A Phase 2, Two-Group, Two-Stage, Open-Label Study of Avelumab in Patients With MSS, MSI-H and POLE-mutated Recurrent or Persistent Endometrial Cancer, Avelumab / Talazoparib in Patients With MSS Recurrent or Persistent Endometrial Cancer, and Avelumab / Axitinib in Patients With MSS Recurrent or Persistent Endometrial Cancer
Phase: PHASE2
Conditions: Metastatic Endometrial Cancer
Sponsor: Dana-Farber Cancer Institute

DF/HCC Protocol #: 16-322 
Protocol Version Date: August 16, 2023 
 
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DF/HCC Protocol #: 
16-322 
 
TITLE:  A Phase 2, Two-Group, Two-Stage, Open-Label Study of Avelumab in 
Patients with MSS, MSI-H and POLE-mutated Recurrent or Persistent 
Endometrial Cancer, Avelumab / Talazoparib in Patients with MSS Recurrent 
or Persistent Endometrial Cancer, and Avelumab / Axitinib in Patients with 
MSS Recurrent or Persistent Endometrial Cancer  
 
 
Coordinating Center:  
 Dana-Farber/Harvard Cancer Center 
 
Principal Investigator (PI): Panagiotis A. Konstantinopoulos MD, PhD 
 Dana-Farber Cancer Institute 
 YC-1424, 450 Brookline Ave 
 Boston, MA 02215 
 Telephone: 617-632-5269 
 Fax: 617-582-7921 
 Panagiotis_Konstantinopoulos@dfci.harvard.edu  
 
Other Investigators:            Page Widick, MD 
                                               Beth Israel Deaconess Medical Center 
                                               pwidick@bidmc.harvard.edu 
 
                                               Richard Penson, MD 
                                               Massachusetts General Hospital 
                                               Penson.Richard@mgh.harvard.edu   
 
 
       
 
     
Statistician: 
Su-Chun Cheng, ScD  
Dana-Farber Cancer Institute 
450 Brookline Ave. 
Boston, MA 02215 
Phone: 617-582-7257 
SCheng@jimmy.harvard.edu 
Responsible Project Manager:  
Madeline Polak 
Dana-Farber Cancer Institute 
450 Brookline Ave. 
Boston, MA 02215 
Phone: 617-632-3743 
Madeline_Polak@dfci.harvard.edu 
 
 
 
 

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Responsible Research Nurse: 
   
Sarah Hindenach, RN 
 
450 Brookline Avenue 
 
Boston, MA 02215 
 
Phone: 617-632-3472 
 
 
Fax: 617-582-7921 
           
Sarah_Hindenach@dfci.harvard.edu 
 
 
Agents: Avelumab, Pfizer; Talazoparib, Pfizer; Axitinib, Pfizer 
IND #:  130693 
IND Sponsor:  Panagiotis A. Konstantinopoulos MD, PhD 
Protocol Version Date: August 16, 2023 

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SCHEMA 
 
This is a non-randomized, open-label, two-cohort, two-stage, phase 2 trial, of avelumab 
in two cohorts of endometrial cancer patients: i) MSI or POLE-mutated endometrial 
cancers (MSI/POLE cohort) and ii) MSS endometrial cancers (MSS cohort). 
 
Given that avelumab single agent activity in the MSS cohort did not meet study criteria 
to move on to stage II, we are now adding a new cohort of MSS patients who will be 
receiving avelumab plus talazoparib to assess whether this combination will be 
efficacious against these tumors. 
 
MSI/POLE Cohort:  Avelumab as a 1-hour intravenous (IV) infusion once every 2 
weeks until disease progression or unacceptable toxicity (one cycle=28 days including 
two infusions) 
 
MSS Cohort: Avelumab as a 1-hour intravenous (IV) infusion once every 2 weeks and 
oral talazoparib every day until disease progression or unacceptable toxicity (one 
cycle=28 days including two infusions) 
 
MSS Cohort, additional: Avelumab as a 1-hour intravenous (IV) infusion once 
every 2 weeks and oral axitinib twice daily, until disease progression or unacceptable 
toxicity (one cycle = 28 days, including two infusions) 
 

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TABLE OF CONTENTS 
 
SCHEMA .........................................................................................................................................3 
1. 
SYNOPSIS & OBJECTIVES ..............................................................................................8 
1.1 
Study Design ............................................................................................................8 
1.2 
Primary Endpoints ...................................................................................................8 
1.3 
Secondary Endpoints ...............................................................................................8 
1.4 
Exploratory Endpoints .............................................................................................9 
2. 
BACKGROUND .................................................................................................................9 
2.1 
Study Disease ...........................................................................................................9 
2.2 
Investigational Agent .............................................................................................11 
2.3 
Rationale ................................................................................................................30 
2.4 
Correlative Studies Background ............................................................................38 
3. 
PARTICIPANT SELECTION ...........................................................................................40 
3.1 
Eligibility Criteria ..................................................................................................40 
3.2 
Exclusion Criteria ..................................................................................................42 
3.3 
Inclusion of Women and Minorities ......................................................................46 
4. 
REGISTRATION PROCEDURES ...................................................................................46 
4.1 
General Guidelines for DF/HCC Institutions ........................................................46 
4.2 
Registration Process for DF/HCC Institutions .......................................................46 
4.3 
General Guidelines for Other Investigative Sites ..................................................46 
4.4 
Registration Process for All Sites ..........................................................................47 
5. 
TREATMENT PLAN ........................................................................................................47 
5.1 
Treatment Regimens ..............................................................................................47 
5.2 
Pre-Treatment Criteria ...........................................................................................48 
5.3 
Administration .......................................................................................................50 
5.4 
Concomitant Medication and Supportive Care Guidelines ...................................56 
5.5 
Tumor Response Assessments ...............................................................................58 
5.6 
Treatment After Initial Evidence of Radiologic Disease Progression ...................59 
5.7 
Duration of Therapy / Criteria for Taking a Participant Off Protocol Therapy .....59 
5.8 
Duration of Follow Up ...........................................................................................60 
5.9 
Criteria for Taking a Participant Off Study ...........................................................60 
6. 
DOSING DELAYS, MODIFICATIONS, AND MANAGEMENT OF SPECIFIC 
ADVERSE EVENTS .........................................................................................................61 
6.1 
Dose Reductions of Talazoparib ............................................................................61 
6.2  
Dose Reductions of Axitinib ..................................................................................62 
6.3 
Study Treatment Modifications for Avelumab & Talazoparib Drug-Related 
Toxicity ..................................................................................................................63 
6.4  
Study Treatment Modifications for Avelumab & Axitinib....................................66 
6.5  
Treatment Modifications for Infusion-Related Reactions Associated with 
Avelumab ...............................................................................................................72 

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6.6   
Immune-related Adverse Events/Toxicity Management .......................................73 
7. 
ADVERSE EVENT: List and REPORTING Requirements .............................................82 
7.2 
Expected Toxicities ................................................................................................82 
7.3 
Adverse Event Characteristics ...............................................................................85 
7.4 
Expedited Adverse Event Reporting to Overall PI ................................................86 
7.5 
Expedited Reporting to Pfizer Inc..........................................................................87 
7.6 
Expedited Reporting to the Food and Drug Administration (FDA) ......................91 
7.7 
Expedited Reporting to Hospital Risk Management .............................................91 
7.8 
Routine Adverse Event Reporting .........................................................................91 
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DRUG FORMULATION INFORMATION .....................................................................92 
8.1 
Avelumab ...............................................................................................................92 
8.2  
Talazoparib ............................................................................................................95 
8.3 
Axitinib ..................................................................................................................97 
9 
BIOMARKER, CORRELATIVE AND SPECIAL STUDIES .........................................99 
9.1 
Sample Collection ..................................................................................................99 
9.2 
Planned Biomarker and Correlative Studies ........................................................101 
10 
STUDY CALENDAR .....................................................................................................102 
11 
MEASUREMENT OF EFFECT......................................................................................104 
11.1 
Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 
Guidelines ............................................................................................................104 
11.2 
Immune-related Response Criteria Derived from RECIST 1.1 (irRECIST) .......108 
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DATA REPORTING & REGULATORY REQUIREMENTS .......................................110 
12.1 
Data Reporting .....................................................................................................110 
12.2 
Data Safety Monitoring........................................................................................110 
12.3 
Multicenter Guidelines.........................................................................................111 
13 
STATISTICAL CONSIDERATIONS.............................................................................111 
13.1 
Study Design/Endpoints.......................................................................................112 
13.2 
Sample Size, Accrual Rate and Study Duration ..................................................114 
13.3 
Stratification Factors ............................................................................................115 
13.4 
Analysis of Secondary Endpoints ........................................................................115 
13.5 
Reporting and Exclusions ....................................................................................116 
14 
PUBLICATION PLAN ...................................................................................................117 
REFERENCES ............................................................................................................................117 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ................................................124 
APPENDIX B: Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan
..........................................................................................................................................125 
1. 
INTRODUCTION ...........................................................................................................127 

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1.1 
Purpose .................................................................................................................127 
1.2 
Multi-Center Data and Safety Monitoring Plan Definitions ................................127 
2. 
GENERAL ROLES AND RESPONSIBILITIES ...........................................................128 
2.1 
DF/HCC Sponsor .................................................................................................128 
2.2 
Coordinating Center .............................................................................................129 
2.3 
Participating Institution ........................................................................................129 
3. 
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS............................130 
3.1 
Protocol Distribution ............................................................................................130 
3.2 
Protocol Revisions and Closures .........................................................................130 
3.3 
Informed Consent Requirements .........................................................................131 
3.4 
IRB Documentation .............................................................................................131 
3.5 
IRB Re-Approval .................................................................................................132 
3.6 
Participant Confidentiality and Authorization Statement ....................................132 
3.7 
DF/HCC Multi-Center Protocol Registration Policy ...........................................132 
3.8 
DF/HCC Protocol Case Number ..........................................................................133 
3.9 
Safety Assessments and Toxicity Monitoring .....................................................134 
3.10 
Data Management ................................................................................................135 
4. 
REQUISITIONING INVESTIGATIONAL DRUG........................................................136 
5. 
MONITORING: QUALITY CONTROL ........................................................................136 
5.1 
Ongoing Monitoring of Protocol Compliance .....................................................136 
5.2 
Monitoring Reports ..............................................................................................137 
5.3 
Accrual Monitoring ..............................................................................................137 
6. 
AUDITING: QUALITY ASSURANCE .........................................................................137 
6.1 
Audit Plan: DF/HCC Sponsored Trials................................................................137 
6.2 
Audit Notification ................................................................................................138 
6.3 
Audit Reports .......................................................................................................138 
6.4 
Participating Institution Performance ..................................................................138 
 

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1. SYNOPSIS & OBJECTIVES 
  
1.1 
Study Design 
 
This is a non-randomized, open-label, multi-cohort, two-stage, phase 2 trial, of: 
1. avelumab in MSI or POLE-mutated endometrial cancers (MSI/POLE cohort) 
2. avelumab in MSS endometrial cancers (MSS cohort) 
3. combination of avelumab + talazoparib in MSS endometrial cancers (MSS cohort) 
4. combination of avelumab + axitinib in MSS endometrial cancers (MSS cohort) 
 
It entails a two-stage Optimum design for each MSI/POLE and MSS cohort to inform whether that 
cohort’s treatment (avelumab alone, avelumab + talazoparib, or avelumab + axitinib) has significant 
clinical activity that is worthy of further evaluation in each of the cohorts.   
 
Statistical considerations are developed for co-primary objectives to evaluate the objective response 
rate (ORR) and rate of progression-free survival at 6 months (PFS), with a two-stage design that 
allows for early stopping for futility for each cohort. 
 
Maximum target enrollment is 105, 35 per cohort, assuming that each cohort will meet criteria for 
moving into stage II. The total sample size will be adjusted to allow for replacement of participants 
who never began protocol therapy for reasons including ineligibility, inevaluability, and participant 
drop out. While the maximum target accrual is 105 patients, up to 115 patients can be enrolled to 
allow for replacement.  
 
1.2 
Primary Endpoints 
 
Primary endpoints for avelumab & avelumab/talazoparib: 
To assess the activity of avelumab in patients with recurrent or persistent endometrial cancer 
classified by MSI/POLE and MSS genomic cohorts as well as the activity of avelumab plus 
talazoparib in patients with recurrent MSS endometrial cancers as determined by the frequency of 
patients who survive progression-free for at least 6 months (PFS6) after initiating therapy or have 
objective tumor response. 
 
Co-primary endpoints for combination avelumab/axitinib: 
a. To assess the clinical activity of combination avelumab/axitinib in patients with MSS 
recurrent or persistent endometrial cancer, as determined by the frequency of patients who 
survive progression-free for at least 6 months (PFS6) 
b. To assess the clinical activity of combination avelumab/axitinib in patients with MSS 
recurrent or persistent endometrial cancer, as determined by the objective response rate 
(ORR) measured by RECIST 1.1 
 
 
1.3 
Secondary Endpoints 
 
Secondary endpoints for avelumab & avelumab/talazoparib: 
a. To determine the duration of progression-free survival and overall survival for each cohort. 

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b. To determine the nature and degree of toxicity of avelumab or avelumab/talazoparib for each 
cohort as classified by the common terminology criteria for adverse events (CTCAE) version 
4.0. 
c. To determine Immune-related objective response rate for each cohort as described in Section 11.2 
d. Immune-related progression-free survival (irPFS) rate for each cohort defined as time from cohort 
assignment to death or to immune-related progression of disease (irPD) as defined in Section 11.2. 
 
Secondary endpoints for combination avelumab/axitinib: 
a. To assess the clinical activity of combination avelumab/axitinib as measured by median 
progression-free survival (PFS) and median overall survival (OS) 
b. To assess the clinical activity of combination avelumab/axitinib as measured by the 
immune-related ORR, as measured by irRECIST criteria 
c. To assess the clinical activity of combination avelumab/axitinib as measured by the 
immune-related PFS (irPFS) 
d. To determine the safety and toxicity of combination avelumab/axitinib, as classified by the 
CTCAE v4.0 
 
 
1.4 
Exploratory Endpoints 
 
• Assessment of CD3+ tumor infiltrating lymphocytes (TILs) and circulating lymphocytes, 
CD8+ TILs, CD8+/CD4+FOXP3+ TIL ratio, CD137+CD8+ TILs, 
D137+CD8+/CD4+FOXP3+ TIL ratio and correlation with response 
• Assessment of myeloid, stromal and other immunoactive cell types from blood, tissue and 
fluid samples and correlation with response 
• Assessment of the expression pre-, during, and at time of progression of immune 
checkpoints including TIM-3, LAG-3, CTLA-4, PD-L2, PD-L1, PD-1, IDO and correlation 
with response 
• Whole exome sequencing (WES) for specific DNA gene repair mutations and neoantigen 
assessment as well as for single nucleotide polymorphisms (SNPs) in immunologically 
relevant genes and correlation with response 
• Presence of anti-avelumab antibodies and correlation with response 
 
 
2. BACKGROUND 
 
2.1 
Study Disease 
 
2.1.1 Epidemiology 
 
Endometrial cancer is the most common gynecologic malignancy with an annual incidence of 
40,000 cases (Jemal et al., 2009). The majority of women with endometrial cancer are diagnosed 
with early stage cancer which is typically treated surgically with overall excellent outcomes.  
However, women with recurrent disease or metastatic disease have limited treatment options. These 
patients account for the approximate 8,000 annual death rate from this cancer (Jemal et al., 2009). 
As such, this disease represents an important unmet medical need. The recent identification of 
distinct genomic subtypes of endometrial cancer from The Cancer Genome Atlas has opened the 

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opportunity to stratify response to therapy by subtype generally and specifically has identified 
distinct subtypes with high mutational burdens and a correspondingly increased number of 
neoepitopes that may be particularly likely to respond to checkpoint blockade and other immune-
activating therapies (The Cancer Genome Atlas Research Network, 2013). 
 
2.1.2 Current Treatment Paradigms 
 
There have been several randomized studies performed to ascertain the optimal therapy patients 
with recurrent or metastatic disease. These studies have focused on three active chemotherapy 
agents identified to have significant activity as monotherapy in phase II trials: doxorubicin, 
platinum agents, and paclitaxel. In GOG-0107 (Thigpen et al., 2004), 281 women were randomized 
to doxorubicin alone (60 mg/m2) versus doxorubicin (60 mg/m2) plus cisplatin (50 mg/m2) (AP). 
There was a statistically significant advantage to combination therapy with regard to response rate 
(RR) (25% versus 42%; p=0.004) and PFS (3.8 vs 5.7 months; HR 0.74 [95% CI 0.58, 0.94; 
p=0.14), although no difference in OS was observed (9 vs 9.2 months). Phase II data published by 
the GOG in 1996 (Ball et al., 1996) demonstrated that paclitaxel had significant single agent 
activity with a response rate of 36% in advanced or recurrent endometrial cancer. Thus 317 patients 
were randomized to paclitaxel and doxorubicin or the standard arm of AP in GOG-0163 (Fleming et 
al., 2004b). This trial failed to demonstrate a significant difference in RR, PFS, or OS between the 
two arms, and AP remained the standard of care. However, since both platinum and paclitaxel had 
demonstrated high single agent activity, there was a strong interest in including paclitaxel and 
cisplatin in a front-line regimen for advanced and recurrent endometrial cancer. Subsequently, 
GOG-0177 (Fleming et al., 2004a) randomized 263 patients to AP versus TAP: doxorubicin (45 
mg/m2) and cisplatin (50 mg/m2) on day 1, followed by paclitaxel (160 mg/m2 IV over 3 hours) on 
day 2 (with G-CSF support). TAP was superior to AP in terms of ORR (57% vs 34%; p<0.01), 
median PFS (8.3 vs 5.3 months; p<0.01) and OS with a median of 15.3 (TAP) versus 12.3 months 
(AP) (p=0.037). This improved efficacy came at the cost of increased toxicity. In GOG-0209 TAP 
was compared in a randomized fashion to paclitaxel and carboplatin (CT) in an attempt to address 
the issue of toxicity; CT was found to be not inferior to TAP in terms of PFS and OS. At the 
reported interim analysis, the median PFS was 14 months in both arms (HR, 1.03), while median 
OS was 32 months vs. 38 months in patients treated with CT vs. TAP (not significant, HR, 1.01). 
Additionally, CT was better tolerated than TAP. 
 
Given these studies, first line treatment for metastatic or recurrent disease remains a combination 
regimen of a platinum agent with either a taxane, anthracycline or both. However, once this initial 
therapy has been delivered, either in the adjuvant or advanced disease setting, there are limited 
treatment options, with no established standard options available. 
 
Hormonal therapies, when given to chemotherapy naïve patients, can result in response rates of up 
to 33%, but responses are of short duration (median PFS of approximately 3 months) (Lentz et al., 
1996; Thigpen et al., 1999; Thigpen et al., 2001; Whitney et al., 2004). 
 
Phase II studies of the rapalogs (everolimus, temsirolimus, AP23573), which target mTOR 
(specifically mTORC1), a downstream target of AKT, suggest the clinical utility of these agents 
(Colombo et al., 2013; Oza et al., 2008; Slomovitz et al., 2010). Trials of single agent use of these 
drugs in pre-treated endometrial cancer revealed modest results, with both objective responses as 
well as clinically significant disease stabilization. Briefly, the investigators of everolimus reported a 

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0% partial response and 44% of patients with stable disease at 8 weeks. The study of temsirolimus 
revealed a 7.4% partial response rate and 44% had stable disease (with a median duration of 3.5 
months).  
 
Other agents that have been investigated in Phase II trials through the GOG include: trastuzumab 
(181B), thalidomide (229B), gefitinib (229C), lapatinib (229D), bevacizumab (229E), brivanib 
(229I), bevacizumab + temsirolimus (229G), and AZD6244 (229H). Bevacizumab was well 
tolerated and active based on PFS at 6 months (13.5% ORR and 40.4% PFS6) while the 
combination of temsirolimus and bevacizumab was active based on both objective tumor response 
and PFS at 6 months (24.5% ORR and 46.9% PFS 6) in recurrent or persistent EMC but was 
associated with significant toxicity (Aghajanian et al., 2011; Alvarez et al., 2012). Single agent 
trastuzumab failed to demonstrate significant activity in a phase II study in stage III/IV recurrent 
endometrial cancer (GOG-181B) (Roque et al. 2013) but a phase II study of carboplatin/paclitaxel 
with or without trastuzumab in patients with advanced or recurrent endometrial serous cancers 
confirmed to be HER2/Neu positive by immunohistochemistry or fluorescent in situ hybridization 
reported improved PFS (8 vs. 12.6 months, p=0.005) among patients treated with trastuzumab 
(Fader et al, 2018). 
 
 
2.2 
Investigational Agent 
 
2.2.1 Avelumab 
 
2.2.1.1 Investigational Agent Rationale 
 
Avelumab (also referred to as MSB0010718C) is a human IgG1 antibody directed against PD-L1. 
Avelumab binds PD-L1 and blocks the interaction between PD-L1 and its receptors PD-1 and B7.1. 
This removes the suppressive effects of PD-L1 on anti-tumor CD8+ T cells, resulting in the 
restoration of cytotoxic T cell response. The PD-1 receptor is expressed on activated CD4+ and 
CD8+ T cells. By interaction with its ligands, PD-L1 and PD-L2, PD-1 delivers a series of strong 
inhibitory signals through its cytoplasmic tail to inhibit T cell functions (Chemnitz et al., 2004; Keir 
et al., 2008; Riley, 2009). PD-L1 (also called B7-H1 and CD274) can be detected on resting and 
activated T cells, B cells, macrophages, dendritic cells, and mast cells; PD-L1 expression is greatly 
up-regulated after activation or interferon treatment (Keir et al., 2008). Numerous results from in 
vitro cellular assays have demonstrated that blockade of the PD-1/PD-L1 interaction enhances T 
cell responses, such as increases in proliferation and cytokine production (Bennett et al., 2003; 
Blank et al., 2004; Blank et al., 2006; Brown et al., 2003; Dong et al., 1999; Freeman et al., 2000; 
Waeckerle-Men et al., 2007). In PD-1–/– mice both T and/or B cells responses are unregulated 
resulting in an array of autoimmune pathologies (Okazaki and Honjo, 2006, 2007). Breaking 
tolerance through, blocking PD-1 interaction with its ligands, and thus PD-1 signaling, can be 
applied to enhance T cell activity towards chronic pathologies such as cancer (Blank et al., 2005). 
External (Okazaki and Honjo, 2007) and internal immunohistochemistry studies have demonstrated 
that PD-L1 is also expressed by a variety of human tumors, both by the tumor cells, as well as by 
the immune cells that are present in the tumor microenvironment. In contrast to very strong 
expression on syncytiotrophoblasts in the placenta and in cancer cells, low levels of PD-L1 
expression were detected in some normal tissues including fetal cardiac tissue (Brown et al., 2003). 
High levels of PD-L1 expression have been found to be associated with disease progression, 

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increased metastasis, poor response to treatment, and decreased survival in a number of human 
cancers (Okazaki and Honjo, 2007). Importantly anti-PD-L1 blockade has demonstrated therapeutic 
efficacy in a variety of murine tumor models as monotherapy and has shown synergistic effect in 
combination therapy setting (Blank et al., 2004; Hirano et al., 2005; Iwai et al., 2002; Iwai et al., 
2005; Nomi et al., 2007; Strome et al., 2003; Zhang et al., 2009). 
 
Clinical Phase I/II trials with MoAbs targeting either PD-L1 or PD-1 have shown promising hints 
for clinical efficacy, i.e., objective tumor response in indications such as NSCLC, melanoma, and 
ovarian cancer (Brahmer et al., 2012; Hamid et al., 2013; Topalian et al., 2012). Avelumab has two 
main mechanisms of action for exerting its anti-tumor effects:  
1. PD-L1 on tumor cells can interact with PD-1 or B7-1 on activated T cells. These interactions 
have been shown to significantly inhibit T cell activities. Therefore, blocking PD-L1 interaction 
with PD-1 or B7-1 by anti-PD-L1 can release T cells from immunosuppression, and lead to 
elimination of tumor cells by T cells.  
2. Tumor cells may express high levels of PD-L1 on their surface compared with normal tissues. As 
a fully human IgG1 MoAb, avelumab has ADCC potential. Upon binding to PD-L1 on tumor cells 
and binding with their Fc part to Fc-gamma receptors on leukocytes, avelumab can trigger tumor-
directed ADCC. Therefore, blocking PD-L1 inhibitory mechanisms by interactions with not only 
PD-1 but also the other ligand, B7-1, avelumab offers unique therapeutic potential compared with 
MoAbs targeting PD-1. 
 
2.2.1.2 Rationale for Dose Selection: 
 
Dose selection was determined following review of the PK, PD, receptor occupancy, and 
preliminary clinical safety and efficacy data observed in the ongoing Phase I Trial EMR 100070-
001.  
 
2.2.1.3 Pharmacokinetics and Target Occupancy  
 
Avelumab plasma levels leading to full TO on PBMCs resulted in tumor growth inhibition in a 
murine disease model. Therefore, full TO on PBMCs can be considered a PD marker for the ability 
of avelumab to act on its target and to show clinical activity.  
 
Target occupancy on peripheral blood CD3+ T-cells was therefore investigated in human blood in 
vitro by flow cytometry after spiking of whole blood samples from 8 healthy volunteers with 
avelumab over a concentration range of 0.003-10 μg/mL. Fifty percent (50%) receptor occupancy 
was observed at a drug concentration of 0.122 μg/mL ± 0.042 μg/mL and a plateau indicating at 
least 95% receptor occupancy was reached in all donor blood samples at 1 µg/mL. 
 
PK profiles obtained during the dose escalation phase of Trial EMR 100070-001 were utilized to 
investigate whether this concentration of at least 1 µg/mL was achieved throughout the dosing 
interval. The median ± standard deviation trough concentration at the end of the first cycle after 
administration of the 10 mg/kg dose is 21 ± 12 µg/mL (n=283). This median trough concentration 
increases during the subsequent cycles to 25 ± 16 µg/mL (second cycle) (n=269), 27 ± 17 µg/mL 
(third) (n=202), and remains between 27 and 36 µg/mL during the subsequent cycles (n=55–171).  
 
These data were confirmed in ex-vivo samples taken at minimum trough concentration (Cmin) after 

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the first dose (Day 15) in a small number of subjects during the initial dose escalation part of the 
Phase Ib Trial EMR 100070-001 (n=9). For doses of 10 mg/kg, TO for 4 subjects was greater than 
90%, at trough serum levels ranging between 12.69 to 26.87 μg/mL. Also for doses of 3 mg/kg 
available TO data for 2 subjects with trough levels ranging from 4.56 to 6.99 μg/mL, showed 
greater than 90% TO at trough exposure levels. At dose level 1 mg/kg, 2 out of 3 subjects displayed 
less than 90% TO at trough serum concentrations. Avelumab serum concentrations were below the 
quantification limit of 0.2 μg/mL in these 2 subjects.  
 
Further evidence for a full TO achieved with the 10 mg/kg dose throughout the entire dosing 
interval was derived from the population PK model based on data of 410 subjects from ongoing 
studies EMR 100070-001 and EMR 100070-002. Eighty-three subjects with rich PK profiles, 9 
subjects with peak and trough concentrations and 318 subjects with only trough concentrations were 
included in this analysis. A two compartment model with mixed linear plus Michaelis-Menten 
elimination was evaluated. Limited by very few observations collected in low concentration range 
showing non-linear elimination, a Michaelis-Menten elimination was only observed at very low 
concentrations (Vmax [maximal elimination]=0.07 mg/h [Relative standard error (RSE)=94%], 
Michaelis-Menten constant [KM]=0.9 μg/mL [RSE=448%]). 
 
Based on these results, it can be assumed that at doses of 10 mg/kg and greater, administered every 
2 weeks, a high TO is achieved in subjects throughout the entire dose interval. 
 
2.2.1.4 Clinical Safety Data Related to Dose 
 
As of the safety cutoff date of 01 June 2015, 770 subjects have received at least one dose of 
avelumab at doses ranging from 1.0 to 20 mg/kg in the Phase I Trial EMR 100070-001, and were 
followed for at least 4 weeks. Overall, 717 subjects have received the proposed dose of 10 mg/kg in 
the expansion cohorts, of which 184 subjects have NSCLC, 120 subjects have gastric cancer, 75 
subjects have ovarian cancer and 44 subjects have urothelial carcinoma. 
 
In the dose escalation portion of the Trial EMR 100070-001, there was no evidence of differences 
in the safety profile across all administered dose levels from 1 mg/kg to 20 mg/kg. The MTD was 
not reached. Ongoing review of the safety data by the SMC suggests an acceptable safety profile of 
avelumab administered at the 10 mg/kg every 2 weeks dose and schedule. Treatment-related 
treatment emergent adverse events (TEAEs) were observed in 498 (69.5%) subjects in the pooled 
expansion cohort. The most frequently observed treatment related TEAE was infusion-related 
reaction reported in 134 subjects (18.7%), followed by fatigue reported in 130 subjects (18.1%) and 
nausea reported in 74 subjects (10.3%). Grade ≥ 3 treatment-related TEAEs were observed in 77 
subjects (10.7%) in the pooled expansion cohort, of which 13.0%, 9.2%, 6.7%, and 4.5% occurred 
in the NSCLC, gastric cancer, ovarian cancer, and urothelial carcinoma expansion cohorts, 
respectively. Infusion-related reactions including hypersensitivity reactions and immune-mediated 
adverse reactions have been identified as expected adverse drug reactions of avelumab. The safety 
profile is consistent with findings reported for other anti-PD-1 or anti-PD-L1 antibodies. 
 
2.2.1.5 Clinical Efficacy Data Related to PK 
 
Preliminary efficacy results of the 184 subjects treated with 10 mg/kg of avelumab once every 2 
weeks in the NSCLC treatment expansion cohort of Phase I Trial EMR 100070-001 with a 

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minimum follow-up of at least 6 months as of 15 January 2015, are available. The ORR according 
to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (including confirmed and 
unconfirmed responses) among the 184 NSCLC subjects treated at 10 mg/kg of avelumab was 
13.6%, which includes one complete response (CR) (0.5%) and 24 PR (13.0%). In 19 of the 25 
responders (with either a CR or PR) (76.0%), the responses were ongoing at the time of the data 
cutoff. The ovarian cancer expansion cohort had a data cutoff of 13 February 2015, approximately 
13 weeks after the start of avelumab treatment on the last subject who was included in this pre-
planned interim analysis on this expansion cohort. The ORR based on confirmed and unconfirmed 
responses for subjects treated in the ovarian cancer expansion cohort was 10.7% (8 of 75 subjects). 
 
A descriptive analysis was performed for the NSCLC expansion cohort to explore whether there 
was any correlation between the efficacy readouts and exposure as measured by Cmin after the first 
(Day 15) or second dose (Day 29) of avelumab administration. These analyses were separately 
performed with the 2 sets of Cmin data: Cmin after the first dose on Day 15 and Cmin after the 
second dose on Day 29. The analysis set consisted of all treated subjects (at least one fully 
administered dose within 80% to 120% of the intended dose) from the NSCLC expansion cohort for 
which preliminary trough PK concentrations (Cmin) and efficacy data were available (n=158 for 
Day 15 and n=143 for Day 29). Splitting the NSCLC subject cohort into categories characterized by 
unconfirmed Best Overall Response according to RECIST 1.1 (non-evaluable, progressive disease, 
stable disease [SD], PR, CR) showed no difference in median and distribution of the drug exposure 
between these cohorts as measured by Cmin. Moreover, there was no correlation between Cmin 
data on Day 15 or Day 29 and tumor response as measured by percent change from baseline to best 
post-baseline assessment achieved throughout the trial (r2 < 0.01 for both analyses using Day 15 
and Day 29 PK data). 
 
Based on these data, tumor response was not related to the drug concentrations at the end of the 
dosing interval. 
 
Based on the PK results and the receptor occupancy data, sufficient trough concentrations appear to 
be achieved for full TO in the blood in all subjects receiving the 10 mg/kg dose. At the doses of 10 
and 20 mg/kg, no target mediated drug disposition was observed in PK and population PK analyses, 
indicating a high receptor occupation at the end of the dosing interval. Within the dose range of 1 
mg/kg to 20 mg/kg, AE data were not dose dependent resulting in no clear signaling that lowering 
the dose below 10 mg/kg would improve or enhance subject safety. Within the subject cohort 
receiving 10 mg/kg every 2 weeks to treat NSCLC, the efficacy parameters were not correlated with 
the achieved drug concentrations. 
 
Based on these data, a dose of 10 mg/kg once every 2 weeks is considered the biologically optimal 
dose and was selected for further evaluation of avelumab in NSCLC subjects. The dose of 10 mg/kg 
once every 2 weeks is considered to have a favorable risk benefit profile and thus represents an 
appropriate dose for further evaluation in ongoing and planned avelumab trials. 
 
2.2.1.6 Nonclinical Pharmacology:  
 
An overview of pharmacology studies with avelumab is presented in Table 1 and Table 2. 
 

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2.2.1.7 Nonclinical Pharmacokinetics: 
 
The PK of avelumab was evaluated in mice and cynomolgus monkeys after single IV 
administration. Additional PK data were obtained during the course of repeated dose toxicity 
studies. These studies are summarized in Table 3. 
 
 

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2.2.1.8 Toxicology: 
 
The toxicological profile of avelumab was evaluated in repeat dose toxicity studies of 4-week 
duration with weekly IV bolus injection/infusion in mice, rats and cynomolgus monkeys (Studies 
RF2710, RF2740, RF4990, RF3310, and T16228). An additional repeat dose toxicity study with 
intermittent once weekly IV infusion over 13 weeks followed by an 8-week recovery period was 
performed in cynomolgus monkeys (Study RF4990). Investigations on the local tolerability were 
integrated in the repeat-dose toxicity studies. 
 
The repeat-dose rodent studies were performed under non-Good Laboratory Practice (GLP) 
conditions and the studies with cynomolgus monkeys were conducted according to GLP. In 
addition, an in vitro cytokine release assay in human and cynomolgus monkey whole blood and 
PBMCs was performed (non-GLP; StudiesT17985, T17986, and 14-DA471-N0) as well as a TCR 
study in normal human and cynomolgus monkey tissues according to GLP (Study 20015186 and 
Study20015187). 
 
The non-GLP studies were conducted according to quality management system standard in order to 
ensure quality and data integrity. 
 
An overview of the toxicology studies performed with avelumab and major findings is provided in 
Table 4. 
 
 

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2.2.1.9 Toxicology Summary: 
 
The toxicological profile of avelumab was investigated in vivo in mice, rats, and cynomolgus 
monkeys (Studies RF2710, RF2740, RF4990, RF3310, and T16228). In addition, an in vitro 
cytokine release assay in human and cynomolgus monkey whole blood and PBMCs (Studies 
T17985, T17986, and 14-DA471-N0) as well as a TCR study in normal human and cynomolgus 
monkey tissues was performed (Study20015186 and Study20015187). 
 
On the basis on the binding affinity data, the cynomolgus monkey and the mouse were selected as 
relevant species for the nonclinical safety testing of avelumab. However, in the repeat dose-toxicity 
studies in CD-1 mice with avelumab IV bolus injection mortality occurred mainly after the 3rd 
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immune-mediated hypersensitivity reaction, the mechanism of which is highly likely to be 
anaphylaxis (immunoglobulin E [IgE]/IgG mediated reaction). Due to severe hypersensitivity 
reactions after repeated administration in mice and the low binding affinity in rats, rodent species 
are not considered appropriate for nonclinical safety testing of avelumab and therefore, a single 
species approach (cynomolgus monkey only) is envisaged. 
 
Accordingly, repeat dose-toxicity studies of 4 and 13 weeks duration have been conducted in 
cynomolgus monkeys. Neither in the pilot 4-week IV repeat-dose toxicity study nor in the pivotal 
13-week study, clinical signs of hypersensitivity have been seen after repeated treatment with 
avelumab at dose levels of 20, 60, and 140 mg/kg, respectively. For the pilot 4-week study as well 
as for the pivotal 13-week IV repeat-dose toxicity study, a NOAEL of 140 mg/kg for systemic 
toxicity was established. Available toxicokinetic data in monkeys showed a t1/2 of 60 to 70 hours 
and linear kinetics of avelumab in this species. 
 
Initial CRA in human and cynomolgus monkey whole blood and PBMCs revealed no clear-cut 
evidence for release of pro-inflammatory cytokines. However, a subsequent, optimized CRA 
demonstrated evidence of potential cytokine release in PHA pre-stimulated PBMCs. Clinical 
experience has demonstrated that the relative risk of an infusion reaction is low (approximately 2%) 
and with premedication drops to a very low level (less than 1%) indicating that the optimized CRA 
substantially overestimates the risk of cytokine release in a clinical setting. 
 
2.2.1.10 Interactions: 
No formal drug interaction trials have been conducted with avelumab in humans. 
 
2.2.2 Talazoparib 
 
2.2.2.1 Investigational Agent Rationale 
 
Talazoparib is a potent, orally bioavailable, small molecule PARP inhibitor in development for the 
treatment of a variety of human cancers.  
 
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 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, 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 proposed dose of 1 mg 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. The most common TEAEs associated with talazoparib (>20%) 
occurring in patients who received 1 mg QD talazoparib were 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%).  

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Serious AEs (SAEs) occurred in 52 of 164 patients (31.7%) who received 1 mg QD 
talazoparib. SAEs 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 study 673-301, 308 patients with locally advanced or metastatic breast 
cancer were treated as of the cutoff date. An estimated 206 patients were receiving talazoparib and 
102 were receiving another single-agent chemotherapy of physician’s choice, based on the 2:1 
randomization scheme. A serious TEAE of veno-occlusive disease of the liver leading to death was 
assessed as related to talazoparib by the Investigator in a 34-year old female patient with advanced 
breast cancer metastatic to the axilla and bone who developed asymptomatic Grade 3 liver test 
abnormalities (ALT and AST with normal bilirubin) while receiving talazoparib at 0.75 mg. Ten 
days after talazoparib dosing was discontinued due to Grade 4 thrombocytopenia, the patient had 
acute hepatic failure attributed to veno-occlusive disease of the liver by the Investigator. The 
Sponsor considered veno-occlusive disease of the liver an unlikely etiology, a consideration 
supported by 2 independent hepatologists who reviewed the case. 
 
Clinical Efficacy in Patients with Advanced Solid Tumors 
 
A total of 110 patients with advanced tumors with DNA repair pathway abnormalities, 
particularly those associated with BRCA and phosphatase tensin homolog (PTEN) dysfunction, 
were enrolled in the Phase 1 study PRP-001, which was completed in March 2015. The maximum 
tolerated dose (MTD) of talazoparib was defined as 1 mg QD and it was used in the expansion 
phase of the study in patients with breast, ovarian/primary peritoneal, and pancreatic cancer with 
deleterious germline mutations; small cell lung cancer (SCLC); and Ewing sarcoma. As of 13 
February 2015, the proportion of patients with breast, ovarian/primary peritoneal, and pancreatic 
cancers with BRCA mutations who were treated with talazoparib at 1 mg QD and had objective 
responses according to RECIST v1.1 was 50% (7 of 14; 95% CI: 23.0, 77.0), 41.7% (5 
of 12; 95% CI: 15.2, 72.3), and 20.0% (2 of 10), respectively. Cancer patients harboring BRCA 
mutations who are resistant to platinum-based chemotherapy display decreased sensitivity to PARP 
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not include patients who progressed within 6 months of starting previous platinum-based 
chemotherapy. This is aligned with the approach followed for other indications in this study. 
Responses were also reported in 2 patients with SCLC (8.7%; 2 of 23; 95% CI: 1.1, 28.0). 
 
2.2.2.2 Rationale for Dose Selection 
 
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 QD and the recommended 
dose for further development was determined to be 1 mg QD. Data from that study at 1 mg/day 
demonstrated objective responses or clinical benefit (CR, PR, or SD 
≥24 weeks) in patients with breast, ovarian/peritoneal, pancreatic cancer, SCLC, and Ewing 
sarcoma. The dose level of 1 mg QD is currently being used in the ongoing randomized Phase 3 
study 673-301 in patients with locally advanced or metastatic breast cancer. 
 
2.2.2.3 Pharmacokinetics and Target Occupancy 
 
The PK of talazoparib as a single agent was evaluated in 142 adult patients with cancer, including 
109 patients with solid tumors (Study PRP-001) and 33 with hematologic 
malignancies (Study PRP-002). Doses of 0.025 mg to 2 mg were administered orally as a single 
dose or as QD doses. This dose range bracketed the 1 mg QD dose used in ongoing safety and 
efficacy studies, and provided a framework for assessing dose linearity. As the PK of talazoparib 
was similar in patients with solid tumors and hematologic malignancies, and no differences were 
apparent between males and females, the results are summarized collectively. Oral absorption of 
talazoparib was rapid and independent of dose after administration of single or QD doses. Peak 
talazoparib concentrations were generally reached approximately 1 to 8 hours post-dose. Exposure 
increased approximately dose-proportionally with increasing doses. At 1 mg/day, the mean t1/2 was 
approximately 2 days; the mean apparent volume of distribution (V/F) was 415 L, indicating 
extensive extravascular distribution. Steady state was reached in approximately 2 to 3 weeks with 
daily administration. Apparent oral clearance (CL/F) of talazoparib appeared to be dose linear, with 
a mean CL/F across doses of approximately 5 L/h. Renal excretion was a major elimination 
pathway for unchanged parent talazoparib. Following oral administration, 44% to 90.6% of the dose 
was recovered in urine as unchanged parent drug over 24 hours at steady state for doses up to 1 mg 
QD.  
 
Mean renal clearance ranged from 1.38 L/h to 4.96 L/h independent of dose, suggesting linear 
urinary elimination kinetics. Following repeated administration at 1 mg QD, talazoparib 
accumulated approximately 2.4-fold relative to a single dose.  
 
At steady state, the mean maximum plasma concentration (Cmax) was 21.0 ng/mL (55 nM), the 
mean plasma trough concentration (Ctrough) was 3.72 ng/mL (9.87 nM), and the mean area under 
the plasma concentration-time curve (AUC) was 202 ng*h/mL (532 nM*h). The Ctrough of 
talazoparib at steady state at 1 mg QD is above the Ctrough values at the efficacious dose of 0.33 
mg/kg daily used in some of the xenograft models (1.3 nM). 
 

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PK data from a food-effect study showed that food had no effect on the extent of absorption of 
talazoparib (AUC) but decreased the rate of absorption (Cmax was 46% lower and time to Cmax 
[Tmax] was 2.63 hours later); however, this reduction in the rate of absorption following a single 
dose is not clinically relevant because talazoparib accumulates 2.4-fold at steady state after 1 mg 
QD dosing. Furthermore, AUC or Ctrough is thought to drive efficacy, not Cmax; therefore, 
talazoparib can be taken with or without food. Talazoparib is being administered without regard to 
food in ongoing safety and efficacy studies.  
 
A preliminary population PK analysis used data from patients in Studies PRP-001 and PRP-002 to 
assess the effects of renal function on the PK of talazoparib. The talazoparib CL/F in patients with 
mild renal impairment (creatinine clearance [CLCR] 60-89 mL/min) was similar compared with 
patients with normal renal function (CLCR ≥90 mL/min). In patients with moderate renal 
impairment (CLCR 30-59 mL/min), the talazoparib CL/F was decreased by 44% from normal, 
resulting in higher talazoparib exposure. The talazoparib starting dose for patients with moderate 
renal impairment is discussed in Section 1.2.6.2. The effect of renal impairment on talazoparib PK 
is also being investigated in the ongoing study MDV3800-01. 
 
The effect of hepatic impairment on talazoparib PK is being investigated in the ongoing MDV3800-
02 study. 
 
The potential for talazoparib to affect the PK of other drugs was assessed through in vitro 
experiments and described in the talazoparib IB (Investigator’s Brochure of talazoparib (MDV3800, 
BMN673), dated 07 Jul 2017.). 
 
 
2.2.2.4 Clinical Safety Data Related to Dose 
Based on preliminary population PK analysis from patients in Studies PRP-001 and PRP-002, the 
talazoparib CL/F was decreased by 44% from normal in patients with moderate renal impairment 
(CLCR 30-59 mL/min), and therefore in those patients the 1 mg QD talazoparib starting dose should 
be reduced to 0.75 mg QD, as discussed in the talazoparib IB (Investigator’s Brochure of 
talazoparib (MDV3800, BMN673), dated 07 Jul 2017). In the Phase 1b portion of this study, only 
patients with a creatinine clearance of ≥60 mL/min (as estimated using the Cockcroft-Gault 
formula) will be eligible for enrollment. The entirety of the available clinical data, including data 
from the ongoing study MDV3800-01 in patients with renal impairment when available, at the 
conclusion of the Phase 1b portion will be used to determine the appropriate starting dose for 
talazoparib in Phase 2 portion in patients with moderate renal impairment. 
 
Since avelumab is an immunoglobulin (Ig)G1 mAb eliminated by intracellular lysosomal 
proteolytic degradation throughout the entire body while talazoparib is a small molecule cleared 
primarily via excretion of unchanged parent drug and metabolized to a minor extent via oxidation 
and dehydrogenation, no PK DDI is anticipated between avelumab and talazoparib when given in 
combination. Nevertheless, concentration-time data will be measured on this study for both 
avelumab and talazoparib following coadministration at single dose and at steady state, and will 
be compared with historical PK data for avelumab and talazoparib as single agents. 
 

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2.2.2.5 Interactions 
 
No formal drug interaction trials have been conducted with talazoparib in humans. 
 
 Axitinib 
 
2.2.3.1 Rationale for Axitinib 
Abnormal vasculature is a hallmark of solid tumors, including gynecologic cancers.  Tumor-related 
blood vessels are irregular secondary to disordered, immature growth stimulated by VEGF as well 
as by physical intra- and peri-tumoral compression by cancer cells, fibroblasts, and components of 
the extracellular matrix.  Abnormal vasculature contributes to a hypoxic state, leading to a cascade 
of tumor-survival changes, including induction of epithelial-mesenchymal transition pathways, 
promotion of a cancer “stem cell” phenotype, switch to anaerobic metabolism, and generation of an 
immunosuppressive microenvironment (Jain et al, 2014).  Therefore, much work has been focused 
on modifying tumor vasculature to thwart these changes, and in parallel, improve intratumoral 
delivery of chemotherapy or immunotherapy.  
 
Axitinib is a small molecule inhibitor that binds to the catalytic domain of non-activated (non-
phosphorylated) receptor tyrosine kinase.  It is a highly potent inhibitor of VEGF receptors 1, 2, and 
3 (VEGFR1-3). 
 
2.2.3.2 Preclinical efficacy 
 
Axitinib is a highly potent inhibitor of VEGFR 1, 2 and 3, with IC50 of approximately 0.09, 0.2, and 
0.1-0.29nM respectively.  Axitinib had weaker inhibitory activity against PDGF receptor α 
(PDGFRα), PDGFRβ, and KIT, with respective IC50 values of 5.0, 1.6, and 1. nM.   
 
In vitro, axitinib inhibited VEGF-mediated endothelial cell adhesion and migration and induced 
endothelial cell apoptosis within 6 hours of treatment of cell cultures.  Anti-angiogenic activity was 
demonstrated in several xenograft tumor models, in which axitinib treatment led to reduced tumor 
microvessel density, tumor blood flow/permeability, tumor cell proliferation, and was associated 
with increased tumor apoptosis (Axitinib Investigator’s Brochure).  These effects were similarly 
seen in murine models of spontaneous pancreatic islet-cell tumors and lung carcinomas: axitinib 
decreased endothelial cell fenestrations, vascular sprouting, patency, blood flow, and VEGFR2/3 
expression.  Single agent axitinib was effective in orthotopic murine models of colon and lung 
carcinomas, RCC, and HCC, with maximum tumor growth inhibition (TGI) of 96%, 75%, 74%, and 
54% respectively. 
 
2.2.3.3 Clinical Pharmacokinetics 
 
As of June 2018, 45 studies evaluate the safety, efficacy, and PK of axitinib were completed or 
were ongoing, including 15 Phase I studies involving 532 healthy subjects (inclusive of one study in 
participants with hepatic impairment) and 30 studies encompassing 3016 cancer patients receiving 
axitinib monotherapy (n=1824) or in combination (n=1192). 
 
In humans, the plasma pharmacokinetics of axitinib at steady state were generally linear.  Axitinib 
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administration.  Mean absolute bioavailability (in healthy volunteers) was 58%.  Axitinib 
administered at 5mg orally achieved a maximal plasma concentration (Cmax) of 32 ng/mL with t1/2 of 
5.2 hours. 
 
Metabolism of axitinib occurs primarily through the CYP3A4 enzyme, and to a lesser extent by the 
CYP1A2, CYP2C19, and UGT1A1 enzymes as determined from in vitro studies.  Axitinib 
elimination occurs through hepatobiliary excretion; renal excretion does not contribute to 
elimination of axitinib.  Axitinib was evaluated in subjects with hepatic impairment, finding that 
plasma pharmacokinetics of a single dose of axitinib were not altered in those with mild hepatic 
impairment (Child Pugh Class A).  However, there was a 2-fold increase in AUCinf and a 1.3-fold 
increase in Cmax in subjects with moderate hepatic impairment (Child Pugh Class B).  A Phase II 
study in patients with HCC suggested that no dose adjustment is required when administering 
axitinib to patients with mild hepatic impairment (Child Pugh Class A), but that the starting dose of 
axitinib can be reduced by approximately half (to 2mg BID) in those with moderate hepatic 
impairment (Child Pugh Class B).  Axitinib has not been studied in patients with severe hepatic 
impairment (Child Pugh Class C). 
 
No significant difference in axitinib clearance was seen in patients with mild to severe renal 
impairment (CrCl 15-89 mL/min), suggesting that no dose adjustment is needed for patients with 
mild to severe renal impairment.   
 
Axitinib plasma pharmacokinetics were not statistically different when studied in Caucasian, 
Chinese, and Japanese subjects. 
 
A food effect study evaluating crystal polymorph Form XLI of axitinib determined that there was 
no clinically meaningful food-effect for Form XLI FCIR tablets. 
 
2.2.3.4 Clinical Safety 
 
In patients with solid tumors treated with single agent axitinib in the first-in-human (FIH) trial, 10 
of 10 subjects in the first cohorts developed hypertension, with 5 of Grade 3 or 4 severity.  
Hypertension was responsive to antihypertensive medications and resolved with cessation of 
axitinib treatment.  Two participants had seizures that may have been associated with hypertension, 
one receiving 20mg BID and the other receiving 10mg BID.  In subsequent cohorts in which 
patients received doses <20mg BID, hypertension was a DLT in 1 of 6 patients receiving 15mg 
once daily.  Zero of 14 patients receiving axitinib 5mg BID had hypertension that could not be 
managed with standard antihypertensive medications.  In the second cohort of the FIH study, 1 
patient with NSCLC developed fatal hemoptysis that was considered related to axitinib.  Other 
bleeding events in the other 36 participants were epistaxis, breast hemorrhage, hematochezia, rectal 
hemorrhage, and vaginal hemorrhage, all Grade 1 and considered unrelated to axitinib.   
 
Fourteen patients were ultimately treated at the MTD within the FIH trial.  Of these patients, one 
patient experienced a DLT of Grade 2 stomatitis, one experienced a DLT of Grade 3 diarrhea, and 6 
patients experienced Grade 1-3 hypertension that was not dose limiting and was managed with 
standard antihypertensive medications.   
 
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showed the most common treatment-emergent all-causality AEs were diarrhea 55%, hypertension 
51%, fatigue 47.1%, decreased appetite 40%, nausea 32.6%, decreased weight 32.3%, dysphonia 
31.1%, palmar-plantar erythryodysesthesia syndrome 29.4%, hypothyroidism and vomiting 22.6%, 
constipation 20.3%, proteinuria 20.1%.  The most frequent Grade ≥3 AEs were hypertension 
20.7%, fatigue 10.2%, and diarrhea 10.1%.  The most frequent Grade 3 or 4 hematologic 
abnormalities were lymphocytes 8.8%, hemoglobin 2.4%, and neutrophils 1.5%.  The most frequent 
Grade 3 or 4 laboratory abnormalities were lipase 8.9%, hyponatremia 7.4%, hyperkalemia 5.1%, 
hyperglycemia 4.8%, hypophosphatemia 4.7%, amylase 4.3%, AST 4.1%, ALT 3.4%, hypokalemia 
2.5%, hypocalcemia 1.7%, and total bilirubin 2.3%. 
 
2.2.3.5 Clinical efficacy 
 
Single agent axitinib demonstrated early evidence of clinical efficacy in Phase II trials across 
NSCLC (Schiller et al 2009), radioactive iodine-refractory thyroid cancer (Cohen et al, 2008), 
melanoma (Axitinib Investigator’s Brochure), and metastatic RCC (Rixe et al 2007). 
 
A subsequent Phase III trial of single agent axitinib in previously-treated advanced RCC 
demonstrated higher ORR compared to sorafenib (19.4% vs 9.4%, p=0.0001) and improved median 
PFS compared (6.7 mo vs 4.7 mo, p<0.0001) (Motzer et al 2013), however there was no statistically 
significant improvement in median OS (20.1mo vs 19.2mo, p=0.374).  Similarly, in treatment-naïve 
advanced RCC, single agent axitinib led to higher ORR compared to sorafenib (32% vs 15%, 
p=0.0006) and improved median PFS (10.1 mo vs 6.5 mo, p=0.038), without improvement in 
median OS (21.7 mo vs 23.3 mo, p-0.4883) (Hutson et al, 2017).  Overall, this data suggested that 
single agent axitinib was not sufficient to produce a meaningful difference in overall survival, and 
that combination strategies may be needed. 
 
2.3 
Rationale 
 
2.3.1 Rationale for avelumab alone 
 
It has been suggested that tumors with higher mutational load may harbor more tumor-specific 
neoantigens that may lead to increased tumor-infiltrating lymphocytes (TILs) (Rooney et al., 2015).  
In this regard, recent analyses of TCGA data have implicated neoantigen load in driving T cell 
responses(Brown et al., 2014) and have identified novel associations between specific genomic 
alterations and increased immune infiltrates in various tumors(Hussein et al., 2015; Rajasagi et al., 
2014; Rutledge et al., 2013). Furthermore, high mutational loads have been associated with high 
neoantigen loads and an elevated number of TILs which is counterbalanced by overexpression of 
immune checkpoints (Hussein et al., 2015; Llosa et al., 2014; Xiao and Freeman, 2015). The Cancer 
Genome Atlas project identified 2 groups of endometrioid endometrial cancers (ECs) with high 
mutation frequency: an ultramutated group (7% of all tumors) that harbored mutations in the 
exonuclease domain of polymerase e (POLE), and a hypermutated group (28% of tumors) with 
microsatellite instability (MSI), the majority of which harbored MLH1 promoter methylation.  It 
has recently been demonstrated that POLE and MSI ECs are associated with significantly increased 
predicted neoepitopes and numbers of CD3+ and CD8+ TILs compared with microsatellite stable 
(MSS) tumors (Howitt et al., 2015). Specifically, POLE mutated endometrial tumors had almost 15-
fold higher predicted neoantigen load compared to MSI tumors (two-sided t-test, p<0.001) and MSI 
tumors had an almost 7-fold higher median number of predicted neoepitopes per sample than MSS 

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tumors (two-sided t-test, p<0.001) (Howitt et al., 2015). Furthermore, PD-1 was significantly 
overexpressed in TILs and peritumoral lymphocytes of POLE and MSI compared with MSS ECs 
suggesting that POLE and MSI tumors may be excellent candidates for immunotherapies targeting 
the PD-1 pathway (Howitt et al., 2015; van Gool et al., 2015).   
 
Furthermore, the anti-PD-1 antibody pembrolizumab has demonstrated very promising activity in 
mismatch repair deficient colorectal and non-colorectal cancers (Le et al., 2015). Specifically, the 
immune-related objective response rate and immune-related progression-free survival rate were 
40% (4 of 10 patients) and 78% (7 of 9 patients), respectively, for mismatch repair–deficient 
colorectal cancers; the median progression-free survival and overall survival were not reached in 
the cohort with mismatch repair–deficient colorectal cancer. Patients with mismatch repair–
deficient noncolorectal cancer had responses similar to those of patients with mismatch repair–
deficient colorectal cancer (immune-related objective response rate, 71% [5 of 7 patients]; immune-
related progression-free survival rate, 67% [4 of 6 patients]). 
 
Finally, although in the study published in JAMA Oncology (Howitt et al. 2015) MSS tumors were 
in average associated with lower neoantigen load, lower number of tumor infiltrating lymphocytes 
(TILs) and lower expression of PD-1 and PD-L1 compared to POLE-mutated and MSI-tumors, it is 
important to underscore that a sizeable fraction of MSS tumors exhibited a high number of TILs, 
and high expression of PD-1 and PD-L1.  Specifically: 
• 34% of MSS tumors were associated with presence of peritumoral CD3+ T-cells in 
the stroma surrounding the epithelial component 
• 28% of MSS tumors were associated with expression of PD-1 in intraepithelial 
lymphocytes 
• 28% of MSS tumors were associated with expression of PD-1 in peritumoral 
lymphocytes 
• 13% of MSS tumors were associated with PD-L1 expression in intraepithelial 
immune cells 
• 19% of MSS tumors were associated with PD-L1 expression in tumors cells and 
• 56% of MSS tumors were associated with PD-L1 expression in peritumoral immune 
cells.   
 
Based on these data, although we expect that MSS endometrial tumors will be less responsive to 
PD-L1 inhibition than POLE and MSI endometrial cancers, our data support that a sizeable fraction 
of MSS tumors may also respond to PD-L1 blockade.  Therefore, we include a cohort of patients 
with MSS tumors to specifically address the question of whether these tumors may also respond to 
PD-L1 blockade.  
 
2.3.2 Rationale for avelumab in combination with talazoparib 
 
2.3.2.1 MSS cohort did not respond to single agent avelumab  
The preliminary results for this phase II two-stage study of avelumab revealed that among the 16 
patients enrolled in the MSS cohort, 14 patients developed progressive disease. One patient had 
confirmed partial response and one patient had irRECIST PFS6 but not RECIST PFS6. Given these 
results a second stage was not warranted for this cohort. (Konstantinopoulos, et al; results presented 
at SGO 2018 Meeting, New Orleans, LA) 

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However, based on the mechanisms of action discussed above, talazoparib and avelumab have 
the potential to produce additive or synergistic anti-tumor activity, with talazoparib functioning 
to promote immune priming and tumor immunogenicity and avelumab functioning to overcome 
PD-L1-mediated inhibition of any resulting anti-tumor immune response. 
2.3.2.2 Some endometrial cancers exhibit homologous recombination deficiency and respond 
to PARP inhibition 
 
There is a growing body of evidence that PARP inhibitors may have efficacy in a variety of tumors 
with homologous recombination (HRR) defects, including a subset of endometroid endometrial 
adenocarcinomas. (Reinbolt, et al, 2013) A recent case report A 42-year-old woman with a germline 
BRCA2 mutation and recurrent low-grade endometrioid endometrial adenocarcinoma experienced 
clinical and radiographic response to the PARP inhibitor, olaparib. This patient remains in clinical 
remission after 15+ months of treatment. (Gockley, et al; 2018) 
 
Deficiency of the tumor suppressor gene PTEN is associated with homologous recombination 
defects similar to BRCA mutations. When exposed to PARP inhibitors, PTEN deficient cells suffer 
synthetic lethality similar to the mechanism triggered in BRCA-deficient cells treated with PARP 
inhibitors. (Mendes-Pereira, A.M., et al., 2009) In ovarian cancer, a focal deletion region at 
10q23.31 that includes only PTEN has been found in approximately 7% of HGSOCs.  These tumors 
exhibit homozygous PTEN deletion which is also associated with downregulation of PTEN at the 
mRNA level. (TCGA, 2011) PTEN deficiency has been shown to be synthetically lethal with PARP 
inhibition or compound PARP-PI3K inhibition (Dedes, K.J., et al.,2010 and  Bian, X., et al., 2017), 
and one of the proposed mechanisms is transcriptional downregulation of RAD51 (Mendes- Pereira, 
A.M., et al., 2009 and Bian, X., et al., 2017). Specifically, in an in-vitro study, deficiency of the 
tumor suppressor PTEN in endometrioid endometrial cancer cell lines was associated with increased 
sensitivity to olaparib. (Dedes, K.J., et al., 2010) Furthermore, in a case report of a 58-year-old 
woman who presented with metastatic endometrioid endometrial adenocarcinoma and had several 
platinum-sensitive relapses, olaparib treatment (as part of a phase 1 trial) was associated with 
significant reduction in the size of her brain metastases and subjective improvement in her 
symptoms after 10 weeks. At 8 months the patient had progression of her tumor and a biopsy at that 
time revealed intact somatic BRCA 1 and 2 but a loss of PTEN. (Forster, et al., 2011) However, 
another study showed that PTEN deficient endometrioid endometrial cancer cells are not responsive 
to PARP inhibitor olaparib monotherapy, but instead show superior sensitivity 
to compound inhibition with the PI3K inhibitor BKM120. (Bian, X., et al., 2017) These apparently 
conflicting data indicate that the association of PTEN deficiency with HRR deficiency and response 
to PARP-inhibitors is likely context-specific. However, these studies suggest that further 
investigation into this area is likely to identify which patients with gynecologic malignancies may 
benefit from PARP inhibition. 
 
 
2.3.2.3 PARP inhibitors may induce immune priming for response to immune checkpoint 
inhibitors 
 
Since 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 (Chen, et al., 2013) Talazoparib, via its ability to promote increased 

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DNA damage, has the potential to promote several of these key stages of the immune response. 
Figure 1 
 
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 (Galluzi, et al., 2017). Secondly, DNA damage promotes inflammation via 
two 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) (Ioannidou, et al., 2016) and the second being activation of the STING pathway via 
generation and detection of cytosolic DNA (Hartlova, et al., 2015 and Parkes, et al., 2016).  
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 (Wang, et al., 2017). Finally, 
DNA damage has been shown to lead to up-regulation of MHC, NKG2DL, and ICOSL, 
(Soriani, et al., 2009 and Tang, et al, 2014). which would be expected to increase the intrinsic 
immunogenicity of tumor cells and enhance their recognition and killing by T cells and NK 
cells. 
In keeping with these critical links between DNA damage and immune priming, talazoparib has 
been shown to drive the activation of STING and downstream target genes in cultured cell lines 
(Figure 2) and to promote T cell and NK cell infiltration and activation in a mouse model of 
ovarian cancer (Huang, et al., 2015). 
However, talazoparib treatment has also been shown to lead to 2-3 fold increased expression 
of PD-L1 by tumor cells,18 suggesting that this may represent a mechanism of resistance to 
possible talazoparib-mediated anti-tumor immunity, and suggesting that the combination of 
talazoparib and anti-PD-L1 may further enhance anti-tumor activity. This hypothesis is 

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supported by preclinical studies in syngeneic mouse models of ovarian (Figure 3) and 
colorectal cancer, which demonstrate a significant improvement in overall survival (OS) in 
mice treated with the combination of talazoparib and an anti-mouse PD-L1, but not in mice 
treated with either talazoparib or anti-mouse PD-L1 alone. 
Figure 2: Analysis of the STING Pathway Downstream Target Induction by Talazoparib (BMN 
673) 
 
 
Figure 3: Combination of Talazoparib (BMN 673) and Anit-mouse PDL-1 Treatment Significantly 
Prolongs Survival in an Ovarian Cancer Model 
 
 
2.3.2.4 Evidence of PARP inhibitor/PD-1/PDL-1 inhibitor combined efficacy 
 
Prior studies have suggested that the combination of PD-L1 blockade and PARP inhibition may 
lead to tumor inhibition. The combination of olaparib with durvalumab was evaluated in a Phase 1/2 
study in 10 patients with metastatic castration resistant prostate cancer. Overall, 8 out of 10 patients 

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had a reduction in PSA level, including 5 patients who had declines in PSA level ≥50% from 
baseline. PSA level reductions were observed in patients with bone-only disease, in those who had 
bone disease and soft-tissue or visceral metastases, and in patients with or without mutations in 
DNA repair pathways (Karzai FH, et al.,2017). 
 
While prior work suggests that PARP inhibitors alone have limited activity outside of BRCA 
mutations with a reported ORR of ~ 5% in BRCA wild type patients (Gelmon, et al. 2011), new 
work suggests that this limitation may be overcome with addition of PD-1 blockade. In the ovarian 
cancer cohort of the TOPACIO/Keynote -162 study, platinum resistant ovarian cancer patients with 
up to 5 prior lines of chemotherapy were treated pembrolizumab (anti-PD-1) and niraparib (PARP 
inhibitor) combination therapy and a 25% ORR was observed.  When this cohort was evaluated 
across biomarker populations, BRCA mutated patients had a 25% ORR, but interestingly, 
encouraging ORR was seen among HRD positive patients (25%) as well as wild-type BRCA (24%) 
and HRD negative patients (27%).  This study suggests that platinum resistant ovarian cancer 
patients may benefit from the combination of PD-1 blockade/PARP inhibition regardless of their 
BRCA or HRD status. (Konstantinopoulos, et al; presented at the 2018 ASCO Annual Meeting, 
Chicago, IL)   
 
Importantly, in order to limit patient exposure to an inactive agent, our study follows a two-stage 
design that allows for early stopping for futility.   
 
Based on the above data, this trial will interrogate the activity and toxicity of avelumab and 
talazoparib in a second cohort of MSS patients based on initial study which suggested that single 
agent avelumab was ineffective in these patients.  
 
 Rationale for avelumab in combination with axitinib 
 
Single agent axitinib is insufficient for meaningful clinical response 
As noted in Section 2.2, single agent axitinib yielded an improvement in median PFS but did not 
improve median overall survival in either the front-line or subsequent treatment of advanced renal 
cell carcinoma, suggesting that relying on anti-VEGFR as the sole mechanism of antitumor activity 
is insufficient.   
 
Disordered tumor vasculature promotes immune suppression 
The vasculature of solid tumors is abnormal morphologically, with disordered growth and 
inefficient vessel branches, and functionally, with leaky vessel walls.  These abnormal blood vessels 
are further compressed by tumor cells, fibroblasts, and tumor stroma, leading to reduced delivery of 
drugs, disease-directed therapies, and immune cells. The hypoxic environment promotes an overall 
immunosuppressive state, predominantly mediated by HIF1 α.  HIF1α attracts myeloid-derived 
suppressor cells (MDSC) and promotes their differentiation into tumor-associated macrophages, 
which in turn suppress T cells (Corzo et al 2010; Doedens et al 2010), as well as attracting 
regulatory T cells (Tregs) into the tumor microenvironment (Clambey et al, 2012).  This is 
compounded by HIF1α-mediated upregulation of inhibitory PD-L1 on myeloid derived suppressor 
cells, dendritic cells, and tumor cells (Noman et al 2014).  VEGF, secreted by tumor cells either in 
response to HIF1α or through oncogene upregulation, also promotes an immunosuppressive 
environment by decreasing cytotoxic T cell trafficking and effector function, promoting MDSC 
expansion, promoting Treg proliferation and differentiation, and inhibiting the appropriate 

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maturation of antigen-presenting dendritic cells (Datta et al 2019; Jain et al 2014).  
 
Therefore, by using ant-angiogenic agents to restore the tumor vasculature to a more normal 
morphology, distribution, and function, tumor perfusion can be improved.  This has the effects of 
(1) enhancing delivery of oxygen, chemotherapeutics, and immune cells, thereby (2) reducing 
hypoxia and converting the immunosuppressive tumor microenvironment into an 
immunostimulatory one.   
 
Preclinical efficacy of combination anti-angiogenic therapy and immune checkpoint blockade 
(CPB) 
In murine models of melanoma, several studies using anti-VEGF therapy combined with a T-cell 
directed therapy led to increased anti-tumor activity compared to either agent alone and was 
associated with enhanced infiltration of T cells into tumors.  Increased numbers of activated 
dendritic cells were seen, and conversely Tregs were decreased (Shrimali et al 2010; Li et al 2006).  
In a murine model of HCC, intratumor infiltration and activation of CD8+ T cells was only seen 
when anti-PD1 therapy was added to sorafenib and CXCR4 inhibition (Chen et al 2015).  Similar 
effects were seen in murine models of breast cancer treated with VEGFR2 inhibition and a cancer 
vaccine, and in a murine model of colorectal cancer combining VEGF inhibition with a GM-CSF-
secreting vaccine (Huang et al 2012; Li et al 2006).  This preclinical suggested that combinations of 
anti-angiogenic therapies and immunotherapies may be promising. 
 
Clinical efficacy of combination anti-angiogenic therapy and immune checkpoint blockade 
(CPB) 
The combination of axitinib (anti-VEGFR1-3) and avelumab (anti-PD-L1) was studied first in the 
JAVELIN Renal 100 Phase 1b trial in advanced clear cell RCC.  There was preliminary indication 
of clinical efficacy, with 32 of 55 (58%) treated patients demonstrating confirmed objective 
responses (Choueiri et al 2018).  The MTD was established as axitinib 5mg BID with avelumab 
10mg/kg every 2 weeks.  One patient died due to treatment-related autoimmune myocarditis.  Grade 
3 or worse palmar-planter erythrodysesthesia, elevated ALT, elevated amylase, and elevated lipase 
were seen in 4 patients each (7%).  Grade 3 or worse hypertension was seen in 16 patients (29%).  
This was followed by a randomized Phase III trial of combination avelumab/axitinib vs sunitinib, in 
previously treated advanced RCC (Motzer et al 2019).  A total of 442 patients received avelumab 
10mg/kg every 2 weeks + axitinib 5mg BID, compared to 444 patients who received sunitib.  
Among all-comers, avelumab/axitinib was associated with a median PFS of 13.8 months compared 
to 8.4 months with sunitinib, with HR 0.69 (CI 0.56-0.84, p<0.001); a confirmed ORR of 51.4% 
was seen with avelumab/axitinib compared to 25.7% with sunitinib. This benefit in all-comers was 
comparable to those with PD-L1 positive tumors (i.e. 63.2% of treated patients), in whom median 
PFS was 13.8 months with avelumab/axitinib compared to 7.2 months with sunitinib (HR 0.62, CI 
0.47-0.79, p<0.001).  In PD-L1 positive patients the confirmed ORR was 55.2% with 
avelumab/axitinib compared to 25.5% with sunitinib.  At the time of data cutoff, patients were 
continuing to be followed for overall survival, though at a median follow-up for overall survival of 
11.6 months and 10.7 months in the two treatment groups for PD-L1-positive patients, 37 patients 
and 44 patients had died, respectively. Based on these results, the combination of avelumab and 
axitinib was approved by the FDA in May 2019 for the first-line treatment of advanced RCC.  
 
 

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Results from Phase III trial of avelumab/axitinib vs sunitinib in RCC (Motzer et al 2019) 

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Given these encouraging results suggesting synergistic activity of dual antiangiogenic and immune 
CPB agents, a similar combination was recently studied in uterine cancer.  Lenvatinib (a 
multikinase inhibitor of VEGFR1-3) and pembrolizumab (anti-PD-1 agent) were combined in a 
single arm Phase II trial of 53 patients with metastatic endometrial cancer, who notably were not 
selected for PD-L1 nor microsatellite status.  Patients predominantly had serous histology (38%) 
and had received prior platinum doublet therapy (98%).  Three patients (6%) had received prior 
bevacizumab (anti-VEGF).   Thirteen patients (25%) were PD-L1 positive, 11 (21%) were negative, 
and 29 (55%) were unknown.  Four patients (8%) were MSI-H, 45 (85%) were MSS, and 4 (8%) 
had unknown microsatellite status.  The primary endpoint was proportion of patients with an 
objective response at week 24.  At week 24, 21 of 54 patients (39.6%) had achieved an objective 
response by investigator review; by independent review 24 patients (45.3%) had achieved an 
objective response at week 24.  The best overall response by independent review was CR in 3 
patients (5.7%), PR in 22 patients (41.5%), and SD in 19 patients (35.8%).  Eleven patients 
achieved responses lasting at least 6 months, and 8 patients achieved responses lasting at least 12 
months.  The estimated median PFS was 7.4 months in the per-protocol population. 
 
Based on the above data, and based on a previous cohort in this protocol showing low activity of 
single agent avelumab in MSS endometrial cancer (ORR 6.3%), a new cohort evaluating 
combination avelumab/axitinib in MSS endometrial cancer will determine whether addition of anti-
VEGFR activity will enhance immune CPB in this population. 
 
2.4 
Correlative Studies Background 
 
The identification of predictive correlates to response to treatment with checkpoint blockade has 
proven a critical, but elusive goal, with numerous proposed approaches across different tumor types, 
but none that has thus far gained widespread clinical acceptance (Ascierto, 2013; Herbst et al., 
2014). Several efforts have focused on the identification of PD-L1 expression via 
immunohistochemistry (IHC) on the surface of tumor, or infiltrating immune cells. Some studies 
have suggested a significant correlation between tumoral PD-L1 expression and response in non-
small cell lung cancer (Garon et al., 2015), although others utilizing a similar approach have failed 
to identify a significant correlation (Borghaei et al., 2015; Brahmer et al., 2015). Notable challenges 
in this strategy include the lack of standardization among IHC assays, the use of differential 
thresholds for assay positivity and a lack of consensus regarding the importance of explicitly 
accounting for PD-L1 expression on infiltrating immune cells. Complicating the development of 
these approaches are concerns that inadequate negative predictive value and full understanding of 
the underlying immune dynamics between the host and tumor may result in the exclusion of 
patients who may benefit from treatment.  
 
For this trial we will characterize PD-L1 and PD-L2 expression on tumor cells and infiltrating 
immune cells in baseline formalin fixed paraffin embedded (FFPE) blocks of cancer tissue (which 
are required for eligibility) and in optional biopsy specimens where available in conjunction with 
the Dana-Farber Cancer Institute Center for Immunooncology. We will also characterize CD3+ T-
cells, CD8+ T-cells and CD4+ T-cells as well as other immune cell markers and checkpoints in 
baseline FFPE blocks of cancer tissue and in optional biopsy and blood specimens. 
 

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Although less advanced in clinical development and practice, characterization of ex vivo surface 
markers on tumor cells, T-cells and other immune cells via multiparametric analysis (e.g. via flow 
cytometry or mass cytometry) has significant potential to reveal predictive biomarkers given the 
ability to measure multifarious combinations and to identify combinatorial patterns of expression 
among diverse cell populations. Using multiparametric assays developed in conjunction with the 
Dana-Farber Cancer Institute Center for Immunooncology, we will determine evaluate the relative 
frequencies of T-cell subsets and evaluate the expression of immune checkpoints and other 
immunologically relevant molecules as noted in Section 9.  
 
Genomic predictive correlates for response to checkpoint blockade have taken several forms. First, 
and serving as a critical line of evidence supporting this trial, numerous studies have suggested a 
correlation between mutational and neoepitope burden and response to checkpoint blockade (Le et 
al., 2015; Rizvi et al., 2015; Snyder et al., 2014). Furthermore, as noted above, identification of 
microsatellite instability resulting from defects in the mismatch repair pathway and specifically 
within MLH1, MSH2, MSH6 and PMS2 have been suggested to portend a significantly improved 
response to checkpoint blockade (Le et al., 2015). As such, we will plan to pursue genomic 
characterization of tumor and blood samples as noted in Section 9.  
 
At Dana-Farber Cancer Institute, in the Department of Pathology Center for Advanced Molecular 
Diagnostic at Brigham and Women’s Hospital, we have developed a cancer genomic assay to detect 
somatic mutations, copy number variations and structural variants in tumor DNA extracted from 
fresh, frozen or formalin-fixed paraffin-embedded samples “(Wagle et al. High-throughput 
detection of actionable genomic alterations in clinical tumor samples by targeted, massively parallel 
sequencing. Cancer Discovery 2012.)” The Oncopanel assay surveys exonic DNA sequences of 
various cancer genes and multiple regions across genes for rearrangement detection. DNA is 
isolated from tissue containing at least 20% tumor nuclei and analyzed by massively parallel 
sequencing using a solution-phase Agilent SureSelect hybrid capture kit and an Illumina HiSeq 
2500 sequencer. The Oncopanel assay assesses genes including mutations and copy number 
variations in TP53, CCNE1, MYC, ATR, ATM, PTEN and HR pathway and NER pathway genes. 
This assay will be performed in archival FFPE specimens if it has not already been performed (it is 
now standard for patients at Dana-Farber Cancer Institute). In cases where Oncopanel sequencing 
has already been performed on patient samples clinically or through DF/HCC protocols 11-104, 17-
000, or 20-000, we will plan to access these results to conserve primary patient samples for 
additional analyses.  

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3. PARTICIPANT SELECTION 
 
3.1 Eligibility Criteria  
 
Participants must meet the following criteria on screening examination to be eligible to participate 
in the study:  
 
Inclusion criteria applicable to all participants: 
 
 Participants must be classified into one of the following cohorts of recurrent or 
persistent endometrial cancer of any histology: 
 
▪ The MSI/POLE cohort includes endometrial cancers that are:  
MSI-H as determined by immunohistochemical complete loss of expression (absence of 
nuclear immunoreactivity) of at least one of the mismatch repair genes MSH2, MSH6, 
MLH1 and PMS2. This test is now done routinely for every newly diagnosed 
endometrial cancer patient in most centers in the US. 
 
AND/OR: 
 
POLE-mutated, i.e. endometrial cancers known to harbor mutations in the exonuclease 
domain (amino acid residues 268–471) of polymerase e (POLE) as determined by 
targeted sequencing or other next generation sequencing assay. Any Clinical Laboratory 
Improvement Amendments (CLIA)-approved genomic test documenting mutations in 
the exonuclease domain of POLE gene (amino acid residues 268–471) in the tumor will 
be accepted as proof of presence of POLE mutations and will lead to classification into 
this patient cohort. 
 
▪ The MSS cohorts include: 
Endometrial cancers that are MSS as determined by normal immunohistochemical 
nuclear expression of all the mismatch repair genes MSH2, MSH6, MLH1 and PMS2. 
Tumors which have not been sequenced for POLE mutations (i.e. their POLE mutations 
status is unknown) but are MSS, will be included in this cohort. 
 
 All patients must have measurable disease as defined by RECIST 1.1. Measurable 
disease is defined as at least one lesion that can be accurately measured in at least one 
dimension (longest diameter to be recorded). Each lesion must be >= 10 mm when 
measured by CT, MRI or caliper measurement by clinical exam; or >= 20 mm when 
measured by chest x-ray. Lymph nodes must be > 15 mm in short axis when measured 
by CT or MRI. 
 
 Prior Therapy:  
There is no upper limit of prior therapies but patients must have had one prior 
chemotherapeutic regimen for management of endometrial carcinoma. Initial treatment may 
include chemotherapy, chemotherapy and radiation therapy, and/or 
consolidation/maintenance therapy. Any platinum based chemotherapy (single agent 
platinum or any platinum doublet) administered in conjunction with primary radiation as a 

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radio-sensitizer WILL be counted as a systemic chemotherapy regimen. Furthermore, 
patients who have only received chemotherapy in the adjuvant setting will be eligible for the 
study. 
▪ Prior hormonal therapy is allowed (no washout period is required after hormonal 
therapy).  
▪ Patients must NOT have received any class of drugs targeted to the PD-1/PD-L1 
pathway. 
▪ Patients must NOT have received any prior PARP inhibitor therapy (for patients 
being considered for the avelumab/talazoparib cohort only). 
▪ Patients must NOT have received prior axitinib (for patients being considered for the 
avelumab/axitinib cohort only) 
 
 Age of 18 or greater years. Because insufficient dosing or adverse event data are 
available on the use of Avelumab, talazoparib, and/or axitinib in participants < 18 
years of age, children are excluded from the study. Endometrial cancer is very rare in 
the pediatric population. 
 
 ECOG performance status 0 or 1 (reference Appendix A for ECOG performance 
status criteria).   
 
 Availability of a formalin fixed paraffin embedded (FFPE) block of cancer tissue OR 
15 unstained 5-micron slides from the original surgery or biopsy or from a biopsy of 
recurrent disease.  
 
 Participants must have normal organ and marrow function as defined below: 
 
absolute neutrophil count 
>1,500/mcL 
platelets 
 
 
>100,000/mcL 
hemoglobin   
 
≥ 9g/dL 
total bilirubin 
 
within normal institutional limits 
AST(SGOT)/ALT(SGPT) 
      ≤2.5 × institutional upper limit of normal 
Creatinine 
 
≤ institutional upper limit of normal 
OR 
 
creatinine clearance ≥ 30 mL/min/1.73 m2 for participants with creatinine levels above  
 
institutional normal. 
 
CLCR should be estimated according to the Cockcroft-Gault formula as: 
CLCR={[(140–age) × weight)]/(72 x SCR)} × 0.85 where CLCR (creatinine clearance) is 
measured in mL/min, age is expressed in years, weight in kilograms (kg), and SCR 
(serum creatinine) in mg/dL. 
 
NOTE: Patients with moderate renal impairment (defined as an estimated creatinine 
clearance of 30-59 mL/min) will receive a reduced starting dose of Talazoparib at 0.75 
mg PO QD.  
 
 

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 Participant must not be pregnant or breastfeeding given that avelumab is an agent 
with unknown effects in pregnancy and breastfeeding and the potential for 
teratogenesis. Females of childbearing potential are defined as those who are not 
surgically sterile (i.e., bilateral tubal ligation, bilateral oophorectomy, or complete 
hysterectomy) or post-menopausal (defined as ≥ 12 months with no menses without an 
alternative medical cause). Serum pregnancy test (for females of childbearing 
potential) negative at screening. 
 
 The effects of avelumab on the developing human fetus are unknown.  For this reason 
and because some immunomodulatory agents are known to be teratogenic, women of 
child-bearing potential must agree to use adequate contraception (hormonal or barrier 
method of birth control; abstinence) prior to study entry, for the duration of study 
participation, and for at least 30 days after last avelumab treatment administration.  
Should a woman become pregnant or suspect she is pregnant while she or her partner 
is participating in this study, she should inform her treating physician immediately.   
 
 Toxicities of prior therapy (excepting alopecia and sensory neuropathy) should be 
resolved to < grade 2 per the revised NCI Common Terminology Criteria for Adverse 
Events (CTCAE) version 4. All appropriate treatment areas should have access to a 
copy of the CTCAE version 4. A copy of the CTCAE version 4 can be downloaded 
from the CTEP website at: http://ctep.cancer.gov. 
 
 Ability to understand and the willingness to sign a written informed consent document. 
 
Additional inclusion criteria for the avelumab/axitinib cohort: 
 
 Participants must have adequately controlled blood pressure (BP) with or without 
antihypertensive medications, defined as systolic BP that must be ≤140 mmHg and 
diastolic BP that must be ≤90 mmHg on two separate BP readings taken at least 1 hour 
apart at screening.  
 
 Participants must have LVEF ≥ lower limit of normal (LLN) as assessed by either 
multigated acquisition (MUGA) scan or echocardiogram (ECHO). 
 
 
3.2 
Exclusion Criteria 
 
Participants who exhibit any of the following conditions at screening will not be eligible for 
admission into the study. 
 
Exclusion criteria applicable to all participants: 
 
 Participants who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for 
nitrosoureas or mitomycin C) prior to entering the study or those who have not 
recovered from adverse events due to agents administered more than 4 weeks earlier. 
 
 Participants who are receiving any other investigational agents. 

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 Participants with known brain metastases should be excluded from this clinical trial 
because of their poor prognosis and because they often develop progressive neurologic 
dysfunction that would confound the evaluation of neurologic and other adverse 
events. 
 
 History of allergic reactions attributed to avelumab or any component in its 
formulations, or compounds of similar chemical or biologic composition to avelumab. 
Known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥ 3 NCI 
CTCAE v 4.03), any history of anaphylaxis, or uncontrolled asthma (that is, 3 or more 
features of partially controlled asthma) 
 
 Participants with a history of treatment with an anti-PD-1, anti-PD-L1, anti-CTLA-4 
or other investigational agents that target immune checkpoint inhibitors. 
 
 Known human immunodeficiency virus (HIV) or acquired immunodeficiency 
syndrome (AIDS) related illness, which may compromise the efficacy of 
immunostimulatory therapy.  
 
 Positive test for HBV surface antigen.  
 
 Positive Hepatitis C antibody and positive confirmatory HCV RNA test. The 
confirmatory HCV RNA test is not required if the HCV antibody is negative. If 
Hepatitis C antibody is positive, the confirmatory HCV RNA test should be done and if 
it is negative, then participants are eligible.  
 
 Subjects requiring hormone replacement with corticosteroids are eligible if the steroids 
are administered only for the purpose of hormonal replacement and at doses ≤ 10 mg 
or 10 mg equivalent prednisone per day. 
 
 Active infection requiring systemic therapy. 
 
 Current or prior use of immunosuppressive medication within 7 days prior to 
enrollment with the following exceptions to this exclusion criterion:  
▪ Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra-articular 
injection); 
▪ Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone 
or equivalent; 
▪ Steroids as premedication for hypersensitivity reactions (e.g., CT scan 
premedication). 
 
 Active autoimmune disease that might deteriorate when receiving an 
immunostimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, hypo- or 
hyperthyroid disease not requiring immunosuppressive treatment are eligible.  
 
 Prior organ transplantation including allogeneic stem-cell transplantation. 
 

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 Severe gastrointestinal conditions such as clinical or radiological evidence of bowel 
obstruction within 4 weeks prior to study entry, uncontrolled diarrhea in the last 4 
weeks prior to enrollment, or history of inflammatory bowel disease.  
 
 Uncontrolled intercurrent illness including, but not limited to symptomatic congestive 
heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social 
situations that would limit compliance with study requirements. 
 
 Clinically significant (i.e., active) cardiovascular disease: cerebral vascular 
accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months 
prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart 
Association Classification Class II), or serious cardiac arrhythmia requiring 
medication. 
 
 Known alcohol or drug abuse.  
 
 Individuals with a history of a different malignancy are ineligible except for the 
following circumstances: Individuals with a history of other malignancies are eligible if 
they have been disease-free for at least 5 years or if they are deemed by the investigator 
to be at low risk for recurrence of that malignancy. Individuals with the following 
cancers are eligible if diagnosed and treated within the past 5 years: breast cancer in 
situ, cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin. 
 
 All other significant diseases (for example, inflammatory bowel disease, uncontrolled 
asthma), which, in the opinion of the Investigator, might impair the subject’s tolerance 
of trial treatment. 
 
 Any psychiatric condition that would prohibit the understanding or rendering of 
informed consent. 
 
 Vaccination within 4 weeks of the first dose of avelumab and while on trial is 
prohibited except for administration of inactivated vaccines. 
 
 Patients may not use natural herbal products or other “folk remedies” while 
participating in this study. Herbal medications include, but are not limited to St. 
John’s Wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone 
(DHEA), yohimbe, saw palmetto, and ginseng.   
 
Additional exclusion criteria for the avelumab/axitinib cohort: 
 
 Participants having >1+ proteinuria on urinalysis or UPCR >1 will undergo a 24-hour 
urine collection for quantitative assessment of proteinuria.  Participants with urine 
protein >1 g/24-hours will be ineligible. 
 
 Participants with concern for bowel wall involvement or bowel serosal disease will be 
ineligible, due to the risk of perforation or fistulization with anti-angiogenic agents.  
Patients with liver serosal or pleural or peritoneal serosal disease are eligible. 

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 Participants will be ineligible if they have active gastrointestinal bleeding, as evidenced 
by clinically significant hematemesis, hematochezia, or melena in the past 3 months 
without evidence of resolution documented by endoscopy or colonoscopy. 
 
 Participants will be ineligible if using anticoagulant therapy with oral vitamin K 
antagonists, novel oral anticoagulants (NOACs), or direct oral anticoagulants 
(DOACs), inclusive of direct thrombin inhibitors and direct factor Xa inhibitors.  
Therapeutic use of low molecular weight heparin is allowed.  Low dose heparin 
required for maintenance of patency of central venous access devices are allowed. 
 
 Grade ≥3 hemorrhage within 4 weeks preceding Cycle 1 Day 1 treatment. 
 
 Ongoing cardiac dysrhythmias of CTCAE Grade≥2, or prolongation of the QTc 
interval to >500 msec. 
 
 Current use or anticipated need for treatment with drugs or foods that are known to 
be either: 
▪ Strong CYP3A4/5 inhibitors, including administration within 10 days prior to Cycle 
1 Day 1 treatment, including but not limited to grapefruit juice, grapefruit-related 
fruits (Seville oranges, pomelos), ketoconazole, miconazole, itraconazole, 
voriconazole, posaconazole, clarithromycin, telithromycin, indinavir, saquinavir, 
ritonavir, nelfinavir, amprenavir, fosamprenavir nefazodone, lopinavir, 
troleandomycin, mibefradil, conivaptan.  The topical use of these medications is 
allowed if systemic absorption is considered minimal. 
▪ Strong CYP3A4/5 inducers, including administration within 10 days prior to Cycle 1 
Day 1 treatment, including but not limited to phenobarbital, rifampin, phenytoin, 
carbamazepine, rifabutin, rifapentine, clevidipine, St. John’s wort. 
 
 

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3.3 
Inclusion of Women and Minorities 
 
Women of all races and ethnic groups are eligible for this trial. This disease does not affect men. 
 
 
4. REGISTRATION PROCEDURES 
 
4.1 
General Guidelines for DF/HCC Institutions 
 
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore. Registrations must occur prior to the initiation of protocol therapy. Any participant not 
registered to the protocol before protocol therapy begins will be considered ineligible and 
registration will be denied. 
 
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist. 
 
Following registration, participants may begin protocol therapy. Issues that would cause treatment 
delays should be discussed with the Overall Principal Investigator (PI). If a participant does not 
receive protocol therapy following registration, the participant’s registration on the study must be 
canceled. Registration cancellations must be made in OnCore as soon as possible. Participants who 
do not begin protocol therapy for reasons including ineligibility, inevaluability, and participant drop 
out will be replaced. 
 
4.2 
Registration Process for DF/HCC Institutions 
 
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject Protocol 
Registration (SOP #: REGIST-101) must be followed. Please note that all sites must submit the 
eligibility documents required in section 4.4 and that eligibility must be confirmed by the 
coordinating center prior to participant registration. 
 
4.3 
General Guidelines for Other Investigative Sites 
 
Eligible participants will be entered on study centrally at the Dana-Farber Gynecologic Oncology 
Disease Center by the Project Manager.  All sites should contact the Project Manager Madeline 
Polak at Madeline_Polak@dfci.harvard.edu or 617-632-3743 when they have a potential participant 
to confirm the study status and enrollment availability.  
 
Following registration, participants should begin protocol therapy within 7 days. Issues that would 
cause treatment delays should be discussed with the Overall PI.  If a participant does not receive 
protocol therapy following registration, the participant’s registration on the study must be canceled.  
The Project Manager should be notified of cancellations as soon as possible. 
 
 
 
 

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4.4 
Registration Process for All Sites  
 
To register a participant, the following documents should be collected by the research nurse or data 
manager and faxed (617-582-7921) or e-mailed (Madeline_Polak@dfci.harvard.edu) to Madeline 
Polak, the Project Manager: 
• Copy of required laboratory tests: complete blood count with differential, liver 
functional tests, chemistries 
• Copy of the screening visit clinic note, including medical history.  
• Copy of the pathology report 
• Copy of CT or MRI report 
• Documentation for consent process 
• Signed participant consent form 
• HIPAA authorization form 
• Eligibility Checklist 
• Confirmation that sufficient archival tissue is available  
 
The FFPE block or 15 unstained slides should be mailed to the study coordinator at DFCI.  Send 
FFPE block via overnight post to the following address: 
 
Josephine Smith  
Dana-Farber Cancer Institute 
450 Brookline Ave, DA-122 
Boston, MA 02215 
Email contact: Josephine_smith@dfci.harvard.edu  
 
To complete the registration process, the Project Manager will:  
• Follow the DF/HCC Standard Operating Procedure for Human Subject Research Titled 
Subject Protocol Registration (SOP #: REGIST-101) and register the participant on the 
protocol  
• Fax or email the research nurse or data manager at the participating site with the participant 
study number, and to confirm registration. Treatment may not begin without 
confirmation from the Coordinating Center that the participant has been registered.   
  
NOTE: Registration can only be conducted during the business hours of 8:00 AM and 5:00 
PM Eastern Time Monday through Friday. Same day treatment registrations will only be 
accepted with prior notice and discussion with the DF/HCC Project Manager.   
 
5. TREATMENT PLAN 
 
5.1 
Treatment Regimens 
 
All treatment will be administered on an outpatient basis.   
 
Applicable to all cohorts: Avelumab may be administered up to 3 days before or after the scheduled 
day of administration of each cycle due to administrative reasons. A minimum of 11 days must pass 
between consecutive avelumab infusions. Avelumab will be administered as a 1-hour IV infusion. 

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In order to mitigate infusion-related reactions, a premedication with an antihistamine and with 
paracetamol (acetaminophen) 30 to 60 minutes prior to each dose of avelumab is mandatory (for 
example, 25-50 mg diphenhydramine and 500-650 mg paracetamol IV or oral). This may be 
modified based on local treatment standards and guidelines, as appropriate. Sites should make every 
effort to target avelumab infusion timing to be as close to 1 hour as possible. However, given the 
variability of infusion pumps from site to site, time windows of minus 10 minutes and plus 20 
minutes is permitted (i.e., infusion time is 50-80 minutes). The exact duration of infusion should be 
recorded in source documents. 
 
In the MSI/POLE cohort: Avelumab will be administered at 10 mg/kg intravenously on Day 1 and 
Day 15 of each 4-week cycle (one cycle = 28 days including two infusions) after all 
procedures/assessments have been completed.  
 
In the MSS cohort receiving avelumab alone: Avelumab will be administered at 10 mg/kg 
intravenously on Day 1 and Day 15 of each 4-week cycle (one cycle = 28 days including two 
infusions) after all procedures/assessments have been completed.  
 
In the MSS cohort receiving avelumab + talazoparib: Avelumab will be administered at 10 mg/kg 
intravenously on Day 1 and Day 15 of each 4-week cycle (one cycle = 28 days, including two 
infusions) in combination with 1mg PO QD of talazoparib.  
 
In the MSS cohort receiving avelumab + axitinib: Avelumab will be administered as 800mg 
intravenously on Day 1 and Day 15 of each 28-day cycle (one cycle = 28 days, including two 
infusions), and axitinib will be administered 5mg twice daily orally.  
 
Reported adverse events and potential risks are described in Sections 7.  Appropriate dose 
modifications are described in Section 6.  No investigational or commercial agents or therapies 
other than those described below may be administered with the intent to treat the participant's 
malignancy. 
 
5.2 
Pre-Treatment Criteria 
 
 Pre-Treatment Criteria for Avelumab and Avelumab/Talazoparib Cohorts 
 
Cycle 1, Day 1 (or within 7 days prior to Cycle 1, Day 1) 
• Absolute neutrophil count > 1,500/mcL 
• Platelets > 100,000/mcL 
•    Hemoglobin ≥ 9g/dL 
• Total bilirubin within normal institutional limits 
• AST (SGOT) / ALT (SGPT) ≤ 2.5 × institutional upper limit of normal 
• Creatinine ≤ institutional upper limit of normal or creatinine clearance ≥ 
30mL/min/1.73 m2 for subjects with creatinine levels above institutional 
normal 
• All toxicities of previous therapy (aside from alopecia and sensory 
neuropathy) must have resolved to ≤ grade 1 
• ECOG performance status of 1 or less 

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• No evidence of life-threatening medical problems 
 
Subsequent Visits (Days 1 and 15)*  
• Absolute neutrophil count > 1,000/mcL 
• Platelets ≥ 50,000/mcL 
• AST (SGOT)/ALT (SGPT) ≤ 2.5 × institutional upper limit of normal 
• Creatinine ≤ institutional upper limit of normal or creatinine clearance ≥ 30 
mL/min/1.73 m2 for subjects with creatinine levels above institutional normal 
• All toxicities of previous cycles must have resolved to ≤ grade 2 
• ECOG performance status of 2 or less. 
• No evidence of life-threatening medical problems 
 
For patients who do not achieve hematological recovery on scheduled day of avelumab 
treatment, complete blood counts should be performed twice weekly until the above defined 
limits are achieved. 
 
*If the criteria are not met, see Section 6 for applicable dose modifications and holding. 
Please note that dose holds are based on which drug the toxicity is attributed to and study 
drugs may be held independently of each other, this includes hematologic toxicities. If 
applicable based on Section 6, patients who do not meet treatment criteria may be treated 
with the non-offending agent.  
 
 
 Pre-Treatment Criteria for Avelumab/Axitinib Cohort 
 
Cycle 1 Day 1 (or within preceding 7 days) 
 
Patients must meet eligibility parameters, as detailed in Section 3. 
 
Subsequent Visits (Days 1 & 15)* 
• Absolute neutrophil count ≥ 500 /mcL 
• Platelets ≥ 25,000/mcL 
• Urine protein 0 or 1+ (by urine dipstick) – Day 1 only (may be repeated on Day 15 if 
deemed necessary by treating investigator) 
• Blood pressure ≤150/100 
• All toxicities of previous cycles must have resolved to ≤ grade 2 
• ECOG performance status of 2 or less 
• No evidence of life-threatening medical problems 
 
*If the criteria are not met, see Section 6 for applicable dose modifications and holding. 
Please note that dose holds are based on which drug the toxicity is attributed to and study 
drugs may be held independently of each other, this includes hematologic toxicities. If 
applicable based on Section 6, patients who do not meet treatment criteria may be treated 
with the non-offending agent.  
 
 
 

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5.3 
Administration 
 
Only qualified personnel who are familiar with procedures that minimize undue exposure to them 
and to the environment should undertake the preparation, handling, and safe disposal of 
chemotherapeutic and investigational agents. Investigational product should be prepared and 
dispensed by an appropriately qualified and experienced member of the study staff (e.g., physician, 
nurse, physician’s assistant, practitioner, or pharmacist) as allowed by local, state, and institutional 
guidance. 
 
 Avelumab  
 
Avelumab Administration & Premedications 
 
Avelumab will be administered at 10 mg/kg on Day 1 and Day 15 of each 4-week cycle for 
participants in the MSI/POLE cohort, the MSS cohort receiving single agent Avelumab, and the 
MSS cohort receiving Avelumab in combination with Talazoparib. Avelumab will be administered 
as 800mg intravenously on Day 1 and Day 15 of each 4-week cycle for participants in the MSS 
cohort receiving Avelumab in combination with Axitinib. Avelumab may be administered up to 3 
days before or after the scheduled day of administration of each cycle due to administrative reasons.  
A minimum of 11 days must pass between consecutive avelumab infusions. 
 
Avelumab will be administered as a 1-hour IV infusion. In order to mitigate infusion-related 
reactions, a premedication with an antihistamine and with paracetamol (acetaminophen) 30 to 60 
minutes prior to the first 4 infusions of avelumab is mandatory (for example, 25-50 mg 
diphenhydramine and 500-650 mg paracetamol IV or oral). This may be modified based on local 
treatment standards and guidelines, as appropriate. Premedication should be administered for 
subsequent avelumab infusions based upon clinical judgment and presence/severity of prior 
infusion reactions 
 
Sites should make every effort to target avelumab infusion timing to be as close to 1 hour as 
possible. However, given the variability of infusion pumps from site to site, time windows of minus 
10 minutes and plus 20 minutes is permitted (i.e., infusion time is 50-80 minutes). The exact 
duration of infusion should be recorded in source documents. Possible modifications of the infusion 
rate for the management of infusion-related reactions are described in later sections. 
 
Management of Avelumab-related Infusion Reactions 
 
As with all monoclonal antibody 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. 
 
Following avelumab infusions, patients must be observed for 30 minutes post-infusion for potential 
infusion-related reactions. Patients should be instructed to report any delayed reactions to the 

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Investigator immediately.  Avelumab infusion-related reactions should be treated according to the 
table below. 
 
 Prophylactic steroids are NOT permitted.  
 
 
Treatment Modification for Symptoms of Infusion-Related Reactions Caused by Avelumab 
 
NCI-CTCAE Grade 
Treatment Modification for Avelumab 
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 h 
• Temporarily discontinue avelumab infusion 
• Resume 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 subject 
• Subjects have to be withdrawn 
immediately from avelumab treatment 
and must not receive any further 
avelumab treatment 
IV: intravenous; NCI-CTCAE: National Cancer Institute-Common Terminology Criteria for 
Adverse Event; 
NSAIDs: nonsteroidal anti-inflammatory drugs. 
 

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If avelumab infusion rate has been decreased by 50% or interrupted due to an infusion reaction, it 
must remain decreased for the next scheduled infusion.  If no infusion reaction is observed in the 
next scheduled infusion, the infusion rate may be returned to baseline at the subsequent infusions 
based on investigator’s medical judgment.. 
 
If an infusion-related reaction has occurred previously, then for subsequent infusions the following 
additional pre-medications can be considered: ibuprofen 800mg PO x1, Zyrtec 10mg PO x1, and 
famotidine 20mg IVx1, all administered 30-60 minutes prior to subsequent avelumab infusions. 
Furthermore, 250-500 ccs of normal saline IV continuous infusion while avelumab infusion can be 
considered.   
 
Additionally, if a previous infusion-related reaction occurred, patients must be observed for 4 hours 
post-infusion in the subsequent avelumab infusion; this observation period can be incrementally 
decreased by 1 hour in each subsequent infusion (i.e. 3 hours and then 2 hours) until the minimum 
observation period of 30 minutes post-infusion is reached. The observation period of 30 minutes 
post-infusion can be omitted for patients who have received 12 or more cycles.   
 
Management of Avelumab Severe Hypersensitivity Reactions and Flu-like Symptoms 
 
If hypersensitivity reaction occurs, the patient must be treated according to the best available 
medical practice. Patients should be instructed to report any delayed reactions to the Investigator 
immediately. 
 
Symptoms include impaired airway, decreased oxygen saturation (<92%), confusion, lethargy, 
hypotension, pale or clammy skin, and cyanosis. These symptoms can be managed with epinephrine 
injection and dexamethasone. Patients should be placed on monitor immediately, and the ICU 
should be alerted for possible transfer if required. 
 
For prophylaxis of flu-like symptoms, 25 mg of indomethacin or comparable nonsteroidal anti-
inflammatory drug (NSAID) dose (for example, ibuprofen 600 mg, naproxen sodium 500 mg) may 
be administered 2 hours before and 8 hours after the start of each dose of avelumab IV infusion. 
Alternative treatments for fever (for example, paracetamol) may be given to patients at the 
discretion of the investigator. 
 
 Talazoparib 
 
Talazoparib Administration 
 
Talazoparib will be taken QD at 1 mg PO starting on Cycle 1 Day 1 (C1D1) and treatment should 
continue until EOT. Patients with moderate renal impairment (defined as an estimated creatinine 
clearance of 30-59 mL/min) will receive a reduced starting dose of Talazoparib at 0.75 mg PO QD. 
This dose is based on the recommended phase 2 dose (RP2D) based on the Phase 1 trial of 
avelumab/talazoparib in advanced tumors. The combination of avelumab and talazoparib was 
evaluated in a Phase 1 clinical trial in patients with locally advanced or metastatic solid tumors. 
This study was open in our institution (DFHCC protocol 17-687) and established that the 
recommended phase 2 dose of talazoparib in combination with avelumab is 1 mg PO QD.  

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For patients with moderate renal impairment (defined as an estimated creatinine clearance of 30-59 
mL/min) a reduced starting dose of Talazoparib at 0.75 mg PO QD is recommended as per the 
talazoparib IB (Investigator’s Brochure of talazoparib (MDV3800, BMN673).On Days 1 and 15 of 
each cycle, when the patient returns to the clinic for avelumab administration, 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. 
 
Patients should self-administer talazoparib orally QD, 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 day 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 
instructed not to “make it up” but to resume subsequent doses the next day as prescribed. A missed 
dose for Talazoparib is defined as >12 hours after the scheduled dosing time. 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 cycle. 
 
 Axitinib 
 
Axitinib Administration 
 
Axitinib will be taken orally twice daily starting on Cycle 1 Day 1 (C1D1).  Doses should be taken 
approximately 12 hours apart and at approximately the same times each day.  Axitinib tablets 
should be swallowed whole with a glass of water.  Tablets must not be crushed, split, dissolved, or 
chewed.  Axitinib can be taken with or without food. 
 
Patients must be instructed that if they miss a dose or vomit any time after taking a dose, they must 
not “make it up” with an extra dose, but instead resume subsequent doses as prescribed.  Any 
missed dose may be taken late, up to 3 hours before the next scheduled dose of that day, otherwise, 
it should be skipped and dosing resumed with subsequent doses as prescribed. 
 
Patients should complete the Dosing Diary and record all doses (including missed, vomited, or extra 
doses). 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 cycle. 
 
Effect of Antacids 
 
No change in axitinib dosing is recommended in the presence of antacids.  The commercial 
formulation of axitinib utilizes crystal polymorph Form XLI of axitinib, which was determined to 
have similar plasma exposure (AUC) in either the presence or absence of antacids.  
 
 

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Effect of Food/Meals 
 
A definitive food effect study (A4061053) was conducted in healthy volunteers, showing no 
clinically significant change in axitinib plasma exposure (AUC) or Cmax in the presence of food.  
Axitinib can be taken with or without food. 
 
 
Blood Pressure Monitoring with Axitinib 
 
Patients will be instructed to obtain blood pressure cuffs for home monitoring and instructed to 
measure their BP at least once daily before taking the morning dose of axitinib.  All BP 
measurements will be recorded in a diary and brought to the nurse or study coordinator at each 
clinic visit. 
 
Patients should be instructed to contact the site immediately for guidance if their systolic blood 
pressure rises above 150 mm Hg, diastolic blood pressure rises above 100 mm Hg, or if they 
develop symptoms perceived to be related to elevated blood pressure (e.g., headache, visual 
disturbances), although a different blood pressure threshold for contacting the site may be used 
according to the investigator’s clinical judgment.  See Section 6.1.4 for management of axitinib-
related hypertension. 
 
 Avelumab & Talazoparib Combination Therapy Administration 
 
On Days 1 and 15 of each cycle, when both avelumab and talazoparib are administered at the 
investigative site, the following must occur in the order specified: 
• 
All required tests and assessments will be performed, as per the Schedule of Activities 
and blood will be drawn for PK and ADA assessments (when scheduled); 
 
• 
Avelumab premedication, as described in Section 5.3.1, and talazoparib will be 
administered to the patient in any order chosen by the qualified site personnel; 
 
• 
Avelumab infusion will start within 30-60 minutes after the avelumab premedication was 
administered and after dosing with talazoparib; 
 
• 
Blood will be drawn for PK assessments (when scheduled) immediately at the end of the 
avelumab infusion and the patient will remain in the clinic for observation for at least 30 
minutes after the avelumab infusion. 
 
Treatment with avelumab and talazoparib will continue until disease progression is confirmed by 
the Investigator (except where treatment is allowed beyond progression, as per Section 5.3.6), 
patient refusal, unacceptable toxicity, or until the study is terminated by the Sponsor, whichever 
occurs first. 
 
 

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 Avelumab & Axtinib Combination Therapy Administration 
 
On Days 1 and 15 of each cycle, when both avelumab and axitinib are administered at the 
investigative site, the following must occur in the order specified:  
 
• All required tests and assessments will be performed, as per the Schedule of Activities 
• Avelumab premedication, as described in Section 5.3.1, and axitinib will be administered to 
the patient in any order chosen by the qualified site personnel 
• Avelumab infusion will start within 30-60 minutes after the avelumab premedication was 
administered, and after dosing with axitinib 
• In the event that the morning dose of axitinib cannot be administered in clinic with the 
avelumab infusion (e.g. due to the scheduled infusion time), the patient may take their 
morning dose at home in order to maintain the regular axitinib schedule and avoid omitted 
doses. 
 
Treatment with avelumab and axitinib will continue until disease progression is confirmed by the 
Investigator (except where treatment is allowed beyond progression, as per Section 5.6), patient 
refusal, unacceptable toxicity, or until the study is terminated by the Sponsor, whichever occurs 
first. 
 
  Investigational Product Storage 
 
The Investigator, or an approved representative, e.g., 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, which is the IB, will be superseded by the 
storage conditions stated on the product labels. Reference Investigational Product Manual for 
storage and administration instructions. 
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. 

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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. 
 
5.4 
Concomitant Medication and Supportive Care Guidelines 
 
Concomitant treatment considered necessary for the patient’s well-being may be given at discretion 
of the treating physician. 
 
Concomitant medications and treatments will be recorded from 28 days prior to the start of study 
treatment and up to 30 days after the last dose of study treatment. All concomitant medications and 
Non-Drug Supportive Interventions should be recorded in the CRF including supportive care drugs 
(e.g., antiemetic treatment and prophylaxis), and the drugs used to treat adverse events or chronic 
diseases, and non-drug supportive interventions (e.g., transfusions). 
 
Medications intended solely for supportive care (i.e., antiemetics, analgesics, megestrol acetate for 
anorexia) are allowed. 
 
 Concomitant Surgery 
 
In case of surgical procedure trial treatment should be delayed. Re-initiation should be discussed 
with the Overall PI. 
 
 Concomitant Radiotherapy 
 
Palliative radiotherapy to specific sites of disease is permitted if considered medically necessary by 
the treating physician. All attempts should be made to rule out disease progression in the event of 
increased localized pain. 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. 
 
 Growth Factors 
 
Primary prophylactic use of granulocyte-colony stimulating factors is not permitted during the first 
4 weeks (1 cycle) of treatment but they may be used at any time to treat treatment-emergent 
neutropenia as indicated by the current American Society of Clinical Oncology (ASCO) guidelines. 
 
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 darbepoietin may continue this treatment, and patients may start either drug during 

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the study at the discretion of the treating physician. 
 
 
 
 Steroid Use 
 
Data indicate that corticosteroids have an adverse effect on T cell function and that they inhibit and 
damage lymphocytes (Schleimer et al., 1984). Furthermore, as with all immunotherapies intended 
to augment cell-mediated immunity, there is a risk that concomitant immunosuppressives such as 
steroids will counteract the intended benefit of the proposed study treatment. However, studies with 
anti-CTLA4 compounds indicate that short-term use of steroids may be employed without 
compromising clinical outcomes (Weber et al., 2012).  Therefore, the use of steroids during this 
trial is restricted as follows: 
 
• Therapeutic use: for the treatment of infusion-related reactions and short-term treatment of 
irAEs, steroids are permitted according to the modalities indicated in Table 6, Avelumab 
Management of Immune-related Adverse Events. 
 
• Physiologic use: steroid replacement for adrenal insufficiency at doses equivalent to ≤10 mg 
prednisone daily is acceptable. 
 
• Prophylactic use, e.g., for the prevention of acute infusion-related reactions: is prohibited.  
 
 Prohibited Concomitant Medications and Therapies 
 
Patients are prohibited from receiving the following therapies during the treatment phase of 
this trial: 
 
• Any anti-cancer systemic chemotherapy or biologic therapy, including vitamins that 
are used as anti-cancer treatments, other than avelumab, talazoparib and axitinib 
depending on the cohort 
• Immunotherapy not specified in this protocol 
• Any investigational agents other than Avelumab or talazoparib and axitinib 
depending on the cohort 
• Any vaccination for the prevention of infectious disease while on avelumab 
treatment except for the administration of inactivated vaccines. 
• Herbal remedies with immunostimulating properties or known to potentially 
interfere with major organ function 
• P-gp inhibitors (amiodarone, carvedilol, clarithromycin, cobicistat, darunavir, 
dronedarone, erythromycin, indinavir, itraconazole, ketoconazole, lapatinib, 
lopinavir, propafenone, quinidine, ranolazine,ritonavir, saquinavir, telaprevir, 
tipranavir, valspodar, and verapamil) while on talazoparib treatment. The following 

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inhibitors of P-gp may be taken with additional caution, at the Investigator’s 
discretion:  P-gp inhibitors (atorvastatin, azithromycin, conivaptan, diltiazem, 
diosmin, eliglustat, felodipine, flibanserin, fluvoxamine, piperine, quercetin, and 
schisandra chinensis tract). 
• P-gp inducers (avasimibe, carbamazepine, phenytoin, rifampin, and St. John’s wort) while 
on talazoparib treatment. 
• BCRP inhibitors (curcumin, cyclosporine, elacridar [GF120918], and eltrombopag) while 
on talazoparib treatment. 
• Strong CYP3A4/5 inhibitors (e.g. ketoconazole, itraconazole, clarithromycin, 
atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, and 
telithromycin) while taking axitinib. 
• Strong CYP3A4/5 inducers (e.g. rifampin, dexamethasone, phenytoin, 
carbameazepine, rifabutin, rifapentine, phenobarbital, St John’s wort) while taking 
axitinib. 
• Grapefruit and grapefruit juice should be avoided while taking axitinib   
 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. If there is a clinical 
indication for one of the medications or vaccines specifically prohibited during the trial, 
discontinuation from study treatment may be required. The Investigator should consult with the 
sponsor about individual cases. 
 
 
5.5 
Tumor Response Assessments 
 
Tumor assessments will include all known or suspected disease sites. Imaging may include chest, 
abdomen, and pelvis CT or magnetic resonance imaging (MRI) scans. Brain CT or MRI scan at 
baseline is only required when there is suspected brain metastases or new lesion during the study. 
The CT 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. 
 
Antitumor activity will be assessed through radiological tumor assessments conducted at baseline 
(screening) of starting therapy and every 8 weeks thereafter. In addition, radiological tumor 
assessments will also be conducted whenever disease progression is suspected (e.g., symptomatic 
deterioration) and at the time of withdrawal from the treatment (if not done in the previous 4 
weeks). Complete, partial responses and progressive disease must be confirmed on repeated 
imaging ≥ 4 weeks after initial documentation, but not more than 8 weeks after initial 
documentation. 
 

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Assessment of response will be made using RECIST version 1.1 and as per immune-related 
RECIST criteria (irRECIST).  
 
 
 
5.6 
Treatment After Initial Evidence of Radiologic Disease Progression 
 
Immunotherapeutic agents such as avelumab may produce antitumor effects by potentiating 
endogenous cancer-specific immune responses. The response patterns seen with such an approach 
may extend beyond the typical time course of responses seen with chemotherapeutic agents, and 
may manifest as a clinical response after an initial increase in tumor burden or even the appearance 
of new lesions. 
 
If radiologic imaging shows progression, tumor assessment should be repeated > 6 weeks later in 
order to rule out pseudo-progression, at the investigator’s discretion. Depending on the cohort, 
Avelumab and/or Talazoparib and/or Axitinib may be continued at the investigator’s discretion 
during this period. If repeat imaging shows CR, PR or SD compared to the first scan that showed 
disease progression, treatment with avelumab and/or Talazoparib and/or Axitinib may be continued 
or resumed.  
 
If the repeat imaging demonstrates PD compared to the first scan that showed disease progression, 
patients should be discontinued from all study treatment. Patients may receive avelumab and/or 
Talazoparib and/or Axitinib during this period if they are clinically stable as defined by the 
following criteria: 
 
• Absence of clinical signs and symptoms (including worsening of laboratory values) of 
disease progression. 
• No decline in ECOG performance status. 
• Absence of rapid progression of disease by radiographic imaging as assessed by treating 
clinician. 
• Absence of progressive tumor at critical anatomical sites (e.g., cord compression) requiring 
urgent alternative medical intervention. 
 
 
5.7 
Duration of Therapy / Criteria for Taking a Participant Off Protocol Therapy 
 
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse events, treatment may continue 
indefinitely or until one of the following criteria applies: 
 
• Disease progression, 
• Intercurrent illness that prevents further administration of treatment, 
• Unacceptable adverse event(s) as defined in Section 6 or in the judgment of the treating 
clinician, 
• Participant decides to withdraw from the study, 
• Pregnancy 

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• General or specific changes in the participant's condition render the participant  
unacceptable for further treatment in the opinion of the treating investigator, or 
• The drug manufacturer can no longer provide the study agent(s) 
 
Participants will be removed from the protocol therapy when any of these criteria apply.  The 
reason for removal from protocol therapy, and the date the participant was removed, must be 
documented in the case report form (CRF). Alternative care options will be discussed with the 
participant. 
 
For Centralized Subject Registrations, the research team submits a completed Off Treatment/Off 
Study form to ODQ when a participant comes off study. This form can be found on the ODQ 
website or obtained from the ODQ registration staff.  
 
For Decentralized Subject Registrations, the research team updates the relevant Off Treatment/Off 
Study information in OnCore.  
 
In the event of unusual or life-threatening complications, treating investigators must immediately 
notify the Overall Principal Investigator, Panagiotis Konstantinopoulos, MD, at 617-632-3000 
(pager) and pkonstantinopoulos@partners.org. 
 
5.8 
Duration of Follow Up 
 
Participants will be followed for 3 years by phone after removal from study or until death, 
whichever occurs first. Survival status should be checked every 6 months during that time. 
Participants removed from study for unacceptable adverse events will be followed until resolution 
or stabilization of the adverse event. Date and cause of death should be provided for participants 
who become deceased within the 3-year interval following removal from the study. Should a 
participant become pregnant while on trial, the patient will be withdrawn from the study. However, 
the outcome of the pregnancy and the newborn’s health, if the pregnancy is carried to term, will be 
monitored. 
 
5.9 
Criteria for Taking a Participant Off Study 
 
Participants will be removed from study when any of the following criteria apply: 
• Lost to follow-up 
• Withdrawal of consent for data submission 
• Death 
• Pregnancy 
 
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF). 
 
For Centralized Subject Registrations, the research team submits a completed Off Treatment/Off 
Study form to ODQ when a participant comes off study. This form can be found on the ODQ 
website or obtained from the ODQ registration staff.  
 

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For Decentralized Subject Registrations, the research team updates the relevant Off Treatment/Off 
Study information in OnCore.  
 
 
6. 
DOSING DELAYS, MODIFICATIONS, AND MANAGEMENT OF SPECIFIC ADVERSE 
EVENTS 
 
Every effort should be made to administer study treatment on the planned dose and schedule. 
 
In the event of significant 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. Patients are to be instructed to notify 
Investigators at the first occurrence of any adverse symptom.  
 
Avelumab: No dose reductions are permitted in this study, but the next infusion may be 
omitted based on persisting toxicity. If Day 1 Avelumab is held, the dose will be omitted 
and resumed on Day 15 of the cycle as long as the pre-treatment criteria in section 5.2 
are met. The same will apply if Day 15 is held, the dose will be omitted and resumed on 
Day 1 of the next cycle as long as pre-treatment criteria are met.  
 
Talazoparib: Dose modifications (dose interruptions or dose reductions) may be 
implemented to manage toxicities. 
 
Axitinib: Dose modifications (dose interruptions or reductions) may be implemented to 
manage toxicities. 
 
All dose modifications must be clearly documented in the patient's medical chart and in the CRF. In 
addition to dose modifications, Investigators are encouraged to employ best supportive care 
according to local institutional clinical practices. 
 
Dose delays and modifications will be made as indicated in the following table(s). The descriptions 
and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 will be utilized for dose delays and dose modifications. A copy of the 
CTCAE version 4.0 can be downloaded from the CTEP website 
 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
In the event of a treatment interruption for reasons other than treatment-related toxicity (e.g., 
elective surgery) for >7 consecutive days, treatment resumption will be decided in consultation with 
the Sponsor. 
 
 
6.1 
Dose Reductions of Talazoparib 
 
Following dosing interruption due to toxicity at any time in the study, the talazoparib dose may 
need to be reduced, based on the worst toxicity reported, when treatment is resumed. Dose 
reduction should be made in accordance with the guidance provided in the following table. Dose 
reduction of talazoparib by 1 dose level at a time will be allowed depending on the starting dose and 

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type and severity of toxicity encountered. Doses less than 0.25 mg are not permitted. Patients 
unable to tolerate 0.25 mg QD, will be permanently discontinued from the talazoparib, but may 
continue on single agent avelumab. Available dose levels for dose reductions are listed in the table 
below. 
 
Dose Levels for Dose Reductions of Talazoparib 
 
Dose Level 
Talazoparib Dose (Oral) 
D-0  
1mg QD 
D-1 
0.75mg QD 
D-2 
0.5mg QD 
D-3 
0.25mg QDa 
      a Talazoparib dose de-escalation below 0.25 mg QD is not allowed. 
                                 D = dose; QD = once daily 
 
Once a dose has been reduced for a given patient, all subsequent cycles should be administered at 
that dose level, unless further dose reduction is required. Intra-patient dose re-escalation is not 
allowed. 
 
If a dose reduction is required, the patient may need to return to the clinic to receive new drug 
supply prior to the next scheduled visit since dosage strengths of the capsules may be different. Site 
personnel must ensure the patients are instructed how to take the reduced dose and that the patients 
have the correct dosage strength for the reduced dose. 
 
6.2  
Dose Reductions of Axitinib 
 
The dose of axitinib may need to be reduced due to toxicity, based on the worst toxicity reported, at 
any time during the study.  Dose reduction should be made in accordance with the guidance 
provided in the table below: 
 
Dose Levels for Dose Reductions of Axitinib 
 
Dose Level 
Axitinib Dose (Oral) 
D-0  
5mg BID 
D-1 
3mg BID 
D-2 
2mg BID 
                                 BID=twice daily 
 
Once a dose has been reduced for a given patient, all subsequent cycles should be administered at 
that dose level, unless further dose reduction is required. Intra-patient dose re-escalation is not 
allowed. 
 
If a dose reduction is required, the patient may need to return to the clinic to receive new drug 
supply prior to the next scheduled visit since dosage strengths of the tablets may be different. Site 

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personnel must ensure the patients are instructed how to take the reduced dose and that the patients 
have the correct dosage strength for the reduced dose. 
 
 
 
6.3 Study Treatment Modifications for Avelumab & Talazoparib Drug-Related Toxicity  
 
These modifications are excluding infusion-related reactions and immune-related adverse events.  
For patients receiving avelumab, either as a single agent or in combination with talazoparib, any AE 
suspected to be immune-related should be managed according to the guidance for management of 
irAEs in Section 6.1.6. 
 
Recommended avelumab and talazoparib treatment modifications in case of investigational product 
related toxicity are shown in Table 6. The specific guidelines are applicable in cases which can be 
attributed to one of the investigational products. The instructions should be 
followed in the column regarding the investigational product that toxicity is attributed to. In cases 
where an AE is possibly related to both investigational products, the guidelines in both columns for 
both investigational products should be followed. Patients who stop avelumab or talazoparib for 
unacceptable toxicity may continue treatment with the investigational product that is not considered 
to be responsible for the toxicity observed. Dose holds can be independent of one another. Hold 
only the drug that is suspected to be causing the toxicity. Talazoparib may be resumed 
independently of Avelumab.  
 
The Thyroid function tests do not need to be resulted before treatment begins if the previous cycle’s 
results were within normal limits (WNL).  
Thyroid function test results will need to be resulted and reviewed before treatment begins if the 
previous cycle’s results were not WNL and required therapeutic intervention. 
 
Table 6. Talazoparib and Avelumab Treatment Modifications for Drug-Related Toxicity 
(Excluding Infusion-Related Reactions and Immune-Related AEs) 
 
Talazoparib 
Avelumab 
Hematologic Toxicities 
• 
Grade 1 and Grade 2 
• 
No requirement for dose 
interruption or dose reduction. 
• 
Continue as per schedule. 
• 
Anemia Grade ≥3 
(hemoglobin <8 g/dL) 
• 
Hold talazoparib and monitor 
weekly until resolves to >9g/dL. 
• 
Resume Talazoparib at a reduced 
dose, per Section 6.1.1 
• 
Permanently discontinue if persists 
for >4 weeks without recovery to 
baseline. Refer to hematologist for 
evaluation including assessment of 
possible MDS/AML. 
• 
Hold avelumab. 
• 
Re-initiate avelumab once 
toxicity Grade ≤1 or baseline. 
• 
Permanently discontinue avelumab 
if toxicity does not resolve to Grade 
≤1 or baseline within 12 weeks or if 
the same Grade 3 toxicity recurs (if 
talazoparib had already been 
discontinued and recurrent event 
occurs on avelumab only). 

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• 
Neutropenia Grade ≥3 
(ANC <1000/µL) 
• 
Hold talazoparib and monitor 
weekly until resolves to ANC 
≥1500/µL. 
• 
Resume Talazoparib at a reduced 
dose, per Section 6.1.1 
• 
Permanently discontinue 
talazoparib if persists for 
>4 weeks without recovery to ANC 
≥1000/µL. Refer to hematologist 
for evaluation including assessment 
of possible MDS/AML. 
• 
Hold avelumab. Re-initiate 
avelumab once toxicity Grade ≤2 
(ANC ≥1000/µL) or baseline. 
• 
Permanently discontinue avelumab 
if toxicity does not resolve to Grade 
≤1 or baseline within 12 weeks or 
if the same Grade 3 toxicity recurs 
(if talazoparib had already been 
discontinued and recurrent event 
occurs on avelumab only). 
• 
Thrombocytopenia  
Grade ≥3 (platelets <50,000/µL) 
• 
Hold talazoparib and monitor 
weekly until resolves to 
≥50,000/µL 
• 
Resume talazoparib reduced by 1 
dose level, per Section 6.1.1 
• 
Permanently discontinue 
talazoparib if persists for 
>4 weeks without recovery to 
platelets ≥50,000/µL. Refer to 
hematologist for evaluation 
including assessment of possible 
MDS/AML. 
• 
Hold avelumab. 
• 
Re-initiate avelumab once 
toxicity Grade ≤2 or baseline. 
• 
Permanently discontinue avelumab 
if toxicity does not resolve to Grade 
≤1 or baseline within 12 weeks or 
if the same Grade 3 toxicity recurs 
(if talazoparib had already been 
discontinued and recurrent event 
occurs on avelumab only). 
Non-hematologic Toxicities 
Grade 1 and Grade 2 
• 
No requirement for dose 
interruption or dose reduction. 
• 
For suspected immune-related 
toxicities due to avelumab that 
require avelumab delay or 
discontinuation as per 
Section 6.6, talazoparib should 
also be placed on hold until 
toxicity is Grade ≤1 or baseline. 
• 
Continue as per schedule. 
• 
For suspected immune-related 
toxicities due to avelumab follow 
guidance in Section 6.6. 
Grade 3 
• 
Hold talazoparib. 
• 
Resume talazoparib reduced by 1 dose 
level, per Section 6.1 if toxicity 
resolves to Grade ≤1 or baseline 
within 4 weeks. 
• 
Exceptions are: 
Nausea, vomiting, or diarrhea 
lasting ≤72 hours; fatigue lasting 
<5 days; hypertension controlled 
with medical therapy; increase in 
indirect bilirubin indicative of 
Gilbert’s syndrome; serum lipase 
or amylase lasting 
≤7 consecutive days without 
clinical signs or symptoms of 
pancreatitis; endocrinopathies 
controlled with hormonal 
therapy; laboratory values that 
do not have any clinical 
correlate. 
• 
Hold avelumab. 
• 
Resume once toxicity is Grade 
≤1 or baseline. 
• 
Permanently discontinue if toxicity 
does not resolve to Grade ≤1 or 
baseline within 12 weeks or if the 
same Grade 3 toxicity recurs. 
• 
Exceptions are: Laboratory 
values that do not have any 
clinical correlate. 
• 
For suspected immune-related 
toxicities follow guidance in Section 
6.6. 

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• 
If the same Grade 3 toxicity 
recurs, reduce by 1 dose level. 
• 
Permanently discontinue if 
toxicity does not improve to 
Grade ≤1 or baseline within 4 
weeks. 
• 
Exceptions are: 
Laboratory values that do not 
have any clinical correlate. 
• 
Permanently discontinue if Grade 
3 liver test abnormality. 
Rechallenge may be considered 
once toxicity is Grade ≤1 or 
baseline, if an alternative cause 
for the abnormal liver tests (ALT, 
AST, total bilirubin) is identified. 
• 
For suspected immune-related 
toxicities due to avelumab that 
require avelumab delay or 
discontinuation as per 
Section 6.6, talazoparib should 
also be placed on hold 
until toxicity is Grade ≤1 or 
baseline. 
 
Grade 4 
• 
Permanently discontinue 
talazoparib 
• 
Exceptions are: 
Laboratory values that do not have 
any clinical correlate. 
• 
For suspected immune-
related toxicities follow 
guidance in Section 6.6 
 
• 
Permanently discontinue 
avelumab 
• 
Exceptions are: 
Laboratory values that do not 
have any clinical correlate. 
• 
For suspected immune-
related toxicities follow 
guidance in Section 6.6 
 
Abbreviation ANC: Absolute Neutrophil Count; MDS=Myelodysplastic Syndrome. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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6.4  
Study Treatment Modifications for Avelumab & Axitinib 
 
These modifications are excluding infusion-related reactions and immune-related adverse events.  
For patients receiving avelumab, either as a single agent or in combination with axitinib, any AE 
suspected to be immune-related should be managed according to the guidance for management of 
irAEs in Section 6.1.6. 
 
Recommended avelumab and axitinib treatment modifications in case of investigational product 
related toxicity are shown in the following table. The specific guidelines are applicable in cases 
which can be attributed to one of the investigational products. The instructions should be followed 
in the column regarding the investigational product that toxicity is attributed to. In cases where an 
AE is possibly related to both investigational products, the guidelines in both columns for both 
investigational products should be followed. Patients who stop avelumab or axitinib for 
unacceptable toxicity may continue treatment with the investigational product that is not considered 
to be responsible for the toxicity observed. Dose holds can be independent of one another. Hold 
only the drug that is suspected to be causing the toxicity.  Axitinib may be resumed independently 
of avelumab.  Treatment may be held at the discretion of the treating physician to ensure patient 
safety.  If axitinib is held, treatment may be resumed at the same dose level or reduced by 1 dose 
level at the discretion of the treating physician.  
 
The Thyroid function tests do not need to be resulted before treatment begins if the previous cycle’s 
results were within normal limits (WNL). Thyroid function test results will need to be resulted and 
reviewed before treatment begins if the previous cycle’s results were not WNL and required 
therapeutic intervention. 

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Axitinib Dose Modifications and Avelumab Infusion Omissions for Investigational Product-Related Toxicity 
 
Toxicity 
NCI CTCAE 
Severity Grade 
Axitinib 
Avelumab 
Dose Modification 
Treatment Modification 
Hematologic 
Abnormalities 
Grade 1 
• 
Continue at the same dose level. 
• 
Continue as per schedule. 
Grade 2 
• 
Continue at the same dose level. 
• 
Continue as per schedule. 
Grade 3 
• 
Continue at the same dose level. 
• 
Withhold avelumab. 
• 
Re-initiate avelumab once toxicity is Grade 
≤1 or baseline. 
• 
Permanently discontinue avelumab if 
toxicity does not resolve to Grade ≤1 or 
baseline within 12 weeks (consider consult 
with the medical monitor before 
permanently discontinuing the treatment). 
 
Exceptions are: 
Laboratory values that do not have any 
clinical correlate. 
Grade 4 
• 
Withhold until recovery to Grade ≤2. 
• 
Then, reduce by 1 dose level and resume 
treatment. 
• 
For Grade 4 lymphopenia not associated with 
clinical events (e.g., opportunistic infection) 
axitinib treatment may continue without 
interruption. 
• 
Permanently discontinue avelumab 
(consider consult with medical monitor 
before permanently discontinuing the 
treatment). 
 
Exceptions are: 
Laboratory values that do not have any 
clinical correlate. 
Proteinuria 
Dipstick negative or 
shows 1+ (Grade 1) 
• 
Continue at the same dose level. 
• 
Continue as per schedule. 
If dipstick shows >1+, perform 24 hour urine collection.  
Dosing may continue while waiting for test results 
<2 g proteinuria/ 
24 hour 
• 
Continue at the same dose level. 

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Toxicity 
NCI CTCAE 
Severity Grade 
Axitinib 
Avelumab 
Dose Modification 
Treatment Modification 
2 g proteinuria/ 
24 hours 
• 
Withhold until proteinuria is <2 g/24 hours. 
• 
Repeat 24-hour urine collection for 
proteinuria and creatinine clearance (interval 
at investigator discretion) until proteinuria is 
<2 g/24 hours. 
• 
Then, resume at the same dose level or reduce 
by 1 dose level as per investigator judgment. 
Hypertension 
2 systolic BP readings 
separated by at least 
1 hour show systolic 
pressure 150 mm Hg 
(one or both readings) 
And 
2 diastolic BP 
readings separated by 
at least 1 hour show 
diastolic pressure 
100 mm Hg (one or 
both readings) 
• 
Continue at the same dose level. 
• 
See below for monitoring/management of 
axitinib-related hypertension. 
• 
Continue as per schedule. 
2 systolic BP readings 
separated by at least 
1 hour show systolic 
pressure >150 mm Hg 
OR 
2 diastolic BP 
readings separated by 
at least 1 hour show 
diastolic pressure 
>100 mm Hg 
• 
If not on maximal antihypertensive treatment, 
institute new or additional antihypertensive 
medication and continue at the same dose 
level. 
• 
If on maximal antihypertensive treatment, 
reduce by 1 dose level. 
• 
See below for monitoring/management of 
axitinib-related hypertension. 
• 
Continue as per schedule. 

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Toxicity 
NCI CTCAE 
Severity Grade 
Axitinib 
Avelumab 
Dose Modification 
Treatment Modification 
2 systolic BP readings 
separated by at least 
1 hour show systolic 
pressure >160 mm Hg 
OR 
2 diastolic BP 
readings separated by 
at least 1 hour show 
diastolic pressure 
>105 mm Hg 
• 
Withhold until BP is less than 150/100 mm 
Hg1 and adjust antihypertensive medication. 
• 
Then, reduce by 1 dose level and resume 
treatment. 
1 If axitinib dosing is temporarily 
discontinued, patients receiving 
antihypertensive medications should monitor 
closely for hypotension. The plasma half-life 
of axitinib is 2-4 hours and BP usually 
decreases within 1-2 days following dosing 
interruption. 
• 
See below for monitoring/management of 
axitinib-related hypertension. 
• 
Continue as per schedule. 
Recurrent 
hypertension 
following previous 
dose reduction 
(2 systolic BP 
readings separated by 
at least 1 hour show 
systolic pressure 
>150 mm Hg) 
OR 
Recurrent diastolic BP 
>100 mm Hg (2 BP 
readings separated by 
at least 1 hour) 
following previous 
dose reduction 
• 
Repeat dose reduction by one lower dose 
level. 
• 
See below for monitoring/management of 
axitinib-related hypertension. 
• 
Continue as per schedule. 

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Toxicity 
NCI CTCAE 
Severity Grade 
Axitinib 
Avelumab 
Dose Modification 
Treatment Modification 
Infusion-related 
Reaction 
Grade 1-4 
• 
Continue at the same dose level. 
• 
See Section 5.3.1 
Hypersensitivity 
reactions 
Grade 3-4 
• 
Continue at the same dose level. 
• 
See Section 5.3.1 
Tumor lysis syndrome 
Grade 1-4 
• 
See Other Non-Hematologic 
Toxicities and/or Laboratory Abnormalities. 
• 
Treat TLS as per standard of care 
institutional guidelines 
Immune-related AE 
(irAE) 
Grade 1-4 
• 
Grade 1: continue at the same dose level. 
• 
Grade 2-4: hold treatment until recovery to 
Grade ≤1 and restart axitinib at the same dose 
level for Grade 2 and at reduced dose level for 
Grade 3-4. 
• 
See Section 6.6 
Stevens-Johnson 
syndrome 
Grade 3-4 
• 
Permanent discontinuation 
• 
Permanent discontinuation 
Other Non-hematologic 
Toxicities and 
Laboratory 
Abnormalities 
Grade 1 
• 
Continue at the same dose level. 
• 
Continue as per schedule 
Grade 2 
• 
Continue at the same dose level. 
• 
Continue as per schedule 

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Toxicity 
NCI CTCAE 
Severity Grade 
Axitinib 
Avelumab 
Dose Modification 
Treatment Modification 
Other Non-hematologic 
Toxicities and 
Laboratory 
Abnormalities 
(continued) 
Grade 3 
• 
Reduce by 1 dose level. 
• 
Grade 3 toxicities controlled with 
symptomatic medications, or Grade 3 
asymptomatic biochemistry laboratory 
abnormalities: continue at the same dose or 
reduce by 1 dose level as per investigator 
judgment. 
• 
Withhold avelumab. 
• 
Re-initiate avelumab once toxicity is 
Grade 1 or baseline. 
• 
Permanently discontinue avelumab if 
toxicity does not resolve to Grade 1 or 
baseline value within 12 weeks (consider 
consult with medical monitor before 
permanently discontinuing the treatment). 
 
Exceptions are: 
• 
Laboratory values that do not have any 
clinical correlate (e.g., amylase or 
lipase abnormality that is not 
associated with symptoms or clinical 
manifestations of pancreatitis). 
• 
Nausea and vomiting controlled by 
medical therapy. 
• 
Tumor flare phenomenon defined as local 
pain, irritation, or rash localized at sites of 
known or suspected tumor. 
Other Non-hematologic 
Toxicities and 
Laboratory 
Abnormalities 
(continued) 
Grade 4 
• 
Hold treatment until recovery to Grade 2. 
• 
Then, reduce by 1 dose level and resume 
treatment. 
• 
Grade 4 asymptomatic biochemistry 
laboratory abnormality: study treatment may 
continue without interruption. 
• 
Permanently discontinue avelumab 
(consider consult with the medical monitor 
before permanently discontinuing the 
treatment). 
 
Exceptions are: 
• Laboratory values that do not have any 
clinical correlate. 
 
 
 
 

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Decline in LVEF 
In case of LVEF decline in patients treated with the axitinib plus avelumab combination, 
Investigators are encouraged to consult with the Sponsor to discuss the management of axitinib 
therapy independently of any actions implemented for avelumab and the Investigator’s causality 
assessment of the event. 
 
Management of Axitinib-Related Hypertension 
To treat an increase in BP, standard antihypertensives may be used (for example, thiazide or 
thiazide-like diuretics, angiotensin II receptor blockers, angiotensin converting-enzyme 
inhibitors, and dihydropyridine (DHP) calcium channel blockers), although bradycardic agents 
(such as beta-adrenergic blockers with or without alpha-blocking properties, and non-DHP 
calcium channel blockers, clonidine, digoxin) should be avoided to the extent possible. 
 
6.5  
Treatment Modifications for Infusion-Related Reactions Associated with Avelumab 
 
Recommended treatment modifications in case of avelumab infusion-related reactions are shown 
in the following table. 
 
Treatment Modification for Symptoms of Infusion-related Reactions 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.a  
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 subject. 
• 
Subjects have to be withdrawn immediately from 
avelumab treatment and must not receive any further 
avelumab treatment. 
a. 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 for Adverse Event; 
NSAIDs=nonsteroidal anti-inflammatory drugs; IV=intravenous. 

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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 (e.g., famotidine or ranitidine), meperidine, or ibuprofen to the mandatory 
premedication. Prophylactic corticosteroids are not permitted. 
 
6.6   
Immune-related Adverse Events/Toxicity Management 
 
For patients receiving avelumab, any AE suspected to be immune-related (i.e. an irAE) should 
be managed according to the guidance for management of irAEs per the table below. 
 
Treatment of irAEs is mainly dependent on severity (NCI CTCAE grade): 
 
• 
Grades 1 to 2: treat symptomatically or with moderate dose steroids, more frequent 
monitoring. 
 
• 
Grades 1 to 2 (persistent): manage similar to Grades 3 to 4 AE. 
 
• 
Grades 3 to 4: treat with high dose corticosteroids; if suspected to be related to 
avelumab, talazoparib should be withhold until toxicity resolves to Grade 1 or 
baseline. 
 
For Grade ≥3 immune-related toxicities suspected to be related to avelumab, talazoparib 
should be withheld until toxicity resolves to Grade ≤1 or baseline. 
 
Specific management of irAEs should proceed as described in the table below. 
 
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 
(e.g. 
loperamide) 
Close monitoring for 
worsening symptoms 
Educate subject 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 
Withhold avelumab 
therapy 
Symptomatic treatment 
 
If improves to Grade ≤ 1: 
Resume avelumab therapy. 
 
If persists > 5-7 days or 

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ADL 
Colitis: abdominal pain; blood in 
stool 
recurs: 
Treat as Grade 3 or 4 
Grade 3 to 4 
Diarrhea (Grade 3): ≥ 7 stools per 
day over Baseline; incontinence; 
IV fluids ≥ 24h; 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 
Dermatologic irAEs 
Grade of Rash 
(NCI-CTCAE v4.03) 
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 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 
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 
If improves to Grade ≤ 1:  
Taper steroids over at least 1 
month; resume avelumab 
therapy following steroids 
taper (for initial Grade 3). 

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Grade 3. 
Consider skin biopsy 
Dermatology consult 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent 
Add prophylactic 
antibiotics 
for opportunistic 
infections 
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 or for recurrent 
Grade 2: 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 
Add prophylactic 
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, 

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antibiotics for 
opportunistic infections 
Consider bronchoscopy, 
lung 
biopsy 
 
cyclophosphamide, IV 
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 > 5-7 
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 

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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 
Creatinine increased > 1.5 and ≤ 6 
x 
ULN 
Withhold avelumab 
therapy 
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 
If returns to Grade ≤1: 
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 (e.g. 
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 
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 

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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. 
 
myocarditis. 
Immune-mediated myocarditis 
Permanently discontinue 
avelumab. 
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. 
Once improving, taper 
steroids over at least 1 month. 
 
If no improvement or 
worsening, consider 
additional 
immunosuppressants (e.g. 
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=1
001 
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 
Continue hormone 
replacement/suppression and 
monitoring of endocrine 
function as appropriate. 

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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 (i.e. 
hypopituitarism / 
hypophysitis) 
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 
(i.e. hypopituitarism / 
hypophysitis) 
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. 
Hypopituitarism/Hypophysitis 
(secondary endocrinopathies) 
If secondary thyroid 
and/or adrenal 
insufficiency is 
confirmed (i.e. 
subnormal serum FT4 
with 
Resume avelumab once 
symptoms 
and hormone tests improve to 
Grade ≤ 1 (with or without 
hormone 
replacement). 

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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 
 
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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taper during at least 1 
month. 
• Add prophylactic 
antibiotics for 
opportunistic 
infections.   
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  
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. 
Grade 4 
Permanently discontinue 
avelumab therapy 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent 
and/or other 
immunosuppressant as 
needed 
If improves to Grade ≤ 1: 
Taper steroids over at least 1 
month 

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Add prophylactic 
antibiotics for 
opportunistic infections 
Specialty consult. 
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. 
 
7. ADVERSE EVENT: LIST AND REPORTING REQUIREMENTS 
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of reported and/or potential AEs (Section 7.1) and the characteristics of an 
observed AE (Section 7.2) will determine whether the event requires expedited reporting in 
addition to routine reporting. 
 
7.1 Expected Toxicities 
 
 Adverse Event List(s) for Avelumab (MSB0010718C) 
 
Frequent toxicities (between a 10-50% chance that this will happen): Tiredness, and reactions 
(including allergic reactions) that occur during or following infusion (may include chills, fever, 
muscle pain, shortness of breath, low or high blood pressure).  
 
Occasional toxicities (between a 1-10% chance that this will happen): Nausea, diarrhea, which is 
frequent, loose watery stools, which can cause dehydration and may require hospitalization and 
treatment with intravenous fluids. Severe and prolonged diarrhea can be life-threatening. Chills, 
reduced appetite, joint pain, underactive thyroid gland (possible weight gain, heart failure, and/or 
constipation), itchy skin, vomiting, flu-like symptoms including aches, fever and chills, and skin 
rash. Low number of red blood cells that can causes tiredness and shortness of breath, and may 
require a blood transfusion. Abnormally high levels of enzymes produced by the liver meaning 
that the liver is not functioning properly and can cause fatigue, and jaundice (yellowing of the 

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skin and eyes). Although this is usually mild and reversible, this can be serious or life 
threatening. Muscle pain, weakness, headache, and constipation.  
 
Reactions (including allergic reactions) that occur during or following the infusion (may include 
chills, fever, muscle pain, shortness of breath, and decrease or increase in blood pressure) are 
mostly mild or moderate and should resolve with a slowdown or discontinuation of the infusion 
and administration of medications to control the symptoms such as anti-allergic and pain-killer 
drugs.  In some cases these reactions may be severe (less than 1% of patients) and could require 
intensive medical support and even life threatening reactions may occur. 
 
Side effects resulting from an increased activity of the immune system have also been observed. 
Most of these side effects are reversible, which means they will stop once treatment with 
avelumab is discontinued, however in some cases these reactions may be severe (approximately 
2% of patients) and could lead to death in rare cases.  The reactions that are more severe may 
require treatment with drugs that decrease the immune system function, also called 
immunosuppressant drugs (like corticosteroids or more potent drugs, such as infliximab).  
 
The side effects resulting from an increased activity of the immune system that were observed in 
patients receiving avelumab include the following: 
• Immune side effects observed in 5%-10% of participants: inflammation of the skin 
(could include skin rash, itchy skin, redness or blisters in the skin).  
• Immune side effects observed in 1%-5% of participants: abnormal function of the 
thyroid gland. Low thyroid function may cause fatigue, weight gain, fluid retention, 
sensitivity to cold & mental apathy. Can be serious or life threatening. High thyroid 
function may cause weight loss, rapid heartbeat, sweating, trouble with heat, 
nervousness. May require medical intervention to resolve symptoms.  Inflammation of 
the thyroid could cause possible tenderness in the neck. Inflammation of the lungs (this 
could cause cough, difficulty breathing and require hospitalization). Immune side effects 
observed in less than1% of participants: inflammation of the large intestine which may 
cause stomach pain with loose or watery stools. Inflammation of the liver which may 
cause you to feel not hungry, tired, have a mild fever, muscle or joint aches, nausea and 
vomiting and stomach pain. Low function of the adrenal glands causing fatigue, loss of 
appetite, depression, weight loss and low blood pressure. Inflammation of the eyes 
causing blurred vision, light sensitivity and/or redness. Inflammation of the muscles 
causing cramping and muscle pain. Inflammation of the heart may cause chest pain, or 
heart failure. 
 
 Adverse Events for Axitinib 
 
The safety of axitinib has been evaluated in 715 patients in monotherapy studies, which included 
537 patients with advanced RCC. The data described reflect exposure to axitinib in 359 patients 
with advanced RCC who participated in a randomized clinical study versus sorafenib. 
 

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The most common (≥20%) adverse reactions observed following treatment with axitinib were 
diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia, palmar-plantar 
erythrodysesthesia (hand-foot) syndrome, weight decreased, vomiting, asthenia, and 
constipation.  
 
Selected adverse reactions (all grades) that were reported in <10% of patients treated with 
axitinib included dizziness (9%), upper abdominal pain (8%), myalgia (7%), dehydration (6%), 
epistaxis (6%), anemia (4%), hemorrhoids (4%), hematuria (3%), tinnitus (3%), lipase increased 
(3%), pulmonary embolism (2%), rectal hemorrhage (2%), hemoptysis (2%), deep vein 
thrombosis (1%), retinal-vein occlusion/thrombosis (1%), polycythemia (1%), transient ischemic 
attack (1%), and RPLS (<1%). 
 
Hypertension & Hypertensive Crisis  
In a controlled clinical study with axitinib for the treatment of patients with RCC, hypertension 
was reported in 145/359 patients (40%) receiving axitinib. Grade 3/4 hypertension was observed 
in 56/359 patients (16%) receiving axitinib; hypertensive crisis was reported in 2/359 patients 
(<1%) receiving axitinib.  The median onset time for hypertension (systolic blood pressure >150 
mmHg or diastolic blood pressure >100 mmHg) was within the first month of the start of axitinib 
treatment and blood pressure increases have been observed as early as 4 days after starting 
axtinib. Hypertension was managed with standard antihypertensive therapy. Discontinuation of 
axitinib treatment due to hypertension occurred in 1/359 patients (<1%) receiving axitinib. 
 
Arterial Thromboembolic Events 
In clinical trials, arterial thromboembolic events have been reported, including deaths. In a 
controlled clinical study with axitinib for the treatment of patients with RCC, Grade 3/4 arterial 
thromboembolic events were reported in 4/359 patients (1%) receiving axitinib, and fatal 
cerebrovascular accident was reported in 1/359 patients receiving axitinib.  In clinical trials with 
axitinib, arterial thromboembolic events (including transient ischemic attack, cerebrovascular 
accident, myocardial infarction, and retinal artery occlusion) were reported in 17/715 patients 
(2%), with two deaths secondary to cerebrovascular accident.  
 
Venous Thromboembolic Events 
In clinical trials, venous thromboembolic events have been reported, including deaths. In a 
controlled clinical study with axitinib for the treatment of patients with RCC, venous 
thromboembolic events were reported in 11/359 patients (3%) receiving axitinib.  Grade 3/4 
venous thromboembolic events were reported in 9/359 patients (3%) receiving axitinib 
(including pulmonary embolism, deep vein thrombosis, retinal vein occlusion and retinal vein 
thrombosis). Fatal pulmonary embolism was reported in 1/359 patients (<1%) receiving axitinib.   
In clinical trials with axitinib, venous thromboembolic events were reported in 22/715 patients 
(3%), with two deaths secondary to pulmonary embolism.  
 
Hemorrhage 
In a controlled clinical study with axitinib for the treatment of patients with RCC, hemorrhagic 
events were reported in 58/359 patients (16%) receiving axitinib. Grade 3/4 hemorrhagic events 

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were reported in 5/359 (1%) patients receiving axitinib (including cerebral hemorrhage, 
hematuria, hemoptysis, lower gastrointestinal hemorrhage, and melena). Fatal hemorrhage was 
reported in 1/359 patients (<1%) receiving axitinib (gastric hemorrhage). 
 
Gastrointestinal Perforation and Fistula Formation 
In a controlled clinical study with axitinib for the treatment of patients with RCC, 
gastrointestinal perforation was reported in 1/359 patients (<1%) receiving axitinib. In clinical 
trials with axitinib, gastrointestinal perforation was reported in 5/715 patients (1%), including 
one death. In addition to cases of gastrointestinal perforation, fistulas were reported in 4/715 
patients (1%).  
 
Thyroid Dysfunction 
In a controlled clinical study with axitinib for the treatment of patients with RCC, 
hypothyroidism was reported in 69/359 patients (19%) receiving axitinib. Hyperthyroidism was 
reported in 4/359 patients (1%) receiving axitinib. In patients who had thyroid stimulating 
hormone (TSH) <5 μU/mL before treatment, elevations of TSH to ≥10 μU/mL occurred in 
79/245 patients (32%) receiving axitinib. 
 
Reversible Posterior Leukoencephalopathy Syndrome 
In a controlled clinical study with axitinib for the treatment of patients with RCC, reversible 
posterior leukoencephalopathy syndrome (RPLS) was reported in 1/359 patients (<1%) receiving 
axitinib. There were two additional reports of RPLS in other clinical trials with axitinib. RPLS is 
a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness 
and other visual and neurologic disturbances. Mild to severe hypertension may be present. 
Magnetic resonance imaging is necessary to confirm the diagnosis of RPLS.  
 
Proteinuria 
In a controlled clinical study with axitinib for the treatment of patients with RCC, proteinuria 
was reported in 39/359 patients (11%) receiving axitinib. Grade 3 proteinuria was reported in 
11/359 patients (3%) receiving axitinib.  
 
Elevation of Liver Enzymes 
In a controlled clinical study with axitinib for the treatment of patients with RCC, alanine 
aminotransferase (ALT) elevations of all grades occurred in 22% of patients on both arms, with 
Grade 3/4 events in <1% of patients on the axitinib arm and 2% of patients on the sorafenib arm. 
 
7.2 Adverse Event Characteristics  
 
• CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version  
4.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 

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• For expedited reporting purposes only:    
- 
AEs for the agent(s) that are listed above should be reported only if the adverse event 
varies in nature, intensity or frequency from the expected toxicity information which 
is provided.  
 
• Attribution of the AE:  
-  Definite – The AE is clearly related to the study treatment.  
-  Probable – The AE is likely related to the study treatment.  
-  Possible – The AE may be related to the study treatment.  
-  Unlikely – The AE is doubtfully related to the study treatment.  
-  Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.3 Expedited Adverse Event Reporting to Overall PI 
 
7.3.1 Investigators must report within 1 business day of investigator awareness to the 
Overall PI any serious adverse event (SAE) that occurs from the time that the subject 
provides informed consent, which is obtained prior to the subject’s participation in the 
study, i.e., prior to undergoing any study-related procedure and/or receiving 
investigational product, through and including 30 calendar days after the last 
administration of the study treatment. 
 
7.3.2 For multi-institution studies where a DF/HCC investigator is serving as the Overall 
Principal Investigator, each participating institution must abide by the reporting 
requirements set by the DF/HCC. This applies to any medical event equivalent to an 
unexpected grade 2 or 3 with a possible, probable or definite attribution, unexpected 
grade 4 toxicities, and grade 5 (death) regardless of study phase or attribution 
 
7.3.3 DF/HCC Expedited Reporting Guidelines  
  
Investigative sites within DF/HCC will report AEs directly to the DFCI Office for  
Human Research Studies (OHRS) per the DFCI IRB reporting policy.   
  
Other investigative sites will report AEs to their respective IRB according to the local 
IRB’s policies and procedures in reporting adverse events. A copy of the submitted 
institutional AE form should be forwarded to the Overall PI within the timeframes 
detailed in the table below.    
 
 
 
 
Attribution 
DF/HCC Reportable AEs 
Gr. 2 & 3 
AE 
Expected 
Gr. 2 & 3 AE 
Unexpected 
Gr. 4 AE 
Expected 
Gr. 4 AE 
Unexpected 
Gr. 5 AE 
Expected or 
Unexpected 
Unrelated 
Not required 
Not required 
5 calendar 
5 calendar 
24 hours* 

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Unlikely 
days# 
days 
Possible 
Probable 
Definite 
 
Not required 
 
5 calendar 
days 
 
5 calendar 
days# 
 
5 calendar 
days 
 
24 hours* 
# If listed in protocol as expected and not requiring expedited reporting, event does not need to 
be reported. 
* For participants enrolled and actively participating in the study or for AEs occurring within 
30 days of the last intervention, the AE should be reported within 1 business day of learning of 
the event. 
The Overall PI will submit AE reports from outside institutions to the DFCI OHRS 
according to DFCI IRB policies and procedures in reporting adverse events.  
 
7.4 Expedited Reporting to Pfizer Inc. 
 
All observed or volunteered AEs regardless of study treatment or suspected causal relationship to 
the study treatment(s) will be reported as described in the following sections. 
 
 For all AEs, the Investigator must pursue and obtain information adequate both to determine the 
outcome of the AE and to assess whether it meets the criteria for classification as an SAE 
requiring immediate notification to Pfizer or its designated representative.  For all AEs, sufficient 
information should be obtained by the Investigator to determine the causality of the AE.  The 
Investigator is required to assess causality.  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.  
 
 
As part of ongoing safety reviews conducted by the Sponsor-Investigator, any non-serious 
adverse event that is determined by the Sponsor-Investigator to be serious will be reported by the 
Sponsor-Investigator 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 trial. 
 
7.4.1 Reporting Period 
 
For SAEs, the active reporting period to Pfizer or its designated representative begins from the 
time that the subject provides informed consent, which is obtained prior to the subject’s 
participation in the study, i.e., prior to undergoing any study-related procedure and/or receiving 
investigational product, through and including 30 calendar days after the last administration of 
the study treatment.   
 
SAEs occurring to a subject after the active reporting period has ended should be reported to the 
sponsor-investigator if the investigator becomes aware of them; at a minimum, all SAEs that the 

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investigator believes have at least a reasonable possibility of being related to study treatment are 
to be reported to the sponsor-investigator.  
 
AEs (serious and non-serious) should be recorded on the case report form (CRF) from the time 
the subject has taken at least 1 dose of study treatment through 30 calendar days after the last 
administration of the study treatment.  
 
During the post-treatment safety follow-up (beyond 30 days through 90calendar days after last 
study treatment administration), AEs serious or non-serious, suspected to be related to the study 
treatment based on investigator’s assessment, should be recorded on the CRF.   
 
If a patient begins a new anticancer therapy, the AE reporting period for nonserious AEs ends at 
the time the new treatment is started.  Death must be reported if it occurs during the SAE 
reporting period after the last dose of study treatment, irrespective of any intervening treatment. 
 
7.4.2 Serious Adverse Event Reporting to Pfizer Inc. 
 
If an SAE occurs, Pfizer is to be notified within 1 business day of Investigator awareness of the 
event.  In particular, if the SAE is fatal or life-threatening, notification to Pfizer must be made 
immediately, irrespective of the extent of available AE information.  This timeframe also applies 
to additional new information (follow-up) on previously forwarded SAE reports as well as to the 
initial and follow-up reporting of exposure during pregnancy, exposure via breastfeeding cases 
and occupational exposure. 
 
Steps for reporting Serious Adverse Events to Pfizer Worldwide Safety: 
• All SAEs, whether related or unrelated to avelumab and all pregnancies must be reported 
to Pfizer (by the investigator or designee) within 24 hours (i.e. 1 business day) using the 
Pfizer Reportable Event Fax Cover sheet and MedWatch Form FDA 3500A-Mandatory 
Reporting or Pfizer ISR SAE Report Form.  
• All SAEs should be reported via confirmed facsimile (fax) transmission to:  
 
Pfizer U.S. Clinical Trial Department SAE Fax Number: 1-866-997-8322. 
 
OR scanned and reported via electronic mail to:  
 
SAE Email Address: USA.AEReporting@pfizer.com 
 
In the rare event that the Investigator does not become aware of the occurrence of an SAE 
immediately (e.g., if an outpatient study patient initially seeks treatment elsewhere), the 
Investigator is to report the event within 24 hours (i.e. 1 business day) after learning of it and 
document the time of his/her first awareness of the AE. 
 
For all SAEs, the Investigator is obligated to pursue and provide information to Pfizer in 

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accordance with the timeframes for reporting specified above.  In addition, an Investigator may 
be requested by Pfizer to obtain specific additional follow-up information in an expedited 
fashion.  This information collected for SAEs is more detailed than that captured on the AE CRF.  
In general, this will include a description of the AE in sufficient detail to allow for a complete 
medical assessment of the case and independent determination of possible causality.  Information 
on other possible causes of the event, such as concomitant medications, vaccines and/or 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 or its designated representative. 
 
7.4.3 Serious Adverse Events 
 
An SAE is any untoward medical occurrence at any dose that:  
• Results in death;  
• Is life-threatening (immediate risk of death);  
• Requires inpatient hospitalization ≥ 24 hours 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;  
• 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 
safety reporting 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 safety reporting period, then the event leading to death 
must be recorded as an AE and as an SAE with CTCAE (version 4.03) Grade 5. 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. Examples 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. 
 
7.4.4 Potential Cases of Drug-Induced Liver Injury 
 
Abnormal values in aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) 
levels concurrent with abnormal elevations in total bilirubin level that meet the criteria outlined 
below in the absence of other causes of liver injury are considered potential cases of drug-
induced liver injury (potential Hy’s Law cases) and should always be considered important 
medical events.  
 
The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the patient’s individual baseline values and underlying conditions.  Patients who 
present with the following laboratory abnormalities should be evaluated further to definitively 

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determine the etiology of the abnormal laboratory values:  
• Patients with AST or ALT and total bilirubin baseline values within the normal range 
who subsequently present with AST or ALT values > 3times the upper limit of normal 
(XULN) concurrent with a total bilirubin values > 2X ULN with no evidence of 
hemolysis and an alkaline phosphatase value < 2X ULN or not available.  
• For patients with preexisting ALT OR AST OR total bilirubin values above the upper 
limit of normal, the following threshold values should be used in the definition mentioned 
above: 
o For patients with pre-existing AST or ALT baseline values above the normal 
range: AST or ALT values > 2 times the baseline values and > 3 times ULN or > 
8 times ULN (whichever is smaller). 
• Concurrent with 
o For patients with pre-existing values of total bilirubin above the normal range: 
Total bilirubin level increased from baseline by an amount of at least 1 × ULN or 
if the value reaches > 3 × ULN (whichever is smaller). 
 
The patient should return to the investigational 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.  The possibility of hepatic 
neoplasia (primary or secondary) should be considered.  In addition to repeating measurements 
of AST and ALT, laboratory tests should include albumin, creatine kinase, total bilirubin, direct 
and indirect bilirubin, gamma-glutamyl transferase, prothrombintime (PT)/INR, and alkaline 
phosphatase.  A detailed history, including relevant information, such as review of ethanol, 
acetaminophen, recreational drug and supplement consumption, family history, occupational 
exposure, sexual history, travel history, history of contact with a jaundiced patient, surgery, 
blood transfusion, history of liver or allergic disease, and work exposure, should be collected.  
Further testing for acute hepatitis A, B, or C infection and liver imaging (e.g., biliary tract) may 
be warranted.  All cases confirmed on repeat testing as meeting the laboratory criteria defined 
above, with no other cause for LFT abnormalities identified at the time should be considered 
potential Hy’s Law cases irrespective of availability of all the results of the investigations 
performed to determine etiology of the abnormal LFTs.  Such potential Hy’s Law cases should 
be reported as SAEs. 
 
7.4.5 Hospitalization 
 
Hospitalization is defined as any initial admission (even less than 24hours) 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 (e.g., 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 should be assessed for medical 
importance. Hospitalization does not include the following:  
• Rehabilitation facilities;  

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• Hospice facilities;  
• Respite care (e.g., caregiver relief);  
• Skilled nursing facilities; Nursing homes;  
• Routine emergency room admissions;  
• 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 (e.g., for work-up of 
persistent pre-treatment lab abnormality);  
• Social admission (e.g., patient has no place to sleep);  
• Administrative admission (e.g., for yearly physical exam);  
• Protocol-specified admission during a study (e.g., for a procedure required by the study 
protocol);  
• Optional admission not associated with a precipitating clinical AE (e.g., for elective 
cosmetic surgery);  
• Hospitalization for observation without a medical AE;  
• Pre-planned treatments or surgical procedures 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 non-invasive and invasive procedures, such as surgery, should not be 
reported as AEs.  However, the medical condition for which the procedure was performed should 
be reported if it meets the definition of an AE.  For example, an acute appendicitis that begins 
during the AE reporting period should be reported as the AE, and the resulting appendectomy 
should be recorded as treatment of the AE. 
 
7.5 Expedited Reporting to the Food and Drug Administration (FDA) 
 
The Overall PI, as study sponsor, will be responsible for all communications with the FDA. The 
Overall PI will report to the FDA, regardless of the site of occurrence, any serious adverse event 
that meets the FDA’s criteria for expedited reporting following the reporting requirements and 
timelines set by the FDA 
 
7.6 Expedited Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any participant  
safety reports or sentinel events that require reporting according to institutional policy.   
  
7.7 Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions to the Overall PI on the  

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toxicity case report forms.  AEs reported through expedited processes (e.g., reported to the  
IRB, FDA, etc.) must also be reported in routine study data submissions. 
 
 
8 DRUG FORMULATION INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational agents 
administered in this study can be found in Section 7. 
 
8.1 Avelumab 
 
 Description  
 
The active pharmaceutical ingredient in avelumab drug product is a fully human antibody of the 
IgG1 isotype that specifically targets and blocks the ligand (PD-L1) for PD-1. 
 
The calculated molecular weight of the molecule is 143,832 Dalton. The antibody is produced by 
mammalian cell culture in a serum-free growth medium. The antibody is purified by affinity, 
ion-exchange, and mix-mode chromatography. The process also includes specific viral 
inactivation and removal steps. The antibody is then transferred into formulation buffer and 
brought to the desired concentration. 
 
 Form 
 
Avelumab is a sterile, clear, and colorless solution intended for IV administration. Avelumab is 
formulated as a 20 mg/mL solution and is supplied by the Sponsor in single-use glass vials, 
stoppered with a rubber septum and sealed with an aluminum polypropylene flip-off seal. 
 
Each single-use 10 mg/mL vial contains 80 mg of avelumab as a preservative-free 
acetate-buffered solution (pH 5.5) containing Mannitol, Methionine, and Polysorbate 20 
(Tween 20). Each single-use 20 mg/mL vial contains 200 mg of avelumab as a preservative-
free acetate-buffered solution (pH 5.2) containing Mannitol, and Polysorbate 20 (Tween 20). 
For avelumab drug product, only excipients that conform to the current Ph. Eur. and/or the 
current USP are used. 
 
 Storage and Stability 
 
Avelumab drug product must be stored at 2°C to 8°C until use. The storage condition is based on 
data from ongoing long-term stability studies with avelumab.  Do not freeze. Protect from light. 
Do not shake vigorously. See the Investigational Product Manual for storage conditions of 
avelumab once diluted. 
 

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Avelumab drug product stored at room (23°C to 27°C) or higher temperatures for extended 
periods of time might be subject to degradation. Avelumab drug product must not be frozen. 
Rough shaking of the solution must be avoided. 
 
For application in clinical trials, avelumab drug product must be diluted with 0.45% or 0.9% 
saline solution (sodium chloride injection) supplied in an infusion bag. The chemical and 
physical in-use stability for the infusion solution of avelumab in 0.45% or 0.9% saline solution 
has been demonstrated for a total of 24 hours at room temperature. However, from a 
microbiological point of view, the diluted solution should be used immediately and is not 
intended to be stored unless dilution has taken place in controlled and validated aseptic 
conditions. If not used immediately, in-use storage times and conditions prior to administration 
are the responsibility of the user. 
 
No other drugs should be added to the solution for infusion containing avelumab. 
 
 Preparation and Handling 
 
For administration in this trial, avelumab must be diluted with 0.9% sodium chloride (normal 
saline solution). 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 DAI. Must use 
tubing with in-line, low protein binding 0.2 micron filter made of polyether sulfone (PES) during 
administration.  
 
The dose amount required to prepare the avelumab infusion solution will be based on the 
patient’s weight in kilograms (kg). All patients should be weighed within 3 days prior to dosing 
for every cycle to ensure they did not experience either a weight loss or gain ≥10% from the 
weight used for the last dose calculation. For weight change less than 10% the decision to 
recalculate the avelumab dose can be in accordance with institutional practice. If the patient 
experienced either a weight loss or gain ≥10% compared to the weight used for the last dose 
calculation, the amount of study drug must be recalculated. 
 
To prepare the dilutions, subsequent preparation steps must be accomplished by adequately 
trained personnel under a laminar flow box using aseptic techniques: 
 
Prior to the preparation of the dilution for final infusion, allow each vial to equilibrate to room 
temperature. Use a disposable syringe equipped with a needle of suitable size to remove a 
volume of sodium chloride solution to be replaced by avelumab from the infusion bag and 
discard the removed solution. Use a new disposable syringe equipped with a needle of suitable 
size to inject a volume of avelumab drug product identical to the discarded volume of sodium 
chloride solution into the infusion bag. Gently invert the mixture 10 times. Infusion bags must 
not be shaken, in order to avoid foaming or excessive shearing of the protein solution. The 
preparation must be carefully inspected as it should result in a homogeneous looking clear 
solution, free of visible particles. 
 

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Qualified personnel, familiar with procedures that minimize undue exposure to themselves and 
the environment, should undertake the preparation, handling, and safe disposal of the 
chemotherapeutic agent in a self-contained and protective environment.  
 
 Investigational Product Supplies 
 
Each site is responsible for requesting the investigational product from Pfizer Inc. using the Drug 
Supply Request Form. Investigational product supplies will be shipped to the study sites by 
Pfizer Global Clinical Supply (GCS), Worldwide Research and Development (WRD), and will 
include 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 take all steps to maintain appropriate records 
and ensure appropriate supply, storage, handling, distribution, and usage of investigational 
product in accordance with the protocol and any applicable laws and regulations. 
 
 Administration 
 
Avelumab will be administered intravenously via a 1-hour infusion every 14 days according to 
the protocol and dosing schedule described in Section 5.  
 
Sites should make every effort to target avelumab infusion timing to be as close to 1 hour as 
possible. However, given the variability of infusion pumps from site to site, time windows of 
minus 10 minutes and plus 20 minutes is permitted (i.e., infusion time is 50-80 minutes). The 
exact duration of infusion should be recorded in source documents. Possible modifications of the 
infusion rate for the management of infusion-related reactions are described in later sections. 
 
 Accountability 
 
The Investigative site must maintain adequate records documenting the receipt, use, loss, or other 
disposition of the investigational product.  In either case, the forms must identify the 
investigational product, including batch or code numbers, and account for its disposition on a 
patient-by-patient basis, including specific dates and quantities.  
 
The prescribed dose must be recorded in the patient’s medical records.  Drug dispensing must 
follow institutional policies.  Copies must be provided to Pfizer.  
 
At the end of the trial, or at appropriate points during the trial, Pfizer will provide instructions as 
to disposition of any unused investigational product.  If Pfizer authorizes destruction at the trial 
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.  
Destruction must be adequately documented.  If drug destruction is not permitted locally, Pfizer 
should be contacted for further directions. 
 
 Destruction and Return 

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Expired or unused investigational product will be destroyed per institutional policy.  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. 
 
8.2 
Talazoparib 
 
 Description 
 
Talazoparib is a potent, orally bioavailable small molecule PARP inhibitor. 
 
 Form  
 
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. 
 Storage and Stability 
 
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. 
 
 Preparation and Handling 
 
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.40 
Patients should be advised that oral anti-cancer agents are toxic substances and that other  
caregivers should always use gloves when handling the capsules. 
 

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 Investigational Product Supplies 
 
Each site is responsible for requesting the investigational product from Pfizer Inc. using the Drug 
Supply Request Form. Investigational product supplies will be shipped to the study sites by 
Pfizer Global Clinical Supply (GCS), Worldwide Research and Development (WRD), and will 
include 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 take all steps to maintain appropriate records 
and ensure appropriate supply, storage, handling, distribution, and usage of investigational 
product in accordance with the protocol and any applicable laws and regulations 
 
 Administration  
 
Talazoparib will be taken QD at 0.25mg, 0.5 mg, 0.75 mg, or 1 mg starting on Cycle 1 Day 1 
(C1D1) and treatment should continue until EOT. Patients with moderate renal impairment 
(defined as an estimated creatinine clearance of 30-59 mL/min) will receive a reduced starting 
dose of Talazoparib at 0.75 mg PO QD. On Days 1 and 15 of each cycle, when the patient 
returns to the clinic for avelumab administration, 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. 
Patients should self-administer talazoparib orally QD, 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 day 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 
instructed not to “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 cycle. 
 
 Accountability 
 
The investigative 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 talazoparib must be returned to the Investigator or designated investigative site 
personnel by each patient on Day 1 of every the trial in order to perform and document drug 

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accountability 
 Destruction and Return 
 
Expired or unused investigational product will be destroyed per institutional policy.  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. 
 
8.3 
Axitinib 
 
8.3.1 Description 
 
Axitinib is a potent, orally bioavailable small molecule inhibitor of VEGF receptors 1-3.  
Axitinib has the chemical name N-methyl-2-[3-((E)2-pyridin-2-yl-vinyl)-1H-indazol-6-
ylsulfanyl]-benzamide. 
 
8.3.2 Form 
Axitinib will be supplied as red, film-coated tablets containing either 1 mg or 5 mg of axitinib 
together with microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, 
magnesium stearate, and Opadry® II red 32K15441 as inactive ingredients. The Opadry II red 
32K15441 film coating contains lactose monohydrate, HPMC 2910/Hypromellose 15cP, 
titanium dioxide, triacetin (glycerol triacetate), and red iron oxide 
 
8.3.3 Storage and Stability 
 
Axitinib tablets are red film-coated, triangular tablets debossed with “Pfizer” on one side and “5 
XNB” on the other; available in bottles of 60: NDC 0069-0151-11.  
 
Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). 
 
Site staff will instruct patients on the proper storage requirements for take home investigational 
product, as axitinib will be self-administered at home by patients 
 
8.3.4 Preparation and Handling 
 
Axitinib 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. 
 
8.3.5 Investigational Product Supplies 

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Each site is responsible for requesting the investigational product from Pfizer Inc. using the Drug 
Supply Request Form. Investigational product supplies will be shipped to the study sites by 
Pfizer Global Clinical Supply (GCS), Worldwide Research and Development (WRD), and will 
include 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 take all steps to maintain appropriate records 
and ensure appropriate supply, storage, handling, distribution, and usage of investigational 
product in accordance with the protocol and any applicable laws and regulation 
 
8.3.6 Administration 
 
Axitinib will be taken 5mg twice daily by mouth starting on Cycle 1 Day 1 (C1D1) and 
treatment should continue until EOT.  
On Days 1 and 15 of each cycle, when the patient returns to the clinic for avelumab 
administration, the daily dose of axitinib 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. 
Patients should self-administer axitinib orally BID, with or without food. The tablets should 
be swallowed whole with a glass of water without chewing, dissolving, or opening them 
prior to swallowing.  Doses should be taken approximately 12 hours apart and at 
approximately the same times each day.  
 
If the patient vomits or misses a dose, an additional dose should NOT be taken.  The next 
prescribed dose should be taken at the usual time. 
 
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 cycle. 
 
8.3.7 Accountability 
 
The investigative 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 axitinib must be returned to the Investigator or designated investigative site personnel 
by each patient on Day 1 of every the trial in order to perform and document drug accountability. 
 
8.3.8 Destruction and Return 
 

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Expired or unused investigational product will be destroyed per institutional policy.  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. 
 
9 
BIOMARKER, CORRELATIVE AND SPECIAL STUDIES 
 
As noted in Section 2.4, the development of biomarkers for response and for toxicity associated 
with avelumab and other checkpoint inhibitors represents a substantial priority for the 
development of immunotherapeutic strategies in oncology. As such, we will request collection 
and banking of serial samples of blood as well as optional (although encouraged) core biopsies 
throughout the course of the trial as noted in Section 9.1.  
 
9.1 Sample Collection 
 
9.1.1 
Blood Sample Collection for HLA-typing, anti-avelumab antibodies, and 
Exploratory Biomarker Assessment 
 
Blood biospecimens (30 mL of blood: 20 mL into two purple top [EDTA] tubes (10 mL blood per 
tube) and 10 mL into one red top tube) will be collected from patients before the start of the first 
infusion on Cycle1, Day1; Cycle2, Day1; Cycle3, Day1; and at End of Treatment, with the 
option for further collection while on study protocol.  If a sample was collected at screening it 
does not have to be collected at Day 1 prior to the infusion.   
 
A.      Processing for Red-Topped Tube (~10ml for plasma/serum):  
• Spin down for 10 min at 2600 RPM, after which the plasma is taken as supernatant. 
• Gives rise to 2 cryovials for plasma. 
• Each daughter cryovial has ~2ml of plasma.  
 
B.      Processing for TWO Purple-Topped Tube (~20ml for whole blood): 
• Aliquot ~2mL of whole blood into each cryovial.  
• (Gives rise to 8 cryovials for whole blood.) 
 
All tubes will be stored in cryovials in -80°C freezers and batched shipped on dry ice to: 
 
Josephine Smith 
Dana-Farber Cancer Institute 
450 Brookline Ave, DA-122 
Boston, MA 02215 
Phone: 617-632-2164 
Email: Josephine_Smith@dfci.harvard.edu 
 

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Samples will be used for HLA-typing, to identify or characterize cells, DNA, RNA, or protein 
markers known or suspected to be of relevance to the mechanisms of action, or the development 
of resistance to avelumab or other immunotherapeutics, or the identification of those patients 
who might benefit from treatment with avelumab or other immunotherapeutics. Samples will 
also be assayed for anti-avelumab antibody using a validated analytical method.  All of the 
samples that are positive for ADA may also undergo characterization for neutralizing antibodies 
(NAb).  
 
 
9.1.2 
Mandatory FFPE Tumor Tissue 
 
A mandatory archived formalin-fixed, paraffin-embedded (FFPE) tumor tissue block must be 
provided that is of sufficient size to allow for sectioning of fifteen (15) 5-micron tissue sections.  
If an FFPE tumor tissue block cannot be provided, sites should provide fifteen (15) unstained 
slides each containing a 5-micron tissue section cut serially from the same FFPE block.  If tissue 
from multiple surgeries is available, the most recent specimen should be submitted. Archived or 
de novo tumor tissue from cytologic sampling (e.g., fine needle aspiration, including FFPE cell 
pellet material) is not adequate and should not be submitted. 
 
The FFPE block or 15 unstained slides should be mailed to the study coordinator at DFCI. 
Send FFPE block via overnight post to the following address: 
 
Josephine Smith 
Dana-Farber Cancer Institute 
450 Brookline Ave, DA-122 
Boston, MA 02215 
Phone:  617-632-2164 
Email contact: Josephine_Smith@dfci.harvard.edu  
 
9.1.3 
Optional Core Biopsies for Exploratory Assessment 
 
Collection of a de novo (i.e., new biopsy) tumor sample prior to enrollment is optional although 
encouraged unless clinically contraindicated. In addition, an optional de novo tumor sample is 
encouraged at End of Treatment regardless of the reason for treatment discontinuation (e.g. 
progression of disease or toxicity).   
 
Biopsies should be obtained under radiologic or other guidance, as appropriate, per institutional 
procedures.  A minimum of 2 and up to 3 core biopsies are requested; however, less than the goal 
amount of tissue is acceptable, and should be based upon the clinical judgment of the clinician 
performing the procedure.  Biopsy cores should be placed in neutral buffered formalin and then 
embedded in FFPE (Formalin Fixed Paraffin Embedded) no more than 16 hours after exposure to 
neutral buffered formalin. Biopsies will be batched shipped to: 
 
Josephine Smith 

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Dana-Farber Cancer Institute 
450 Brookline Ave, DA-122 
Boston, MA 02215 
Phone: 617-632-2164 
Email: Josephine_Smith@dfci.harvard.edu  
 
 
9.1.4 
Utilization of Resected Tumor Samples for Exploratory Assessment 
 
Collection of any fresh tumor tissue not used for direct pathological and clinical assessment or 
mandated for other use per existing institutional protocol for possible future assessment will be 
endeavored for direct studies of immune infiltrates and host-tumoral-immune dynamics.  
 
9.2 Planned Biomarker and Correlative Studies 
 
Planned correlative and exploratory analyses in blood, tissue and or fluid samples may include 
but are not limited to: 
 
• Assessment of CD3+ tumor infiltrating lymphocytes (TILs) and circulating lymphocytes, 
CD8+ TILs, CD8+/CD4+FOXP3+ TIL ratio, CD137+CD8+ TILs, 
CD137+CD8+/CD4+FOXP3+ TIL ratio; 
• Assessment of myeloid, stromal and other immunoactive cell types from blood, tissue 
and fluid samples; 
• Assessment of the expression pre-, during, and at time of progression of immune 
checkpoints including TIM-3, LAG-3, CTLA-4, PD-L2, PD-L1, PD-1, IDO 
• Ex vivo stimulation assays to interrogate the functional response of T-cell in the presence 
and absence of immunomodulatory agents;  
• Whole exome sequencing (WES) for specific DNA gene repair mutations and neoantigen 
assessment as well as for single nucleotide polymorphisms (SNPs) in immunologically 
relevant genes; 
• HLA-typing 
• Anti-avelumab antibodies 
• Multigene next generation sequencing assay (Oncopanel Assay) 
 
Studies may entail the use of ex-vivo biopsy samples, blood and resection samples as available 
and will be pursued in conjunction with the Dana-Farber Cancer Institute and DNA Repair 
Center and the Center for Immunooncology depending on funding availability. 
 
 
 
 
 
 

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10 STUDY CALENDAR 
 
Screening assessments, excluding scans and x-rays, are to be conducted within 14 days prior to 
start of protocol therapy. Scans and x-rays must be done <4 weeks prior to the start of therapy.  
In the event that the participant’s condition is deteriorating, laboratory evaluations should be 
repeated within 48 hours prior to initiation of the next cycle of therapy. Assessments must be 
performed prior to administration of avelumab. Study assessments and avelumab infusions (Days 
1 and 15) should be administered within + 3 days of the protocol-specified date, unless otherwise 
noted. For patients who are receiving talazoparib, it will be taken daily as described in section 5. 
For patients receiving combination avelumab/axitinib, axitinib will be taken twice daily as 
described in Section 5. 
 
Pre- 
Study 
C1/D1 
C1/D15 
C2a/D1 
C2a/D15 
Off 
Treatmentb 
Avelumab 
 
X 
X 
X 
X 
 
Talazoparib* 
 
QD 
 
Axitinib** 
 
BID 
 
Informed consent 
X 
 
 
 
 
 
Archival FFPE sample 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
Concurrent Medications 
X 
X 
X 
X 
 
 
Physical exam 
X 
X 
X 
X 
 
X 
Vital signsc 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
ECOG Performance 
Status 
X 
X 
X 
X 
X 
X 
CBC w/diff, plts 
X 
X 
X 
X 
X 
X 
Serum chemistryd 
X 
X 
X 
X 
X 
X 
TSH and Free T4h 
X 
X 
 
X 
 
X 
HBV surface antigen and 
HCV antibody testsi 
X 
 
 
 
 
 
Urinalysis** 
X 
X 
 
X 
 
X 
Adverse event evaluation 
X 
X 
X 
X 
X 
X 
CT or MRI scan (chest, 
abdomen, pelvis) and 
Tumor assessments 
(RECIST 1.1 and 
X 
Tumor measurements are repeated every 8 
weeks.  Documentation (radiologic) must 
be provided for participants removed from 
study for progressive disease. 
X 

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irRECIST)e 
B-HCGf 
X 
 
 
 
 
 
Urine pregnancy testf 
 
 
 
X 
 
 
Research blood drawg 
 
X 
 
X 
 
X 
Optional biopsy 
X 
 
 
 
 
X 
EKG & assessment of 
LVEF (MUGA or 
Echocardiogram)**j 
X 
 
 
 
 
 
a. Cycle 2 and subsequent cycles. 
b: Off-Treatment evaluation. Reassessments for toxicity, disease progression, and survival will 
be performed up to 30 days after last treatment dose. Participants will be followed for 3 years 
after removal from study or until death, whichever occurs first. Survival status should be 
checked every 6 months during that time.   
c: Vital signs will include resting heart rate, blood pressure, temperature and weight at the 
screening visit will include height. After Screening, height will not be measured. Vital signs 
and weight will be obtained prior to chemotherapy administration according to institutional 
practice.  
d: Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, 
creatinine, glucose, LDH, phosphorus, potassium, total protein, SGOT [AST], SGPT [ALT], 
sodium. **For participants in the Avelumab/Axitinib cohort only: serum Lipase and amylase 
at baseline and when clinically indicated. 
e: Patients will be restaged every 8 weeks [±7 days]. The same method of assessment and the 
same technique must be used to characterize each identified and reported lesion at baseline and 
during subsequent imaging procedures. Patients continuing study treatment for a minimum of 
1 year may have the tumor imaging assessments expanded to every 12 weeks [±7 days] unless 
they are continuing treatment beyond progression per Section 5.6. 
f: For women of childbearing potential: a Serum pregnancy test ≤72 hours prior to first dose of 
study treatment. Thereafter, a urine pregnancy test will be performed every 4 weeks while on 
treatment with study drug. Results of the most recent pregnancy test should be available prior 
to the administration of study intervention.  
g: 30 mL of blood will be drawn (20 mL into two purple top [EDTA] tubes (10 mL blood per 
tube) and 10 mL into one red top tube) before the start of infusion on C1D1; C2D1; C3D1; 
and at End of Treatment, 
h: Pre-study and prior to the first 2 cycles, then as clinically indicated, and at off-study visit. 
i.  If HCV antibody test is positive the confirmatory HCV RNA test should be done.  
j. And as clinically indicated 
*   for participants in the avelumab/talazoparib cohort only 
** for participants in the avelumab/axitinib cohort only 
QD = daily 
BID = twice daily 

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11 MEASUREMENT OF EFFECT 
 
As noted elsewhere, measurement of effect will be assessed by both the Response Evaluation 
Criteria in Solid Tumors (RECIST) Version 1.1 and by the Immune-related Response Criteria 
Derived from RECIST 1.1 (irRECIST).  
 
11.1 Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 Guidelines 
 
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 10mm or greater 
when assessed by CT or MRI (slice thickness 5-8mm).  
• Lesions with longest diameter at least 20mm when assessed by Chest X-ray. 
•  Superficial lesions with longest diameter 10mm or greater when assessed by caliper. 
•  Malignant lymph nodes with the short axis 15mm 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 14.9mm) 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. 
 
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.  

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• Normal nodes: Nodes with short axis <10mm 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 treatment 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 on study. 
 
 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 a target 
lesion becomes too small to measure, 0mm should be recorded if the lesion is considered to have 
disappeared; otherwise a default value of 5mm should be recorded.  
 
NOTE: When nodal lesions decrease to <10mm (normal), the actual measurement should 
still be recorded.  
 
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, PRESENT/NOT INCREASED, 
INCREASED.  Multiple non-target lesions in one organ may be recorded as a single item on the 
case report form (e.g., ‘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 must be 
discussed with the radiologist to determine if substitution is possible.  If not, subsequent 
objective statuses are indeterminate.  

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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 
<10mm).  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.  The short diameter is used in the sum for 
target nodes, while the longest diameter is used in the sum for all other target lesions. All 
target lesions must be assessed.  
• Stable: 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, 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 5mm.  
• Indeterminate.  Progression has not been documented, and  
• One or more target measurable 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 (e.g., 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. 
 
Non-target disease  
 
• CR: Disappearance of all non-target lesions and normalization of tumor marker levels.  
All lymph nodes must be ‘normal’ in size (<10mm short axis).  
• Non-CR/Non-PD: Persistence of any non-target lesions and/or tumor marker level 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.  
• Indeterminate: Progression has not been determined and one or more non-target sites 
were not assessed or assessment methods were inconsistent with those used at baseline. 
 
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 

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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.  
 
Objective/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 objective progression even after discontinuation of 
treatment. 
 
For Participants with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once >4 
wks from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**       Only for non-randomized trials with response as primary endpoint. 
***      In exceptional circumstances, unequivocal progression in non-target lesions may be 
            accepted as disease progression. 
 
Note:  Participants with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 

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If the protocol allows enrollment of patients with only non-target disease, the following table 
should be used:  
 
For Participants with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign 
this category when no lesions can be measured is not advised 
 
Determination of Best Overall Response  
 
The best overall response is the best response recorded from the start of the treatment 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 study entry at a minimum interval of 6 weeks. 
 
11.2 Immune-related Response Criteria Derived from RECIST 1.1 (irRECIST) 
 
Increasing clinical experience indicates that traditional response criteria may not be sufficient to 
fully characterize activity in this new era of targeted therapies and/or biologics.   
 
This is particularly true for immunotherapeutic agents such as anti-CTLA-4 and anti-PD-1 / anti 
PD-L1 which exert the antitumor activity by augmenting activation and proliferation of T-cells, 
thus leading to tumor infiltration by T-cells and tumor regression rather than direct cytotoxic 
effects (Hodi et al., 2008; Hoos et al., 2010). Clinical observations of patients with advanced 
melanoma treated with ipilimumab, for example, suggested that conventional response 
assessment criteria such as Response Evaluation Criteria in Solid Tumors (RECIST) and WHO 
criteria are not sufficient to fully characterize patterns of tumor response to immunotherapy 
because tumors treated with immunotherapeutic agents may show additional response patterns 
that are not described in these conventional criteria (Nishino et al., 2014; Wolchok et al., 2009). 
 
Furthermore, the conventional tumor assessment criteria (RECIST and WHO criteria) have been 
reported as not capturing the existence of a subset of patients who have an OS similar to those 
who have experienced CR or PR but were flagged as PD by WHO criteria (Nishino et al., 2012; 
Wolchok et al., 2009). 

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On these grounds, a tumor assessment system has been developed that incorporates these delayed 
or flare-type responses into the RECIST 1.1 criteria (irRECIST) (Nishino et al., 2014). 
 
For irRECIST, only target and measurable lesions are taken into account. In contrast to the 
RECIST 1.1, the irRECIST criteria  
 
• require confirmation of both progression (at the investigator’s discretion) and response by 
imaging at least 4 weeks from the date first documented, and  
• do not necessarily score the appearance of new lesions as progressive disease if the sum 
of lesion diameters of target lesions (minimum of 10 mm per lesion, maximum of 5 target 
lesions, maximum of 2 per organ) and measurable new lesions does not increase by >= 
20%.  
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported target lesion(s) at baseline and throughout the trial.  
 
irRECIST criteria are defined as follows:  
• Overall immune-related complete response (irCR): Complete disappearance of all lesions 
(whether measurable or not) and no new lesions. All measurable lymph nodes also must 
have a reduction in short axis to <10 mm.  
• Overall immune-related partial response (irPR): Sum of the diameters (longest for non-
nodal lesions, shortest for nodal lesions) of target and new measurable lesions decreases 
>= 30%.  
• Overall immune-related stable disease (irSD): Sum of the diameters (longest for non-
nodal lesions, shortest for nodal lesions) of target and new measurable lesions neither 
irCR, irPR, (compared to baseline) or immune-related progressive disease (irPD, 
compared to nadir).  
• Overall immune-related progressive disease (irPD): Sum of the diameters (longest for 
non-nodal lesions, shortest for nodal lesions) of target and new measurable lesions 
increases >= 20% (compared to nadir), confirmed by a repeat, consecutive observation at 
least 4 weeks from the date first documented, at the investigator’s discretion.  
 
New measurable lesions: Incorporated into tumor burden (ie, added to the target lesion 
measurements). A lymph node has to be >= 15 mm in short axis to be a measurable new lesion 
and its short axis measurement is included in the sum. Up to 2 new lesions per organ and up to 5 
new lesions in total can be added to the measurements.  
 
New non-measurable lesions: Do not define progression but preclude irCR.  
 
Overall responses derived from changes in index, non-index, and new lesions are outlines in the 
following table. 
 

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Overall Response Derived from Changes in Index, Non-index and New Lesions 
 
Measurable 
Response 
Non-measurable response 
Overall Response 
using irRECISTb 
Index and New 
Measurable Lesions 
(Tumor Burden)a 
Non-Index Lesions 
New non-
measurable Lesions 
 
Decrease 100% 
Absent 
Absent 
irCR 
Decrease 100% 
Stable 
Any 
irPR 
Decrease 100% 
Unequivocal 
progression 
Any 
irPR 
Decrease ≥ 30% 
Absent / stable 
Any 
irPR 
Decrease ≥ 30% 
Unequivocal 
progression 
Any 
irPR 
Decrease < 30% and 
increase < 20% 
Absent / stable 
Any 
irSD 
Decrease < 30% and 
increase < 20% 
Unequivocal 
progression 
Any 
irSD 
Increase ≥ 20% 
Any 
Any 
irPD 
a. Decrease assessed relative to baseline. Increase assessed relative to nadir. 
b. Response (irCR and irPR) must be confirmed by a second, consecutive assessment at least 4 
weeks apart. Progression (irPD) should be confirmed at the investigator’s discretion. 
 
12 DATA REPORTING & REGULATORY REQUIREMENTS  
 
12.1 
Data Reporting 
 
Method 
 
The ODQ will collect, manage, and perform quality checks on the data for this study. 
 
Responsibility for Data Submission 
 
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or 
data forms to the ODQ according to the schedule set by the ODQ. 
 
12.2      Data Safety Monitoring 
 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. The committee is composed of clinical specialists with 
experience in oncology and who have no direct relationship with the study. Information that 
raises any questions about participant safety will be addressed with the Overall PI and study 
team. 

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The DSMC will review each protocol up to four times a year or more often if required to review 
toxicity and accrual data. Information to be provided to the committee may include: up-to-date 
participant accrual; current dose level information; DLT information; all grade 2 or higher 
unexpected adverse events that have been reported; summary of all deaths occurring with 30 
days of intervention for Phase I or II protocols; for gene therapy protocols, summary of all deaths 
while being treated and during active follow-up; any response information; audit results, and a 
summary provided by the study team. Other information (e.g. scans, laboratory values) will be 
provided upon request.  
 
12.3 
 Multicenter Guidelines 
 
This protocol will adhere to the policies and requirements of the DF/HCC Multi-Center Data and 
Safety Monitoring Plan.  The specific responsibilities of the Overall PI, Coordinating Center, and 
Participating Institutions and the procedures for auditing are presented in Appendix B. 
• The Overall PI/Coordinating Center is responsible for distributing all IND Action Letters 
or Safety Reports to all participating institutions for submission to their individual IRBs 
for action as required. 
 
• Mechanisms will be in place to ensure quality assurance, protocol compliance, and 
adverse event reporting at each site. 
 
• Except in very unusual circumstances, each participating institution will order the study 
agent(s) directly from supplier.  A participating site may order the agent(s) only after the 
initial IRB approval for the site has been forwarded to the Coordinating Center. 
 
 
13 STATISTICAL CONSIDERATIONS 
 
We propose a non-randomized, open-label, two-cohort, two-stage, phase 2 trial, of avelumab in 
two cohorts of endometrial cancer patients: MSI/POLE cohort and MSS cohort. We propose a 
two-stage design for both MSI/POLE and MSS cohorts to inform whether avelumab has significant 
clinical efficacy that is worth of further evaluation in each of the 2 cohorts.  Furthermore, for the 
new MSS cohort to be treated with avelumab/talazoparib, the same two stage design will be 
employed to inform whether the avelumab/talazoparib combination has significant clinical 
efficacy that is worth of further evaluation in this (MSS) cohort. 
 
For the MSS cohort receiving avelumab/axitinib, a two-stage Optimum design will be used to 
allow early stopping for futility. 
 
 

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13.1 Study Design/Endpoints 
 
Primary Endpoints 
To assess the activity of avelumab in patients with recurrent or persistent endometrial cancer 
classified by MSI/POLE genomic cohorts by evaluating the frequency of patients who survive 
progression-free for at least 6 months (PFS6) after initiating therapy or have objective tumor 
response.  
 
Statistical considerations are developed for co-primary objectives to evaluate the objective 
response rate (ORR) by RECIST 1.1 and rate of progression-free survival at 6 months (PFS6), 
with a two-stage design that allows for early stopping for futility. 
 
For each of the 2 cohorts (MSI/POLE vs MSS) and the new MSS cohort treated with 
avelumab/talazoparib a two-stage test was constructed using the method of Sill, Rubinstein, 
Litwin and Yothers (Sill et al., 2012) with the goal of stopping early for futility to limit patient 
exposure to an inactive agent while restricting the probabilities of type I and type II errors to 
approximately 10% and 15%, respectively. For the co-primary endpoints, a true ORR of 5% or 
less and a rate of progression-free survival at 6 months of (PFS6) 10% or less would not be of 
clinical interest (H0: πOR ≤ 5%   AND   πPFS6  ≤ 10%), whereas an improvement to a 20% 
objective response rate or 30% PFS6 rate would warrant further investigation of avelumab.  In 
the first stage, 16 patients will be enrolled. If there are at least two objective responses or two 
patients progression-free at 6 months, accrual will continue to the second stage where an 
additional 19 patients will be enrolled. If at the end of the trial there are at least 4 treated patients 
with an objective response or 8 patients progression-free at 6 months, avelumab will be 
considered worthy of further study in the corresponding cohort.  
 
Specifically, analysis of historical data (GOG129 and GOG229 series) based on similar 
population of patients with endometrial cancer where the levels of activity were believed to be 
inactive to modestly active shows that an unacceptable rate for objective response πOR is 5% and 
for PFS6 (πPFS6) is 10%, respectively. A bivariate test of the co-primary endpoints is constructed 
as follows: 
H0:  πOR ≤ 5%   AND   πPFS6 ≤ 10% 
vs. 
H1:  πOR > 5%   OR   πPFS6 > 10% 
 
Targeted alternative hypothesis:  An absolute improvement in the rate of OR by 15% or PFS6 by 
20% would be of clinical interest. Power is determined under two specific hypotheses (Hr: πOR = 
20%, πPFS6= 10%) and (Hs: πOR = 5%, πPFS6 = 30%) where sufficient activity is seen in only each 
endpoint, respectively. Sample size is selected to have sufficient power to reject the null under 
cases that assume either (a) independence or (b) dependence among the co-primary endpoints. 
The decision rules and operating characteristics of the two-stage design are summarized in the 
Table below: 
 
 

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Table: Decision rules and operating characteristics of the two-stage design 
 
Endpoint 
Objective 
Response 
PFS6 
Null hypothesis 
5% 
10% 
Alternative hypothesis 
20% 
30% 
Stage 1 
Number of patients 
16 
Minimum number of events to 
continue to Stage 2 
2 
2 
PET (Independence) 
0.417 
PET (Dependence) 
0.502 
Stage 2 
Number of patients 
35 
Minimum number of events to 
reject the null hypothesis  
4 
8 
alpha (Independence) 
0.098 
alpha (Dependence) 
0.088 
Power (Independence) 
0.889 
0.873 
Power (Dependence) 
0.846 
0.862 
 
Similarly, using the same statistical design, for the new MSS cohort to be treated with 
avelumab/talazoparib, in the first stage, 16 patients will be enrolled. If there are at least two 
objective responses or two patients progression-free at 6 months, accrual will continue to the 
second stage where an additional 19 patients will be enrolled. If at the end of the trial there are at 
least 4 treated patients with an objective response or 8 patients progression-free at 6 months, 
avelumab/talazoparib will be considered worthy of further study in the MSS cohort.  
 
For the MSS cohort receiving avelumab/axitinib, similar statistical considerations were used to 
evaluate the co-primary objectives ORR and PFS6.  This cohort will be evaluated using a two-
stage test constructed using the method of Sill, Rubinstein, Litwin, and Yothers (Sill et al, 2012), 
with the goal of stopping early for futility to limit patient exposure to an inactive agent while 
restricting the probabilities of Type I error to 10% and Type II error to 15%.  This is derived 
from historical data (the GOG 129 and GOG 229 series) based on a similar patient population 
where the levels of activity believed to be inactive to modestly active showed that an 
unacceptable rate for ORR πOR is 5% and for PFS6 (πPFS6) is 10%, respectively. A bivariate test 
of the co-primary endpoints is constructed as follows: 
 
H0:  πOR ≤ 5%   AND   πPFS6 ≤ 10% 
vs. 
H1:  πOR > 5%   OR   πPFS6 > 10% 
   
For the co-primary endpoints, a true ORR of 5% or less and a rate of progression-free survival at 
6 months (PFS6) of 10% or less would not be of clinical interest (H0: πOR ≤ 5% AND πPFS6 ≤ 
10%), whereas an improvement to a 20% objective response rate or 30% PFS6 rate would 

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warrant further investigation of axitinib/avelumab.  
 
Using these parameters, in the first stage, 16 patients will be enrolled. If there are at least 2 
objective responses or 2 patients progression-free at 6 months, accrual will continue to the 
second stage where an additional 19 patients will be enrolled. If at the end of the trial there are at 
least 4 treated patients with an objective response or 8 patients progression-free at 6 months, 
axitinib/avelumab will be considered worthy of further study. 
 
 
13.2 Sample Size, Accrual Rate and Study Duration 
 
The planned total sample size is a maximum of 105 patients. The total sample size will be 
adjusted to allow for replacement of participants who never began protocol therapy for reasons 
including ineligibility, inevaluability, and participant drop out. While the maximum target 
accrual is 105 patients, up to 115 patients can be enrolled to allow for replacement. The planned 
maximum sample size for the  MSS cohort receiving avelumab/talazoparib will be 35 patients 
(16 for the first stage and 19 for the second). Based on the accrual of the previous MSS cohort, 
we estimate a monthly accrual of 4-5 patients during periods of active enrollment. Patients will 
be followed for a maximum of 3 years.  
 
For the MSS cohort receiving avelumab/axitinib, the planned maximum sample size will be 35 
patients (16 for Stage 1 and 19 for Stage 2).  We anticipate enrollment to the first stage to be 
completed within 2-3 months, based on enrollment of the previous cohorts using avelumab alone 
and combination avelumab/talazoparib.  The duration of the study will depend on whether the 
study will move to the second stage and the timing of each cohort.  Across all cohorts and stages, 
we estimate a total accrual duration of 5.5 years. 
 
The planned enrollment report is shown in the following Table. 
 
PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 
American Indian/ 
Alaska Native 
0 
0 
0 
0 
0 
Asian 
15 
0 
0 
0 
15 
Native Hawaiian or 
Other Pacific Islander 
0 
0 
0 
0 
0 

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Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 
Black or African 
American 
7 
0 
3 
0 
10 
White 
69 
0 
11 
0 
80 
More Than One Race 
0 
0 
0 
0 
0 
Total 
91 
0 
14 
0 
105 
 
13.3 Stratification Factors 
 
Participants will be classified into one of two cohorts of recurrent or persistent endometrial cancer 
of any histology: 
a. The first cohort (MSI/POLE cohort) includes endometrial cancers that are:  
MSI-H as determined by immunohistochemical complete loss of expression (absence of nuclear 
immunoreactivity) of at least one of the mismatch repair genes MSH2, MSH6, MLH1 and PMS2. 
This test is now done routinely for every newly diagnosed endometrial cancer patient in most 
centers in the US. 
And/OR: 
POLE-mutated, i.e. endometrial cancers known to harbor mutations in the exonuclease domain 
of polymerase e (POLE) as determined by targeted sequencing or other next generation sequencing 
assay. 
 
b. The second cohort (MSS cohort) includes: 
Endometrial cancers that are MSS as determined by normal immunohistochemical nuclear 
expression of all the mismatch repair genes MSH2, MSH6, MLH1 and PMS2. Tumors which have 
not been sequenced for POLE mutations (i.e. their POLE mutations status is unknown) but are 
MSS, will be included in this cohort. 
 
13.4 Analysis of Secondary Endpoints 
 
The distributions of progression-free- and overall survival times in each cohort will be estimated 
by using Kaplan-Meier analysis. Immune-related objective response rate for each cohort will be 
estimated as described in Section 11.2. Immune-related progression-free survival (irPFS) rate for 
each cohort is defined as time from cohort assignment to death or to immune-related progression 
of disease (irPD) as defined in Section 11.2. 

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All analyses of exploratory endpoints in this study are exploratory in nature. Patients who have 
tumors that are amenable to biopsy will be asked to undergo pre- and posttreatment biopsies. 
These studies will be optional. For baseline continuous endpoint data, such as PD-L1 and CD8, 
descriptive statistics, including the mean, standard deviation, median, minimum, and maximum 
values, will be provided for each cohort. For baseline categorical data, the number and 
percentage of patients in each category will be provided by treatment arm. Appropriate statistical 
methods may be used to investigate any possible relationship of biomarker levels with avelumab 
anti-tumor efficacy in each cohort. 
 
13.5 Reporting and Exclusions 
 
13.5.2 Evaluation of Toxicity 
 
All participants will be evaluable for toxicity from the time of their first treatment. 
 
13.5.3 Evaluation of the Primary Efficacy Endpoint 
 
All participants included in the study must be assessed for response to treatment, even if there 
are major protocol treatment deviations or if they are ineligible. Each participant should be 
assigned one of the following categories: 1) complete response, 2) partial response, 3) stable 
disease, 4) progressive disease, 5) early death from malignant disease, 6) early death from 
toxicity, 7) early death because of other cause, or 9) unknown (not assessable, insufficient data). 
By arbitrary convention, category 9 usually designates the "unknown" status of any type of data 
in a clinical database. 
All participants who have measurable disease present at baseline, have received at least one 
cycle of therapy, and have had their disease re-evaluated will be considered evaluable for 
response. Participants in response categories 5-9 will not be considered evaluable but will remain 
within the intention to treat analysis. 
 
Patients who develop brain metastasis on study, but continue on study after definitive treatment 
of their cranial disease, will be considered to have had progressive disease at the point of the 
diagnosis of the initial brain metastasis. 
 
All conclusions should be based on all evaluable participants. Subanalyses may then be 
performed on the basis of a subset of participants, excluding those for whom major protocol 
deviations have been identified (e.g., early death due to other reasons, early discontinuation of 
treatment, major protocol violations, etc.). However, these subanalyses may not serve as the 
basis for drawing conclusions concerning treatment efficacy, and the reasons for excluding 
participants from the analysis should be clearly reported. The 95% confidence intervals should 
also be provided. 
 
 

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14 PUBLICATION PLAN 
 
Publication guidelines exist within the DF/HCC Gynecologic Oncology Program. The study 
principal investigator will be responsible for collection of data, interpretation of data, monitoring 
of toxicities, and publication of abstracts and final manuscripts. The principal investigator 
chooses the different authorship slots per the DF/HCC gynecologic oncology program 
guidelines. 
 
The results should be made public within 24 months of reaching the end of the study. The end of 
the study is the time point at which the last data items are to be reported, or after the outcome 
data are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate 
and Study Duration. If a report is planned to be published in a peer-reviewed journal, then that 
initial release may be an abstract that meets the requirements of the International Committee of 
Medical Journal Editors. A full report of the outcomes should be made public no later than three 
(3) years after the end of the study.  
 
 
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1. . 
 
 
 
 
 
 

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APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 

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APPENDIX B: DANA-FARBER/HARVARD CANCER CENTER MULTI-CENTER 
DATA AND SAFETY MONITORING PLAN 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TABLE OF CONTENTS 
1. 
INTRODUCTION ...........................................................................................................127 
1.1 
Purpose .................................................................................................................127 
1.2 
Multi-Center Data and Safety Monitoring Plan Definitions ................................127 
2. 
GENERAL ROLES AND RESPONSIBILITIES ...........................................................128 
2.1 
DF/HCC Sponsor .................................................................................................128 
2.2 
Coordinating Center .............................................................................................129 
2.3 
Participating Institution ........................................................................................129 

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3. 
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS............................130 
3.1 
Protocol Distribution ............................................................................................130 
3.2 
Protocol Revisions and Closures .........................................................................130 
3.3 
Informed Consent Requirements .........................................................................131 
3.4 
IRB Documentation .............................................................................................131 
3.5 
IRB Re-Approval .................................................................................................132 
3.6 
Participant Confidentiality and Authorization Statement ....................................132 
3.7 
DF/HCC Multi-Center Protocol Registration Policy ...........................................132 
3.8 
DF/HCC Protocol Case Number ..........................................................................133 
3.9 
Safety Assessments and Toxicity Monitoring .....................................................134 
3.10 
Data Management ................................................................................................135 
4. 
REQUISITIONING INVESTIGATIONAL DRUG........................................................136 
5. 
MONITORING: QUALITY CONTROL ........................................................................136 
5.1 
Ongoing Monitoring of Protocol Compliance .....................................................136 
5.2 
Monitoring Reports ..............................................................................................137 
5.3 
Accrual Monitoring ..............................................................................................137 
6. 
AUDITING: QUALITY ASSURANCE .........................................................................137 
6.1 
Audit Plan: DF/HCC Sponsored Trials................................................................137 
6.2 
Audit Notification ................................................................................................138 
6.3 
Audit Reports .......................................................................................................138 
6.4 
Participating Institution Performance ..................................................................138 
 
 
 

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1. INTRODUCTION 
 
The Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan 
(DF/HCC DSMP) outlines the procedures for conducting a DF/HCC Multi-Center research 
protocol. The DF/HCC DSMP should serve as a reference for any sites external to DF/HCC 
that will be participating in the research protocol. 
 
1.1 
Purpose 
 
To establish standards that will ensure that a Dana-Farber/Harvard Cancer Center Multi-
Center protocol will comply with Federal Regulations, Health Insurance Portability and 
Accountability Act (HIPAA) requirements and applicable DF/HCC Standard Operating 
Procedures. 
 
1.2 
Multi-Center Data and Safety Monitoring Plan Definitions 
 
DF/HCC Multi-Center Protocol:  A research protocol in which one  or more outside 
institutions are collaborating with Dana-Farber/Harvard Cancer Center where  a DF/HCC 
investigator is the sponsor. DF/HCC includes Dana-Farber/Partners Cancer Care (DF/PCC) 
Network Clinical Trial Affiliates.  
 
Lead Institution:  One of the Dana-Farber/Harvard Cancer Center consortium members 
(Dana-Farber Cancer Institute (DFCI), Massachusetts General Hospital (MGH), Beth Israel 
Deaconess Medical Center (BIDMC), Boston Children’s Hospital (BCH), Brigham and 
Women’s Hospital (BWH)) responsible for the coordination, development, submission, and 
approval of a protocol as well as its subsequent amendments per the DFCI IRB and 
applicable regulatory guidelines (CTEP, Food and Drug Administration (FDA), Office of 
Biotechnology Activities (OBA) etc.).  The Lead Institution is typically the home of the 
DF/HCC Sponsor. The Lead Institution also typically serves as the Coordinating Center for 
the DF/HCC Multi-Center Protocol.   
 
DF/HCC Sponsor:  The person sponsoring the submitted Multi-Center protocol.  Within 
DF/HCC, this person is the Overall Principal Investigator who takes responsibility for 
initiation, management and conduct of the protocol at all research locations. In applicable 
protocols, the DF/HCC Sponsor will serve as the single liaison with any regulatory agencies 
(i.e. FDA, etc.). The DF/HCC Sponsor has ultimate authority over the protocol and is 
responsible for the conduct of the study at DF/HCC and all Participating Institutions. In 
most cases the DF/HCC Sponsor is the same person as the DF/HCC Overall Principal 
Investigator; however, both roles can be filled by two different people.  
 
Participating Institution:  An institution that is outside the DF/HCC and DF/PCC 
consortium that is collaborating with DF/HCC on a protocol where the sponsor is a DF/HCC 
Investigator.  The Participating Institution acknowledges the DF/HCC Sponsor as having 
the ultimate authority and responsibility for the overall conduct of the study.    

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Coordinating Center: The entity (i.e. Lead Institution, Medical Monitor, Contract 
Research Organization (CRO), etc.) that provides administrative support to the DF/HCC 
Sponsor in order that he/she may fulfill the responsibilities outlined in the protocol 
document and DSMP, and as specified in applicable regulatory guidelines (i.e. CTEP Multi-
Center Guidelines). In general, the Lead Institution is the Coordinating Center for the 
DF/HCC Multi-Center Protocol. Should the DF/HCC Sponsor decide to use a CRO, the 
CRO will be deemed the Coordinating Center.   
 
DF/HCC Office of Data Quality: A group within DF/HCC responsible for registering 
human subjects for trials, ensuring high-quality standards are used for data collection and 
the ongoing management of clinical trials, auditing, and data and safety monitoring. ODQ 
also coordinates quality assurance efforts related to multi-center clinical research. 
 
2. GENERAL ROLES AND RESPONSIBILITIES 
 
For DF/HCC Multi-Center Protocols, the DF/HCC Sponsor, the Coordinating Center, and 
the Participating Institutions are expected to adhere to the following general responsibilities:  
 
2.1 
DF/HCC Sponsor 
 
The DF/HCC Sponsor, Panagiotis A. Konstantinopoulos, MD, will accept responsibility 
for all aspects of conducting a DF/HCC Multi-Center protocol which includes but is not 
limited to:  
• Oversee the coordination, development, submission, and approval of the protocol as 
well as subsequent amendments.  
• Ensure that the investigators, study team members, and Participating Institutions are 
qualified and appropriately resourced to conduct the protocol.   
• Include the Multi-Center Data and Safety Monitoring Plan as an appendix to the 
protocol. 
• Ensure all Participating Institutions are using the correct version of the protocol. 
• Ensure that each participating investigator and study team member receives 
adequate protocol training and/or a Site Initiation Visit prior to enrolling participants 
and throughout trial’s conduct as needed. 
• Ensure the protocol will be provided to each participating site in a language 
understandable to all applicable site personnel when English is not the primary 
language.  
• Monitor progress and overall conduct of the study at all Participating Institutions.  
• Ensure all DFCI Institutional Review Board (IRB), DF/HCC and other applicable 
(i.e. FDA) reporting requirements are met.  
• Review data and maintain timely submission of data for study analysis.  
• Act as the single liaison with FDA (investigator-held IND trials). 

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• Ensure compliance with all requirements as set forth in the Code of Federal 
Regulations, applicable DF/HCC requirements, HIPAA requirements, and the 
approved protocol. 
• Commit to the provision that the protocol will not be rewritten or modified by 
anyone other than the DF/HCC Sponsor. 
• Identify and qualify Participating Institutions and obtain accrual commitments prior 
to extending the protocol to that site. 
• Monitor accrual and address Participating Institutions that are not meeting their 
accrual requirements.  
 
2.2 
Coordinating Center  
 
The general responsibilities of the Coordinating Center may include but are not limited to: 
• Assist in protocol development.  
• Maintain FDA correspondence, as applicable. 
• Review registration materials for eligibility and register participants from 
Participating Institutions with DF/HCC ODQ. 
• Distribute protocol and informed consent document updates to Participating 
Institutions as needed. 
• Oversee the data collection process from Participating Institutions. 
• Maintain documentation of Serious Adverse Event (SAE) reports and 
deviations/violation submitted by Participating Institutions and provide to the 
DF/HCC Sponsor for timely review.   
• Distribute serious adverse events reported to the DF/HCC Sponsor that fall under 
the DFCI IRB Adverse Event Reporting Policy to all Participating Institutions. 
• Provide Participating Institutions with information regarding DF/HCC requirements 
that they will be expected to comply with. 
 
• Carry out plan to monitor Participating Institutions either by on-site or remote 
monitoring.  
• Maintain Regulatory documents of all Participating Institutions which includes but 
is not limited to the following: local IRB approvals/notifications from all 
Participating Institutions, confirmation of Federalwide Assurances (FWAs) for all 
sites,  all SAE submissions, Screening Logs for all sites, IRB approved consents 
for all sites 
• Conduct regular communications with all Participating Institutions (conference 
calls, emails, etc.) and maintain documentation all relevant communications. 
 
2.3 
Participating Institution 
 
Each Participating Institution is expected to comply with all applicable federal regulations 
and DF/HCC requirements, the protocol and HIPAA requirements.  
 

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The general responsibilities for each Participating Institution may include but are not limited 
to: 
• Document the delegation of research specific activities to study personnel. 
• Commit to the accrual of participants to the protocol. 
• Submit protocol and/or amendments to their local IRB. 
• Maintain regulatory files as per sponsor requirements. 
• Provide the Coordinating Center with regulatory documents or source documents as 
requested. 
• Participate in protocol training prior to enrolling participants and throughout the trial 
as required (i.e. teleconferences). 
• Update Coordinating Center with research staff changes on a timely basis. 
• Register participants through the Coordinating Center prior to beginning research 
related activities.  
• Submit Serious Adverse Event (SAE) reports to local IRB per local requirements 
and to the Coordinating Center, in accordance with DF/HCC requirements 
• Submit protocol deviations and violations to local IRB per local requirements and 
to the DF/HCC Sponsor in accordance with DF/HCC requirements. 
• Order, store and dispense investigational agents and/or other protocol mandated 
drugs per federal guidelines and protocol requirements. 
• Have office space, office equipment, and internet access that meet HIPAA standards. 
• Participate in any quality assurance activities and meet with monitors or auditors at 
the conclusion of a visit to review findings. 
• Promptly provide follow-up and/or corrective action plans for any monitoring 
queries or audit findings. 
 
3. DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS 
  
The following section will clarify DF/HCC Requirements and further detail the expectations 
for participating in a DF/HCC Multi-Center protocol.  
 
3.1 
Protocol Distribution 
 
The Coordinating Center will distribute the final DFCI IRB approved protocol and any 
subsequent amended protocols to all Participating Institutions.    
 
3.2 
Protocol Revisions and Closures 
 
The Participating Institutions will receive notification of protocol revisions and closures 
from the Coordinating Center.  It is the individual Participating Institution’s responsibility 
to notify its IRB of these revisions. 
 
• Non life-threatening revisions: Participating Institutions will receive written 
notification of protocol revisions regarding non life-threatening events from the 

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Coordinating Center. Non-life-threatening protocol revisions must be IRB approved 
and implemented within 90 days from receipt of the notification. 
 
• Revisions for life-threatening causes: Participating Institutions will receive 
immediate notification from the Coordinating Center concerning protocol revisions 
required to protect lives with follow-up by fax, mail, e-mail, etc.  Life-threatening 
protocol revisions will be implemented immediately followed by IRB request for 
approval. 
 
• Protocol closures and temporary holds: Participating Institutions will receive 
notification of protocol closures and temporary holds from the Coordinating Center. 
Closures and holds will be effective immediately.  In addition, the Coordinating 
Center, will update the Participating Institutions on an ongoing basis about protocol 
accrual data so that they will be aware of imminent protocol closures. 
 
3.3 
Informed Consent Requirements 
 
The DF/HCC approved informed consent document will serve as a template for the 
informed consent for Participating Institutions. The Participating Institution consent form 
must follow the consent template as closely as possible and should adhere to specifications 
outlined in the DF/HCC Guidance Document on Model Consent Language for PI-Initiated 
Multi-Center Protocols.  This document will be provided separately to each Participating 
Institution. 
 
Participating Institutions are to send their version of the informed consent document and 
HIPAA authorization, if a separate document, to the Coordinating Center for review and 
approval prior to submission to their local IRB. The approved consent form must also be 
submitted to the Coordinating Center after approval by the local IRB for all consent 
versions. 
 
The Principal Investigator (PI) at each Participating Institution will identify the physician 
members of the study team who will be obtaining consent and signing the consent form for 
therapeutic protocols. Participating institutions must follow the DF/HCC requirement that 
only attending physicians obtain informed consent and re-consent to interventional trials 
(i.e. drug and/or device trials).   
 
3.4 
IRB Documentation 
 
The following must be on file with the Coordinating Center: 
• Initial approval letter of the Participating Institution's IRB.  
• Copy of the Informed Consent Form(s) approved by the Participating Institution’s 
IRB.  
• Participating Institution’s IRB approval for all amendments. 

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• Annual approval letters by the Participating Institution's IRB. 
 
 
3.5 
IRB Re-Approval 
 
Verification of IRB re-approval from the Participating Institutions is required in order to 
continue research activities.  There is no grace period for continuing approvals. 
 
The Coordinating Center will not register participants if a re-approval letter is not received 
from the Participating Institution on or before the anniversary of the previous approval date.   
 
3.6 
Participant Confidentiality and Authorization Statement 
 
In 1996, congress passed the first federal law covering the privacy of health information 
known as the Health Insurance Portability and Accountability Act (HIPPA). Any 
information, related to the physical or mental health of an individual is called Protected 
Health Information (PHI). HIPAA outlines how and under what circumstances PHI can be 
used or disclosed.  
 
In order for covered entities to use or disclose protected health information during the course 
of a study, the study participant must sign an authorization statement.  This authorization 
statement may or may not be separate from the informed consent document.  The 
Coordinating Center, with the approval from the DFCI IRB, will provide a consent template, 
with information regarding authorization for the disclosure of protected health information.  
 
The DF/HCC Sponsor will use all efforts to limit its use of protected health information in 
its trials. However, because of the nature of these trials, certain protected health information 
must be collected. DF/HCC has chosen to use authorizations, signed by the participant in 
the trial, rather than limited data sets with data use agreements. 
 
3.6.1  DF/HCC Multi-Center Protocol Confidentiality 
 
All documents, investigative reports, or information relating to the participant are strictly 
confidential. Whenever reasonably feasible, any participant specific reports (i.e. Pathology 
Reports, MRI Reports, Operative Reports, etc.) submitted to the Coordinating Center should 
be de-identified. It is recommended that the assigned DF/HCC ODQ case number (as 
described below) be used for all participant specific documents. Participant initials may be 
included or retained for cross verification of identification.  
 
3.7 
DF/HCC Multi-Center Protocol Registration Policy 
 
3.7.1  Participant Registration  
Refer to Section 4 of the protocol for the participant registration process.  

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3.7.2  Initiation of Therapy 
 
Participants must be registered with the DF/HCC ODQ before receiving treatment.  
Treatment may not be initiated until the Participating Institution receives confirmation of 
the participant’s registration from the Coordinating Center. The DF/HCC Sponsor and DFCI 
IRB must be notified of any violations to this policy. 
 
3.7.3  Eligibility Exceptions 
 
The DF/HCC ODQ will make no exceptions to the eligibility requirements for a protocol 
without DFCI IRB approval. The DF/HCC ODQ requires each institution to fully comply 
with this requirement. 
 
3.8 
DF/HCC Protocol Case Number 
 
At the time of registration, ODQ requires the following identifiers for all subjects: initials, 
date of birth, gender, race and ethnicity. Once eligibility has been established and the 
participant successfully registered, the participant is assigned a unique protocol case 
number.  Participating Institutions should submit all de-identified subsequent 
communication and documents to the Coordinating Center, using this case number to 
identify the subject.   
 
3.8.1 Protocol Deviations, Exceptions and Violations 
 
Federal Regulations require an IRB to review proposed changes in a research activity to 
ensure that researchers do not initiate changes in approved research without IRB review 
and approval, except when necessary to eliminate apparent immediate hazards to the 
participant. DF/HCC requires all departures from the defined procedures set forth in the 
IRB approved protocol to be reported to the DF/HCC Sponsor, who in turn is responsible 
for reporting to the DFCI IRB. 
 
 
For reporting purposes, DF/HCC uses the terms “violation”, “deviation” and “exception” 
to describe departures from a protocol. All Participating Institutions must adhere to these 
requirements for reporting to the DF/HCC Sponsor and will follow their institutional policy 
for reporting to their local IRB. 
 
3.8.2  Definitions 
 
Protocol Deviation: Any departure from the defined procedures set forth in the IRB-
approved protocol which is prospectively approved prior to its implementation. 
 
Protocol Exception:  Any protocol deviation that relates to the eligibility criteria, e.g. 
enrollment of a participant who does not meet all inclusion/exclusion criteria. 

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Protocol Violation: Any protocol deviation that was not prospectively approved by the IRB 
prior to its initiation or implementation.  
 
 
3.8.3  Reporting Procedures 
 
DF/HCC Sponsor: is responsible for ensuring that clear documentation is available in the 
medical record and/or regulatory documents to describe all protocol exceptions, deviations 
and violations. The DF/HCC Sponsor will also be responsible for ensuring that all protocol 
violations/deviations are promptly reported per DFCI IRB guidelines.  
 
Participating Institutions: Protocol deviations require prospective approval from the DFCI 
IRB. The Participating Institution must submit the deviation request to the Coordinating 
Center who will then submit the deviation request to the DFCI IRB. Upon DFCI IRB 
approval the deviation is submitted to the Participating Institution IRB, per institutional 
policy. A copy of the Participating Institution’s IRB report and determination will be 
forwarded to the Coordinating Center within 10 business days after the original submission.  
 
All protocol violations must be sent to the Coordinating Center in a timely manner.  
 
Coordinating Center:  Upon receipt of the violation/deviation report from the Participating 
Institution, the Coordinating Center will submit the report to the DF/HCC Sponsor for 
review. Subsequently, the Participating Institution’s IRB violation/deviation report will be 
submitted to the DFCI IRB for review per DFCI IRB reporting guidelines.  
 
3.9 
Safety Assessments and Toxicity Monitoring 
 
The study teams at all participating institutions are responsible for protecting the safety, 
rights and well-being of study participants. Recording and reporting of adverse events that 
occur during the course of a study help ensure the continuing safety of study participants.  
 
All participants receiving investigational agents and/or other protocol mandated treatment 
will be evaluated for safety. The safety parameters include all laboratory tests and 
hematological abnormalities, physical examination findings, and spontaneous reports of 
adverse events reported by participants.  All toxicities encountered during the study will 
be evaluated according to the NCI criteria specified in the protocol. Life-threatening 
toxicities must be reported immediately to the DF/HCC Sponsor via the Coordinating 
Center.  
 
Additional safety assessments and toxicity monitoring will be outlined in the protocol. 
 
3.9.1 Guidelines for Reporting Serious Adverse Events  
 

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Guidelines for reporting Adverse Events (AEs) and Serious Adverse Events (SAEs) are 
detailed in protocol section 7. 
 
 
 
 
 
 
Participating Institutions must report the SAEs to the DF/HCC Sponsor and the 
Coordinating Center following the DFCI IRB Adverse Event Reporting Policy.  
 
The Coordinating Center will maintain documentation of all Participating Institution 
Adverse Event reports and be responsible for communicating to all participating 
investigators, any observations reportable under the DFCI IRB Reporting Requirements.  
Participating Institutions will review and submit to their IRB according to their institutional 
policies and procedures. 
 
 
3.9.2 Guidelines for Processing IND Safety Reports  
 
FDA regulations require sponsors of clinical studies to notify the FDA and all participating 
investigators of any adverse experience associated with the use of the investigational agent 
that is both serious and unexpected. The DF/HCC Sponsor will review all IND Safety 
Reports and ensure that all IND Safety Reports are distributed to the Participating 
Institutions. Participating Institutions will review and submit to their IRB according to their 
institutional policies and procedures. 
 
 
 
 
3.10 
Data Management 
  
The DF/HCC ODQ develops case report forms (CRF/eCRFs), for use with the protocol.  
These forms are designed to collect data for each study. The DF/HCC ODQ provides a web-
based training for eCRF users. 
   
3.10.1 Data Forms Review 
 
Data submissions are monitored for timeliness and completeness of submission. 
Participating Institutions are notified of their data submission delinquencies in accordance 
with the following: 
 
Incomplete or Questionable Data 
If study forms are received with missing or questionable data, the submitting institution will 
receive a written or electronic query from the DF/HCC ODQ Data Analyst, Coordinating 
Center or designee.  Responses to all queries should be completed and submitted within 14 
calendar days.  Responses may be returned on the written query or on an amended paper 
case report form, or in the case of electronic queries, within the electronic data capture 
(eDC) system. In the case of a written query for data submitted on a paper case report form, 
the query must be attached to the specific data being re-submitted in response.   
 

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Missing Forms 
If study forms are not submitted on schedule, the Participating Institution will receive a 
Missing Form Report from the Coordinating Center noting the missing forms.  These reports 
are compiled by the DF/HCC ODQ and distributed on a monthly basis.  
 
4. REQUISITIONING INVESTIGATIONAL DRUG 
 
The ordering of investigational agent is specified in the protocol section 8.1.5 and 8.2.5. 
 
 
 
5. MONITORING: QUALITY CONTROL 
 
The quality control process for a clinical trial requires verification of protocol compliance 
and data accuracy. The Coordinating Center, with the aid of the ODQ provides quality 
control oversight for the protocol. 
 
5.1 
Ongoing Monitoring of Protocol Compliance 
  
The Participating Institutions may be required to submit participant source documents to the 
Coordinating Center for monitoring. Participating Institution may also be subject to on-site 
monitoring conducted by the Coordinating Center.  
 
The Coordinating Center will implement ongoing monitoring activities to ensure that 
Participating Institutions are complying with regulatory and protocol requirements, data 
quality, and participant safety. At a minimum, the DF/HCC Lead Institute, or designee, will 
monitor each participating site twice a year while patients are receiving treatment. Should a 
Participating Institution be monitored once and then not accrue any additional patients or 
participant visits, then a second monitoring visit may not be necessary. Additional 
monitoring practices may include but are not limited to; source verification, review and 
analysis of the following: eligibility requirements of all participants, informed consent 
procedures, 
adverse 
events 
and 
all 
associated 
documentation, 
study 
drug 
administration/treatment, regulatory files, protocol departures, pharmacy records, response 
assessments, and data management.  
 
Participating institutions will be required to participate in Coordinating Center initiated 
teleconferences, as scheduled. The Coordinating Center will keep in close touch with the 
Participating Institutions via email and phone. Source documents from Participating 
Institutions, will be collected at specific data points that support the primary and or 
secondary endpoints. 
 
On-Site Monitoring: On-site monitoring will occur on an as-needed basis. Participating 
Institutions will be required to provide access to participants’ complete medical record and 
source documents for source documentation verification during the on-site visit. In addition, 

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upon request from a monitor or auditor, Participating Institutions should provide access to 
regulatory documents, pharmacy records, local policies related to the conduct of research, 
and any other trial-related documentation maintained by the participating site. If there are 
concerns for protocol compliance, issues that impact subject safety or the integrity of the 
study are found, or trends identified based on areas of need, additional monitoring visits 
may be scheduled. On site monitoring visits can be supplemented with virtual monitoring 
assessments, provided that the minimum monitoring frequencies are adhered to. 
 
Remote Monitoring: The Coordinating Center will request source documentation from 
Participating Institutions as needed to complete monitoring activities. Participating 
Institutions will be asked to forward de-identified copies of participants’ medical record and 
source documents to the Coordinating Center to aid in source documentation verification. 
 
5.2 
Monitoring Reports 
 
The DF/HCC Sponsor will review all monitoring reports for on-site and remote monitoring 
of Participating Institutions to ensure protocol compliance. The DF/HCC Sponsor may 
increase the monitoring activities at Participating Institutions that are unable to comply with 
the protocol, DF/HCC Sponsor requirements or federal and local regulations. Participating 
Institutions may also be subject to an audit as determined by the DF/HCC Sponsor. 
 
5.3 
Accrual Monitoring 
 
Prior to extending a protocol to an external site, the DF/HCC Sponsor will establish 
accrual requirements for each participating institution. Accrual will be monitored for each 
participating institution by the DF/HCC Sponsor or designee. Sites that are not meeting 
their accrual expectations may be subject to termination. 
 
A minimum of 3 participants per site annually is recommended for Phase II trials. 
However, given the additional regulatory burden and cost of overseeing each site, a 
consideration of 5 per site/annually should be a minimum target for each site. 
 
 
6. AUDITING: QUALITY ASSURANCE 
 
Auditing is a method of Quality Assurance. Its main focus is to measure whether standards 
and procedures were followed. Auditing is the systematic and independent examination of 
all trial related activities and documents.  Audits determine if evaluated activities were 
appropriately conducted and whether data was generated, recorded and analyzed, and 
accurately reported per the protocol, Standard Operating Procedures (SOPs), and the Code 
of Federal Regulations (CFR). 
 
6.1 
Audit Plan: DF/HCC Sponsored Trials 
 

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One on-site audit will be scheduled by the ODQ, assuming at least three participants have 
been treated on protocol at the site. Approximately 3-4 participants would be audited at the 
site over a 2-day period.  If violations which impact participant safety or the integrity of the 
study are found, more participant records may be audited.  
 
6.2 
Audit Notification 
 
It is the Participating Institution’s responsibility to notify the Coordinating Center of all 
scheduled audit dates (internal or NCI) and re-audit dates (if applicable), which involve this 
protocol. All institutions will forward a copy of final audit and/or re-audit reports and 
corrective action plans (if applicable) to the Coordinating Center, within 12 weeks after the 
audit date.  
 
6.3 
Audit Reports  
 
The DF/HCC Sponsor will review all final audit reports and corrective action plans if 
applicable. The Coordinating Center, must forward these reports to the DF/HCC ODQ per 
DF/HCC policy for review by the DF/HCC Audit Committee. Based upon the audit 
assessments the DF/HCC Audit Committee could accept or conditionally accept the audit 
rating and final report. Conditional approval could require the DF/HCC Sponsor to 
implement recommendations or require further follow-up.  For unacceptable audits, the 
DF/HCC Audit Committee would forward the final audit report and corrective action plan 
to the DFCI IRB as applicable. 
 
6.4 
Participating Institution Performance 
 
The DF/HCC Sponsor, and DFCI IRB, is charged with considering the totality of an 
institution’s performance in considering institutional participation in the protocol. 
 
6.4.1 Corrective Actions 
 
Participating Institutions that fail to meet the performance goals of accrual, submission of 
timely and accurate data, adherence to protocol requirements, and compliance with state 
and federal regulations, may be recommended for a six-month probation period. Such 
institutions must respond with a corrective action plan and must demonstrate during the 
probation period that deficiencies have been corrected, as evidenced by the improved 
performance measures. Participating Institutions that fail to demonstrate significant 
improvement will be considered by the DF/HCC Sponsor for revocation of participation. A 
DF/HCC Sponsor and/or the DFCI IRB may terminate a site’s participation if it is 
determined that a site is not fulfilling its responsibilities as described above.