6 
0 
0.9 
6 
1 
1.0 
6 
0 
1.1 
6 
2 
 
    Abbreviations: DLT=dose limiting toxicity; QD=once daily. 
Weakly informative normal priors are assumed for 𝜇𝜇1𝑡𝑡 and 𝜇𝜇2𝑡𝑡, with means corresponding to 
a 50% chance of DLT at talazoparib=1.0 mg, and a doubling in dose leading to a doubling in 
the odds of the risk of a DLT, respectively.  Priors for τ1𝑡𝑡 and τ2𝑡𝑡 are assigned such that (1) 
their medians correspond to moderate between trial heterogeneity, and (2) their uncertainty 
(95% prior interval) cover plausible between-trial standard deviations.   
Table 20. Prior Distributions for the Parameters of the MAP Model Used to Derive 
the Prior for the Single-Agent Talazoparib Model Parameters 
Parameter 
Prior distribution 
𝜇𝜇1𝑡𝑡 
N(mean = 0, sd = 2) 
𝜇𝜇2𝑡𝑡 
N(mean = 0, sd=1) 
τ1𝑡𝑡 
log-normal(mean = log(0.25), sd = log(2)/1.96) 
τ2𝑡𝑡 
log-normal(mean = log(0.125), sd = log(2)/1.96) 
ρ𝑡𝑡 
uniform(-1,1) 
A.3.2.2. Prior Distribution for the Interaction Parameters 
Based on pharmacometrics assessment, no two-way or three-way drug-drug interaction is 
expected, although uncertainty remains.  Based upon this, normal priors for the log-odds 
multipliers 𝜂𝜂12, 𝜂𝜂13, 𝜂𝜂23,𝜂𝜂123  are used.  All priors are centered on an assumption of no 
drug-drug interaction, but with appropriate uncertainty that allows for both synergistic and 
antagonistic toxicity.  The prior for 𝜂𝜂12, 𝜂𝜂13, 𝜂𝜂23,𝜂𝜂123 are specified as percentiles of increase 
in the odds of DLT due to possible interaction in combination therapy at reference doses; 
𝜂𝜂12 is normally distributed, with mean 0 and sd 0.639 (corresponds to no increase in 
DLT odds at median and 3.5-fold increase in DLTs at 97.5th percentile) 


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𝜂𝜂23 is normally distributed, with mean 0 and sd 0.207 (corresponds to no increase in 
DLT odds at median and 1.5-fold increase in DLTs at 97.5th percentile) 
𝜂𝜂13 is normally distributed, with mean 0 and sd 0.207 (corresponds to no increase in 
DLT odds at median and 1.5-fold increase in DLTs at 97.5th percentile) 
𝜂𝜂123 is normally distributed, with mean 0 and sd 0.025 (corresponds to no increase in DLT 
odds at median and 1.05-fold increase in DLTs at 97.5th percentile). 
A.3.2.3. Summary of Prior Distributions  
The prior distributions of the model parameters are provided in Table 21.  Table 22 and 
Table 23 illustrate the resulting prior distribution of DLT rate derived from the prior given in 
Table 21 for the doublet combination and the triplet combination, respectively.  Based on the 
available information the starting dose avelumab= 10 mg/kg and binimetinib= 45 mg for the 
doublet satisfies the EWOC criteria.  
Table 21. Prior Distribution for the Model Parameters  
Parameter 
Mean 
Standard deviations 
Correlation 
Avelumab single agent parameters: BVN MAP  Prior  
 ൫log(𝛼𝛼1), log(𝛽𝛽1)൯ 
-2.665,-0.056 
0.961, 0.825 
-0.234 
Binimetinib single agent parameters: BVN MAP Prior 
൫log(𝛼𝛼2), log(𝛽𝛽2)൯  
-2.795,  0.313  
0.578,  0.854  
-0.313 
Talazoparib single agent parameters: BVN MAP Prior 
൫log(𝛼𝛼3), log(𝛽𝛽3)൯ 
-1.757, 0.657   
0.727, 0.888 
0.191 
Interaction parameters: Normal prior 
𝜂𝜂12 
0 
0.639 
 
𝜂𝜂13 
0 
0.207 
 
𝜂𝜂23 
0 
0.207 
 
𝜂𝜂123 
0 
0.0249 
 
𝜂𝜂12: Two-way interaction between avelumab and binimetinib; 
𝜂𝜂13: Two-way interaction between avelumab and talazoparib; 
𝜂𝜂23: Two-way interaction between binimetinib and talazoparib; 
𝜂𝜂123: Three-way interaction between avelumab, binimetinib and talazoparib. 
 
Table 22. Summary of Prior Distribution of Dose Limiting Toxicity Rates for the 
Doublet Combination of Avelumab in Combination with Binimetinib 
Binimetinib 
dose (mg 
BID) 
Prior probabilities that DLT rate 
is in the interval: 
Mean 
SD 
Quantiles 
[0, 0.16) 
[0.16, 0.33) 
[0.33,1] 
2.5% 
50% 
97.5% 
 
In combination with  Avelumab =  10 mg/kg, Talazoparib = 0 mg 
30 
0.716 
0.234 
0.050 
0.132 
0.098 
0.022 
0.106 
0.397 
45 
0.598 
0.302 
0.100 
0.165 
0.120 
0.028 
0.133 
0.486 
Abbreviations: BID=twice a day; DLT=dose limiting toxicity; SD=Standard Deviation 


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From Table 23: in absence of doublet data, avelumab= 10mg/kg, binimetinib= 30 mg and 
talazoparib= 0.75 mg is an acceptable starting dose.  However, the final starting dose for the 
triplet will be determined after the dose-DLT data for the doublet combination is available.  
Some hypothetical examples are shown in Table 25.  
Table 23. Summary of Prior Distribution of DLT Rates for the Triplet Combination of 
Avelumab in Combination with Binimetinib and Talazoparib 
Bini 
dose 
(mg 
BID) 
Tala 
dose 
(mg 
QD) 
Prior probabilities that DLT rate is in 
the interval: 
Mean 
SD 
Quantiles 
[0, 0.16) 
[0.16, 0.33) 
[0.33,1] 
2.5% 
50% 
97.5% 
30 
0.5 
0.522 
0.374 
0.104 
0.180 
0.113 
0.036 
0.154 
0.465 
30 
0.75 
0.383 
0.447 
0.170 
0.217 
0.123 
0.050 
0.193 
0.521 
30 
1.0 
0.212 
0.464 
0.324 
0.282 
0.142 
0.074 
0.258 
0.614 
45 
0.5 
0.438 
0.385 
0.177 
0.211 
0.137 
0.038 
0.180 
0.557 
45 
0.75 
0.334 
0.412 
0.254 
0.248 
0.149 
0.048 
0.217 
0.610 
45 
1.0 
0.208 
0.395 
0.397 
0.309 
0.169 
0.066 
0.281 
0.694 
Avelumab dose fixed at 10 mg/kg every 2 weeks.  
Abbreviations: BID=twice a day; Bini=Binimetinib; QD=once daily; SD=Standard Deviation; Tala=Talazoparib 
A.3.3. Hypothetical on-Study Data Scenarios 
To illustrate the performance of the Bayesian model used to guide dose finding, hypothetical 
dose finding scenarios following the provisional dose levels specified in the protocol are 
displayed.  In each case, the possible recommended dose that can be used in the next cohort 
of patients is shown.  These recommended doses are determined using the model-based 
assessment of the risk of DLT in future patients, EWOC criteria and maximum amount of 
escalation allows (100% of current dose).  In practice, the dose recommended by the adaptive 
Bayesian logistic model may be regarded as guidance.  The final recommendation will be 
based on overall safety profile and PK data. 
Table 24 shows some hypothetical dose escalation data scenarios for the doublet combination 
and the corresponding recommendations for the next dose.  For example, in Scenario 1, if no 
DLT is observed among 3 DLT-evaluable patients at the starting dose, the recommendation 
is to remain at the same dose level with probability of overdosing of 0.03.  Note that the 
starting dose is already the maximum possible dose for the doublet combination.  In Scenario 
3, if 2 patients experience a DLT out of 3 DLT-evaluable patients at the starting dose, the 
recommendation is to de-escalate the dose of binimetinib to 30 mg with avelumab remaining 
at 10 mg/kg; this lower dose combination has a probability of overdosing of 0.21.  Scenarios 
2, 4, 5 and 6 show clinically plausible next dose recommendations. 
 
 
 


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Table 24. Doublet Combination: Data Scenarios, Next Dose Recommendation, and the 
Interval Probability of Target Toxicity and Overdosing at Next Dose. 
 
Dose Evaluated 
 
 
D/N* 
Next Dose (ND)   
Pr(TT) 
at ND 
Pr(OD) 
at ND 
Scenarios 
Ave 
(mg/kg 
Q2W) 
Bini 
(mg 
BID) 
Tala 
mg 
(QD) 
Ave 
(mg/kg 
Q2W) 
Bini 
(mg 
BID) 
Tala 
(mg 
QD) 
 
 
1 
(10) 
45 
- 
0/3 
(10) 
45 
- 
0.231 
0.031 
2 
(10) 
45 
- 
1/3 
(10) 
45 
- 
0.422 
0.133 
3 
(10) 
45 
- 
2/3 
(10) 
30 
- 
0.465 
0.212 
4 
(10) 
45 
- 
2/6 
(10) 
45 
- 
0.507 
0.170 
5 
(10) 
45 
- 
3/6 
(10) 
30 
- 
0.528 
0.198 
6 
(10) 
45 
- 
3/6 
(10) 
30 
- 
0.580 
0.225 
 
(10) 
30 
- 
1/3 
 
 
 
 
 
Abbreviations: Ave=avelumab; BID=twice a day; Bini=Binimetinib; *D=number of patients with DLT, N=number of DLT-
evaluable patients; ND=next dose; Pr(TT)=probability of target toxicity; Pr(OD)=probability of overdosing; 
Tala=Talazoparib; QD=once daily; Q2W=every 2 weeks. 
Table 25 shows the plausible starting dose level(s) for the triplet combinations given 
hypothetical data from the doublet combination.  If the dose-DLT profile of the doublet is 
safe at avelumab= 10mg/kg, binimetinib= 45mg (Scenarios 1 and 2), triplet dose escalation 
can begin at avelumab= 10mg/kg, binimetinib= 45mg and talazoparib= 0.75mg.  If 2-3 
patients with DLT observed out of 12 DLT-evaluable patients at avelumab= 10mg/kg, 
binimetinib= 45mg, the starting dose will be avelumab= 10mg/kg, binimetinib= 30mg and 
talazoparib= 0.75mg (Scenarios 3 and 4). 
Table 25. Triplet Combination: Clinically Meaningful Starting Dose Given 
Hypothetical Data from the Doublet Combination, and the Interval 
Probability of Target Toxicity and Overdosing at Starting Dose. 
 
Doublet Dose  
 
 
D/N* 
Triplet starting dose (SD)  
Pr(TT) at 
SD 
Pr(OD)  
at SD 
Scenarios 
Ave 
(mg/kg 
Q2W) 
Bini 
(mg 
BID) 
Tala 
(mg 
QD) 
Ave 
(mg/kg 
Q2W) 
Bini 
(mg 
BID
) 
Tala 
(mg 
QD) 
 
 
1 
(10) 
45 
- 
0/9 
(10) 
45 
0.75 
0.354 
0.070 
2 
(10) 
45 
- 
1/12 
(10) 
45 
0.75 
0.449 
0.113 
3 
(10) 
45 
- 
2/12 
(10) 
30 
0.75 
0.544 
0.125 
4 
(10) 
45 
- 
3/12 
(10) 
30 
0.75 
0.586 
0.217 
Abbreviations: Ave=avelumab; BID=twice a day; Bini=Binimetinib; *D=number of patients with DLT, N=number of DLT-
evaluable patients; ND=next dose; Pr(TT)=probability of target toxicity; Pr(OD)=probability of overdosing; Tala= 
Talazoparib;  
Table 26 shows data scenarios for the triplet combination and the corresponding 
recommendations for the next dose. 


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Table 26. Triplet Combination: Data Scenarios (Given Hypothetical Doublet Data), 
Next Dose Recommendation, and the Interval Probability of Target Toxicity 
and Overdosing at Next Dose. 
 
Dose evaluated  
 
 
D/N* 
Next Dose (ND) 
Pr(TT) 
at ND 
Pr(OD) at 
ND 
Scenarios 
Ave  
(mg/kg 
Q2W) 
Bini 
(mg 
BID
) 
Tala 
(mg 
QD) 
Ave  
(mg/k
g 
Q2W) 
Bini 
(mg 
BID
) 
Tala 
(mg 
QD) 
 
 
1 
(10) 
45 
- 
0/9 
(10) 
45 
1.0 
0.408 
0.103 
  
(10) 
45 
0.75 
0/3 
 
 
 
 
 
2 
(10) 
45 
- 
0/9 
(10) 
45 
0.75 
0.463 
0.099 
  
(10) 
45 
0.75 
1/3 
 
 
 
 
 
3 
(10) 
45 
- 
0/9 
(10) 
30 
0.75 
0.572 
0.172 
 
(10) 
45 
0.75 
2/3 
 
 
 
 
 
4 
(10) 
45 
- 
0/9 
(10) 
 30 
0.5  
0.566 
0.170 
 
(10) 
45 
0.75 
3/3 
 
 
 
 
 
5 
(10) 
45 
- 
3/12 
(10) 
45 
0.75 
0.571 
0.225 
 
(10) 
30 
0.75 
0/3 
 
 
 
 
 
6 
(10) 
45 
- 
3/12 
(10) 
 30 
0.75  
 0.617 
0.239 
 
(10) 
30 
0.75 
1/3 
 
 
 
 
 
7 
(10) 
45 
- 
3/12 
(10) 
 30 
0.5  
0.624 
0.249 
 
(10) 
30 
0.75 
2/3 
 
 
 
 
 
Abbreviations: Ave=avelumab; BID=twice a day; Bini=Binimetinib; *D=number of patients with DLT; N=number of DLT-
evaluable patients; ND=next dose Pr(TT)=probability of target toxicity; Pr(OD)=probability of overdosing; QD=once daily; 
Q2W=every 2 weeks; Tala=Talazoparib.    
Based on Table 24 and Table 26, the recommended next dose is adequate for all considered 
scenarios.  
A.3.4. Operating Characteristics  
A simulation study is used to illustrate the properties of the dose finding model guided by 
BLRM.  Several example scenarios were investigated (Appendix 3.4.1) and in each scenario 
1000 trials were simulated, with results summarized in Appendix 3.4.3. 
A.3.4.1. Simulation Scenarios  
Several scenarios are considered for doublet and triplet combinations.  Scenario 1 represents 
the case when the distribution of DLT coincides with prior, ie, the true DLT probability 
equals to mean of prior DLT.  Scenarios 2-3 of the doublet combination and scenarios 2-3 of 
the triplet combination represent an increased DLT rate compared to Scenario 1.  The true 
DLT rates under different scenarios for doublet and triplet combinations are shown in Table 
27 and Table 28, respectively.  Scenario 4 in Table 28 represents a true toxicity profile with 
dose combinations in both under-dose and over-dose regions. 


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Table 27. Doublet Combination: Dose Limiting Toxicity Rate Scenarios (Fixed 
Avelumab Dose 10mg/kg Every 2 Weeks) 
 
Scenarios  
Binimetinib (mg BID) 
30 
45 
1.    Prior means 
0.132 
0.165 
2.   50% more toxic 
0.199 
0.248 
3.   Higher dose is overly toxic 
0.200 
0.400 
Abbreviations: BID=twice a day; mg=milligramme 
Table 28. Triplet Combination: Dose Limiting Toxicity Rate Scenarios (Fixed 
Avelumab Dose 10mg/kg Every 2 Weeks) 
 
Binimetinib (mg 
BID) 
Talazoparib (mg QD) 
0.5 
0.75 
1.0 
0.5 
0.75 
1.0 
 
Scenario 1. prior means 
Scenario 2. 25% more toxic 
30 
0.180 
0.217 
0.282 
0.225 
0.272 
0.352 
45 
0.211 
0.248 
0.309 
0.264 
0.310 
0.387 
 
Scenario 3. 50% more toxic 
Scenario 4. With underdose and 
overdose 
30 
0.270 
0.326 
0.423 
0.05 
0.15 
0.35 
45 
0.317 
0.372 
0.464 
0.10 
0.25 
0.50 
Abbreviations: BID=twice a day; QD=once daily; Q2W=every 2 weeks. 
A.3.4.2. Simulation Details  
Simulations were performed using R version 3.3.2 (The R-project for Statistical Computing.  
https://www.r-project.org/), and JAGS 4.0 to perform the MCMC analyses.  
For each scenario, data for 1000 trials were generated, with a cohort size of 3.  At any time 
during the course of dose finding, escalation to doses where the risk of overdose exceeds 
25% is not permitted.  The ‘next dose recommendation’ is the dose with maximum 
probability of overdose among all dose levels that meet the EWOC criteria. 
For the doublet combination, the starting dose was avelumab 10 mg/kg (fixed) and 
binimetinib 45 mg.  The maximum number of patients per trial was set to 30.  The trial was 
stopped when the following criteria were met: 
1. At least 6 patients have been treated at the recommended MTD 𝑑𝑑̃. 
2. The dose 𝑑𝑑̃ satisfies one of the following conditions: 
• The probability of target toxicity at dose 𝑑𝑑̃ exceeds 50%, 
ie, Pr(0.16 ≤ 𝜋𝜋𝑑𝑑෨ <0.33)≥50%;  
• A minimum of 9 patients have been treated in the trial; 


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A simulation of the triplet combination is performed using the starting dose of avelumab 
10 mg/kg , binimetinib 30mg, and talazoparib 0.5mg.  No doublet combination data is 
considered in this exercise.  The maximum number of patients per trial was set to 60.  Each 
trial was stopped when the following criteria were met: 
1. At least 6 patients have been treated at the recommended MTD 𝑑𝑑̃. 
2. The dose 𝑑𝑑̃ satisfies one of the following conditions: 
• The probability of target toxicity at dose 𝑑𝑑̃ exceeds 50%, 
ie, Pr(0.16 ≤ 𝜋𝜋𝑑𝑑෨ <0.33)≥50%; 
• A minimum of 15 patients have been treated in the trial. 
The following metrics were assessed in the simulations: 
1. Percentage of patients receiving dose combination(s) in the target toxicity interval;  
2. Percentage of patients receiving an overdose; 
3. Percentage of patients receiving an underdose; 
4. Probability that recommended MTD at the end of the trial is in the target toxicity 
interval; 
5. Probability that recommended MTD is an overdose; 
6. Probability that recommended MTD is an underdose; 
7. Percentage of trials stopped without MTD declaration; 
8. Average sample size. 
A.3.4.3. Simulation Results  
Operating characteristics for the doublet and the triplet combinations are presented in Table 
29 and Table 30, respectively.  The percentage of trials with a correctly identified MTD 
ranges from 67.4% to 99%.  Furthermore, the percentage of patients treated at overly toxic 
doses is well controlled.  The average sample size for the doublet combination is between 
9 and 11 patients, and the average sample size for the triplet combination is between 9 to 
17 patients. 
Table 29. Doublet Combination: Operating Characteristics  
 
Scenarios  
Patient allocation (%) 
Pr (declare MTD) 
% stop (no 
MTD) 
Average 
sample 
size 
TT 
OD 
UD 
TT 
OD 
UD 
1.    Prior means 
95.7 
0 
4.3 
0.927 
0 
0 
7.3 
9 
2.   50% more toxic 
100 
0 
0 
0.857 
0 
0 
14.3 
9 
3.   Higher dose level 
is overly toxic 
48.6 
51.4 
0 
0.674 
0 
0 
32.6 
11 
Abbreviations: MTD=maximum tolerated dose: OD=overdose; TT=target toxicity; UD=underdose;  


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Table 30. Triplet Combination: Operating Characteristics  
 
Scenarios  
Patient allocation 
(%) 
Pr (declare MTD) 
% stop (no 
MTD) 
Average 
sample size 
TT 
OD 
UD 
TT 
OD 
UD 
1.  Prior means 
100 
0 
0 
0.922 
0 
0 
7.8 
14 
2.  25% more toxic 
83.6 
16.4 
0 
0.877 
0 
0 
12.3 
13 
3. 50% more toxic 
89.6 
10.4 
0 
0.831 
0 
0 
16.9 
9 
4. With underdose 
and overdose 
35.0 
28.9 
36.0 
0.990 
0 
0 
1.0 
17 
Abbreviations: MTD=maximum tolerated dose; OD=overdose; TT=target toxicity; UD=underdose;  
 


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Appendix 4. Detailed Dose Escalation/De-escalation Scheme for BLRM Design -per 
implementation of Protocol Amendment 3. 
This appendix provides the details of the statistical model, the derivation of prior 
distributions using historical data, analyses and respective dosing decisions for some 
hypothetical data scenarios, and a simulation study to evaluate the long-run operating 
characteristics for the model based dose-escalation of the binimetinib (7 days on/7 days off, 
7d/7d) + talazoparib doublet and the avelumab + binimetinib (7d/7d) + talazoparib triplet 
combinations.  If the binimetinib 5 days on/2 days off (5d/2d) dosing schedule is explored 
upon the completion of the binimetinib (7d/7d) + talazoparib doublet, the prior distributions 
of the model parameters for the binimetinib 5d/2d dosing schedule will be adjusted 
appropriately to account for new information prior to the initiation.   
Note that the fixed dose of 800 mg to be investigated in this study is expected to be 
equivalent to the 10 mg/kg dose. 
A.4.1 Statistical Model 
The statistical model comprises single-agent toxicity parts, which allow the incorporation of 
single-agent toxicity data, and interaction parts. 
A.4.1.1 Single Agent Parts  
Let 𝜋𝜋1(𝑑𝑑1) be the risk of DLT for talazoparib given as a single agent at dose 𝑑𝑑1; 𝜋𝜋2(𝑑𝑑2) be 
the risk of DLT for binimetinib given as a single agent at dose 𝑑𝑑2; and 𝜋𝜋3(𝑑𝑑3) be the risk of 
DLT for avelumab given as a single agent at dose 𝑑𝑑3.  These single agent dose-DLT models 
are logistic: 
talazoparib: 
logit൫𝜋𝜋1(𝑑𝑑1)൯ =  log(𝛼𝛼1) + 𝛽𝛽1 log(𝑑𝑑1 𝑑𝑑1
∗
⁄
) 
binimetinib: 
logit൫𝜋𝜋2(𝑑𝑑2)൯ =  log(𝛼𝛼2) + 𝛽𝛽2 log(𝑑𝑑2 𝑑𝑑2
∗
⁄
) 
avelumab: 
logit൫𝜋𝜋3(𝑑𝑑3)൯ =  log(𝛼𝛼3) + 𝛽𝛽3 log(𝑑𝑑3 𝑑𝑑3
∗
⁄
) 
where 𝑑𝑑1
∗=1.0 mg, 𝑑𝑑2
∗ =45 mg, and 𝑑𝑑3
∗= 10 mg/kg are used to scale the doses of talazoparib, 
binimetinib, and avelumab, respectively.  Hence, 𝛼𝛼1,  𝛼𝛼2 , and 𝛼𝛼3 (all >0) are the single-agent 
odds of a DLT at 𝑑𝑑1
∗ mg, 𝑑𝑑2
∗ mg, and 𝑑𝑑3
∗mg/kg, respectively; and 𝛽𝛽1, 𝛽𝛽2, and 𝛽𝛽3(>0) are the 
increase in the log-odds of a DLT by a unit increase in log-dose. 
A.4.1.2 Interaction Parts 
Under an assumption that there is no interaction, the risk of a DLT at dose 𝑑𝑑1 of talazoparib, 
dose 𝑑𝑑2 of binimetinib, and dose 𝑑𝑑3 of avelumab is: 
𝜋𝜋123
0 (𝑑𝑑1,𝑑𝑑2,𝑑𝑑3) = 1 − ൫1 −𝜋𝜋1(𝑑𝑑1)൯൫1 −𝜋𝜋2(𝑑𝑑2)൯൫1 −𝜋𝜋3(𝑑𝑑3)൯ 


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To model the interaction between talazoparib, binimetinib, and avelumab, the following four 
odds multipliers are introduced. 
• 𝜂𝜂12: two-way interaction between talazoparib and binimetinib. 
• 𝜂𝜂13: two-way interaction between talazoparib and avelumab. 
• 𝜂𝜂23: two-way interaction between binimetinib and avelumab. 
• 𝜂𝜂123: three-way interaction among talazoparib, binimetinib and avelumab. 
The risk of DLT for combination dose (𝑑𝑑1, 𝑑𝑑2,𝑑𝑑3) is then given by: 
odds൫𝜋𝜋123(𝑑𝑑1, 𝑑𝑑2,𝑑𝑑3)൯= 𝑔𝑔(𝜂𝜂12, 𝜂𝜂13, 𝜂𝜂23,𝜂𝜂123) × odds൫𝜋𝜋123
0 (𝑑𝑑1, 𝑑𝑑2,𝑑𝑑3)൯ 
𝑔𝑔(𝜂𝜂12, 𝜂𝜂13, 𝜂𝜂23,𝜂𝜂123) =   exp(𝜂𝜂12 × 𝑑𝑑1 𝑑𝑑1
∗
⁄
× 𝑑𝑑2 𝑑𝑑2
∗
⁄
) 
                                                                × exp ( 𝜂𝜂13 × 𝑑𝑑1 𝑑𝑑1
∗
⁄
× 𝑑𝑑3 𝑑𝑑3
∗)
⁄
 
                                                                × exp (𝜂𝜂23 × 𝑑𝑑2 𝑑𝑑2
∗
⁄
× 𝑑𝑑3 𝑑𝑑3
∗)
⁄
 
                                                              × exp (𝜂𝜂123 × 𝑑𝑑1 𝑑𝑑1
∗
⁄
× 𝑑𝑑2 𝑑𝑑2
∗
⁄
× 𝑑𝑑3 𝑑𝑑3
∗
⁄
) 
where odds(𝜋𝜋) = 𝜋𝜋(1 −𝜋𝜋)
⁄
; 𝜂𝜂𝑖𝑖𝑖𝑖 is the log-odds ratio between the interaction and no 
interaction model at the reference doses of drug i and j and a zero dose of the third drug.  For 
example, 𝜂𝜂12 is the log-odds ratio between the interaction and no interaction model at 
talazoparib=1.0mg, binimetinib= 45 mg, and avelumab=0 mg.  Therefore, 𝜂𝜂12 + 𝜂𝜂13 + 𝜂𝜂23 +
𝜂𝜂123 is the log-odds ratio between the interaction and no interaction model at the reference 
doses for all three drugs.  Here 𝜂𝜂= 0 corresponds to no interaction, with 𝜂𝜂> 0 and 𝜂𝜂< 0 
representing synergistic and antagonistic toxicity respectively. 
The dose-DLT data of the doublet combination of talazoparib and binimetinib (7d/7d) will be 
modeled using the same model by setting the avelumab dose 𝑑𝑑3 = 0 mg/kg.  The model will 
contain parameters related to single agent effects of talazoparib (log(𝛼𝛼1), log(𝛽𝛽1)), 
binimetinib (log(𝛼𝛼2), log(𝛽𝛽2)), and the interaction between talazoparib and binimetinib 
(𝜂𝜂12). 
A.4.2 Prior Specifications 
The Bayesian approach requires the specification of prior distributions for all model 
parameters, which include the single agent parameters log(𝛼𝛼1), log(𝛽𝛽1) for talazoparib, 
log(𝛼𝛼2), log(𝛽𝛽2) for binimetinib, log(𝛼𝛼3), log(𝛽𝛽3) for avelumab, and the interaction 
parameters 𝜂𝜂= (𝜂𝜂12, 𝜂𝜂13, 𝜂𝜂23,𝜂𝜂123).  A meta-analytic-predictive (MAP) approach was used 
to derive the prior distribution for the single-agent model parameters.  


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A.4.2.1 Prior Distribution for the Logistic Parameters for Single Agent 
This section illustrates the derivation of prior distributions for single agent model parameters 
(log(𝛼𝛼𝑠𝑠), log(𝛽𝛽𝑠𝑠))’s using the available single agent dose-DLT information via a MAP 
approach.   
A.4.2.1.1 Description of the Meta-Analytic-Predictive Approach 
The aim of the MAP approach is to derive a prior distribution for the logistic parameters 
൫log(𝛼𝛼∗),  log(𝛽𝛽∗)൯ of the new trial using DLT data from historical studies.  Let 𝑟𝑟𝑑𝑑𝑑𝑑 and 𝑛𝑛𝑑𝑑𝑑𝑑 
be the number of patients with a DLT, and the total number of patients at dose 𝑑𝑑 in historical 
trial 𝑠𝑠 (𝑠𝑠= 1, …, 〈𝑆𝑆〉).  The corresponding probability of a DLT is 𝜋𝜋𝑑𝑑𝑑𝑑.  The model 
specifications are as follows: 
𝑟𝑟𝑑𝑑𝑑𝑑 | 𝜋𝜋𝑑𝑑𝑑𝑑 ~ Bin(𝜋𝜋𝑑𝑑𝑑𝑑,𝑛𝑛𝑑𝑑𝑑𝑑) 
logit(𝜋𝜋𝑑𝑑𝑑𝑑) = log(𝛼𝛼𝑠𝑠) + 𝛽𝛽𝑠𝑠 log(𝑑𝑑/𝑑𝑑∗) 
 ൫𝑙𝑙𝑙𝑙𝑙𝑙(𝛼𝛼𝑠𝑠), 𝑙𝑙𝑙𝑙𝑙𝑙(𝛽𝛽𝑠𝑠)൯ ห 𝜇𝜇, 𝜓𝜓𝑔𝑔(𝑠𝑠) ~ BVN൫𝜇𝜇, 𝜓𝜓𝑔𝑔(𝑠𝑠)൯,
s = 1,… , 〈𝑆𝑆〉 
൫𝑙𝑙𝑙𝑙𝑙𝑙(𝛼𝛼∗), 𝑙𝑙𝑙𝑙𝑙𝑙(𝛽𝛽∗)൯ ห 𝜇𝜇, 𝜓𝜓𝑔𝑔 (∗) ~ BVN൫𝜇𝜇, 𝜓𝜓𝑔𝑔 (∗)൯ 
The historical trials are partitioned into 〈𝐺𝐺〉 exchangeability groups, with the exchangeability 
group membership of historical trial 𝑠𝑠 being represented by 𝑔𝑔(𝑠𝑠).  The new trial is assigned 
to exchangeability group 𝑔𝑔(∗).  The parameter 𝜇𝜇 = (𝜇𝜇1,𝜇𝜇2)  is the mean for the logistic 
parameters, and 𝜓𝜓𝑔𝑔 is the between-trial covariance matrix for exchangeability group 𝑔𝑔=
1, … ,〈𝐺𝐺〉.  Covariance matrix 𝜓𝜓𝑔𝑔 is defined by the standard deviations (τ𝑔𝑔1, τ𝑔𝑔2), and 
correlation ρ (a common value for ρ is used across all groups).  The parameters τ𝑔𝑔1 and τ𝑔𝑔2 
quantify the degree of between trial heterogeneity for exchangeability group 𝑔𝑔.  With 
different prior distributions for the parameter sets ൫τ𝑔𝑔1,τ𝑔𝑔2൯ it is possible to allow for 
differential discounting for the historical strata.  In this way the quality and relevance of 
historical data can be accounted for in the meta-analysis.  The following priors will be used 
for these parameters:   
• normal priors for 𝜇𝜇1 and 𝜇𝜇2,  
• log-normal priors for τ𝑔𝑔1 and τ𝑔𝑔2, and  
• a uniform prior for ρ. 
The MAP prior for single-agent model parameters in the new trial, ൫𝑙𝑙𝑙𝑙𝑙𝑙(𝛼𝛼∗), 𝑙𝑙𝑙𝑙𝑙𝑙(𝛽𝛽∗)൯, is the 
predictive distribution  
൫𝑙𝑙𝑙𝑙𝑙𝑙(𝛼𝛼∗), 𝑙𝑙𝑙𝑙𝑙𝑙(𝛽𝛽∗)൯ ห (𝑟𝑟𝑑𝑑𝑑𝑑, 𝑛𝑛𝑑𝑑𝑑𝑑∶𝑠𝑠= 1, …, 〈𝑆𝑆〉) 


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Since the predictive distribution is not available analytically, the Markov chain Monte Carlo 
(MCMC) method is used to simulate values from this distribution.  This is implemented 
using JAGS version 4.0. 
A.4.2.1.2 Single Agent Talazoparib 
Dose-DLT data from study PRP-001 (C3441007) (de Bono et al. 2017)6 presented in Table 
31 are used to derive the prior of the single agent logistic parameters for talazoparib. 
Table 31. Historical Dose Limiting Toxicity data from study NCT01286987 
Talazoparib dose 
(mg QD) 
Number of patients 
Number of patients with DLTs 
0.025 
3 
0 
0.05 
3 
0 
0.1 
3 
0 
0.2 
3 
0 
0.4 
3 
0 
0.6 
6 
0 
0.9 
6 
1 
1.0 
6 
0 
1.1 
6 
2 
Abbreviations: DLT=dose-limiting toxicity; QD=once daily; mg=milligram. 
 
Weakly informative normal priors are assumed for 𝜇𝜇1𝑡𝑡 and 𝜇𝜇2𝑡𝑡, with means corresponding to 
a 50% chance of DLT at talazoparib=1.0 mg, and a doubling in dose leading to a doubling in 
the odds of the risk of a DLT, respectively.  Priors for τ1𝑡𝑡 and τ2𝑡𝑡 are assigned such that (1) 
their medians correspond to moderate between trial heterogeneity, and (2) their uncertainty 
(95% prior interval) cover plausible between-trial standard deviations.  The prior 
distributions for the model used for deriving the MAP priors for talazoparib are specified in 
Table 32 below.   
Table 32. Prior Distributions for the Parameters of the MAP Model Used to Derive 
the Prior for the Single-Agent Talazoparib Model Parameters 
Parameter 
Prior distribution 
𝜇𝜇1𝑡𝑡 
N(mean = 0, sd = 2) 
𝜇𝜇2𝑡𝑡 
N(mean = 0, sd=1) 
τ1𝑡𝑡 
log-normal(mean = log(0.25), sd = log(2)/1.96) 
τ2𝑡𝑡 
log-normal(mean = log(0.125), sd = log(2)/1.96) 
ρ𝑡𝑡 
uniform(-1,1) 


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A.4.2.1.3. Single Agent Binimetinib  
A.4.2.1.3.1. Single Agent Binimetinib (Intermittent Dosing) 
No prior Dose-DLT data are available for an intermittent binimetinib dosing schedule. 
Therefore, a mixture of bivariate normal prior is used for (log(α2), log(β2).  The 
components are:  
a. Meta-analysis predictive prior using continuous regimen data for binimetinib. 
b. Weakly informative prior considering higher toxicity that has been observed in the 
continuous regimen. 
A.4.2.1.3.1. Single Agent Binimetinib (Continuous Dosing) 
Dose-DLT data in the binimetinib IB2 from studies ARRAY-162-111 and CMEK162X11 
(continuous dosing schedule) as presented in Table 33 are used to derive the MAP priors of 
the single agent logistic parameters for continuous binimetinib. 
Table 33. Historical Dose Limiting Toxicity Data from Studies ARRAY-162-111 and 
CMEK162X1101 
 
Study ARRAY-162-111* 
Study CMEK162X1101* 
Binimetinib 
dose (mg BID) 
Number of 
patients 
Number of patients 
with DLTs 
Number of patients 
Number of 
patients with 
DLTs 
30 
4 
0 
6 
0 
45 
44 
2 
15 
2 
60 
41 
2 
 
 
80 
4 
2 
 
 
Abbreviations: BID=twice a day; DLT=dose-limiting toxicity; mg=milligram. 
Weakly informative normal priors are assumed for 𝜇𝜇1𝑏𝑏 and 𝜇𝜇2𝑏𝑏, with means corresponding to 
a 50% chance of DLT at binimetinib=45 mg, and a doubling in dose leading to a doubling in 
the odds of the risk of a DLT, respectively.  The priors for between-trial heterogeneity 
parameters are set in the following way:   
• Priors for τ11𝑏𝑏 and τ12𝑏𝑏 (ARRAY-162-111) are assigned such that (1) their medians 
correspond to moderate between-trial heterogeneity, and (2) their uncertainty 
(95% prior interval) cover plausible between-trial standard deviations.   
• Priors for τ21𝑏𝑏 and τ22𝑏𝑏 (CMEK162X1101) are assigned such that (1) their medians 
correspond to large between-trial heterogeneity, and (2) their uncertainty (95% prior 
interval) cover plausible between-trial standard deviations.  


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Study ARRAY-162-111 is a phase 1 study conducted in advanced or metastatic cancer 
patients the United States.  Study CMEK162X1101 is a study in Japanese patients with 
advanced solid tumors whose disease has progressed despite standard therapy or for whom 
no standard therapy exists.  The patient population in study CMEK162X1101 is less similar 
to study B9991033 and hence large between trial heterogeneity is assumed. 
The prior distributions for the model used for deriving the MAP priors for binimetinib are 
specified in Table 34 below. 
Table 34. Prior Distributions for the Parameters of the MAP Model Used to Derive 
the Prior for the Single-Agent Binimetinib Model Parameters 
Parameter 
Prior distribution 
𝜇𝜇1𝑏𝑏 
N(mean = 0, sd =2) 
𝜇𝜇2𝑏𝑏 
N(mean = 0, sd=1) 
τ11𝑏𝑏 
log-normal(mean = log(0.25), sd = log(2)/1.96) 
τ12𝑏𝑏 
log-normal(mean = log(0.125), sd = log(2)/1.96) 
τ21𝑏𝑏 
log-normal(mean = log(1), sd = log(2)/1.96) 
τ22𝑏𝑏 
log-normal(mean = log(0.5), sd = log(2)/1.96) 
ρ𝑏𝑏 
uniform(-1,1) 
(τ11𝑏𝑏, τ12𝑏𝑏) = the degree of between trial heterogeneity for Study ARRAY-162-111; (τ21𝑏𝑏, τ22𝑏𝑏) = the degree of between-
trial heterogeneity for Study CMEK162X1101. 
A.4.2.1.3.2. Weakly Informative Prior for Binimetinib (7d/7d) Regimen 
Higher DLT rates were observed in the avelumab + binimetinib doublet combination than 
that observed in historical binimetinib studies. To account for uncertainty, mixture priors of 
the MAP prior and a weakly informative prior were used for the binimetinib 7d/7d regimen 
single agent model parameters. The default weakly informative multivariate normal (MVN) 
prior of (log(α) and log(β)) is used where (mean1, mean2, standard deviation1, standard 
deviation2, correlation) = (logit(p*), 0, 2, 1, 0).  Where p* is the anticipated DLT rate at the 
scaling dose 45 mg.  Based on historical continuous binimetinib data, the apriori probability 
of DLT at the reference dose 45 mg is exp(-2.795)/(1+exp(-2.795)) ~= 6%.  We used a prior 
of doubling the DLT rate (12%) at the reference dose, ie. (mean1, mean2, standard deviation1, 
standard deviation2, correlation) =(logit(0.12), 0, 2, 1, 0) = (-1.992, 0, 2, 1, 0). 
Apriori 50% weights are assigned to MAP prior and weakly informative priors respectively. 
A.4.2.1.4. Single Agent Avelumab 
Dose-DLT data in the avelumab IB8 from study EMR100070-001 as presented in Table 35 
are used to derive the prior of the single agent logistic parameters for avelumab.  Based on 
clinical review, the population of the current study is moderately similar to study 
EMR100070-001.    


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Table 35. Historical Dose Limiting Toxicity Data from Study EMR100070-001 
Avelumab dose 
(mg/kg Q2W) 
Number of patients 
Number of patients with DLTs 
1 
4 
0 
3 
3 
0 
10 
6 
0 
20 
6 
1 
Abbreviations: mg=milligram: DLT=dose-limiting toxicity; Q2W=every 2 weeks. 
 
Weakly informative normal priors are assumed for 𝜇𝜇1𝑎𝑎 and 𝜇𝜇2𝑎𝑎, with means corresponding to 
a 50% chance of DLT at avelumab=10 mg/kg, and a doubling in dose leading to a doubling 
in the odds of the risk of a DLT, respectively.  Priors for τ1𝑎𝑎 and τ2𝑎𝑎 are assigned such that 
(1) their medians correspond to moderate between trial heterogeneity, and (2) their 
uncertainty (95% prior interval) cover plausible between-trial standard deviations 
(Neuenschwander 2014).    
The prior distributions for the model used for deriving the MAP priors are specified in 
Table 36 below.   
Table 36. Prior Distributions for the Parameters of the MAP Model Used to Derive 
the Prior for the Single-Agent Avelumab Model Parameters 
Parameter 
Prior distribution 
𝜇𝜇1𝑎𝑎 
N(mean = 0, sd = 2) 
𝜇𝜇2𝑎𝑎 
N(mean = 0, sd=1) 
τ1𝑎𝑎 
log-normal(mean = log(0.25), sd = log(2)/1.96) 
τ2𝑎𝑎 
log-normal(mean = log(0.125), sd = log(2)/1.96) 
ρ𝑎𝑎 
uniform(-1,1) 
 
A.4.2.2. Prior Distribution for the Interaction Parameters 
Normal priors for the log-odds multipliers 𝜂𝜂12, 𝜂𝜂13, 𝜂𝜂23,𝜂𝜂123  are used.  Based on 
pharmacometrics assessment, no drug-drug interaction between avelumab and talazoparib 
and between binimetinib and talazoparib, or three-way drug-drug interaction is expected, 
although uncertainty remains.  The priors for these interactions are centered on an 
assumption of no drug-drug interaction, but with appropriate uncertainty that allows for both 
synergistic and antagonistic toxicity.  Based on the data from continuous binimetinib and 
avelumab doublet combination in B9991033, synergistic interaction between these two drugs 
is expected.  The prior for 𝜂𝜂12, 𝜂𝜂13, 𝜂𝜂23,𝜂𝜂123 are specified as percentiles of increase in the 
odds of DLT due to possible interaction in combination therapy at reference doses; 


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𝜂𝜂12 is normally distributed, with mean 0 and sd 0.207 (corresponds to no increase in 
DLT odds at median and 1.5 fold increase in DLTs at 97.5th percentile). 
𝜂𝜂13 is normally distributed, with mean 0 and sd 0.207 (corresponds to no increase in 
DLT odds at median and 1.5 fold increase in DLTs at 97.5th percentile). 
𝜂𝜂23 is normally distributed, with mean 0.140 and sd 0.636 (corresponds to 15% 
increase in DLT odds at median and 4-fold increase in DLTs at 97.5th percentile)𝜂𝜂123 
is normally distributed, with mean 0 and sd 0.025 (corresponds to no increase in DLT 
odds at median and 1.05 fold increase in DLTs at 97.5th percentile). 
𝜂𝜂12: Two-way interaction between talazoparib and binimetinib; 
𝜂𝜂13: Two-way interaction between talazoparib and avelumab; 
𝜂𝜂23: Two-way interaction between binimetinib and avelumab; 
𝜂𝜂123: Three-way interaction among talazoparib, binimetinib and avelumab. 
A.4.2.3. Use of Dose-DLT Data from B9991025 Study 
In this appendix, data from study B9991025 for the combination of avelumab and talazoparib 
was incorporated in the prior distribution of the DLT, feasible starting dose assessment, data 
scenarios and simulations for the avelumab + binimetinib (7d/7d) + talazoparib triplet.  
Based on the preliminary data from the Phase 1b portion of study B9991025, a total of 
12 patients were enrolled at the starting dose level of 800 mg avelumab Q2W in combination 
with talazoparib at 1.0 mg once daily.  All 12 patients were DLT-evaluable with a DLT rate 
of 3/12.  This information was incorporated using a direct down-weighting approach.  The 
weight is calculated using the formula below:  
𝑤𝑤=  
1
1 + 2𝜏𝜏2
𝜎𝜎2  𝑁𝑁
 
where N=12 (total number of patients enrolled in the Phase 1b of study B9991025) 
        σ =2 (population standard deviation) 
        τ = 0.25 (moderate heterogeneity between populations in the Phase 1b of study 
B9991025 and the triplet of this study in terms of DLT). 


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A.4.2.3 Summary of Prior Distributions  
The prior distributions of the model parameters are provided in Table 37.   
Table 37. Prior Distribution for the Model Parameters  
Parameter 
Mean 
Standard deviations 
Correlation 
Talazoparib single agent parameters: BVN MAP  Prior  
൫log(𝛼𝛼1), log(𝛽𝛽1)൯ 
-1.757, 0.657   
0.727, 0.888 
0.191 
 
 
 
 
Binimetinib single agent parameters: BVN MAP Prior 
൫log(𝛼𝛼2), log(𝛽𝛽2)൯  
-2.795,  0.313  
0.578,  0.854  
-0.313 
Binimetinib single agent parameters: Weakly Informative Prior 
൫log(𝛼𝛼2), log(𝛽𝛽2)൯ 
-1.992, 0 
2, 1 
0 
Avelumab single agent parameters*: BVN MAP Prior 
൫log(𝛼𝛼3), log(𝛽𝛽3)൯ 
-2.665,-0.056 
0.961, 0.825 
-0.234  
Interaction parameters: Normal prior 
𝜂𝜂12 
0 
0.207 
 
𝜂𝜂13 
0 
0.207 
 
𝜂𝜂23 
0.140 
0.636 
 
𝜂𝜂123 
0 
0.0249 
 
𝜂𝜂12: Two-way interaction between talazoparib and binimetinib; 
𝜂𝜂13: Two-way interaction between talazoparib and avelumab; 
𝜂𝜂23: Two-way interaction between binimetinib and avelumab; 
𝜂𝜂123: Three-way interaction between avelumab, binimetinib and talazoparib. 
Abbreviations: BVN=bivariate normal; MAP=meta-analytic-predictive. 
Table 38 and Table 39 illustrate the resulting prior distribution of DLT rate derived from the 
prior given in Table 37 for the doublet and the triplet combinations, respectively.  The 
probability of overdosing for the proposed starting dose level for the doublet combination 
with binimetinib 45 mg (7d/7d) and talazoparib 0.75 mg is 0.189, which satisfies the EWOC 
criteria. 


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Table 38. Summary of Prior Distribution of Dose Limiting Toxicity Rates for the 
Binimetinib (7d/7d) + Talazoparib Doublet Combination 
Bini 
dose 
(mg 
BID) 
Tala 
dose 
(mg 
QD) 
Prior probabilities that DLT rate is in 
the interval: 
Mean 
SD 
Quantiles 
[0, 0.16) 
[0.16, 0.33) 
[0.33,1] 
2.5% 
50% 
97.5% 
30 
0.5 
0.719 
0.171 
0.11 
0.153 
0.17 
0.011 
0.096 
0.717 
30 
0.75 
0.581 
0.283 
0.137 
0.191 
0.168 
0.029 
0.139 
0.732 
30 
1.0 
0.323 
0.443 
0.234 
0.257 
0.169 
0.064 
0.211 
0.756 
45 
0.5 
0.625 
0.219 
0.156 
0.193 
0.193 
0.023 
0.124 
0.805 
45 
0.75 
0.475 
0.336 
0.189 
0.23 
0.19 
0.042 
0.167 
0.815 
45 
1.0 
0.243 
0.457 
0.3 
0.293 
0.188 
0.076 
0.24 
0.833 
Abbreviations: Bini=binimetinib; mg=milligram; tala=talazoparib; BID=twice daily; OD=once daily; 
DLT=dose-limiting toxicity; SD=standard deviation. 
 
From Table 39, in absence of the binimetinib (7d/7d) doublet combination data, avelumab= 
10mg/kg, binimetinib= 30 mg (7d/7d) and talazoparib= 0.5 mg is an acceptable starting dose 
for the triplet.  However, the final starting dose for the triplet will be determined after the 
dose-DLT data for the binimetinib (7d/7d) + talazoparib doublet is available.  Some 
hypothetical examples for the starting dose of the triplet are shown in Table 41.  
Table 39. Summary of Prior Distribution of DLT Rates for the Avelumab + 
Binimetinib + Talazoparib Triplet Combination 
Bini 
dose 
(mg 
BID) 
Tala 
dose 
(mg 
QD) 
Prior probabilities that DLT rate is in 
the interval: 
Mean 
SD 
Quantiles 
[0, 0.16) 
[0.16, 0.33) 
[0.33,1] 
2.5% 
50% 
97.5% 
30 
0.5 
0.379 
0.394 
0.227 
0.246 
0.178 
0.044 
0.198 
0.766 
30 
0.75 
0.257 
0.447 
0.296 
0.283 
0.176 
0.064 
0.24 
0.778 
30 
1.0 
0.114 
0.431 
0.454 
0.345 
0.175 
0.101 
0.311 
0.801 
45 
0.5 
0.301 
0.361 
0.338 
0.298 
0.21 
0.046 
0.241 
0.858 
45 
0.75 
0.217 
0.371 
0.412 
0.333 
0.209 
0.061 
0.283 
0.867 
45 
1.0 
0.118 
0.335 
0.547 
0.391 
0.208 
0.088 
0.355 
0.883 
Avelumab dose fixed at 10 mg/kg every 2 weeks.  
Abbreviation: Bini=binimetinib; mg=milligram; tala=talazoparib; BID=twice daily; OD=once daily; 
DLT=dose-limiting toxicity; SD=standard deviation. 
 
A.4.3 Hypothetical on-Study Data Scenarios 
To illustrate the performance of the Bayesian model used to guide dose finding, hypothetical 
dose finding scenarios following the provisional dose levels specified in the protocol are 
displayed.  In each case, the possible recommended dose that can be used in the next cohort 
of patients is shown.  These recommended doses are determined using the model-based 
assessment of the risk of DLT in future patients, EWOC criteria and maximum amount of 
escalation allows (100% of current dose).  In practice, the dose recommended by the adaptive 
Bayesian logistic model may be regarded as guidance.  The final recommendation will be 
based on overall safety profile and PK data. 


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Table 40 shows some hypothetical dose escalation data scenarios for the binimetinib (7d/7d) 
+ talazoparib doublet combination and the corresponding recommendations for the next dose.   
Table 40. Binimetinib (7d/7d) + Talazoparib Doublet Combination: Data Scenarios, 
Next Dose Recommendation, and the Interval Probability of Target Toxicity 
and Overdosing at Next Dose. 
Scenarios 
Dose Evaluated 
D/N* 
Next Dose (ND) 
Pr(TT) at 
ND 
 
Pr(OD) at 
ND 
 
Ave (mg/kg
Q2W) 
Bini 
(mg BID) 
Tala 
(mg QD) 
Ave 
(mg/kg 
Q2W) 
Bini 
(mg BID) 
Tala 
(mg 
QD) 
1 
0 
45 
0.75 
1/5 
0 
45 
1 
0.548 
0.224 
2 
0 
45 
0.75 
1/6 
0 
45 
1 
0.561 
0.186 
3 
0 
45 
0.75 
2/6 
0 
45 
0.75 
0.513 
0.202 
4 
0 
45 
0.75 
3/6 
0 
30 
0.5 
0.380 
0.245 
5 
0 
0 
45 
45 
0.75 
1 
1/6 
2/12 
0 
45 
1 
0.639 
0.058 
6 
0 
0 
45 
45 
0.75 
1 
1/6 
3/12 
0 
45 
1 
0.705 
0.131 
7 
0 
0 
45 
45 
0.75 
0.75 
2/6 
1/6 
0 
0 
45 
30 
0.75 
1.0 
0.574 
0.594 
0.099 
0.191 
8 
0 
0 
45 
45 
0.75 
0.75 
2/6 
2/6 
0 
45 
0.75 
0.599 
0.243 
9 
0 
0 
45 
45 
0.75 
0.5 
3/6 
1/5 
0 
0 
30 
30 
0.75 
0.5 
0.576 
0.476 
0.247 
0.150 
Abbreviations: Ave=avelumab; BID=twice a day; Bini=Binimetinib; mg=milligrams; mg/kg=milligrams per 
kilogram;*D=number of patients with DLT, N=number of DLT-evaluable patients; ND=next dose; tala=talazoparib. 
 
Table 41 shows the plausible starting dose level(s) for the avelumab + binimetinib (7d/7d) + 
talazoparib triplet given hypothetical data from the binimetinib (7d/7d) + talazoparib doublet. 
Table 41. Avelumab + Binimetinib (7d/7d) + Talazoparib Triplet Combination: 
Clinically Meaningful Starting Dose Given Hypothetical Data from the 
Doublet, and the Interval Probability of Target Toxicity and Overdosing at 
Starting Dose. 
Scenarios 
Doublet Dose 
 
 
D/N* 
Triplet starting dose (SD) 
Pr(TT) at 
SD 
Pr(OD)  
at SD 
Ave 
(mg/kg 
Q2W) 
Bini 
(mg 
BID) 
Tala 
(mg 
QD) 
Ave 
(mg/kg 
Q2W) 
Bini 
(mg 
BID) 
Tala 
(mg 
QD) 
1 
0 
0 
45 
45 
0.75 
1.0 
1/6 
2/12 
(10) 
(10) 
30 
45 
0.75 
0.5 
0.525 
0.424 
0.168 
0.215 
2 
0 
0 
45 
45 
0.75 
1.0 
1/6 
3/12 
(10) 
(10) 
30 
45 
0.75 
0.5 
0.530 
0.424 
0.204 
0.245 
3 
0 
0 
45 
45 
0.75 
1.0 
0/6 
1/12 
(10) 
(10) 
30 
45 
1.0 
0.75 
0.548 
0.381 
0.209 
0.198 
4 
0 
45 
0.75 
3/12 
(10) 
30 
0.5 
0.486 
0.180 
5 
0 
45 
0.75 
4/12 
No feasible starting dose for the triplet 


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6 
0 
0 
45 
30 
0.75 
0.5 
3/6 
3/12 
No feasible starting dose for the triplet 
7 
0 
0 
0 
45 
30 
30 
0.75 
0.5 
0.75 
3/6 
1/5 
3/12 
No feasible starting dose for the triplet 
8 
0 
0 
45 
45 
0.75 
1.0 
0/6 
0/12 
(10) 
(10) 
30 
45 
1.0 
0.75 
0.526 
0.409 
0.164 
0.173 
9 
0 
0 
0 
45 
30 
45 
0.75 
0.5 
0.5 
3/6 
0/4 
3/12 
No feasible starting dose for the triplet 
Abbreviations: Ave=avelumab; BID=twice a day; Bini=Binimetinib; mg=milligrams; mg/kg=milligrams per 
kilogram;*D=number of patients with DLT, N=number of DLT-evaluable patients; ND=next dose; Pr(TT)=probability of 
target toxicity; Pr(OD)=probability of overdosing; Tala=Talazoparib; QD=once daily; Q2W=every 2 weeks. 
Table 42 shows data scenarios for the triplet and the corresponding recommendations for the 
next dose. 
Table 42. Avelumab + Binimetinib (7d/7d) + Talazoparib Triplet Combination: Data 
Scenarios (Given Hypothetical Doublet Data), Next Dose Recommendation, 
and the Interval Probability of Target Toxicity and Overdosing at Next 
Dose. 
Scenarios 
Dose evaluated  
 
 
D/N* 
Next Dose (ND) 
Pr(TT) 
at ND 
Pr(OD) at 
ND 
Ave  
(mg/kg 
Q2W) 
Bini 
(mg 
BID) 
Tala 
(mg 
QD) 
Ave  
(mg/kg 
Q2W) 
Bini 
(mg 
BID) 
Tala 
(mg 
QD) 
1 
0 
0 
(10) 
45 
45 
45 
0.75 
1.0 
0.5 
1/6 
2/12 
0/6 
(10) 
  
45 
  
1.0 
0.510 
 
 
0.175 
 
 
2 
0 
0 
(10) 
45 
45 
45 
0.75 
1.0 
0.5 
1/6 
2/12 
1/6 
(10) 
45 
  
0.75 
0.544 
 
 
0.186 
 
 
3 
0 
0 
(10) 
45 
45 
45 
0.75 
1.0 
0.5 
1/6 
2/12 
2/6 
(10) 
30 
  
0.75 
0.641 
 
 
0.207 
 
 
4 
0 
0 
(10) 
45 
45 
45 
0.75 
1.0 
0.5 
1/6 
2/12 
3/6 
Stop (all doses are overdosing) 
5 
0 
0 
(10) 
45 
45 
45 
0.75 
1.0 
0.5 
1/6 
3/12 
0/6 
(10) 
  
45 
  
1.0 
0.517 
 
 
0.229 
 
 
6 
0 
0 
(10) 
45 
45 
45 
0.75 
1.0 
0.5 
1/6 
3/12 
1/6 
(10) 
45 
  
0.75 
0.548 
 
 
0.215 
 
 
7 
0 
0 
(10) 
45 
45 
45 
0.75 
1.0 
0.5 
1/6 
3/12 
2/6 
(10) 
30 
  
0.75 
0.633 
 
 
0.240 
 
 
8 
0 
0 
(10) 
45 
45 
45 
0.75 
1.0 
0.5 
1/6 
3/12 
3/6 
Stop (all doses are overdosing) 
9 
0 
0 
(10) 
45 
45 
30 
0.75 
1.0 
0.75 
1/6 
2/12 
0/6 
(10) 
  
45 
  
1.0 
0.498 
 
 
0.210 
 
 
10 
0 
0 
45 
45 
0.75 
1.0 
1/6 
2/12 
(10) 
30 
45 
1.0 
0.75 
0.614 
0.512 
0.239 
0.209 


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(10) 
30 
0.75 
1/6 
 
 
11 
0 
0 
(10) 
45 
45 
30 
0.75 
1.0 
0.75 
1/6 
2/12 
2/6 
(10) 
30 
  
0.75 
0.620 
 
 
0.215 
 
 
12 
0 
0 
(10) 
45 
45 
30 
0.75 
1.0 
0.75 
1/6 
2/12 
3/6 
Stop (all doses are overdosing) 
13 
0 
0 
(10) 
45 
45 
30 
0.75 
1.0 
0.75 
1/6 
3/12 
0/6 
(10) 
  
30 
45 
1.0 
0.75 
0.609 
0.445 
 
0.167 
0.113 
 
14 
0 
0 
(10) 
45 
45 
30 
0.75 
1.0 
0.75 
1/6 
3/12 
1/6 
(10) 
30 
45 
0.75 
0.75 
0.590 
0.513 
 
0.111 
0.237 
 
15 
0 
0 
(10) 
45 
45 
30 
0.75 
1.0 
0.75 
1/6 
3/12 
2/6 
(10) 
(10) 
30 
30 
  
0.75 
0.5 
0.614 
0.565 
 
0.248 
0.144 
 
16 
0 
0 
(10) 
45 
45 
30 
0.75 
1.0 
0.75 
1/6 
3/12 
3/6 
Stop (all doses are overdosing) 
Abbreviations: Ave=avelumab; BID=twice a day; Bini=Binimetinib; mg=milligrams; mg/kg=milligrams per 
kilogram;*D=number of patients with DLT, N=number of DLT-evaluable patients; ND=next dose; 
Pr(TT)=probability of target toxicity; Pr(OD)=probability of overdosing; Tala=Talazoparib; QD=once daily; Q2W=every 
2 weeks. 
A.4.4. Operating Characteristics  
A simulation study is used to illustrate the properties of the dose finding model guided by 
BLRM.  Several example scenarios were investigated (A.4.4.1) and in each scenario 
1000 trials were simulated, with results summarized in A.4.4.3. 
A.4.4.1 Simulation Scenarios  
The true DLT rates under different scenarios for doublet and triplet combinations are shown 
in Table 43 and Table 44, respectively.  Several scenarios are considered: Scenario 1 
represents the case when the distribution of DLT coincides with prior, ie, the true DLT 
probability equals to mean of prior DLT.  Scenarios 2-3 represent a proportionally 
increased/decreased DLT rate compared to Scenario 1.  Scenario 4 in Table 43 represents a 
true toxicity profile with dose combinations in both under-dose and over-dose regions. 


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Table 43. Binimetinib (7d/7d) + Talazoparib Doublet Combination: True Dose 
Limiting Toxicity Rate Scenarios 
 
Binimetinib (mg 
BID) 
Talazoparib (mg QD) 
0.5 
0.75 
1.0 
0.5 
0.75 
1.0 
 
Scenario 1. prior means of DLT rate 
Scenario 2. 25% more toxic than prior 
means 
30 
0.153 
0.191 
0.257 
0.192 
0.239 
0.321 
45 
0.193 
0.23 
0.293 
0.242 
0.287 
0.366 
 
Scenario 3. 40% more toxic than prior 
means 
Scenario 4. With underdose and 
overdose 
30 
0.215 
0.268 
0.360 
0.100 
0.200 
0.300 
45 
0.271 
0.322 
0.410 
0.150 
0.250 
0.450 
Abbreviations: BID=twice a day; DLT=dose-limiting toxicity; QD=once daily; mg=milligram. 
Table 44. Avelumab + Binimetinib (7d/7d) + Talazoparib Triplet Combination: True 
Dose Limiting Toxicity Rate Scenarios 
 
Binimetinib (mg 
BID) 
Talazoparib (mg QD) 
0.5 
0.75 
1.0 
0.5 
0.75 
1.0 
 
Scenario 1. prior means of DLT rate 
Scenario 2. 10% more toxic than prior 
means 
30 
0.246 
0.283 
0.345 
0.271 
0.311 
0.379 
45 
0.298 
0.333 
0.391 
0.328 
0.366 
0.430 
 
Scenario 3. 10% less toxic than prior 
means 
Scenario 4. With underdose and 
overdose 
30 
0.222 
0.254 
0.310 
0.100 
0.250 
0.350 
45 
0.269 
0.300 
0.352 
0.200 
0.300 
0.450 
Avelumab dose fixed at 10 mg/kg every 2 weeks; Abbreviations: BID=twice a day; DLT=dose-limiting toxicity; 
mg=milligram; QD=once daily. 
A.4.4.2 Simulation Details  
Simulations were performed using R version 3.3.5 (The R-project for Statistical Computing.  
https://www.r-project.org/), and JAGS 4.8 to perform the MCMC analyses.  
For each scenario, data for 1000 trials were generated, with a cohort size of 3.  At any time 
during the course of dose finding, escalation to doses where the risk of overdose exceeds 
0.25 is not permitted.  The ‘next dose recommendation’ is the dose with maximum 
probability of overdose among all dose levels that meet the EWOC criteria. 


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For the doublet, the starting dose was binimetinib 45 mg and talazoparib 0.75 mg.  For the 
triplet, the starting dose is the lowest dose of avelumab 10 mg/kg, binimetinib 30 mg, and 
talazoparib 0.5 mg.  No on-trial binimetinib + talazoparib doublet combination data is 
considered in this exercise.  The maximum number of patients per trial was set to 60.  The 
trial was stopped when the following criteria were met: 
• At least 6 patients have been treated at the recommended MTD 𝑑𝑑̃. 
• The dose 𝑑𝑑̃ satisfies one of the following conditions: 
• The probability of target toxicity at dose 𝑑𝑑̃ exceeds 50%, 
ie, Pr(0.16 ≤ 𝜋𝜋𝑑𝑑෨ <0.33)≥50%; 
• A minimum of 15 patients have been treated in the trial. 
The following metrics were assessed in the simulations: 
• Percentage of patients receiving dose combination(s) in the target toxicity interval;  
• Percentage of patients receiving an overdose; 
• Percentage of patients receiving an underdose; 
• Probability that recommended MTD at the end of the trial is in the target toxicity 
interval; 
• Probability that recommended MTD is an overdose; 
• Probability that recommended MTD is an underdose; 
• Percentage of trials stopped without MTD declaration; 
• Average sample size. 
A.4.4.3 Simulation Results 
Operating characteristics for the doublet and the triplet combinations are presented in 
Table 45 and Table 46 respectively.  The percentage of trials with a correctly identified MTD 
ranges from 67.4% to 99% is reasonable and the percentage of patients treated at overly toxic 
doses is well controlled for most of the scenarios.  The average sample size for the doublet 
combination is between 10 and 11 patients, and the average sample size for the triplet is 
between 9 to 15 patients. 


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Table 45. Binimetinib + Talazoparib (7d/7d) Doublet Combination: Operating 
Characteristics  
 
True DLT Scenarios  
% Patient allocation 
% declare MTD 
% stop 
(no MTD) 
Average 
sample 
size 
TT 
OD 
UD 
TT 
OD 
UD 
1.  Prior means 
97.2 
0 
2.8 
85.2 
0 
0 
14.8 
10 
2.  25% more toxic 
than prior means  
88.8 
11.2 
0 
77.3 
0 
0 
22.7 
10 
3.  40% more toxic 
than prior means 
82.5 
17.5  
0 
59.0 
0 
00 
41.0 
11 
4.  With underdose and 
overdose 
83.9 
12.9 
3.2 
88.0 
0 
00 
12.0 
10 
Abbreviations: DLT=dose-limiting toxicity; MTD=maximum tolerated dose: OD=overdose; TT=target toxicity; 
UD=underdose. 
Table 46. Avelumab + Binimetinib (7d/7d) + Talazoparib Triplet Combination: 
Operating Characteristics  
 
True DLT Scenarios  
% Patient 
allocation 
%declare MTD 
% stop 
(no MTD) 
Average 
sample 
size 
TT 
OD 
UD 
TT 
OD 
UD 
1.  Prior means 
90.5 
9.5 
0 
60.8 
0 
0 
39.2 
11 
2.  10% more toxic than 
3.  prior means 
91.6 
8.4 
0 
56.4 
0 
0 
43.6 
9 
4.  10% less toxic than 
prior means 
100 
0 
0 
65.4 
0 
0 
34.6 
12 
5.  With underdose and 
overdose 
53.0 
3.8 
43.2 
68.4 
0 
17.1 
14.5 
15 
Abbreviations: DLT=dose-limiting toxicity; MTD=maximum tolerated dose; OD=overdose; TT=target toxicity; 
UD=underdose.