Clinical trial NCT04068831
Conditions: Metastatic Renal Cell Carcinoma Fumarate Hydratase Deficient Renal Cell Carcinoma Succinate Dehydrogenase Deficient Renal Cell Carcinoma
Keywords: Talazoparib Avelumab 19-195
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2019-08-22; Completion date: 2023-12-06
Enrollment: 18 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to see whether the combination of avelumab and talazoparib can be an effective treatment for metastatic renal cell carcinoma.

Detailed description:

Arms: arm 1: All patients will receive combination treatment at the previously established recommended phase II dose, 800 mg avelumab every 2 weeks with 1 mg talazoparib daily, in 28-day cycles. arm 2: All patients will receive combination treatment at the previously established recommended phase II dose, 800 mg avelumab every 2 weeks with 1 mg talazoparib daily, in 28-day cycles.
Interventions: intervention 1: Talazoparib intervention 2: Avelumab
Intervention descriptions: intervention 1: 1 mg talazoparib daily intervention 2: 800 mg avelumab every 2 weeks

Protocol documents:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center 
IRB Number: 19-195 A(8) 
Approval date: 01-Dec-2021 
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MSK PROTOCOL COVER SHEET 
TALAZOPARIB AND AVELUMAB IN GENOMICALLY DEFINED METASTATIC 
RENAL CELL CARCINOMA 
 
Principal Investigator/Department: Ritesh Kotecha, MD/Medicine 


Memorial Sloan Kettering Cancer Center 
IRB Number: 19-195 A(8) 
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1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ................................................................... 6 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ............................................................................ 7 
3.0 
BACKGROUND AND RATIONALE ................................................................................. 7 
3.1 
Renal Cell Carcinoma Epidemiology ............................................................................. 7 
3.2 
Renal Cell Carcinoma Subtypes .................................................................................... 7 
3.3 
Renal Cell Carcinoma Genomics ................................................................................... 8 
3.4 
DNA-damage Response (DDR) Pathways ..................................................................... 9 
3.5 
VHL-deficiency and Genomic Maintenance .................................................................. 9 
3.6 
PARPi and RCC ............................................................................................................. 10 
3.7 
Treatment Paradigms for Metastatic RCC ................................................................... 12 
3.8 
Combination PARPi and ICB Rationale ....................................................................... 14 
3.9 
Talazoparib Pre-Clinical and Clinical Experience ....................................................... 14 
3.10 
Avelumab Pre-Clinical and Clinical Experience .......................................................... 15 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ........................................................ 18 
4.1 
Design ........................................................................................................................ 18 
4.2 
Intervention ................................................................................................................. 18 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ....................................................................... 18 
5.1 
Talazoparib Drug Information and Storage ................................................................. 18 
6.1 
Avelumab Drug Information and Storage .................................................................... 19 
6.1 
Avelumab Premedication ............................................................................................. 20 
6.1 
Treatment Interruptions / Delays ................................................................................. 21 
6.1 
Drug Accountability ..................................................................................................... 22 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ....................................................................... 22 
6.1 
Subject Inclusion Criteria ............................................................................................. 22 
6.2 
Subject Exclusion Criteria............................................................................................ 23 
6.3 
Lifestyle Requirements ................................................................................................ 25 
7.0 
RECRUITMENT PLAN .................................................................................................. 26 
8.0 
PRETREATMENT EVALUATION .................................................................................. 27 
9.0 
TREATMENT/INTERVENTION PLAN ........................................................................... 28 
9.1 
Talazoparib Administration .......................................................................................... 28 
9.2 
Avelumab Administration............................................................................................. 28 
9.3 
Talazoparib and Avelumab Combination Administration .......................................... 29 
9.4 
Medication Compliance ................................................................................................ 29 


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9.5 
Talazoparib Dose Modifications .................................................................................. 30 
9.6 
Avelumab Dose Modifications ..................................................................................... 31 
9.7 
Concomitant Medications ............................................................................................ 31 
9.8 
Concomitant Surgery ................................................................................................... 32 
9.9 
Concomitant Radiation ................................................................................................. 32 
9.10 
Hypercalcemia Management ........................................................................................ 33 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION ................................................ 33 
10.1 
Screening ...................................................................................................................... 33 
10.2 
Treatment Period .......................................................................................................... 33 
10.3 
Safety Assessments ..................................................................................................... 34 
10.4 
Pregnancy/Contraception Safety Monitoring for Female Patients of Childbearing 
Potential ................................................................................................................................... 35 
10.5 
Disease Response Evaluation During Treatment ....................................................... 36 
10.6 
Treatment Beyond Progression ................................................................................... 36 
10.7 
Schedule of Activities .................................................................................................. 38 
11.0 
TOXICITIES/SIDE EFFECTS ......................................................................................... 42 
11.1 
Severity Assessments ................................................................................................. 42 
11.2 Adverse Events .............................................................................................................. 42 
11.7 
Talazoparib Toxicity ..................................................................................................... 44 
11.7.1 Hematologic Toxicity Related to Talazoparib ............................................................. 44 
11.7.2 Talazoparib Related Non-Hematologic Toxicity .......................................................... 46 
11.7.3 Talazoparib Related Gastrointestinal Toxicity ............................................................. 47 
11.8 Avelumab Toxicity ........................................................................................................... 47 
11.8.1 Avelumab Related Pulmonary Toxicity ....................................................................... 47 
11.8.2 Avelumab Related Gastrointestinal Toxicity............................................................... 48 
11.8.3 Avelumab Related Endocrine Toxicity ........................................................................ 48 
11.8.4 Avelumab Related Skin Toxicity .................................................................................. 49 
11.8.5 Avelumab Related Renal Toxicity ................................................................................ 49 
11.8.6 Avelumab Related Neurologic Toxicity ...................................................................... 49 
11.9 
Combination Talazoparib / Avelumab – Dose Modifications for Treatment- 
Emergent, Unrelated Adverse Events .................................................................................... 49 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ................... 49 
12.1 
Calculated Study Endpoints ........................................................................................ 52 
12.2 
Short-Term and Long-Term Follow Up ........................................................................ 53 


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12.3 
Study Research Plan .................................................................................................. 53 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ................................................................... 57 
13.1 
Study Treatment Discontinuation ................................................................................ 57 
13.2 
Voluntary Withdrawal of Consent ................................................................................ 58 
13.3 
Lost to Follow-Up ......................................................................................................... 58 
14.0 
BIOSTATISTICS ............................................................................................................ 58 
14.1 
Cohort 1 Enrollment and Statistical Plan .................................................................... 59 
14.2 
Cohort 2 Enrollment and Statistical Plan .................................................................... 60 
14.3 
Sample Size/Accrual Rate ............................................................................................ 60 
14.4 
Exploratory Analyses ................................................................................................... 61 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
61 
15.1 
Research Participant Registration ............................................................................... 61 
15.2 
Randomization ............................................................................................................ 61 
16.0 
DAT A M ANAGEMENT ISSUES .................................................................................... 61 
16.1 
Quality Assurance ....................................................................................................... 62 
16.2 
Data and Safety Monitoring ......................................................................................... 62 
16.3 
Study Treatment Accountability .................................................................................. 62 
16.4 
Conditions for Protocol Modification .......................................................................... 63 
16.5 
Conditions for Termination of Study ........................................................................... 63 
17.0 
PROTECTION OF HUMAN SUBJECTS ........................................................................ 63 
17.1 
Privacy ........................................................................................................................ 64 
17.2 
Serious Adverse Event (SAE) Reporting ..................................................................... 65 
17.2.1 SAE Reporting to Pfizer ............................................................................................... 66 
18.0 
INFORMED CONSENT PROCEDURES ........................................................................ 68 
19.0 
REFERENCES ............................................................................................................... 68 
20.0 
APPENDICES ................................................................................................................ 73 
Appendix 1: Eastern Cooperative Oncology Group (ECOG) Performance Status Chart .... 74 
Appendix 2: iRECIST and RECIST v1.1 Guidelines ............................................................... 75 
Appendix 3: Avelumab Infusion Related Events and Management ..................................... 78 
Appendix 4: Avelumab Immune Related Adverse Events and Management ....................... 79 
Appendix 5: Prohibited Potent P-gp Inhibitors ..................................................................... 87 
Appendix 6: Correlative Laboratory Manual .......................................................................... 88 


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IRB Number: 19-195 A(8) 
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1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
This is a phase II, open-label, single-institution trial to study the combination of talazoparib 
and avelumab in patients with advanced or metastatic renal cell carcinoma (RCC). This 
protocol leverages underlying genomic instability in three genomically defined RCC 
variants and pairs targeted immunotherapy with PARP inhibition. 
RCC represents a heterogenous set of tumors distinguished by histology, molecular and 
genomic features. A hallmark of clear cell RCC, the most common histologic RCC 
subtype, is von Hippel Lindau (VHL) inactivation occurring in >90% of tumors. VHL acts 
as a hypoxic sense regulator and, amongst other functions, supports DNA repair and 
genomic integrity; consequently, VHL loss promotes genomic instability. Similar in effect, 
in two rare RCC subtypes characterized by loss-of-function mutations in fumarate 
hydratase (FH) and succinate dehydrogenase (SDH), downstream oncometabolite 
accumulation leads to DNA repair inhibition, resulting in genomic instability. Further, renal 
medullary carcinoma (RMC) also has been associated with high DNA replication stress. 
All of these settings (VHL, FH/SDH loss, and RMC) have been shown to render cancer 
cells vulnerable to PARP inhibitors. As DNA damage is thought to increase neo-antigen 
repertoires and innate immune effectors, paired PARP inhibition with immune checkpoint 
blockade may achieve additive and/or synergistic effects in both clear and non-clear cell 
cohorts with separate rationales. 
This protocol investigates the use of talazoparib, a potent selective PARP inhibitor, and 
avelumab, an anti-PD-L1 monoclonal antibody blocker, in patients with advanced RCC. 
The protocol will enroll patients in two independent, non-randomized cohorts in parallel 
(Table 1). Cohort 1 will enroll patients with previously treated VHL-deficient RCC in a 
Simon two-stage design: if ≥1/10 patients achieve an objective response in Stage I, the 
trial will then continue to accrue a total of 29 patients for efficacy analysis. Cohort 2 will 
enroll 15 patients with advanced RCC and FH- or SDH- loss or medullary RCC, and 
analysis will be descriptive given disease rarity. 
 
Cohort 
Population 
Target Enrollment 
Talazoparib 
Avelumab 
1 
VHL-deficient RCC 
Stage I: 10 patients 
Stage II: 19 patients 
1 mg daily 
PO 
800 mg IV 
2 
FH-, SDH- deficient RCC, 
RMC 
Total = 15 patients 
1 mg daily 
PO 
800 mg IV 
Table 1. Cohort Design. VHL: von Hippel Lindau; FH: fumarate hydratase, SDH: succinate 
dehydrogenase, PO: oral, IV: intravenous 
All patients will receive combination treatment at the previously established recommended 
phase II dose, 800 mg avelumab every 2 weeks with 1 mg talazoparib daily, in 28-day 
cycles. The primary endpoint will be objective response rate (ORR) measured by 
iRECIST. Secondary endpoints include progression-free survival (PFS), overall survival 
(OS), and safety and tolerability of combination therapy. Exploratory endpoints for both 


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cohorts include analysis of expression-based biomarkers for tissue response, 
characterization of inflammatory recruitment responses, and oncometabolite analysis in 
cohort 2 patients. 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
Primary Aim: To determine the objective response rate (ORR) of combination talazoparib 
and avelumab in all treatment cohorts by iRECIST. 
 
Secondary aims will include: 
1. To determine the progression-free survival (PFS) in all treatment cohorts by RECIST 
v1.1. 
2. To determine the overall survival (OS) in all treatment cohorts by RECIST v1.1. 
3. To evaluate the safety and tolerability, and compliance of combination talazoparib and 
avelumab in all treatment cohorts. 
 
Exploratory aims will include: 
1. Cohorts 1 & 2: 
a. To characterize DNA damage response pathways including homolgous 
recombination deficiency (HRD), large scale transition (LST) scores, 
inflammatory and microenvironment changes. 
2. Cohort 2: 
a. To assess metabolomic changes and oncometabolite generation for 
Cohort 2. 
 
3. 0 
BACKGROUND AND RATIONALE 
3.1 
Renal Cell Carcinoma Epidemiology 
Renal cell carcinoma (RCC) is the most common and lethal form of kidney cancer, 
affecting over 65,000 each year in the United States with a rising incidence (1). The 
growing incidence of RCCs stems from modifiable risk factors including tobacco use, 
hypertension, and obesity, as well as a shift in incidental radiographic diagnoses in 
asymptomatic patients (2). As one-third of patients with RCC present with metastatic 
disease at diagnosis, and one-fourth of patients experience disease relapse following 
nephrectomy, there continues to remain a high unmet need for systemic therapy options 
for patients with advanced disease. 
3.2 
Renal Cell Carcinoma Subtypes 
The World Health Organization (WHO) classifies sixteen distinct kidney cancer subtypes 
based on genomic, molecular, histologic and syndromic features (3). The most common 
RCC variant in the metastatic setting is clear cell RCC, accounting for ~75% of diagnoses, 
followed by other non-clear cell histologies like papillary, chromophobe, and unclassified 
tumors. Although these subtypes occur most commonly as sporadic cancers, many also 
occur in the syndromic setting with several familial syndromes characterized in terms of 


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germline alterations and ensuing pathobiology. Von Hippel Lindau (VHL) syndrome is 
characterized by bi-allelic VHL loss and the development of bilateral and multifocal clear 
cell RCCs with additional tumor developments including hemangioblastomas, 
pheochromocytomas, and neuroendocrine tumors. Hereditary Leiomyomatosis and Renal 
Cell Carcinoma (HLRCC) syndrome usually manifests with papillary RCC tumors 
developing in the context of germline loss of fumarate hydratase (FH), and is characterized 
by the development of cutaneous leiomyomas, leiomyosarcomas and paragangliomas . 
Hereditary paragangliomas and paragangliomas (HPGL/PCC), characterized by germline 
loss of succinate dehydrogenase (SDH) is characterized by RCC as well as 
pheochromocytomas, paragangliomas, and gastrointestinal stromal tumor development. 
Renal medullary carcinoma (RMC) is a rare, lethal form of kidney cancer most notably 
associated with hemoglobinopathies and occurs mainly in young individuals and is highly 
refractory to systemic therapies that are successfully applied in other RCC variants . 
3.3 
Renal Cell Carcinoma Genomics 
The genomic landscape for clear and non-clear RCC variants have been outlined through 
large-scale efforts with The Cancer Genome Atlas (TCGA) and the TRACERx study, 
helping uncover patterns within the context of clinical and tumor evolution (4-6). A hallmark 
event that characterizes >90% of clear cell RCCs is chromotripsis of chromosome 3p, with 
then subsequent gains in chromosome 5q and loss of 15q (4). Haploinsufficiency of VHL 
is insufficient for tumor growth and may precede RCC development by even decades (7), 
and secondary genomic or epigenetic events affecting VHL and other chromosome 3p 
genes are central to disease pathogenesis. Complete loss of pVHL, the encoded protein, 
leads to downstream accumulation of hypoxia inducible factor (HIF) proteins and 
transcriptional upregulation of HIF-dependent pathways that affect cell proliferation, cell 
migration, cell metabolism, and angiogenesis. Functional loss of VHL may be due to 
acquired point or frame mutations, as well as mutations in partnering proteins (i.e. TCEB1) 
and promotor methylation silencing (8-10). 
While chromosome 3p loss remains the linchpin in characterizing clear cell RCC biology, 
other RCC variants (non-clear cell) harbor distinct genomic alterations that contribute to 
disease pathogenesis. This includes loss-of-function (LOF) mutations in FH, a gene that 
encodes for a Krebs cycle enzyme catalyzing the hydration of fumarate to malate, which 
can be lost in sporadic and syndromic papillary variants of RCC (11). FH- loss radically 
shifts metabolism to aerobic glycolysis obliging cells to become dependent on glycolysis 
for subsequent ATP production (12). Similarly, LOF mutations in SDH, a mitochondrial 
enzyme responsible for the oxidation of succinate to fumarate, also leads to metabolic 
dysregulation in other non-clear cell RCC entities. In addition, RMC tumors are almost 
uniformly characterized by SMARCB1 (INI1) (13), which functions as a subunit of the 
SWItch/Sucrose Non-Fermentable (SWI/SNF) complex and has been characterized with 
increased DNA replication stress (14). 
Beyond these well understood mechanisms for clear cell (VHL-deficient) and other tumor 
subtypes (FH / SDH-deficient or SMARCB1-loss medullary), several recent reports have 


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highlighted each of these genes are integral to genomic maintenance described below, 
providing molecular rationale for the present study. 
3.4 
DNA-damage Response (DDR) Pathways 
DNA repair is an essential mechanism for genomic integrity maintenance as unrepaired 
DNA damage ultimately leads to cell death or senescence. Minor alterations in DNA are 
corrected using base or nucleotide excision repair mechanisms, and more lethal DNA 
damage events like strand breaks (single or double) or complex events like interstrand 
cross-linking are usually repaired using two complex pathways: homologous 
recombination (HR) and non-homologous end joining (NHEJ) (15). HR retains the highest 
fidelity, as this process requires a template DNA strand for repair and ligation, whereas 
NHEJ relies on processing terminal end strands only for subsequent DNA ligation. 
Because of the template requirement, HR can only occur in certain cell cycle phases 
compared to NHEJ. DNA double strand breaks (DSBs) are particularly challenging as 
repair relies on the coordination of multiple pathways as detailed below. 
Consequences of ineffective DNA repair have been highlighted through analysis of 
specific DNA damage response (DDR) pathway alterations found in several malignancies 
as well effects from cytotoxic DNA damaging chemotherapies. Multiple DDR pathways 
have been characterized with specific components (16) including: 
1. Nucleotide Excision Repair (NER): ERCC1/2/34/5/6/8, DDB1/2, RPA1/2/3, XPC, 
RAD23B, CETN2, GTF 
2. Mismatch Repair (MMR): MLH1, MSH2, MSH6, PMS1/PMS2 
3. HR: BRCA1/2, PARP1, ATM, ATR, RAD51C, BAP1, PALB2, MRE11A/NBN, 
BARD1/BRIP1, RAD50/51/51B/51D 
4. NHEJ: PRKDC, XRCC5/6, LIG4, XRCC4, NHEJ1 
5. Others: FANCC, FANCA, BLM, CHEK1/2, POLE, ATRX, ATR, RAD1, HUS1, TP53, 
RIF1, CLK2, TOPB1, PER1 
Loss of one or more DDR pathways may lead to increased cancer predisposition (i.e. 
BRCA or ATM mutant malignancies), as well as enhanced susceptibility to DNA damage 
therapies through “synthetic lethality” (17). This has been exploited recently through PARP 
inhibition in patients with underlying BRCA germline mutations in multiple tissue models 
(18-22). Additionally, other DDR losses like MMR deficiency have been shown to have 
higher mutational load correlating with improved response to immune checkpoint blockade 
therapy (23). 
3.5 
VHL-deficiency and Genomic Maintenance 
Besides promotion of the adaptive pseudohypoxia response through HIF-dependent 
pathways, VHL plays an integral role in other cellular processes including extracellular 
matrix regulation, microtubule stabilization, and cell cycle regulation through DNA repair 
and regulation of apoptosis and senescence (24, 25). Interestingly, pre-clinical work 
highlights that VHL loss increases DNA damage and replication stress, with increases in 


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IRB Number: 19-195 A(8) 
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ATR (ATM and RAD-3 related), CHK1, and replication fork stalling, all of which contribute 
to increased genomic instability, replication mechanism collapse, and cell cycle arrest 
(26). In addition, VHL-deficient RCC cells also show impaired NER capacities as well (27). 
BRCAness, the notion that DDR associated genes other than BRCA1 and BRCA2 confer 
similar defects in DNA repair, has increasingly been applied in many tumor models and 
genes (28). Interestingly, an analysis of RCC tumors with associated tumor thrombus, a 
common and poor prognostic feature, has also highlighted that many RCC tumors have 
conferred BRCAness. Based upon identification of BRCAness mutational signatures in 
this select population with associated tumor thrombus, investigators re-analyzed 400 
patients in the TCGA clear cell RCC cohort irrespective of tumor thrombus and identified 
high predominance of a BRCAness mutational signature, accounting for 74.25% of 
patients (297/400 samples) (29). 
VHL-deficient clear cell RCCs have shown to have lower expression of HR and MMR 
genes, with 30-60% reductions of mRNA levels of BRCA1, RAD51, MLH1, and FANCD2 
compared with VHL-wildtype tumor cells (30). Expression changes were confirmed upon 
TCGA interrogation, and VHL-loss specifically was associated with impaired DNA DS 
break repair, conferring a BRCAness phenotype (31). Based on the above studies, this 
BRCAness phenotype is associated with a majority of clear cell RCCs. 
3.6 
PARPi and RCC 
Poly(ADP-ribose) polymerase (PARP) are enzymes that activate upon damaged DNA 
binding, with further functions including: detection of single-stranded and DS breaks, 
recruitment of DNA repair machinery and replication formation at the injured site. PARP 
is usually upregulated during replication stress, with DDR pathway signal transduction and 
protein complex modification through PARylation (32). 
The concept of exploiting synthetic lethal interactions between inherently impaired DNA 
repair and PARP inhibitors (PARPi) has proven successful in human malignancies. For 
instance, as functional BRCA1/2 proteins are integral for DSB repair, BRCA1/2 mutants 
are increasingly vulnerable to PARPi with significant clinical responses in this genomically 
defined population. Interestingly, treatment with niraparib has shown clinical benefit in 
patients irrespective of BRCA status (BRCA wild-type or mutant), and significant clinical 
effects were seen in patients with HR deficient tumors also irrespective of BRCA status 
(21). In total, the FDA has approved multiple agents across tumors in mostly BRCA mutant 
populations (Table 2), and further exploration of other DDR pathway mutants including 
those tumors with BRCAness remains underway. 
 
PARPi 
FDA Approved Indications 
Rucaparib 
1. Treatment of advanced stage, BRCA1/2 mutant ovarian cancer 
refractory to ≥2 prior lines of therapy 
2. Maintenance for advanced stage, recurrent ovarian cancer in CR 
or PR after platinum-based chemotherapy 
Niraparib 
1. Maintenance for patients with advanced stage ovarian cancer who 
are in CR or PR after platinum-based chemotherapy 


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Olaparib 
1. Maintenance therapy for advanced stage, recurrent ovarian 
cancer in CR or PR after platinum-based chemotherapy 
2. Treatment of advanced stage, BRCA1/2 mutant ovarian cancers 
refractory to ≥3 prior lines of therapy. 
3. Treatment for metastatic HER2 negative, BRCA1/2 mutant breast 
cancer refractory to chemotherapy 
Talazoparib 
1. Treatment of BRCA mutated, HER2 negative locally advanced or 
metastatic breast cancer 
Table 2: FDA Approved PARPi in 2018: PARPi=PARP inhibitor; CR=complete response; 
PR=partial response 
Interestingly, tumor hypoxia leads to repression of DNA repair through both HIF- 
dependent and independent mechanisms with suppression of multiple repair mechanisms 
including BRCA1/2 (33), and cells without intrinsic DNA repair defects are increasingly 
sensitive to PARPi in hypoxic microenvironments (34). In RCC, where tumors have 
hypoxic pathway upregulation through HIF dependent pathways, pre-clinical evidence has 
also shown that clear cell RCCs are sensitive to the PARP inhibitor olaparib, with evidence 
of subsequent increase in replication stress, suppression of DNA synthesis, and eventual 
cell cycle arrest. RCC cells that also harbor BAP1 mutations, a known secondary 
chromatin modifying gene mutation with aggressive clinical courses, have also shown 
increased sensitivity to the PARP inhibitor olaparib (35). In line with supportive evidence 
of PARPi in BRCAness tumors, VHL-deficient cells were sensitive to PARPi olaparib and 
talazoparib when compared with VHL-wild type cells (30). 
Interestingly, germline and somatic loss of FH and SDH also contribute to genomic 
instability through accumulation of oncometabolites and HR suppression. Recently, these 
specific mutations have been shown to lead to accumulation of fumarate and succinate 
respectively, resulting in inhibition of α-ketoglutarate (αKG)-dependent dioxygenases and 
eventual accumulation of DNA DSBs through HR impairment and activation of DDR 
pathways (36). Taken a step further, FH- and SDH- deficient tumors were also found to 
be sensitive to the PARP inhibitors olaparib and talazoparib in vitro and in vivo. Selected 
results regarding tumor xenograft models of FH- and SDH- knockdown in nude mice are 
displayed below (36). 


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SDH-deficient 
 
 
 
 
FH-deficient 
 
 
 
 
 
 
Figure 1: FH- and SDH- Sensitivity to Talazoparib: Nude mice tumor xenografts were implanted with FH- 
and SDH-deficient cell lines by shRNA knockdown versus vehicle control. Treatment with talazoparib (BMN - 
673) resulted in significantly delays in growth after tumor implantation. Adapted from (36). 
RMC tumors which are characterized for SMARCB1-loss have also been proposed to be 
sensitive to PARPi therapeutic strategy. Firstly, in vitro growth of SMARCB1-loss cell lines 
have been shown to be inhibited to olaparib and this drug sensitivity appeared more 
profound when compared to BRCA1-mutant cell lines (HCC1395 and HCC1937) (14). 
Moreover, RMC cell lines shown sensitivity to both olaparib and niraparib, and a patient 
derived xenograft (PDX) RMC model demonstrated that niraparib treatment led to a 
significant reduction in tumor volume in vivo (Figure 2). (14) 
 
Figure 2: RMC Sensitivity to PARPi. A RMC PDX model was generated using banked implanted tumor 
tissue implanted into subcutaneous tissue of immunodeficient mouse. Treatment with niraparib (PARPi) led 
to regression in tumor volume compared to vehicle control. Adapted from (14). 
3.7 
Treatment Paradigms for Metastatic RCC 


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Current systemic therapies used for patients with metastatic RCC include vascular 
endothelial growth factor (VEGF) targeted agents, immune checkpoint blockade (ICB), 
and targeted agents against the mTOR pathway. Currently, no predictive biomarker has 
been identified to aid in therapy selection, and treatment is clinically determined based 
upon disease risk assessed by nomograms like the MSKCC and International Database 
of Metastatic RCC (IMDC) (37, 38). Both risk models include clinical and laboratory 
markers which correlate with disease prognosis and ultimately stratify patients into 
favorable, intermediate or poor-risk disease. 
Based on results from CheckMate-214, a randomized phase III study of ipilimumab (anti- 
CTLA-4) and nivolumab (anti-PD-1) versus sunitinib in patients with metastatic clear cell 
RCC, combination ICB is superior in patients with intermediate and poor-risk disease with 
improved overall survival (HR=0.53) and objective response rates (42% ICB versus 27% 
sunitinib) (39). In the second-line setting, nivolumab monotherapy is also superior to 
everolimus (40), and subsequent lines of therapy often employ VEGFR TKI therapies in 
sequential manner. With use of ICB in the first-line setting, focus has shifted towards 
overcoming primary and adaptive mechanisms of treatment resistance. 
For patients with non-clear cell histologies, no sub-type specific large-scale trial has 
defined therapy standards, and VEGFR TKI treatment with sunitinib remains the most 
frequently chosen agent given combined efficacy results in phase II trials conducted 
across all non-clear cell histologies (41, 42). Despite advancements in tumor subtyping at 
the molecular and genomic levels, treatment strategies that incorporate this data continue 
to lag. In patients with major papillary component or HLRCC (sporadic or syndromic), two 
treatment programs have been specifically developed. Combination bevacizumab and 
erlotinib have preliminarily shown an ORR 60% compared to 29% in HLRCC patients 
versus sporadic papillary tumors, respectively, with a significantly prolonged PFS (43), 
however final results regarding the efficacy of this regimen are pending. In a phase II trial, 
combination bevacizumab and everolimus also showed robust response rates in patients 
with major papillary component (ORR 43% versus 29% for all non-clear cell tumors), 
however does not identify genomic features of responding tumors (44). Retrospective 
analyses have shown that treatment naïve and refractory patients also have response to 
monotherapy immune checkpoint blockade (anti-PD-1/PD-L1) with varied ORR 10-20%, 
without any specific subtype / genomic alteration associated with response (45, 46). 
Outcomes for patients with RMC are uniformly poor, with <5% of patients surviving greater 
than 36 months, and treatment guidelines have been proposed for patients based upon 
expert consensus (47, 48). Based upon a retrospective multi-center review, cytotoxic 
chemotherapy was shown to have an ORR of 29%, generally of short duration. The 
reported regimens in the report reflect commonly used therapeutic strategies for RMC and 
included carboplatin / paclitaxel, carboplatin / paclitaxel / bevacizumab, carboplatin / 
gemcitabine, and gemcitabine / doxorubicin. In the same multicenter study, over half of 
the patients were subsequently treated with a targeted agent (sunitinib, bevacizumab, 
pazopanib, sorafenib, everolimus, imatinib), and treatment had a median duration of 8 


Memorial Sloan Kettering Cancer Center 
IRB Number: 19-195 A(8) 
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14 
 
 
weeks with an ORR of 0% (49). This highlights a desperate need to develop new regimens 
for this unfortunate group of young RMC patients. 
3.8 
Combination PARPi and ICB Rationale 
Combination PARPi with immune checkpoint blockade therapy may provide additive or 
synergistic effects based upon several rationales (50). PARPi induced DNA damage may 
increase overall tumor mutational burden (TMB) thereby increasing overall neoantigen 
repertoires for increased cytotoxic T-cell exposure through epitope diversity and enhanced 
immune stimulation. RCC has only modest TMB compared with other tumors which are 
traditionally immune sensitive (51), and mutational burden has been shown to lead to 
enhanced clinical benefits irrespective of PD-L1 status in other tumor models (52, 53). 
Moreover, PARPi induced DNA DS breaks inherently lead to accumulation of cytosolic 
DNA which in turn activates the STING (stimulator of interferon genes)/cGAS innate 
immune pathway for stimulation (54), and therefore PARPi achieves anti-tumor immune 
effects outside of synthetical lethal mechanisms. Interestingly, pre-clinical work has shown 
that PARPi increases PD-L1 expression, and blockade of PD-1/PD-L1 axis through PD-1 
blockade may resensitize tumors to ICB therapy (55), leading to prolonged model survival 
compared with PARPi alone in vivo (54). PARPi treatment also leads to release of many 
pro-inflammatory cytokines like IFN-γ and TNF-α, thereby priming the microenvironment 
for enhanced immune effector responses in combination strategies. 
Importantly, early trials have employed combination PARPi and ICB therapy without 
significant overlapping toxicities seen thus far in early signals. The proposed combination 
of talazoparib and avelumab is being investigated in other tumor models (NCT03330405), 
and other PARP + ICB combinations are being tested in many HR deficient (i.e. BRCA 
mutant) populations (NCT02734004, NCT02484404, NCT02953457). Interestingly, 
preliminary responses have been seen in unselected tumor models (BRCA mutant and 
wild-type) with combination approaches. A phase I trial of pamiparib (BGB-290), a 
selective PARP inhibitor with tisleizumab (anti-PD-1) has shown preliminary efficacy 
across multiple tumor types (NCT02660034), and in both BRCA-mutant and wild-type 
patients (56). 
3.9 
Talazoparib Pre-Clinical and Clinical Experience 
Talazoparib / BMN-673 is a bioavailable, oral PARP1 and PARP2 inhibitor that blocks 
PARP enzyme activity and allows for persistent PARP trapping onto DNA, all of which 
lead to enhanced cytotoxicity via inadequate repair of DNA damage. Talazoparib was FDA 
approved in October 2018 for the treatment of adult patients with deleterious or suspected 
deleterious germline BRCA mutated, HER2 negative, locally advanced or metastatic 
breast cancers, tested with an FDA approved companion diagnostic designation. 
Early phase data has shown that talazoparib pharmacokinetics remain linear with doses 
increased from 0.25 – 2 mg, and median time to maximum plasma concentration is 1-2 
hours after each dose with a steady-state within 2-3 weeks. Talazoparib undergoes 
minimal hepatic metabolism and is mainly renally excreted. Pre-clinical work has also 


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shown that when compared to other PARP inhibitors including olaparib and rucaparib, 
talazoparib has a stronger potency for PARP inhibition and resultant cytotoxicity (57). 
FDA approval was based on the EMBRACA study, a phase III, open-label, multi-center 
study (NCT01945775) which evaluated talazoparib 1 mg daily and physician’s choice 
chemotherapy in patients with treatment refractory BRCA-mutant, locally advanced or 
metastatic breast cancer (20). Enrolled patients were treated until disease progression or 
unacceptable toxicity, and the median duration of study treatment was 6.1 months versus 
3.9 months for talazoparib and physician’s choice chemotherapy, respectively. The major 
efficacy outcome measure was PFS evaluated by RECIST v1.1 assessed by blinded 
independent central review. When compared to chemotherapy, talazoparib monotherapy 
showed a PFS of 7.6 months versus 5.6 months (HR 0.54, p<0.0001), ORR 50.2% versus 
18.4%, and median duration of response of 6.5 months versus 3.9 months. 
Dosing interruptions due to adverse reactions of any grade occurred in 65% of patients 
who received talazoparib, and dose reductions due any causes occurred in 53% of 
patients who received talazoparib versus 40% of patients on chemotherapy. Permanent 
discontinuation due to adverse reactions of talazoparib was only seen in 5.9% of patients 
with talazoparib. In <20% of patients treated with talazoparib on trial, following adverse 
reactions were seen including abdominal pain (19%), dizziness (17%), leukopenia (17%), 
dysgeusia (10%), dyspepsia (10%), stomatitis (8%), and lymphopenia (7%). Adverse 
reactions are outlined (Table 3). 
 
Adverse Reactions (in >20% of 
Patients Receiving Talazoparib) 
in EMBRACA Adverse Reactions 
Talazoparib N=286 (%) 
Chemotherapy N=126 (%) 
Grades 
1-4 
Grade 
3 
Grade 
4 
Grades 
1-4 
Grade 
3 
Grade 
4 
Blood and lymphatic system disorders 
Anemia 
53 
38 
1 
18 
4 
1 
Neutropenia 
35 
18 
3 
43 
20 
16 
Thrombocytopenia 
27 
11 
4 
7 
2 
0 
Metabolism and nutrition disorders 
Decreased appetite 
21 
<1 
0 
22 
1 
0 
Nervous system disorders 
Headache 
33 
2 
0 
22 
1 
0 
Gastrointestinal disorders 
Nausea 
49 
<1 
0 
47 
2 
0 
Vomiting 
25 
2 
0 
23 
2 
0 
Diarrhea 
22 
1 
0 
26 
6 
0 
Skin and subcutaneous tissue disorders 
Alopecia 
25 
0 
0 
28 
0 
0 
General disorders and administration site conditions 
Fatigue 
62 
3 
0 
50 
5 
0 
Table 3: Summary of >20% Adverse Reactions on EMBRACA Phase III Trial. The majority of 
non-hematologic events in talazoparib group were grade I in severity (Adapted from (20)). 
3.10 
Avelumab Pre-Clinical and Clinical Experience 


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Avelumab / MSB0010718C is a human IgG1 monoclonal antibody that blocks PD-L1 
thereby competitively disrupting the immune checkpoint in T-cell regulation. Amongst 
other immune checkpoint blockers, avelumab is uniquely human IgG1 and therefore 
additionally is capable of antibody dependent cell mediated cytotoxicity due to its native 
Fc region (58). 
In the early phase trial (JAVELIN, NCT01772004 (59)) pharmacokinetic analyses have 
shown that there remains a dose proportional exposure of avelumab from 3 mg/kg – 20 
mg/kg, and population studies have shown no significant effects on clearance of avelumab 
from premedications or concomitant therapies like opiates or corticosteroids. Avelumab 
has a drug half-life of 95-99 hours at the 10 mg/kg and 20 mg/kg dose. Receptor target 
occupancy was >90% at 3-10 mg/kg doses. Anti-drug antibodies have been detected in 
minority of patients (4% in early phase trial). Primary excretion of avelumab remains 
intracellular lysosomal proteolytic degradation, with a terminal half-life of 65.1 days in 
patients receiving 10 mg/kg. Avelumab is not expected to interfere with small molecular 
drugs through p450 enzyme modulators or through absorption or elimination. 
Avelumab gained FDA regulatory accelerated approval based on clinical response for 
patients with metastatic Merkel cell carcinoma (MCC) in March 2017. In the JAVELIN 
Merkel 200 trial (NCT02155647), an open-label single-arm multicenter study in patients 
with metastatic treatment refractory MCC, patients received avelumab 10 mg/kg every 2 
weeks with an ORR of 32%, complete response (CR) of 11.4% and partial response (PR) 
of 21.6%. The duration of response was 2.8-23.3+ months, with 45% of patients sustaining 
a clinical response ≥12 months (60). Updated results from JAVELIN Merkel 200a Part B 
testing monotherapy avelumab in the first-line setting continue to show robust and durable 
responses (61). Multidisplinary review of avelumab for accelerated regulatory approval 
showed that simulated AUC for 10 mg/kg Q2 week dosing had similar overall drug 
variability for both body weight based and flat dosing schemes, and a flat dosing regimen 
should be acceptable. As such, the FDA-label for avelumab was updated in October 2018 
for a recommended flat-dose schedule instead of traditional weight-based dosing. 
Recently launched clinical investigations have also incorporated this approach, notably 
the 
JAVELIN-PARP 
phase 
II 
clinical 
trial 
in 
BRCA/ATM 
mutant 
tumors 
(NCT03330405)(62), and other phase II combination treatments (i.e. NCT03704467). 
In May 2017, avelumab received FDA accelerated approval for the use in locally advanced 
or metastatic urothelial carcinoma who have had disease progression during or following 
platinum-containing chemotherapy, and in patients with disease progression within 12 
months of neoadjuvant or adjuvant treatment with platinum containing chemotherapy. 
Results from the urothelial carcinoma cohort of the JAVELIN solid tumor trial showed a 
confirmed ORR of 16.1%, with a CR rate of 5.6% and PR rate of 10.6% with ≥6 months 
follow-up (63). 
Recent early phase data from the JAVELIN phase I solid tumor renal cell carcinoma cohort 
of avelumab 10 mg/kg monotherapy every 2 weeks has shown monotherapy clinical 
activity in both the first-line and second-line settings (Table 4) (64). In JAVELIN Renal 101, 


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IRB Number: 19-195 A(8) 
Approval date: 01-Dec-2021 
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a phase III study combining avelumab and axitinib, a VEGFR TKI, compared to sunitinib, 
superior results were seen with combination therapy, including: ORR 51% versus 26% by 
IRC, improved PFS 13.8 months versus 8.4 months (HR 0.69, p=0.0001) (65, 66). 
 
Treatment 
Line 
Patient # 
Follow- 
Up 
TRAE 
(grade 
>3) 
ORR 
Duration of 
Response 
mPFS 
mOS 
IL 
62 
14.2 
12.9% 
16.1% 
10.4 
8.3 
NE 
patients 
months 
(8- 
(2.8-10.4) 
(6-17) 
27.7%) 
2L 
20 
22.1 
5% 
10% 
NE 
5.6 
16.9 
patients 
months 
(1.2- 
(6.9-NE) 
(2.3- 
(8.3- 
(16-23) 
31.7%) 
8.2) 
NE) 
Table 4: Avelumab Monotherapy in ccRCC. 1L: first-line 2L: second-line TRAE: treatment-related 
adverse events ORR: objective response rate mPFS: median progression-free survival mOS: 
median overall survival 
Pooled safety data regarding monotherapy avelumab from the phase I JAVELIN solid 
tumor and phase II JAVELIN Merkel 200 clinical trial (1650 patients + 88 patients, 
respectively) has been reported (67). Grade ≥3 treatment related adverse events were 
seen in 177 patients (10.2%), with the most common being fatigue 1%, increased lipase 
1%), infusion related reactions (0.6%), and nausea (0.6%). Immune related adverse 
events occurred at any grade in 14.2% of patients (247/1738), with the most common 
including endocrinopathies (6.1%) of which thyroid (5.6%) remained the most 
predominant, as well as rash (5.2%) of any grade. Grade ≥3 immune related adverse 
events occurred in 1.8% of patients only. Other clinical significantly, immune related 
adverse reactions occurring at an incidence of <1% of patients treated with avelumab have 
also included immune-mediated myositis, arthritis, pemphigoid, hypopituaritism, Guillan- 
Barre syndrome, and systemic inflammatory response. 
3.11 
Combination Talazoparib and Avelumab Combination Therapy 
As avelumab is eliminated by proteolytic degradation, it is not expected to be affected by 
small molecule drugs, the cytochrome p450 enzyme system, or the absorption or 
elimination of other small molecule drugs. Therefore, expected drug-drug interactions with 
combination talazoparib and avelumab are low. Furthermore, there does not appear to be 
overlapping toxicities anticipated with this combination given with known individual safety 
profiles. Avelumab has been previously combined with axitinib for patients with advanced 
RCC with no unexpected safety signals in a large-scale randomized study (65). Reported 
treatment emergent events ≥3 in the combination were 71.2% versus 71.5% with sunitinib 
monotherapy. 
Based on the above rationales, this clinical trial is testing the combination of talazoparib 
and avelumab in patients with metastatic renal cell carcinoma in two genomically defined 
populations. Based on the phase Ib portion of the JAVELIN PARP Medley 
(NCT03330405), in which patients were treated with 0.5 mg, 0.75 mg, and 1 mg daily 
talazoparib and 800 mg avelumab the recommended phase II dose (RP2D) was 1 mg 


Memorial Sloan Kettering Cancer Center 
IRB Number: 19-195 A(8) 
Approval date: 01-Dec-2021 
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talazoparib for combination therapy. This RP2D was considered based upon a lower 
observed DLT rate than pre-specified rate per protocol (<0.33). No unexpected AEs were 
also seen with combination avelumab and talazoparib compared to the expected profiles 
of each individual agent, and the incidence and severity of AEs was generally consistent 
with previously observed rates for each individual agent and were generally manageable 
(Summary of Phase Ib Safety Data, Pfizer Internal Communication). 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
4.1 
Design 
This is a phase II, open-label, single institution clinical trial of combination talazoparib and 
avelumab in patients with metastatic RCC. This clinical trial will enroll two separate cohorts 
in parallel. The first cohort of patients will include VHL-deficiency and will enroll in a Simon 
two-stage manner (first stage=10 patients, second stage=19 patients, total=29 patients) 
to allow for early futility analysis and final efficacy analysis. The second cohort will enroll 
15 patients with either FH- or SDH-deficiency or renal medullary carcinoma (RMC), and 
will enroll a total of 15 patients continually given disease rarity for each of these three 
entities. Given the uniformly aggressive nature of RMC, typically with rapidly progressive 
clinical picture without standard treatment options following failure of first-line 
chemotherapy, and considering the fact that SMARCB1 (INI1) is lost in nearly all patients, 
we will not require IHC/NGS testing for RMC patients as part of study eligibility. 
4.2 
Intervention 
Combination talazoparib and avelumab will be administered in 28-day cycles until disease 
progression or unacceptable toxicity. All treatments will be given in the outpatient clinic. 
Avelumab will be administered as a 1-hour intravenous infusion every 2 weeks on days 1, 
15 of each 28-day cycle, at a flat dose of 800 mg. Premedication with acetaminophen and 
diphenhydramine will be included for all patients to minimize risk for infusion-reactions as 
specified in Section 5.3. Talazoparib will be self-administered orally at 1 mg daily on a 
continuous schedule. All study medications will be supplied by Pfizer. 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
5.1 
Talazoparib Drug Information and Storage 
Commercial supply of Talazoparib / BMN-673 will be acceptable for this protocol, and drug 
will be supplied by trial sponsor Pfizer. Drug will be supplied in a dosing container which 
will contain sufficient drug for each treatment period including overage. Talazoparib will 
be stored at room temperatures (15-30ºC, 59-86ºF) or per the approved label. Research 
staff will inform patients on the proper storage requirements for the take home 
investigational drug. Further information regarding talazoparib handling is listed in the 
investigational brochure. Any excursions from the product label storage conditions will be 
reported upon discovery. Deviations from the storage requirements should be 
documented and reported. Once an excursion is identified, the investigational product 


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19 
 
 
must be quarantined and not used until Pfizer provides permission to use the 
investigational product. 
Talazoparib is self-administered orally once daily on a continuous schedule during days 
1-28 of the treatment cycle. Talazoparib should be at the same time, and if a dose is 
missed, it may be taken up to 12 hours after scheduled time. Patients should not take 
more than one dose within a 24-hour period, and if any doses are missed in the cycle, 
they will not be made up and should be recorded as missing in the patient’s diary. The 
reason for the missed dose should be recorded in the diary for study personnel to review. 
The patient is then instructed to resume subsequent doses the next day as prescribed. 
Patients are to self-administer talazoparib orally with or without food. Capsules should be 
swallowed whole with a glass of water without chewing, dissolving or opening prior to 
swallowing. Talazoparib can be taken with a light meal/snack, and then should be 
swallowed whole and not chewed, crushed, dissolved or divided. If vomiting occurs after 
talazoparib is swallowed, the dose itself should only be replaced if intact tablets are seen 
and counted. 
Patients are not to exceed the prescribed dose at any time. The use of study medication 
in doses exceeding that specified in this protocol will be considered an overdose. There 
are no known antidotes for talazoparib in the event of an overdose, and treatment for 
adverse events should be aimed at underlying adverse symptoms. 
6.1 
Avelumab Drug Information and Storage 
Commercial supply Avelumab / MSB0010718C will be acceptable for this protocol, and 
drug will be supplied by Pfizer. Drug will be supplied as a clear, colorless, non-pyrogenic 
solution, packaged in a type I glass vial containing 10 ml of solution with a rubber stopper 
and aluminum overseal and flip off cap. Each single use vial of avelumab contains a 
sufficient amount of product to ensure an extractable volume of 10 ml (200 mg) at 
concentration of 20 mg/Ml, formulated with a preservative-free acetate buffered solution 
at pH 5.2 in the presence of polysorbate 20 and mannitol. Avelumab solutions must be 
prepared in 0.9% sodium chloride (normal saline), with final concentration of avelumab in 
the infusion solutions between 0.15 mg/mL to 8 mg/mL. Total volume of final prepared 
solution must be 250 mL. The parenteral investigational drug products must be inspected 
visually for particulate matter. 
Avelumab must be stored in a refrigerator, at 2-8ºC, 36-46ºF. It is not frozen and must be 
protected from light. It cannot be shaken vigorously. The solution itself must be allowed to 
reach room temperature for a minimum of 30 minutes prior to dose preparation. The 
immediate administration of a prepared solution kept at room temperature is preferred. 
Further information regarding avelumab storage and preparation is provided in the 
investigational brochure. 
Avelumab will be provided to each patient in the outpatient chemotherapy administration 
suite and will be provided on cycle day 1 and day 15 (every 2 weeks). Doses may be given 


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within a 72-hour period per visit window (Schedule of Activities), and if any doses are 
missed in the cycle, they will not be made up and should be recorded as missing. 
Avelumab will be administered with a pre-medication as per below (Section 5.3). 
6.1 
Avelumab Premedication 
Avelumab must be infused with premedication to mitigate the rate of infusion-related 
reactions. Premedication will include antihistamine and acetaminophen 30-60 minutes 
prior to the first 4 infusions. Premedication should be then administered for subsequent 
avelumab infusion based upon clinical judgement and presence/severity of prior infusion 
reactions. Availability for immediate access to intensive care unit or equivalent 
environment for treatment of anaphylaxis is required. This should include access to 
steroids (i.e. dexamethasone), epinephrine (i.e. 1:1000 dilution), allergy medications (IV 
histamines), bronchodilators or equivalents, as well as oxygen. Following the first four 
infusions of avelumab, patients should be observed for at least 60 minutes for potential 
infusion related complications and reactions. Provided no infusion reactions are seen this 
observation period is not required beyond dose #4. If a hypersensitivity reaction occurs, 
the patient should be treated according to the best available medical practice with 
consideration for treatment modification (Table 5). 
Symptoms of hypersensitivity reactions may include, but are not limited to, fevers, chills, 
hypotension, flushing, dyspnea, wheezing, back pain, abdominal pain, urticaria. Patients 
should be instructed to immediately report to the Investigator any delayed reactions that 
occur after clinic. Management of infusion related reactions are listed below, and in 
Appendix 3. 
 
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. 
• 
Next scheduled infusion can be re- 
attempted at original rate, per treating 
investigator’s discretion. 
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 
• 
Next scheduled infusion should be initiated 
at 50% of original rate. Added 
premedication should be considered. 


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IRB Number: 19-195 A(8) 
Approval date: 01-Dec-2021 
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Grade 3 or Grade 4 – severe or 
life-threatening 
• 
Grade 3: Prolonged (for example, not 
rapidly responsive to symptomatic 
medication and/or brief interruption of 
infusion); recurrence of symptoms 
following initial improvement; 
hospitalization indicated for clinical 
sequelae. 
• 
Grade 4: Life-threatening consequences; 
urgent intervention indicated. 
• 
Stop the avelumab infusion immediately 
and disconnect infusion tubing from the 
patient. 
• 
Patients must be withdrawn immediately 
from avelumab treatment and should not 
receive any further avelumab treatment. 
Table 5: Avelumab Infusion Reaction Algorithm. For each NCI CTCAE grade, a treatment 
modification instruction should be followed. 
If the infusion rate of avelumab has been decreased by 50% due to an infusion reaction, 
it should remain at the decreased infusion for the next scheduled dose. If no infusion 
reactions were observed during that next scheduled infusion, the infusion rate may be 
returned to baseline at subsequent infusions. 
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%), systemic corticosteroids should be considered, per treating physician’s 
discretion and with discussion with the PI. At the next dose, the treating physician should 
consider addition of H2 blocker antihistamines (i.e. famotidine or ranitidine), meperidine, 
or ibuprofen to the mandatory premedication. Prophylactic corticosteroids up to the 
equivalent of 10 mg prednisone could be considered for recurrent grade 1-2 reactions 
despite premedication with above medications. 
6.1 
Treatment Interruptions / Delays 
Talazoparib may be maximally interrupted for 28 consecutive days. Avelumab may be 
maximally interrupted for 42 consecutive days. Should treatment toxicities warrant longer 
treatment interruptions than these, the respective agent should be discontinued 
permanently. 
If a treatment-related adverse event is clearly attributable to one, not both, of the two 
investigational agents and triggers a treatment interruption per protocol guidelines, the 
other agent may be continued at the treating investigator’s discretion. In the case of 
permanent discontinuation of either agent despite the absence of disease progression, 
the other drug may be continued as monotherapy, if tolerable. 
For the therapy cycle, it will be acceptable to have therapy delivered within a 72-hour 
window before and after the protocol related date. The exception for this 72-hour window 
rule will be if regularly scheduled treatment dates occur on Fridays, as the window will 
include Tuesday (day -3), and Tuesday (D+4). 


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For each 28-day treatment cycle, the patient may be permitted to have a new cycle 
delayed for up to +7 days without being considered a protocol deviation. 
6.1 
Drug Accountability 
The study team will maintain adequate documentation regarding the receipt, use, loss and 
other dispositions of all investigational drug supplies. All the investigational products 
should be accounted for using a drug accountability form/record. Unused talazoparib must 
be returned to the investigator or study team personnel by each patient on Day 1 of every 
cycle and at the end of the clinical trial participation. 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
6.1 
Subject Inclusion Criteria 
1. Biopsy proven, histological confirmed renal cell carcinoma (RCC) or renal medullary 
carcinoma (RMC). Patients with surgery and biopsy at outside institutions will be 
eligible for this protocol once archival material is reviewed and the above diagnosis 
confirmed by genitourinary pathology review at Memorial Sloan Kettering Cancer 
Center (MSKCC). 
 
2. Cohort 1: 
a. Presence of VHL alteration by next-generation sequencing (NGS) with a 
state- approved assay 
b. Patients must have radiographic evidence of disease progression after 
treatment with at least one prior PD-1 or PD-L1 agent and one prior VEGF 
inhibitor 
c. Maximum 3 prior lines of therapy 
 
3. Cohort 2: 
a. For FH/SDH patients: FH- or SDH- expression-loss by immunohistochemistry 
(IHC) or alteration (somatic or germline) in FH or SDH per NGS with a state- 
approved assay 
b. For Renal Medullary Carcinoma (RMC) patients: histologic confirmation of 
RMC (no IHC/NGS criteria required) 
c. At least one prior line of therapy: 
i. 
For FH/SDH patients: Patients must have radiographic evidence of disease 
progression after treatment with at least one prior line of therapy (one prior 
PD-1/PD-L1 and/or VEGF inhibitor). 
ii. For Renal Medullary Carcinoma (RMC) patients: prior radiographic 
evidence of disease progression on/after at least one line of chemotherapy 
(e.g. carboplatin / paclitaxel, carboplatin / paclitaxel / bevacizumab, 
carboplatin / gemcitabine, and gemcitabine / doxorubicin). 
d. No maximum lines of therapy 


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IRB Number: 19-195 A(8) 
Approval date: 01-Dec-2021 
23 
 
 
Both Cohorts 1 & 2: 
4. Adequate Hematologic Function 
(1) Absolute Neutrophil Count ≥ 1.5 x 109 / L 
(2) Platelet Count ≥ 100 x 109 / L 
(3) Hemoglobin ≥ 9 g/dL 
(4) No transfusion of packed red blood cells or platelets within 21 days of Cycle 1 Day 
1 
5. Adequate Renal Function ≥ 30 ml/min according to Cockcroft-Gault Equation 
(1) Patients with moderate renal impairment (creatinine clearance 30-59 by Cockcroft- 
Gault Equation) will start with a reduced dose of talazoparib. 
6. Adequate Hepatic Function including: 
(1) Total bilirubin ≤ 1.5 x upper limit of normal (ULN) 
(2) AST ≤ 3 x upper limit of normal (ULN) without liver metastasis 
(3) ALT ≤ 3 x upper limit of normal (ULN) without liver metastasis 
(4) AST or ALT ≤ 5 x upper limit of normal (ULN) for patients with liver metastasis 
(5) Patients with known Gilbert’s syndrome may be included if total bilirubin ≤ x 3 ULN 
7. Eastern Cooperative Group (ECOG) Performance Status 0-2. 
8. Patients must have measurable disease by RECIST v1.1. At least one measurable 
lesion should not have been previously irradiated. 
9. Women of childbearing potential must have negative serum pregnancy testing at 
screening. All women will be considered childbearing potential unless meeting criteria 
including: 
(1) Achieved post-menopausal status as defined by cessation of regular menses for 
at least 12 consecutive months with no alternative pathological or physiological 
cause and have follicular stimulation hormone showing postmenopausal state. 
Women who have been amenorrhoeic for ≥12 months are still considered to be of 
childbearing potential if the amenorrhea is possibly due to prior chemotherapy, 
anorexia, low body weight, ovarian suppression, anti-estrogen therapy or other 
medically inducible reasons. 
(2) Documented hysterectomy or bilateral oophorectomy surgery 
(3) Medically confirmed ovarian failure 
(4) Sexually active participants and their partners must agree to use medically 
accepted methods of contraception (i.e. barrier methods including condoms, 
female condom, or diaphragm with spermicidal gel) during the study and for 7 
months after the last dose of the study treatment for females, and 4 months for 
males. 
10. Recovery of baseline CTCAE v5.0 grade ≤1 toxicities related to prior study treatments 
unless adverse events are clinically non-significant and/or stable on supportive therapy if 
needed. 
11. Patients must be willing and able to comply with trial protocol. This includes adhering 
to the treatment plan, scheduled visits, laboratory and other study procedures. 
6.2 
Subject Exclusion Criteria 
1. 
Patients < 18 years old 


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IRB Number: 19-195 A(8) 
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24 
 
 
2. 
Patients who are pregnant or breast-feeding. Fertile patients who are unwilling or 
unable to use two methods of contraception (at least one of which considered highly 
effective) for duration of study and after 7 months after last dose of study treatment 
for female, and 4 months for males. 
3. 
Patients who had prior immune checkpoint blockade therapy (either anti-PD-1, anti- 
PD-L1 and/or anti-CTLA-4) discontinued due to development of an immune related 
adverse event. 
4. 
Prior diagnosis of myelodysplastic syndrome (MDS) or diagnosis of other 
malignancy that requires anti-cancer directed therapy within the last 24 months. 
Exclusions include those cancers that are considered cured by local therapy (i.e. 
Basal cell carcinoma, squamous cell carcinoma, ducal carcinoma in situ of breast, 
bladder of cervix) or other cancers that have low malignant potential and do not 
require systemic therapy (i.e. Gleason-grade <6 prostate adenocarcinoma, 
borderline ovarian malignancy / low malignant potential). 
5. 
Prior treatment with talazoparib or other agents that target PARP 
6. 
Treatment with anti-cancer therapies within 21 days or five half-lives, whichever 
shorter, of start date, including monoclonal antibody, cytotoxic therapy, or another 
investigational agent. There is no specific time window between last PD-1/PD-L1 
therapy and start date of new therapy on protocol. 
7. 
Significant vascular disease (i.e. aortic aneurysm requiring surgical repair, recent 
arterial thrombosis) within 6 months prior to first dose of therapy. 
8. 
Evidence of bleeding diathesis or significant unexplained coagulopathy (i.e. absent 
of anticoagulation) 
9. 
Clinical signs or symptoms of gastrointestinal obstruction requirement parenteral 
hydration, parenteral nutrition, or feeding tube. 
10. 
Uncontrolled effusion management (pleural effusion, pericardial effusion, or 
ascites) which requires recurrent drainage procedures. 
11. 
Patients treated with systemic immunosuppressants; except for 
a) chronic physiologic replacement of ≤ 10mg prednisone (or equivalent) for 
treatment of adrenal insufficiency; Steroids required for pre-medication 
reactions 
b) Local steroid use is permitted (e.g. intranasal, topical, inhaled, or local steroid 
injection, i.e. intra-articular) 
12. 
Patients with autoimmune disease that may worsen during immune checkpoint 
blockade therapy are excluded. Patients with diabetes type I, vitiligo, psoriasis, 
hypo- or hyperthyroid disease not requirement immunosuppressive treatment as 
above are eligible. 
13. 
Prior organ transplantation including allogeneic stem cell transplant. 
14. 
No active infection requiring parenteral antibiotic therapy. 
15. 
Prior diagnosis of HIV/AIDS 
16. 
History of either positive HCV RNA viral load or anti-HCV antibody screening 
detectable; HBV infection with HBV surface antigen detection and/or positive HBV 
DNA viral load. 


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17. 
Known hypersensitivity to talazoparib or avelumab, or any component in 
formulations. Patients with known hypersensitivity to monoclonal antibodies (Grade 
≥3 by CTCAE v5.0) 
18. 
Live vaccination within 4 weeks of first dose of therapy. All vaccines except 
inactivated are prohibited while on study. 
19. 
Severe acute or chronic medical conditions which may significantly increase the 
risk of study participants, per treating investigator’s discretion 
20. 
Radiation therapy to any site (including bone) <2 weeks prior to the first dose of 
therapy. Patients with clinically relevant ongoing complications from prior radiation 
therapy, per investigators’ assessment, are not eligible. 
21. 
Symptomatic brain metastasis or leptomeningeal disease requiring steroid use. 
Patients are eligible if they neurologically stable for 4 weeks, and have completed 
radiation therapy or surgery, and recovered from side effects. Patients must have 
discontinued steroid therapy for at least 2 weeks prior to first dose of study 
treatment. 
22. 
Current or anticipated use of potent P-gp inhibitors within 7 days prior to 
randomization or anticipated use during the study. Please see Appendix 5 for a list 
of potent P-gp inhibitors. 
23. 
Inability to swallow capsules, known intolerance to talazoparib or its excipients, 
known malabsorption syndrome, or other conditions which impair intestinal 
absorption. 
24. 
Investigator site staff members directly involved in study conduct, including but not 
limited to their family members, or patients who are Pfizer members, including their 
family members, who are directly involved in study conduct. 
6.3 
Lifestyle Requirements 
The teratogenic risk of combination talazoparib and avelumab remains unknown. 
Talazoparib has been associated with teratogenic risk. Therefore, all fertile male 
patients and female patients who are of childbearing potential, and who remain 
sexually active during this study and who are at risk for pregnancy must agree for 
2 methods of contraception (one which is considered highly effective), for at least 7 
months after last dose of study treatment for women, and for at least 4 months after 
last dose of study treatment for men. 
Study team personnel including investigators and clinical nursing staff should 
confirm that the patient and their partner have selected 2 appropriate methods of 
contraception from the list of contraceptive methods (as listed below). The study 
team will confirm that the patient has received informed consent regarding proper 
use. Continued confirmation of contraceptive use will be obtained during the study 
protocol at time points outlined, with documentation of affirmation. 
Highly effective contraceptive methods include, but not limited to: 
1. 
Established hormonal methods of contraception associated with ovulation 
inhibition (i.e. oral, inserted, injected or implanted), provided that the patient 


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or male patient’s partner remains on same treatment throughout the entire 
study period. 
2. 
Intrauterine device 
3. 
Male sterilization with absence of sperm in post vasectomy ejaculate 
4. 
Bilateral tubal ligation, bilateral salpingectomy or bilateral tubal occlusive 
procedure. 
5. 
Female partner of male patient who meets criteria for non-childbearing 
potential as defined above, including: 
a. Medically confirmed ovarian failure 
b. Hysterectomy and/or bilateral oophorectomy 
c. Post-menopausal state as defined as a cessation of regular menses >12 
months with no alternative pathologic or physiologic cause, with serum 
follicular stimulating hormone within reference range for postmenopausal 
women by laboratory. 
6. 
All sexually active male patients must agree to prevent potential transfer or 
exposure of study agents through ejaculate by using a condom consistently 
and correctly. Condom use must begin at the first dose of investigational 
product, and for at least 30 days after avelumab or after at least 4 months 
after last dose of talazoparib, whichever is later. 
7.0 
RECRUITMENT PLAN 
Patients will be recruited in the outpatient genitourinary medical oncology service clinics 
at Memorial Sloan Kettering Cancer Center (MSKCC). Investigators listed on this protocol 
will screen patients for eligibility for trial participation. Men and women of all ethnic groups 
are eligible for participation. Alternative treatment options, particularly FDA approved 
regimens will be discussed with each patients, and questions will be answered by the 
treating investigator before written consent is obtained. 
Potential research subjects will be identified by a member of the patient’s treatment team, 
the protocol investigator, or research team at Memorial Sloan-Kettering Cancer Center 
(MSKCC). If the investigator is a member of the treatment team, s/he will screen their 
patient’s medical records for suitable research study participants and discuss the study 
and their potential for enrolling in the research study. Potential subjects contacted by their 
treating physician will be referred to the investigator/research staff of the study. 
 
During the initial conversation between the investigator/research staff and the patient, the 
patient may be asked to provide certain health information that is necessary to the 
recruitment and enrollment process. The investigator/research staff may also review 
portions of their medical records at MSKCC in order to further assess eligibility. They will 
use the information provided by the patient and/or medical record to confirm that the 
patient is eligible and to contact the patient regarding study enrollment. If the patient 
turns out to be ineligible for the research study, the research staff will destroy all 
information collected on the patient during the initial conversation and medical records 
review, except for any information that must be maintained for screening log purposes. 


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In most cases, the initial contact with the prospective subject will be conducted either by 
the treatment team, investigator or the research staff working in consultation with the 
treatment team. The recruitment process outlined presents no more than minimal risk to 
the privacy of the patients who are screened and minimal PHI will be maintained as part 
of a screening log. For these reasons, we seek a (partial) limited waiver of authorization 
for the purposes of (1) reviewing medical records to identify potential research subjects 
and obtain information relevant to the enrollment process; (2) conversing with patients 
regarding possible enrollment; (3) handling of PHI contained within those records and 
provided by the potential subjects; and (4) maintaining information in a screening log of 
patients approached (if applicable). 
8.0 
PRETREATMENT EVALUATION 
Pre-treatment evaluation to be completed ≤30 days prior to study treatment day 1. 
1. History and Physical Examination 
2. Vital Signs 
3. Eastern Cooperative Group (ECOG) Performance Score 
4. Toxicity Assessment via CTCAE v5.0 
5. Assessment of concomitant medications and treatment 
6. 12-lead electrocardiogram 
7. Optional pre-treatment biopsy 
8. Radiographic tumor assessment of chest, abdomen, or pelvis 
9. Radiographic brain imaging 
10. Bone scan if clinically indicated 
11. Verification of tumor alteration status by state-approved NGS assay (MSK IMPACT 
or other) 
12. Confirmation of tissue availability: 
(1) Availability of archival tissue must be confirmed prior to study initiation, but 
specimens do not have to be physically received or processed for determination 
of eligibility; 20 unstained slides should be requested, but there is no minimum 
slide requirement. 
13. Peripheral Blood Tests including: 
(1) 
Complete blood count with differential (including at minimum neutrophils, 
basophils, eosinophils, lymphocytes, monocytes, hematocrit, platelet count, 
hemoglobin, RBC count) 
(2) 
Comprehensive Metabolic Profile (including alkaline phosphatase, AST, ALT, 
Total bilirubin, total protein, albumin, sodium, potassium, chloride, carbon 
dioxide, bicarbonate, calcium, BUN, creatinine, amylase, lipase, glucose) 
(3) 
Lactate Dehydrogenase 
(4) 
Serum Pregnancy Testing for women of childbearing potential 
(5) 
Thyroid Function Testing: TSH, free T4, free T3 
(6) 
Urinalysis; urine protein / creatinine ratio 


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(7) 
Screening for hepatitis B: HBV surface antigen, HBV core antibody, with HBV 
PCR performed reflexively if abnormal results 
(8) 
Screening for hepatitis C: anti-HCV antibody and HCV RNA PCR performed 
reflexively if abnormal results 
9.0 
TREATMENT/INTERVENTION PLAN 
Talazoparib and avelumab will be initiated concurrently on Cycle 1 Day 1 and both will 
be continued until confirmed disease progression (except where treatment is allowed 
beyond progression; refer to section 10.6 for further information), patient refusal, 
unacceptable toxicity, or until the study is terminated by the Sponsor, whichever occurs 
first. 
If talazoparib is held for > 28 consecutive days, it should be permanently discontinued. If 
avelumab is held for > 42 consecutive days, it should be permanently discontinued. 
Should the treating investigator determine that exceptional circumstances apply and that 
it would be clinically beneficial for the patient to re-initiate therapy after a longer treatment 
break, re-initiation must be discussed with and approved by the study PI. In the event 
that treatment-related toxicity is clearly attributable to only one of drugs, the other can be 
continued while the first is being held. 
9.1 
Talazoparib Administration 
Talazoparib / BMN-673 will be provided to study participants in capsules for oral self- 
administration. The 0.25 mg (opaque, white) and 1 mg (opaque, pale pink) capsules are 
supplied in separate bottles and labeled according to regulatory requirements. 
Talazoparib will be packaged in induction sealed, high density polyethylene bottles with 
child resistant caps with 30 capsules of a single strength per bottle. 
On Day 1 of each treatment cycle, talazoparib will be dispensed by the clinical team. The 
patient and/or caregiver should be instructed on how to maintain the product in the bottle 
during treatment cycle, keep investigational products away from children, and will be 
instructed to return the bottle to the site on Day 1 visit of the subsequent treatment cycle. 
Talazoparib is a cytotoxic agent, and therefore precautions regarding the appropriate 
secure storage and handling must be used. To minimize undue exposure to study 
personnel, dispensing, handling and safe disposal of talazoparib should only be done by 
qualified personnel at MSKCC. Patients should be advised that talazoparib is an oral anti- 
cancer therapy and therefore handling of the agent should be done always be used with 
gloves. 
9.2 
Avelumab Administration 
Avelumab / MSB0010718C will be provided to the pharmacy as a sterile, clear, colorless 
solution that can be prepared for intravenous administration. Each participant will receive 
a dose of 800 mg intravenously every 14 days. Therefore, 4 vials of avelumab drug product 
will then be diluted with 0.9% saline solution. Detailed information regarding instructions 


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for avelumab preparation with dilution and subsequent administration is available in the 
Investigational Brochure and above. Any spills that occur during administration should be 
cleaned by facility’s standard cleanup procedures for biological products. 
9.3 
Talazoparib and Avelumab Combination Administration 
For each 28-day cycle, combination talazoparib and avelumab will be administered on 
Days 1 and15. For Cycle 1, Day 1, medications will be administered per the following 
order: 
1. All required tests and assessments will be performed prior to medication dosing. 
2. Avelumab premedication and talazoparib will be administered to the patient in any 
order chosen by the study team. 
3. Avelumab infusion will start within 30-60 minutes after the avelumab premedication 
was administered. 
For subsequent cycles where patients are administered both study agents, patients may 
take talazoparib prior to being seen by the clinical team and are encouraged to continue 
the same dosing order as above. 
9.4 
Medication Compliance 
All doses of avelumab will be administered at MSKCC by trained medical staff. All start 
and stop times of the avelumab infusion, as well as dosing information including infusion 
time, volume administered, interruption to infusion and/or changes in rate will be 
documented in patient medical records. Vials of avelumab that are assigned and prepared 
for patients will be recorded in the pharmacy records, and these records will be made 
available to the Sponsor representatives to verify medication compliance. 
All doses of talazoparib will be given to the patient at the start of each cycle, and all 
patients will be required to return all unused talazoparib at the start of the subsequent 
cycle. The number of capsules returned by the patient will be counted, documented, and 
recorded by investigational personnel and reconciled with the patient’s dosing diary to 
support talazoparib accountability. Study personnel should make reasonable efforts to 
obtain study drug packaging and unused capsules from those patients who do not 
routinely return them at the study site visit, and unreturned capsules will be considered to 
have been taken unless otherwise reported by the patient. 
A medication dosing diary will be given to the patient to aid in patient compliance and 
dosing instructions. The diary will be maintained by the patient and will include entry items 
for the patients to include information regarding taken, missed, or changed talazoparib 
doses. Patients will be required to return this completed patient dosing diary on Day 1 of 
every new cycle for timely review by the study personnel during clinical visit. During the 
medical visit, review of this diary as well as discussion regarding missed doses or 
compliance issues will be done to ensure medication compliance and accurate data entry. 
During this clinic visits in which patients present for avelumab (day 1 and day 15), patients 


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are instructed to delay talazoparib dose administration so that it is performed in clinic, 
witnessed by study personnel. 
Treatment compliance will ultimately be reported as a percentage and will be defined by 
the number of capsules taken during study treatment / number of expected capsules 
taken, multiplied by 100. 
9.5 
Talazoparib Dose Modifications 
Talazoparib dose modifications can be implemented to help manage toxicities 
encountered during treatment. Dose reduction will be done per dosing level scheme listed 
below (Table 6). All patients will start on 1 mg daily (RP2D, Pfizer internal communication) 
and be allowed 1 dose level reduction at a time depending on the starting dose, type and 
severity of the toxicity. For patients with known moderate renal impairment 
(Creatinine Clearance=30-59 mL/min by Cockcroft-Gault Equation) at treatment 
start or if renal impairment unrelated to study drug develops during the study, 
talazoparib should be reduced by one dose level (e.g. starting dose 0.75 mg daily). 
If the renal function improves, per investigator judgement this dose can then be 
increased. 
Patients experiencing dose-limiting toxicities from talazoparib will be dose-reduced to the 
next lower level. In the event of planned dose reduction, patients should hold study 
treatment for at least 48 hours prior to re-initiation of dose reduced therapy. Such dose 
reductions may be performed prior to scheduled initiation of subsequent study cycles, i.e. 
in the course of a treatment cycle. In such cases lower-strength capsules will be dispensed 
mid-cycle, rather than delaying re-initiation of therapy at lower dose. Left-over capsules at 
the prior strength will be returned to the study team at the next scheduled Day 1 clinic visit. 
Once the talazoparib dose has been reduced to a dose level because of toxicity for a 
patient, all subsequent cycles should be administered at that dose level unless further 
reduction is required. Subsequent re-escalation to prior dose levels will not be permitted. 
Patients who are unable to tolerate 0.25 mg (dose level -3) daily will be permanently 
discontinued from the talazoparib but may be considered for continuation of single-agent 
avelumab. 
If talazoparib is held for >28 consecutive days, it should be permanently discontinued. 
Should the treating investigator determine that exceptional circumstances apply and that 
it would be clinically beneficial for the patient to re-initiate therapy after a longer treatment 
break, then re-initiation must be discussed with and approved by the study PI. If 
talazoparib is discontinued, patients may continue avelumab. 
 
Dose Level 
Talazoparib Dose 
Dose Level 0 
1 mg daily 
Dose Level -1 
0.75 mg daily 
Dose Level -2 
0.5 mg 
Dose Level -3 
0.25 mg daily 


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Table 6: Talazoparib Dose Levels for Cohorts 1 and 2. 
9.6 
Avelumab Dose Modifications 
There will be no dose modification for avelumab during the duration of this study. If the 
treatment cannot be delivered due to an immune related adverse event, then avelumab 
will be placed on hold. It is acceptable for the patient to continue avelumab with resolution 
of ≤1 grade I immune related adverse event, and if patient is ≤10 mg prednisone (or 
equivalent) as deemed by investigator. 
If avelumab is held for > 42 consecutive days, it should be permanently discontinued. 
Should the treating investigator determine that exceptional circumstances apply and that 
it would be clinically beneficial for the patient to re-initiate therapy after a longer treatment 
break, then re-initiation must be discussed with and approved by the study PI. If avelumab 
is discontinued, patient may continue talazoparib. 
9.7 
Concomitant Medications 
Concomitant treatments are considered necessary for patients’ well-being (anti-emetics, 
analgesics etc.) and may be given at the discretion of the investigator. All concomitant 
medications including herbal supplements, and supportive medications will be recorded in 
medical record from screening visit to 90 days after last dose of therapy. If after study 
treatment has concluded and patient had started new anti-cancer therapy, then further 
details regarding medications will be recorded until start of new anti-cancer therapy. 
Allowed Therapy 
1. Anti-emetics and antidiarrheal medications are allowed prophylactically according to 
standard clinical practice as indicated. All patients who experience diarrhea should be 
advised to drink liberal quantities of liquids and if sufficient oral intake is not feasible, 
intravenous infusion of fluid and/or electrolytes should be performed. 
2. Bisphosphonates or RANK-L inhibitors may be used to control bone loss if started prior 
to trial initiation or for hypercalcemia treatment if the benefit outweighs risk per 
investigator’s discretion. As osteonecrosis of the jaw has been reported in those 
patients treated with bisphosphonate therapy, oral examination and serial examination 
during study is advised in those patients on bisphosphonate therapy. 
3. Anticoagulation is allowed if the patient can be provided safely and effectively. This 
includes: 
(1) Use of low molecular weight heparin (LMWH) or direct oral anti coagulants (DOAC) 
such as rivaroxaban or apixaban is permitted provided the patient has no evidence 
of untreated brain metastases and has had no complications from thromboembolic 
event on the anticoagulation regimen within 14 days of starting study therapy. 
(2) All anticoagulants must be managed with accepted clinical guidelines. This 
includes standard patient education regarding medication compliance and 
administration, potential adverse drug reactions, monitoring of laboratory 
parameters (i.e. PT/INR/PTT/anti-Xa level), dose adjustments per standard 


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practice (i.e. dose adjustments for renal insufficiency), with consideration of referral 
to benign hematology for continued follow up and monitoring. 
(3) Immunosuppressive drugs are permitted if initiated for management of treatment- 
related adverse events and in accordance with adverse event management 
recommendations in this protocol (See Section 11). Systemic corticosteroids, if 
indicated for management of cancer-related complications (e.g. with palliative 
radiation) are permitted. Depending on dosage (≤ vs. > 10mg prednisone daily or 
equivalent), administration of immunosuppressants may require avelumab 
treatment delays (See Section 11). 
4. Caution and monitoring for potential increased adverse reactions should be used upon 
concomitant use of the following transporter inhibitors with talazoparib: atorvastatin, 
azithromycin, conivaptan, curcumin, cyclosporine, diltiazem, diosmin, eliglustat, 
elacridar [GF120918], eltrombopag, felodipine, flibanserin, fluvoxamine, piperine, 
quercetin, and schisandra chinensis extract. 
 
 
Prohibited Therapy 
 
1. Any other anti-cancer therapy (chemotherapy, biological therapy, immunotherapy, 
vitamins used as cancer therapies) other than talazoparib and avelumab. 
2. Any other investigational agents other than talazoparib or avelumab for anti-cancer 
or non-cancer related therapy. 
3. Immunosuppressive drugs while on avelumab treatment other than indicated as 
above. Patients who have permanently discontinued avelumab for any reason and 
remain on study for talazoparib monotherapy are permitted to receive 
immunosuppressive drugs. 
4. Potent P-gp inhibitors: amiodarone, carvedilol, clarithromycin, cobicistat, 
dronedarone, erythromycin, glecaprevir/pibrentasvir, indinavir, itraconazole, 
ketoconazole, lapatinib, lopinavir, propafenone, quinidine, ranolazine, ritonavir, 
saquinavir, sofosbuvir/velpatasvir/voxilaprevir, telaprevir, tipranavir, valspodar, 
and verapamil) while on talazoparib treatment (see Appendix 5). 
5. EPO stimulating agents: i.e. erythropoietin alpha, darbepoetin alfa, 
6. TPO stimulating agents: i.e. romiplostim, eltrombopag, thrombopoietin 
9.8 
Concomitant Surgery 
As the appropriate timing between surgery and administration of investigational agents is 
unknown, appropriate intervals must be taken to minimize the risk of impaired wound 
healing and bleeding. Therefore, investigational products should be temporarily on hold in 
the case of surgical procedure and be reinitiated on clinical assessment of satisfactory 
surgery recovery. The timing of such treatment interruption will be per treating 
investigator’s discretion. Surgical removal of target lesions should prompt permanent 
discontinuation of study treatment. 
9.9 
Concomitant Radiation 


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Palliative radiation to non-target lesions may be administered in the setting of painful bony 
lesions and other sites as considered medically necessary per investigator. Sites that are 
to be irradiated must be present at the time of prior screening tumor assessment, and the 
investigator must be clear that the requirement for palliative radiation is not truly indicative 
of disease progression. Prior to radiation therapy, attempts should be made to truly rule 
out disease progression in the event there is localized pain. Investigational agents should 
be held during the duration of palliative radiotherapy and can be restarted upon 
satisfactory recovery for any radiotherapy related toxicities, but no sooner than 48 hours 
post-radiotherapy. Radiation of target lesions or radiotherapy prompted by local growth of 
metastatic disease are not permitted. 
9.10 
Hypercalcemia Management 
Bisphosphonate or denosumab therapy can be administered as per loc al clinical practice. 
The need to start or escalate bisphosphonate or denosumab therapy for the management 
of malignant hypercalcemia during investigational drug treatment for those patients >2 
weeks on investigational drug products may be considered a symptom of disease 
progression. As such, radiographic reassessment of disease extent should be considered 
if there is suspicion of disease progression. 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION 
10.1 
Screening 
All screening activities must be completed ≤28 days prior to study enrollment. 
Procedures during screening are detailed under the Schedule of Activities (See Section 
10.7). 
10.2 
Treatment Period 
All activities during treatment period have been detailed under the Schedule of Activities 
(See Section 10.7). During times where multiple tests or procedures are scheduled during 
the same time point, the following priority should be assigned and adhered to in this order: 
1. Vital Signs should be obtained prior to clinical safety laboratory testing but may be 
performed before or after ECG. 
2. Clinical Laboratory Testing 
3. All other study related procedures should be performed as close to scheduled times 
but may be obtained before or after blood specimen collection unless sampling is 
determined to impact results. 
Every effort should be made to ensure that the protocol required tests and procedures are 
completed as described. If it is not feasible for the patient to perform the test, the 
investigator should make all necessary efforts to ensure the safety and well-being of the 
patient. When the protocol-related test cannot be performed, the investigator should 
document the reason for this and any corrective or preventative action to ensure that 


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normal processes are adhered to in the future for that patient. The study team should be 
informed of these incidents in a timely manner. 
10.3 
Safety Assessments 
Safety assessments will include, but are not limited to, collection of adverse events (AEs), 
serious 
adverse 
events 
(SAEs), 
vital 
signs, 
physical 
examination, 
12-lead 
electrocardiogram (ECG), laboratory assessments, pregnancy tests, and verification of 
concomitant medication and treatments. Adverse events will include the type, incidence, 
severity (as graded by NCI CTCAE v5.0), timing, seriousness and relatedness. 
All patients should undergo height and weight (height will be measured at screening only), 
assessment for ECOG performance status, vital signs, and physical examination (full 
physical examination at screening, focused physical exam as indicated during follow-ups) 
prior to study treatment administration. 
All patients will require a baseline ECG, and on-treatment ECGs should be performed as 
clinically indicated. Clinically significant findings on subsequent ECGs should be recorded 
as adverse events and best practice management should be followed including 
consideration of referral to cardiology for further evaluation and/or management. 
Safety monitoring with hematologic and blood chemistry labs will be drawn at the time 
points as described in the Schedule of Activities (see Section 10.7). The required safety 
testing should be reviewed prior to study drug administration on Days 1 and 15 of each 
treatment cycle. Blood chemistry and hematologic assessment must be performed at 
baseline, prior to each avelumab dose, end of treatment visit, and 30 days post-treatment 
for safety follow up. For female patients of childbearing potential, urine pregnancy testing 
must be performed at baseline and at least every month during treatment. Thyroid function 
testing (Free T4, Free T3, TSH) must be performed at baseline, and at least every 4 weeks 
during treatment, and at the end of treatment visit or 30 days post-treatment in safety 
follow up (if not performed within 8 weeks of study treatment end). 
 
Safety 
Lab 
Monitoring 
During 
Treatment 
Lab Parameters 
Hematology 
WBC with differential, hemoglobin, hematocrit, 
Platelets, Absolute Neutrophils, Absolute 
Lymphocytes, Absolute Monocytes, Absolute 
Eosinophils, Absolute Basophils 


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Chemistry 
AST, ALT, Alkaline Phosphatase, Sodium, 
Potassium, Chloride, Total Calcium, Total 
Bilirubin, Urea/BUN, Creatinine, Glucose 
(non-fasted), 
Albumin, 
Total 
protein 
(screening), amylase (screening), Lipase 
(screening), LDH (screening) 
Thyroid Function Testing 
TSH, Free T4, Free T3 
Urinalysis 
Urine dipstick for urine protein – if positive, 
collect microscopic reflex testing. Urine 
dipstick for blood – if positive, collect 
microscopic reflex testing. 
Pregnancy Testing 
For female patients of childbearing potential, 
serum testing with a sensitivity of at least 25 
mIU/mL. 
Table 7: Lab Monitoring During Therapy. Abbreviations: WBC=white blood cell; ALT=alanine 
aminotransferase, AST=aspartate aminotransferase, BUN=blood urea nitrogen, LDH=lactate 
dehydrogenase, TSH=thyroid stimulating hormone, T4=thyroxine, T3=triiodothyronine 
10.4 
Pregnancy/Contraception Safety Monitoring for Female Patients of 
Childbearing Potential 
All pregnancy tests in this study must have a sensitivity of at least 25 mIU/mL human 
chorionic gonadotropin (hCG) and must be performed by a certified laboratory. For those 
female patients enrolled who are of childbearing potential, 2 negative pregnancy tests 
are required before receiving study treatment. These two tests will include negative 
pregnancy test during the screening period, and an additional negative pregnancy test at 
baseline on Cycle 1 Day 1 prior to receiving study treatment. 
Following the negative pregnancy tests obtained at screening for trial enrollment, 
appropriate contraception must be commenced if sexually active. Pregnancy tests will 
then be required at baseline and will be repeated on Day 1 of every treatment cycle prior 
to dosing either study drug during active treatment period, and again at the End of 
Treatment visit to confirm that the patient has not become pregnant during the study 
period. Pregnancy tests will also be done during the study treatment if there is suspicion 
for pregnancy and may be requested by institutional review board (IRB)/ethics 
committees. In the case of a confirmed positive pregnancy test, the patient will be 
immediately withdrawn from the study treatment but may remain the study for follow-up 
purposes only (short term follow-up and long-term follow-up). 


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For female patients who are of childbearing potential and male patients capable for 
fathering children, affirmation that they meet criteria for the correct use of two selected 
methods of contraception must be obtained. The investigator or study personnel should 
discuss with the patient the need for contraceptive use consistently. In addition, patients 
will be instructed by the study personnel to call immediately if one or both selected 
contraception methods are discontinued, or if pregnancy is known or suspected in the 
patient or patient’s partner. 
10.5 
Disease Response Evaluation During Treatment 
Tumor assessments will include all previously known disease sites. At screening, all 
patients will undergo cross-sectional imaging with CT chest/abdomen/pelvis with contrast 
if able, or non-contrast CT chest with paired MRI of abdomen/pelvis with contrast if 
patients are unable to receive CT contrast. Patients who have contraindications to MRI 
imaging but are not deemed candidates to receive iodine-based contrast will proceed with 
CT chest/abdomen/pelvis without IV contrast. 
All patients will also undergo baseline brain MRI or contrast enhanced brain CT at 
screening. Again, patients unable to receive either will proceed with CT brain imaging 
without IV contrast. For those patients who have stable brain metastases present at 
baseline, brain imaging will be performed at each tumor assessment. For those patients 
without baseline brain metastases, brain imaging with MRI or CT will only be performed 
when clinically indicated and if new brain metastases are suspected. 
All CT scans will be performed assuming ≤5 mm thickness. FDG-PET/CT or ultrasound 
measurements will not be allowed in lieu of MRI/CT for tumor assessments in this protocol. 
If a new lesion is identified by ultrasound during study duration, CT and/or MRI should be 
used for confirmation and inclusion of information. 
If feasible, the same imaging technique should be used to characterize each identified and 
reported lesion at baseline screening and in follow-up tumor assessments. Tumor 
assessments will be performed at the end of every 8 weeks for the first 12 months of study 
drug therapy. After 12 months, radiographic assessments are obtained every 12 weeks. 
Timing of disease assessments should follow calendar days and should not be adjusted 
for delays in cycle start times. The allowable time windows for tumor assessments is ±7 
days. Best response to treatment will be determined by iRECIST (further details are 
provided in section 12.0). Date of progression will be determined for progression-free 
survival analysis in secondary endpoint review by RECIST v1.1. Although a clear 
progression of non-target lesions without progression of target lesions is rare, the opinion 
of the treating physician should prevail in all circumstances. Tumor assessments will 
continue until disease progression or if a patient discontinues therapy due to reasons other 
than progression, including toxicity. 
10.6 
Treatment Beyond Progression 


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Immune checkpoint blockade agents including avelumab may produce anti-tumor effects 
by potentiating immune effector responses, and responses may be delayed compared to 
typical response patterns seen with targeted or cytotoxic agents. Clinical responses may 
include an initial increase in tumor burden and/or appearance of new lesions with then 
eventual regression of disease, termed “pseudoprogression”. Therefore, if radiographic 
imaging shows disease progression, tumor assessment should be repeated 4 weeks later 
to confirm true progressive disease (PD) per iRECIST criteria (68). Patients may also 
continue to receive investigational agents at the investigator’s discretion if the patient is 
determined to be clinically benefiting, as defined by: 
1. 
No declines in ECOG performance status 
2. 
Absence of rapid progressive disease by radiographic imaging 
3. 
Absence of clinical signs or symptoms of disease progression (including worsening 
laboratory values) 
4. 
Absence of progressive tumor at critical anatomic sites (i.e. cord compression), 
which may require urgent or emergent alternative medical interventions 
The investigator’s judgement should be based on the overall benefit risk assessment and 
the patient’s clinical condition including performance status, clinical symptoms, adverse 
events, and laboratory data. Before therapy continues at confirmed progressive disease 
(PD) per iRECIST criteria (63), investigators must discuss allowance with the PI, and the 
patient must be re-consented to this protocol with the understanding that they may be 
foregoing approved therapy options with possible clinical benefit. 


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10.7 Schedule of Activities 
 
Activity 
Screening 
Cycle 1-3+ 
Follow-Up 
≤28 days 
C1 
D1 
C1 
D15 
C2 
D1 
C2 
D15 
C3+ 
D1 
C3+ 
D15 
End of 
Treatment 
(EOT)* 
Short 
Term 
Follow- 
Up 
Long 
Term 
Visit Window* 
± 3 
days 
± 3 
days 
± 3 
days 
± 3 days 
± 3 days 
± 3 days 
± 30 days 
± 7 days 
± 28 
days 
Informed 
Consent1 
X 
Medical History2 
X 
Pathology 
Review3 
X 
Optional Tissue 
Biopsy4 
X 
X (± 
7 
days) 
Height5 
X 
Physical 
Examination5 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG 
Performance 
Status6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry7 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Amylase, Lipase, 
Total Protein7 
X 
Perform as clinically indicated 
Urinalysis 8 
X 
Perform as clinically indicated 
Serum 
Pregnancy Test9 
X 
X 
X 
X 
X 
Hepatitis B and 
Hepatitis C 
Serology 
Testing10 
X 
Serum LDH 
X 
Thyroid Function 
Testing11 
X 
X 
X 
Optional Bone 
Scan16 
X 
Perform as clinicallyindicated 
Brain Scan16 
X 
Perform as clinicallyindicated 
12-lead ECG12 
X 
Perform as clinically indicated 
Talazoparib14 
Continuous 
Premedication for 
Avelumab15 
X 
X 
X 
X 
Optional administration per prior 
presence/severity of infusion reactions 
Avelumab 
X 
X 
X 
X 
X 
X 
Tumor 
Assessments (CT 
CAP w/ contrast 
OR CT chest + 
MRI A/P)16 
X 
Perform every 8 weeks for 56 weeks, then every 12 weeks thereafter until disease 
progression (±7 days) 


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Research Blood 
Testing17 
X 
X 
X 
X 
Toxicity 
Assessments18 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Treatment Use 
Assessment19 
X 
Monitored and Recorded Continuously 
X 
Survival20 
X 
* End of Treatment (EOT) visit window may occur within 30 days of last dose. 
 
1. Informed Consent must be obtained prior to undergoing any protocol-related procedures and must be obtained ≤28 days prior to 
enrollment onto study protocol. 
2. Medical History Review: Review of the patient’s medical history should be performed to allow for accurate screening and enrollment 
into protocol. This should include patient’s prior cancer and non-cancer medical history, and concomitant medication use. 
3. Pathology Review: Confirmation of existing documentation of renal cell carcinoma histology through a specialized genitourinary 
pathology review at Memorial Sloan Kettering Cancer Center. 
4. Optional Tumor Biopsy: Patients may undergo screening tumor biopsy of primary or metastatic site, and on-treatment biopsy at 
Cycle 2 D1 (± 7 days). 
5. Vital Signs will include blood pressure, pulse rate, temperature and weight. Height will be recorded on screening visit only. Full 
physical examination will be performed at screening, and subsequent visits should include focused physical exams of major body 
systems. 
6. ECOG Performance Status must be documented in associated toxicity assessment sheet during visits per Appendix 1. 
7. Laboratory Testing: Required safety laboratory tests will include: complete blood count (hemoglobin, platelets, white blood cell with 
differential), blood chemistry (AST, ALT, Alkaline Phosphatase, Sodium, Potassium, Chloride, Total Calcium, Total Bilirubin, 
Urea/BUN, Creatinine, Glucose (non-fasted), Albumin. Amylase, lipase and total protein are checked at baseline. These labs should 
be reviewed prior to study drug administration on Days 1 and days 15 of each treatment cycle. 
8. Urinalysis: Urine dipstick for urine protein – if positive, collect microscopic reflex testing. Urine dipstick for blood – if positive, collect 
microscopic reflex testing. 
9. Serum Pregnancy Testing: for women of childbearing potential, pregnancy test results must be reviewed prior to study drug 
administration on Day 1 of each treatment cycle. See section on childbearing potential (Section 6.1, Section 6.3), and monitoring 
(Section 10.4) 


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10. Hepatitis B and C Screening: HBV surface antigen, HBV core antibody, with HBV PCR performed reflexively if abnormal results. 
Screening for hepatitis C: anti-HCV antibody and HCV RNA PCR performed reflexively if abnormal results 
11. Thyroid Function Testing: TSH, Free T4, Free T3 
12. 12-lead ECG: ECG is to be obtained at screening and as clinically indicated at follow up visits. If mean QTc is prolonged > 500 
msec, ECGs must be obtained to monitor serially during each day 1 of cycle visits. 
13. Enrollment: patients meeting all entry criteria will be enrolled initiate investigational product administration preferable on the same 
day as enrollment. Product administration must begin within 5 days of enrollment. 
14. Talazoparib Administration: On Day 1 and Day 15 of each treatment cycle, the daily dose of talazoparib should not be taken prior 
to the study visit and will be taken in the clinic after all assessments have been completed, and before the avelumab infusion. Drug 
supply will be considered when scheduling visit. 
15. Premedication with Avelumab will be administered in the outpatient infusion suites on Days 1 and 15 of treatment cycle per Section 
5.3. Premedication may be discontinued per presence/severity of infusion reactions seen during Cycle 1 and 2 at Cycle 3 per 
investigator. 
16. Tumor Assessments: Assessments will be performed using iRECIST and RECIST v1.1. Baseline scans are to be performed within 
28 days prior to the first dose of the study treatment. Baseline bone scans are to be performed if clinically indicated. Imaging should 
be performed with contrast agents unless strictly contraindicated for medical reasons. Timing of disease assessment should follow 
calendar days and should not be adjusted for delays in cycle starts. Tumor assessment should also be performed whenever disease 
progression is suspected per individual investigator. For patients who discontinue treatment for reasons other than PD, 
assessments should continue after end of treatment until PD. Repeat imaging obtained 4 weeks after initial documentation of 
response should be performed for response confirmation. End of Treatment (EOT) scan is not required. 
17. Research Blood Testing: Peripheral blood will be collected for exploratory analyses prior to treatment initiation on C1D1, and serially 
during study. Details regarding collection methods are listed in the lab manual (Appendix 6). 
18. Toxicity Assessments will be performed by CTCAE v5.0 grading (See Section 11.1) 
19. Medication reconciliation will be performed at follow-up visits to ensure safe and appropriate concomitant medication use with study 
treatments. 
20. Survival follow up will be logged at long-term follow-up appointments as described (Section 12.2) until start of new anti-cancer 
therapy, death, withdrawal of study consent or study discontinuation, whichever comes first. 


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11.0 
TOXICITIES/SIDE EFFECTS 
11.1 
Severity Assessments 
All patients will be assessed for toxicity assessments per Common Terminology Criteria 
for Adverse Events (CTCAE) v.5.0., to describe the maximum intensity of adverse events. 
If the event is serious, the CTCAE grade must be documented and be consistent with the 
description of the CTCAE grade included in the narrative section of the serious adverse 
event report. 
CTCAE grading is displayed by 1-5, with unique clinical descriptors for each severity of 
AE. The general guideline for this grading scheme relates to the severity of the AE, and 
follows: 
 
Grade I 
Mild, asymptomatic or mild symptoms. Clinical and diagnostic 
observations only, intervention may not be indicated. 
Grade II 
Moderate: minimal, local, or non-invasive intervention may be 
indicated. Limiting age-appropriate instrumental ADLs 
Grade III 
Severe or medically significant, but not immediately life-threatening: 
hospitalization or prolongation of hospitalization may be required. 
Limiting self-care ADLs, disabling. 
Grade IV 
Life-threatening consequences, urgent intervention is required 
Grade V 
Death related to adverse event 
Table 8: CTCAE v5.0 General Grading Guidelines. 
11.2 Adverse Events 
An AE is any untoward medical occurrence in a patient or clinical trial subject administered 
a medicinal product and which does not necessarily have a causal relationship with this 
treatment. An adverse event can therefore be any unfavorable and unintended sign (e.g. 
an abnormal laboratory finding), symptom, or disease temporarily associated with the use 
of a medicinal product, whether considered related to the medicinal product. An adverse 
event can arise from any use of the drug (e.g. off-label use, use in combination with 
another drug) and with any route of administration, formulation, or dose, including an 
overdose. This definition also includes AEs associated with medication errors and uses of 
the investigational product outside what is in the protocol, including misuse and abuse. 
Pre-existing medical conditions that worsen during the study should be recorded as AEs. 
Abnormal laboratory values, ECG findings, or vital signs are to be recorded as AEs if they 
meet the criteria described in this protocol. All untoward events that occur after informed 
consent through 30 days after the decision to discontinue study treatment (or the date the 
subject is deemed to be a screen failure) are to be recorded by the investigational site. 
This requirement includes AEs from unscheduled as well as scheduled visits and includes 
the new onset of or increase in pain during this period. 
Adverse event terms recorded on the CRFs will be mapped to preferred terms using the 
Medical Dictionary for Regulatory Activities (MedDRA). Seriousness, severity grade, and 


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relationship to study treatment will be assessed by the investigator. Severity grade will be 
defined by the current version of the National Cancer Institute (NCI)-Common Terminology 
Criteria for Adverse Events (CTCAE). 
11.3 Relationship to Study Treatment 
Assessment of the relationship of the AE to the study treatment by the investigator is 
based on the following two definitions: 
Not-Related: A not-related AE is defined as an AE that is not associated with the study 
treatment and is attributable to another cause or there is no evidence to support a causal 
relationship; 
Related: A related AE is defined as an AE where a causal relationship between the event 
and the study treatment is a reasonable possibility. A reasonable causal relationship is 
meant to convey that there are facts (e.g., evidence such as de-challenge/re-challenge) 
or other clinical arguments to suggest a causal relationship between the AE and study 
treatment. Possibly and probably related AEs should be documented as related. 
11.4 Follow up of Adverse Events 
Any related SAEs or any AEs assessed as related that led to treatment discontinuation, 
including clinically significant abnormal laboratory values that meet these criteria, ongoing 
30 days after the decision to discontinue study treatment must be followed until either 
resolution of the event or determination by the investigator that the event has become 
stable or irreversible. This follow-up guidance also applies to related SAEs that occur more 
than 30 days after the decision to discontinue study treatment. The status of all other 
continuing AEs will be documented as of 30 days after the decision to discontinue study 
treatment. 
11.5 Pregnancy and Fertility Assessments 
Pregnancy testing is required at screening and recommended monthly until the end of the 
trial. Serum testing should be performed at screening and at the end of the study. Serum 
pregnancy testing should be performed at each new cycle visit every 4 weeks. There are 
no adequate data from the use of this combination in pregnant women. If a subject 
becomes pregnant during the study, she will be taken off study treatment and will be 
followed up until the outcome of pregnancy is known. Women on trial should not breast 
feed. 
11.6 Medication Errors/Overdose 
Any overdose, or study drug administration error that results in an AE, even if it does not 
meet the definition of serious, requires reporting to Pfizer within 2 business days. 


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11.7 
Talazoparib Toxicity 
11.7.1 Hematologic Toxicity Related to Talazoparib 
Myelosuppression related to talazoparib has been reported and usually requires dose 
adjustment as described below. The rate of grade ≥3 anemia, neutropenia, 
thrombocytopenia in solid tumor patients treated with talazoparib was 39%, 21%, and 
15%, respectively, and this led to ultimate discontinuation of treatment in 0.7%, 0.3%, and 
0.3% respectively. Myelodysplastic syndrome (MDS) / acute myeloid leukemia (AML) has 
been reported in 2/584 patients (0.3%) solid tumor patients treated with talazoparib in 
clinical trials. The duration of talazoparib treatment in these patients prior to developing 
MDS/AML was 4 months and 24 months, respectively, and both patients had a history of 
prior chemotherapy. 
For grade ≥3 anemia, neutropenia, thrombocytopenia deemed related to study treatment, 
treatment with talazoparib must be interrupted with weekly blood counts until recovery is 
grade ≤1. At that time point, talazoparib can then be resumed with dose level reduction as 
outlined in Section 9.5. 
Granulocyte colony stimulating factor (GCSF) may be administered to manage febrile 
neutropenic episodes per standard of care guidelines but should not be used routinely. 
Patients who require transfusion of packed red blood cells (PRBC) or platelet transfusion 
or growth factor support with GCSF must therefore undergo dose reduction upon recovery 
if study treatment is to be resumed. Growth factor support for anemia or thrombocytopenia 
is not permitted on the trial. 
If hematologic toxicity has not recovered after 4 weeks in the absence of talazoparib, it will 
be strongly recommended that the patient undergo evaluation by benign hematology for 
further evaluation for etiology. If the patient does not have recovery to baseline within 4 
weeks of dose interruption and/or the patient has undergone 2 dose reductions, then the 
patient should be discontinued from talazoparib. 
If AML/MDS is diagnosed during this study, the patient must be withdrawn from the study. 
 
Hematologic 
Toxicity 
Talazoparib 
Avelumab 
Platelet 
Count 75- 
99, 
1st 
occurrence 
Study medication must be 
interrupted until platelet 
count is ≥100/uL with 
weekly CBC counts until 
recovery. 
If recovery within 4weeks, 
the study medication may 
be resumed at the same 
dose or reduced dose 
based on clinical 
judgement. 
Continue as per schedule 


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Platelet 
Count 75- 
99/uL, 
2nd 
occurrence 
Study medication must be 
interrupted until platelet 
count is ≥100/uL with 
weekly CBC counts until 
recovery. 
If recovery within 4 weeks, 
the study medication may 
be resumed at the same 
dose or reduced dose 
based on clinical 
judgement. 
If 2nd treatment interruption 
occurs in <3 weeks after 
resuming from first 
occurrence, then dose 
reduction should be 
performed. 
Continue as per schedule 
Platelet 
Count < 75 
/uL 
Study medication must be 
interrupted until platelet 
count is ≥100/uL with 
weekly CBC counts until 
recovery. 
If recovery within 4 weeks, 
the study medication may 
be resumed at the reduced 
dose level. 
1. Consider workup for immune related 
thrombocytopenia to evaluate 
causative role for avelumab. 
2. Consider hold of avelumab and 
reinitiate avelumab once toxicity 
Grade ≤1 or baseline. 
Absolute 
Neutrophil 
<1,000 / uL 
Study medication must be 
interrupted until absolute 
neutrophil ≥1000 / uL with 
weekly CBC counts until 
recovery. 
If recovery within 4 weeks, 
the study medication may 
be resumed at the reduced 
dose level. 
1. Consider hold avelumab and 
reinitiate avelumab once toxicity 
Grade ≤1 or baseline. 
2. Permanently discontinue avelumab if 
the same Grade 3 toxicity recurs if 
talazoparib had already been 
discontinued and recurrent event 
occurs on avelumab only. 
Hemoglobin 
<8 g/dL 
Study medication must be 
interrupted until hemoglobin 
is ≥9 g/dL with weekly CBC 
counts until recovery. 
If recovery within 4 weeks, 
the study medication may 
1. Consider workup for hemolytic 
anemia to evaluate causative role for 
avelumab. 
2. Consider hold avelumab and 
reinitiate avelumab once toxicity 
Grade ≤1 or baseline. 


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be resumed at the reduced 
dose level. 
3. Permanently discontinue avelumab if 
the same Grade 3 toxicity recurs (if 
talazoparib had already been 
discontinued and recurrent event 
occurs on avelumab only). 
Table 9: Dose Modification Guide for Hematologic Toxicity for Talazoparib and Avelumab 
11.7.2 Talazoparib Related Non-Hematologic Toxicity 
In EMBRACA, the most common non-hematologic toxicities observed with single agent 
talazoparib (≥20%, all grade) was decreased appetite (21%), headache (33%), nausea 
(49%), vomiting (25%), diarrhea (22%), alopecia (25%), and fatigue (62%). The rate of 
these events at toxicity grade 3 was as follows: decreased appetite <1%, headache 2%, 
nausea <1%, vomiting 2%, diarrhea 1%, alopecia 0%, and fatigue 3%, and none of 
these adverse events were grade 4. 
General management regarding talazoparib management in the setting of non- 
hematologic toxicity is outlined in Table 10. General guidelines regarding management 
of immune-related adverse events suspected to be from avelumab only is outline in later 
sections (starting Section 11.4). 
For toxicities that are unequivocally related to talazoparib, not to avelumab, infusions of 
avelumab may continue per schedule even if talazoparib is held. 
 
Talazoparib-related 
toxicity 
Talazoparib 
Grade 1 
No changes indicated 
Grade 2 
Laboratory 
toxicities, non-heme 
• 
Repeat laboratory assessment within 7 days; 
• 
continuation of talazoparib per investigator’s 
discretion. 
Grade 2 
Non-Laboratory 
toxicities, non-heme 
• 
Repeat investigator assessment in 7-14 days 
• 
continuation of talazoparib per investigator’s 
discretion. 
Grade 3 
• 
hold talazoparib, unless toxicity deemed not 
clinically significant (e.g. increase amylase / 
lipase without imaging or clinical correlate of 
pancreatitis) 
• 
Resume talazoparib if toxicity resolves to 
Grade≤1 or baseline within 4 weeks of dose 
interruption. 
• 
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. 


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• 
Exceptions are laboratory values that do not 
have any clinical correlate. 
Grade 4 
Permanently discontinue talazoparib unless 
laboratory values do not have a clinical correlate 
Table 10: Dose Modification Guide for Non-Hematologic Toxicity for Talazoparib and Avelumab 
11.7.3 Talazoparib Related Gastrointestinal Toxicity 
Gastrointestinal adverse reactions have been reported with talazoparib. In ≥20% of solid 
tumor patients treated on EMBRACA, all grade events included nausea (49%), vomiting 
(25%), and diarrhea (22%). Rates of grade 3 events for nausea, vomiting and diarrhea 
were <1%, 2%, and 1%, respectively, with no grade 4 events reported. 
Rates of gastrointestinal lab parameter changes have been reported with talazoparib. In 
>20% of patients at all grade, the rate of increase in glucose (54%), increase in 
aspartate aminotransferase (AST) (37%), increase in alkaline phosphatase (36%), and 
increase in alanine aminotransferase (ALT) (33%). Grade 3-4 events for each lab 
parameter occurred with an increase in AST 2%, increase in alkaline phosphatase 2%, 
ALT 1%. 
Guidelines regarding talazoparib management in the setting of gastrointestinal toxicity 
can be followed per non-hematologic toxicity guide in Table 10. 
11.8 Avelumab Toxicity 
11.8.1 Avelumab Related Pulmonary Toxicity 
Pulmonary adverse events have been observed following treatment with avelumab, 
including a fatal case with monotherapy avelumab. In the combined safety data of solid 
tumors (67), pneumonitis occurred in 1.2% of patients, and among the 21 patients the 
median time of onset was 2.5 months and duration were 7 weeks (range 4 days-4+ 
months). All patients were treated with systemic corticosteroids, and resolution occurred 
in 12/21 (57%) patients at time of data cut-off. The majority of patient reported cases are 
grade 1 or 2, with study participants presenting with either asymptomatic radiographic 
changes (i.e. focal ground glass opacities, patchy infiltrates etc.) or with symptoms of 
dyspnea, cough or fever. Subjects with reported grade 3 or 4 pulmonary AEs were noted 
to have severe symptoms with more extensive radiographic findings and hypoxia. 
Asymptomatic patients may be initially managed with consideration of dose delay, per 
investigator’s judgement. Subjects with grade 2 pneumonitis will be managed with dose 
delay and treatment with corticosteroids. In subjects who do not initially respond to 
corticosteroids, anti-tumor necrosis alpha (anti-TNFa) therapies like infliximab and/or 
other immunosuppressants like cyclophosphamide may be considered. Please see 
Appendix 4 for toxicity related algorithm. 


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11.8.2 Avelumab Related Gastrointestinal Toxicity 
Gastrointestinal AEs have been observed following treatment with avelumab. Most of 
cases of diarrhea were low grade (grade 1-2), with colitis occurring less frequently than 
diarrhea. High grade cases of diarrhea and colitis were managed are to be managed with 
corticosteroid use and/or non-steroidal immunosuppressants as detailed in toxicity related 
algorithm (please see appendix 4). 
Immune mediated colitis occurred in 1.5% (26/1738 patients), and all patients were treated 
with corticosteroids with 15/26 patients (58%) receiving high dose corticosteroids. 
Resolution occurred in 18/26 patients (70%) at the time of data cut off, with median 
duration of colitis 6 weeks. 
Hepatic adverse events including elevated liver function tests, and infrequently, drug 
induced liver injury, have been observed in patients following treatment with avelumab. 
Most cases are low or moderate grade, with higher-degree of hepatic adverse events 
management with corticosteroids (with or without mycophenolate mofetil). Early 
recognition and treatment of elevated LFTs and DILI are critical for medical management. 
If patients notice jaundice, or if they develop bruising, bleeding or right sided abdominal 
pain, they should be advised to seek medical management immediately. As LFT 
abnormalities are also common in patients with malignancy, it is important to distinguish 
whether LFT changes are due to infection, progression of disease, concomitant 
medications, alcohol etc. Please see Appendix 4 for toxicity related algorithm. 
Immune mediated hepatitis occurred in 0.9% of patients receiving avelumab and led to 
the discontinuation in 0.5% of patients (9/1738 patients). Among the 16 patients who 
demonstrated immune mediated hepatitis, median time to onset was 3.2 months, and 
median duration of hepatitis was 2.5 months, and all patients were treated with 
corticosteroids for a median of 14 days. Resolution of hepatitis occurred in 9/16 patients 
(56%) at time of data cut off. 
11.8.3 Avelumab Related Endocrine Toxicity 
Endocrinopathies may occur during or after treatment with avelumab, and therefore 
continued monitoring during and after treatment is needed. Immune mediated thyroid 
disorders occurred in 6% of patients (98/1738 patients), with the majority of 
hypothyroidism 
(5%) 
of 
patients. 
Most 
cases 
of 
thyroid 
related 
disorders 
(hypothyroidism/hyperthyroidism) are found with changes in thyroid function testing. The 
median time to onset was 2.8 months, and immune mediated thyroid disorders resolved 
in 7% (7/98) patients. More than 1 organ involvement can be seen (i.e. thyroid disorder 
and adrenal disorder). Moderate and high-grade cases are treated with hormone 
replacement therapy, with or without the addition of corticosteroids. Guidelines for the 
recommended management of endocrine related toxicity is provided in Appendix 4. 
Avelumab has been found to cause type I diabetes mellitus (diabetic ketoacidosis) and 
occurred in 0.1% (2/1738) of patients including two cases of grade 3 hyperglycemia which 


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led to permanent discontinuation. Avelumab has also been found to cause adrenal 
insufficiency, occurring in 0.5% (8/1738) of patients. All patients were treated with 
subsequent corticosteroids. 
11.8.4 Avelumab Related Skin Toxicity 
Dermatologic conditions including rash, pruritis has been seen following treatment with 
avelumab. Rashes that occur are most typically maculopapular in appearance, occurring 
in the trunk, back or extremities. In some cases, the rash and pruritis resolves without 
intervention, and in others, topical corticosteroids and anti-histamines are used for the 
rash and pruritis, respectively. Severe cases respond to systemic corticosteroids. 
Guidelines regarding the recommended management of skin AEs are provided in 
Appendix 4. 
11.8.5 
Avelumab Related Renal Toxicity 
Elevated creatinine, as well as biopsy proven tubulointerstitial nephritis and allergic 
nephritis are infrequently observed during treatment with avelumab. Subjects with RCC or 
prior nephrectomy do not appear to be at higher risk. Immune mediated nephritis occurred 
in 0.1% (1/1738) patients and was permanently discontinued in this patient. Please see 
Appendix 4 for toxicity related algorithm. 
11.8.6 
Avelumab Related Neurologic Toxicity 
Neurologic adverse events have been uncommonly described following treatment with 
avelumab. Neurologic adverse events may manifest as central abnormalities (i.e. aseptic 
meningitis, encephalopathy, or encephalitis), or peripheral sensory/motor neuropathies 
(i.e. myasthenia gravis, Guillan-Barre syndrome). Recommended management of 
neurologic AEs is provided in Appendix 4. 
11.9 
Combination Talazoparib / Avelumab – Dose Modifications for Treatment- 
Emergent, Unrelated Adverse Events 
Per FDA label, unrelated Grade 2 renal impairment will require talazoparib dose reduction 
to at most dose level -1 since the drug is renally cleared. 
For grade 3 toxicities related to study treatment both agents should be placed on hold 
during diagnostic workup & AE management; once either drug deemed to have no 
causative role in the development of the adverse event, that agent may be resumed per 
treating investigator’s discretion, while the other drug (the one deemed causative) is held 
/ dose-modified / discontinued as per drug-specific guidelines in the protocol (see Section 
11, above). 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
Measurable disease is defined by disease that is accurately measured in at least one 
dimension (further details below). All tumor assessments will then be recorded in mm. All 


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patients will be evaluated by iRECIST and RECIST v1.1, Appendix 2 (68). Patients are 
evaluable for the primary endpoint if they have received at least 50% of the planned doses 
for each agent during Cycle 1. Patients who have taken less than 50% of the planned 
doses during Cycle 1 will be replaced for the primary endpoint, but will be evaluated in all 
safety and correlative analyses. Patients who have taken at least 50% of the planned dose 
but do not have a second tumor scan due to toxicity will be counted as a failure for the 
primary analyses on efficacy. Note, given unpublished data on this drug, we anticipate 
inevaluability and patients not receiving a second scan to be a rare if not unobserved 
event. 
The following criteria will apply to target and non-target lesions: 
1. Previously irradiated lesions: Lesions that are previously irradiated will not be 
considered measurable unless progression is documented radiographically previously 
or if a biopsy confirms persistence of disease ≥ 90 days following completion of 
therapy. 
2. Malignant Lymph Nodes: Lymph nodes are considered pathologically enlarged and 
measurable if >15 mm in short axis when assessed by CT scan. At baseline and in 
follow-up, only the short-axis will be used in measurement. 
3. Measurable disease, other: Visceral lesions are considered measurable if the longest 
diameter measures >10mm. 
4. Non-measurable disease: Lesions that include small lesions (longest diameter <10 
mm) or pathological lymph nodes with <15 mm in short axis will be considered non- 
measurable. Bone lesions without extraosseous component, leptomeningeal disease, 
malignant ascites, pleural/pericardial effusion, lymphangitic disease, inflammatory 
breast disease is not considered measurable. 
5. Target Lesions: Up to five selected measurable lesions (maximum of 2 lesions per 
organ), will be identified as target lesions by the study radiologist to represent relevant 
distribution of disease burden and will be measured and recorded at baseline. Target 
lesions should be reproducibly measured in follow up. It may be the case that the 
largest lesions do not lend themselves to reproducibility, at which point next largest 
lesions should then be selected. A sum of the diameters of the longest for non-nodal 
lesions and short-axis for nodal lesions should then be used for the target lesion 
calculation and the sum of diameters should be used for baseline. The baseline sum 
will be used as a reference to further characterize any objective tumor response. 
6. Non-Target Lesions: All other lesions or sites of disease including measurable lesions 
over the 5 target lesions chosen should be identified as non-target lesions and should 
be recorded at baseline. Measurement of these lesions is not required, but the 
presence, absence, or unequivocal progression of these should be noted during 
follow-up imaging. 
7. Cystic Lesions: Cystic lesions that meet requirements for radiographic simple cysts 
should not be considered malignant. Cystic lesions that are thought to represent 
metastases can be considered measurable if they meet the above criteria. 
8. Clinical lesions: clinical lesions will only be considered measurable when they are 
superficial (i.e. skin nodules, palpable lymph nodes), and >10 mm in diameter when 


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assessed using calipers. In the case of skin lesions, documentation by color 
photography including ruler to estimate size of lesion is required if used for follow-up. 
 
 
Target Lesions 
Complete 
Response (iCR) 
Disappearance of all target lesions. Any pathological lymph nodes 
must have a reduction in short axis to <10 mm. 
Partial Response 
(iPR) 
At least 30% decline in the sum of diameters of target lesions as 
compared to the reference baseline sum of diameters. 
Unconfirmed 
Progressive 
Disease (iUPD)* 
At least 20% increase in the sum of diameters of target lesions 
compared to the reference of the smallest sum of the study (this 
includes the baseline sum if that is the smallest on the study). In 
addition to the relative increase of 20%, sum must demonstrate an 
absolute increase of at least 5 mm. This will need to be confirmed 
with imaging for iCPD assessment to be performed 4 weeks (± 7 
days) later. 
Stable Disease 
(iSD) 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, compared to reference of the smallest 
sum of diameters while on study 
Non-Target Lesions 
Complete 
Response 
Disappearance of all non-target lesions. All lymph nodes must be 
non-pathological in size <10 mm 
Non-CR / Non- 
PD 
Persistence of one or more non-target lesions 
Unconfirmed 
Progressive 
Disease (iUPD)* 
Appearance of one of more new lesions and/or unequivocal 
progression of existing non-target lesions. Unequivocal 
progression should be representative of overall disease status 
changes and not single lesions increases. 
Treatment beyond iUPD / Confirmation of disease progression 
Confirmed 
Progressive 
Disease (iCPD) 
If further increase in tumor burden, compared to the last 
assessment, is seen as evidenced by one or more of the 
following: 
- if new lesions were previously identified and they have increased 
in size (≥5 mm in sum of measures for new lesion target or any 
increase for new lesion non-target) or number; if no change is 
seen in new lesions (size or number) from last timepoint, 
assignment remains iUPD 
OR 
- Further increase in the size of non-target disease (does not need 
to meet RECIST 1.1 criteria for unequivocal progression) 


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OR 
- further increase in the sum of measures ≥5 mm; otherwise 
assignment remains iUPD 
OR 
- further increase in previously identified target lesion iUPD in sum 
of measures >5 mm or non-target lesion iUPD (previous 
assessment need not have shown unequivocal progression) 
OR 
- further increase in previously identified target lesion iUPD sum 
of measures ≥5 mm, previously identified non-target lesion iUPD 
(does not need to be unequivocal), or an increase in the size or 
number of new lesions previously identified 
OR 
- increase in the size or number of new lesions previously 
identified 
Table 11: iRECIST Criteria for Response Guidelines. Adapted from (68). 
 
*If iUPD remains unconfirmed at the next assessment, then the appropriate response will 
be assigned (iSD, iPR or iCR). Prior iUPD does not preclude subsequent iCR, iPR, or iSD 
on further assessments or as best overall response provided that iCPD is not documented 
at the next assessment after iUPD. 
In the case of dose interruptions, the next cycle should follow the patient’s original 
calendar schedule. Treatment cycle timing will not be delayed for treatment interruptions 
and therefore tumor assessments should continue to occur according to the original 
schedule regardless of whether study treatment is interrupted. If the patient discontinues 
treatment prior to confirmed disease progression, tumor imaging should continue at the 
specific time intervals until progression or until the start of subsequent anti-cancer therapy. 
Disease progression assessments outside of the scheduled windows will not be 
disregarded. 
Patients may be treated by investigator pending radiology read on Day 1 of treatment 
cycle after clinical assessment. If assessment subsequently determines iCPD the study 
team will contact the patient to discontinue talazoparib unless the study team 
determines that the patient is to continue treatment beyond confirmed progression per 
section 10.6. 
12.1 
Calculated Study Endpoints 
1. Objective Response Rate (ORR): proportion of patients with confirmed complete 
response (iCR) or partial response (iPR) assessed by iRECIST, relative to the total 
population of patients evaluable after 4 months. Confirmed responses are those that 
persist on repeat imaging 4 weeks after initial documentation of response. The final 
best response rate will be calculated 4 months after last patient accrued. 
2. Progression-free Survival (PFS): duration of time from start of treatment until death or 
progression of disease by RECIST v1.1. Patients who are progression-free at time of 
analysis will be censored at the time of last valid tumor assessment. Patients with 2 or 


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more consecutive tumor assessments missing will be censored at last valid tumor 
assessment. 
3. Overall Survival (OS): duration of time from start of treatment until death of any cause 
of study participants. Patients who are still alive at the time of analysis and those lost 
to follow-up will be censored at the time of last follow up. 
12.2 
Short-Term and Long-Term Follow Up 
All patients would continue to be followed for safety every 30 days (± 7 days) through 90 
days in short-term follow up, and then every 12 weeks (±14 days) in long-term follow up 
until the start of new anti-cancer therapy, death, withdrawal of study consent, or study 
discontinuation, whichever comes first. 
Patients with ongoing treatment related toxicity following study treatment discontinuation 
will be followed at least every 4 weeks until the toxicity resolution or by clinical judgement 
by study investigator for expectation of further improvement. If a patient has discontinued 
study treatment for reasons other than disease progression, patient should continue to 
undergo assessments during the short-term follow period (+ 90 days) as if they were still 
on therapy, until new anti-cancer therapy starts. For long-term follow up procedures, visits 
may be conducted in the outpatient clinic or by remote contact by telephone. 
12.3 
Study Research Plan 
Tumor Tissue 
Archival tumor tissue will be requested from patients who have undergone biopsy or tumor 
resection as part of routine clinical care prior to study participation. Patients may undergo 
pre-treatment biopsy during the screening period if archival tissue is insufficient for 
baseline analysis. 
Optional tumor biopsies of the primary renal mass or metastatic sites will be offered to all 
patients, to be performed during screening (within 28d of Cycle 1 D1) and at Cycle 2 D1 
(± 7 days). While not a requirement, every effort should be made to perform a tumor biopsy 
at confirmed disease progression or if a patient discontinues study treatment due to 
disease progression, except in instances where the procedure poses an unacceptable risk 
to the patient in clinical research setting. Tumor specimen may include nephrectomy or 
metastatic site specimen and should include 4 core biopsy specimens. 
 
Sample Preparation and Transport 
Fresh tissue: On the date of biopsy, part of the specimen will be transported to the Chan 
Lab. Two core biopsies will be utilized for RNA/DNA extraction, 1 core biopsy will be snap 
frozen, and 1 core biopsy will be formalin fixed and paraffin embedded. Portions of tumors 
and normal tissue can then be prepared for further storage and analysis per laboratory 
guidelines. This will include placement of portions of tissue in aliquoted conical tubes in 
RPMI solution in TPS. The snap frozen specimens may be then stored for future 
investigation, including micro- and microdissection as well as for DNA/RNA extraction, and 
ultimately stored at -80ºC. 


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Archival Tissue: If available, 1-2 paraffin embedded tissue blocks containing formalin-fixed 
tumor slides will be requested. Paraffin blocks may then be processed according to 
standard institutional protocol, with final preparation of 20 unstained slides for available 
analysis. Specifications regarding tumor acquisition, sample processing, and exploratory 
analyses planned are detailed in the protocol’s laboratory manual (Appendix 6). 
 
All specimens will be delivered with the attached specimen submission form. All tissue will 
then be stored at the Chan Lab at IPOP, MSKCC Zuckerman Research Center (417 East 
68th Street, New York, NY). Samples will be processed for in-depth biomarker 
investigation, including nucleic acid extraction for next generation sequencing analysis 
and mass spectrometry-based approaches as detailed in protocol’s laboratory manual 
(Appendix 6). 
 
Peripheral Blood Samples 
Peripheral blood samples will be collected serially, processed and stored for all patients 
registered on the trial. This will include Vacutainer CPT whole blood tubes, EDTA whole 
blood tubes for plasma processing, and Streck BCT tubes for circulating tumor DNA 
assessments. Additional details on the collection plan, sample processing and storage are 
provided in the protocol’s laboratory manual (Appendix 6). 
Time Points: C1D1, C2D1, C3D1, C5D1+ (every 8 weeks), End of Treatment 
 
Materials and Collection: 
Study Time Points** 
Materials§ 
C1D1* 
C2D1 & 
C3D1 
C5D1+ (every 8 
weeks) 
End of Treatment* 
Vacutainer 
CPT Tubes 
(8mL/each 
tube) 
X (3 tubes) 
X (2 tube) 
X (2 tube) 
X (3 tubes) 
Streck BCT 
Tube 
(10mL/each 
tube) 
X (1 tube) 
X (1 tube) 
X (1 tube) 
X (1 tube) 
EDTA Tube 
(6cc/each 
tube) 
X (1 tube) 
X (1 tube) 
X (1 tube) 
X (1 tubes) 
 
Table 12: Peripheral Blood Sample Schedule 
*All blood draws should occur prior to avelumab administration. Collections may occur ±7 days of 
specified time point. 
**An additional two blood draws at different time points beyond those listed is permitted when 
feasible based upon clinical / immunological findings 
§Changes to these methods may be adapted depending upon the most recent, generally accepted 
protocols. 
 
Peripheral Blood Sample Preparation 


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Vacutainer CPT Tubes: The BD Vacutainer CPT Tube (Catalog: 362761), or equivalent, 
will be used. For collection, standard phlebotomy will fill tubes with 8 mL of blood, with 
attempt to obtain full 8 mL during collection attempt. The tube will then be inverted several 
times after collection to ensure adequate mixing. The patient’s name, MRN, adhesive 
stickers will be attached to the tube. The date/time will be noted on the collection 
requisition form. The RSA will then deliver all specimens to Chan Lab at IPOP, MSKCC 
Zuckerman Research Center (417 East 68th Street, New York, NY). 
Streck Tubes: The Streck Cell-Free DNA BCT tube (Streck Catalog No 218961), or 
equivalent, will be used. For collection, standard phlebotomy will fill each tube with 10 mL 
of blood, with attempt to obtain full 10 mL during collection attempt. The tube should be 
inverted several times after collection. The patient’s name, MRN should be documented 
on adhesive stickers to each tube. The date/time will be noted on the requisition form, and 
the tubes will be placed in a biohazard bag at room temperature. The RSA will then deliver 
all specimens to Chan Lab at IPOP, MSKCC Zuckerman Research Center (417 East 68th 
Street, New York, NY). 
EDTA Tubes: The BD lavender tube (BD Catalog: 367863) will be used. For collection, 
standard phlebotomy will fill each tube with 6 mL of blood, with attempt to obtain full 6 mL 
during collection attempt. The tube should be inverted several times after collection. The 
patient’s name, MRN should be documented on adhesive stickers to each tube. The 
date/time will be noted on the requisition form, and the tubes will be placed in a biohazard 
bag at room temperature. The RSA will then deliver all specimens to Chan Lab at IPOP, 
MSKCC Zuckerman Research Center (417 East 68th Street, New York, NY). Samples may 
then be stored at -80ºC per standard practice procedure for future analysis. 
 
Data Entry for Specimen Collection 
MSKCC RSA and/or Chan laboratory personnel will collect information into a secured 
database once samples are collected and transported. If a sample is not fully collected, 
the reasoning for incomplete or partial collection should be documented into the database 
as well for accurate records. 
Select Corelative Planned Studies 
 
Select studies include: 
1. Tissue whole exome sequencing, specifically identifying 
a. DDR Mutations / Homologous Recombination Deficiency (HRD) Mutations: 3 
DNA based HRD-scoring algorithms will be generated, including HRD loss of 
heterozygosity score (LOH), HRD telomeric allelic imbalance score (TAI), and 
HRD large scale transition score (LST). Select genes to be included in evaluation 
include BRCA1, BRCA2, PARP1, ATM, ATR, RAD51C, BAP1, PALB2, MRE11, 
BARD1/BRIP1, RAD50/51/51B/51D, ERCC2, ERCC3, ERCC4, ERCC5, MMR 
genes, POLE, FANCC, FANCA, BLM, CHEK1, CHEK2, RB1, ATRX as well as 
others. 


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b. Tumor Mutational Burden: Tumor mutational burden is defined as the total 
number of mutations in the genome, or number of mutations per DNA mega base 
if derived from targeted sequencing. This analysis will include evaluation of 
INDELs, breakpoint locations and structural rearrangements. 
2. Tumor RNA Sequencing: This will focus on immune deconvolution via computational 
methods including CIBERSORT and single sample gene expression analysis 
(ssGSEA) for Immune Subset Profiling: Characterization of immune cell subsets 
based on PCR based T-cell receptor sequencing, IHC analysis (PD-L1 expression), 
and T-cell enrichment scores, as well as immune deconvolution as above in 
combination with flow cytometry data. 
3. Metabolomics: Characterization of tissue specimens for oncometabolite expressions 
through mass spectrometry, with specific attention to fumarate and succinate levels 
as predicted changes in cohort 2 FH/SDH patients only. 
4. FH/ SDH patients: FH and SDH Functional Assessment: With available tissue 
specimens, all patients in cohort 2 will undergo MSK-IMPACT testing for germline and 
somatic mutational testing. Further, all FH/SDH patient specimens may also undergo 
investigational immunohistochemical staining with research antibody testing (i.e. 2SC) 
to compare functional loss with genomic and state-approved FH/SDH assay testing. 
5. RMC patients: while loss of SMARCB1 (INI1) is not part of eligibility it will be assessed 
in all patients who can provide archival tumor tissue. 
Further specification regarding tumor acquisition, sample processing, and techniques 
used for exploratory analyses planned are detailed in the protocol’s laboratory manual 
(Appendix 6). 
In the course of this research it is possible that some patients whose tumors are analyzed 
through investigational “next-generation” profiling in a research (non-CLIA) environment 
will be found to have somatic or germline mutations in genes that are known to be 
associated with an increased risk of cancer or other diseases. It will be stated in the 
consent that the participants will not receive any specific results from research tests. The 
consent will tell participants that if they wish to have genetic testing done for personal 
reasons than they should make an appointment with the MSK Clinical Genetics Service. 
If in the course of this research a research finding is obtained that, in the opinion of the 
investigator, may be critical to the preventive care of the participant or their family, the 
investigator can communicate that finding to the IRB Genomic Advisory Panel (GAP). The 
finding will be reviewed by the GAP to determine whether the incidental finding should be 
discussed with the participant. For MSK, in the event that the GAP determines that the 
finding should be discussed with the participant, and the participant has consented to be 
re-contacted, then the treating/consenting physician shall be contacted by the panel and 
asked to refer the participant to the Clinical Genetics Service for further discussion of the 
research finding. 
The following information must be provided to GAP for review: 
• Participant Name/MRN # 
• Type of Biospecimen (tissue, blood, saliva) 
• Incidental Finding 


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• Collection Protocol # 
• Contact: rtmgapirb@mskcc.org 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
13.1 
Study Treatment Discontinuation 
Reasons for study treatment withdrawal include, but are not limited to: 
1. Voluntary withdrawal by the patient who is at any time free to discontinue clinical trial 
participation without prejudice for further treatment 
2. Unacceptable toxicity: if attribute to only one of the two investigational study 
treatments, the investigator may continue treatment with the other investigational 
study treatment. If both medications have been interrupted for ≥8 weeks, the patient 
should be discontinued from the study treatment. 
3. Progressive Disease: Patients with confirmed disease progression by iRECIST (iCPD) 
or patients who are no longer experiencing clinical benefit as determined by 
investigator should be discontinued from study treatment. Patients with confirmed 
disease progression who are continuing to derive clinical benefit as assessed by 
treating physician may be eligible to continue study treatment, provided that the 
treating physician has determined that the risks and benefits remain favorable. Study 
drug discontinuation will be applied to all other cases of disease progression. 
4. Global deterioration of health status 
5. Risk to patient as determined by study team and treating physician 
6. Severe non-compliance as determined by investigator team 
7. Incorrect enrollment of patient (i.e. patient does not satisfy inclusion or exclusion 
criteria on review) 
8. Patient becomes pregnant or starts breast feeding during clinical trial 
9. Patient is lost to follow up 
10. Significant protocol deviation 
11. Study termination by trial sponsor 
12. Necessity for other anti-cancer therapy 
13. Sexually active patients who refuse to use medically accepted methods for 
contraception during this study and post-study completion (5 months for women, 7 
months for men). 
14. Study termination or hold by regulatory agencies 
15. Death 
 
Any patient who discontinues study drugs should be seen at 30 days post-discontinuation 
treatment for clinical assessment. At that time, patient’s tumor status should be assessed 
clinically, and if appropriate, disease status or progression should be confirmed by 
radiographic assessment. The investigator will provide best available observation, tests, 
and evaluation, and complete safety assessments for the patient given clinical trial 
participation. After the discontinuation of all medications, all ongoing AEs must be followed 
for resolution, unless deemed unlikely to resolve due to underlying disease by treating 


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physician. Any new AEs that develop in the 30 days period post study treatment 
discontinuation should also be assessed in the setting of late onset immune related 
adverse events. Given the potential risk for delayed immune-related toxicities, safety 
follow-up must be performed up to 90 days after the last dose of avelumab administration. 
Patients should also be continually followed as per iRECIST and RECIST v1.1. 
Patients should be followed for survival follow-up, unless otherwise specified including: 
1. Patient refuses follow-up 
2. Patient is lost to follow-up 
3. Study is terminated by sponsor 
4. Death 
 
13.2 
Voluntary Withdrawal of Consent 
Patients may withdraw consent from clinical trial participation at any time at their own 
request, or they may be withdrawn at the discretion of the investigator team for safety, 
behavioral reasons, or inability to comply with protocol related procedure. The patient is 
free from prejudice regarding future care or treatment. 
 
If a study participant does withdraw from clinical trial participation, the patient should 
continue to be followed for survival unless the patient additionally withdraws consent for 
disclosure of future information or for further contact from study team. In that case, no 
study specific evaluation should be performed, and no additional data will be collected. 
Patients should then notify the investigator in writing of the decision to withdrawal consent 
from future follow up. Upon withdrawal, all unused talazoparib should be returned and the 
patient should be requested to return for final return visit for drug return and to follow up 
with the patient on any unresolved AEs. The withdrawal of consent should be explained 
in detail in the medical records by the investigator as to whether the withdrawal is from 
only further receipt of investigational drug or also from study procedure and/or post- 
treatment follow up. For vital status follow up (i.e. whether the patient is alive or dead), 
publicly available information should also be used as directed in accordance to local law. 
 
13.3 
Lost to Follow-Up 
If a study participant does not return for a protocol related scheduled visit, every effort 
should be made by the study team to contact the patient and report upon the ongoing 
status. All attempts to contact the patient and information received during contact must be 
documented in the patient’s medical record. In any circumstance, every effort should be 
made to document patient outcome if possible. Patient will be deemed lost to follow-up by 
the inability to reach the patient after a minimum of 2 documented phone calls, emails or 
faxes, and lack of response by the patient to an additional 1 registered mail letter. If, after 
all attempts, the patient remains lost to follow-up, then the last known alive data as 
determined by the study team should be reported and documented in the patient’s medical 
record. 
14.0 
BIOSTATISTICS 


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For both cohorts, the primary endpoint will be best ORR as measured after 4 months, with 
independent secondary endpoints including PFS and OS as calculated below: 
1. Objective Response Rate (ORR): proportion of patients with confirmed complete 
response (CR) or partial response (PR) assessed by iRECIST after 4 months from the 
start of therapy, relative to the total population of patients evaluable. Confirmed 
responses are those that persist on repeat imaging 4 weeks after initial documentation 
of response, and if not, they will otherwise be counted as a non-responder during 
assessment of ORR. Additionally, patients with inadequate data for tumor assessment 
will be considered as non-responders. The two-sided exact 90% confidence intervals 
for ORR will be calculated. The final best response rate will be calculated 4 months 
after last patient accrued. 
2. Progression-free Survival (PFS): duration of time from start of treatment until death or 
progression of disease. Patients who do not have an event (PD or death) will be 
censored on the date of last adequate tumor assessment. Additionally, patients who 
start new anti-cancer therapy prior to event or who have 2 or more missing tum or 
assessments will also be censored. 
3. Overall Survival (OS): duration of time from start of treatment until death of any cause 
of study participants. Patients without an event (death) will be censored at the data of 
last contact. 
14.1 
Cohort 1 Enrollment and Statistical Plan 
The primary endpoint is best overall response rate after 4 months of therapy. The first 
cohort is designed using optimal Simon two-stage design, allowing us to terminate the 
study at an interim timepoint if the data do not show preliminary efficacy. In stage 1, we 
will accrue 10 patients. If 1 or more have a response in the first 10 patients, we will continue 
for a total of 29 patients. If no responses are observed in the first 10 patients, then cohort 
1 will be terminated early. If 4 or more of the 29 patients have a response, the study can 
be deemed a success. If the study stops early, or if 3 or less have a response, the study 
will not be deemed a success. If needed (i.e. patients in stage 1 are still on study and we 
have not observed 4 patients with a response), we will hold accrual prior to enrolling 
patients on stage 2. 
This design discriminates between response rates of 5% versus 20% and assumes 80% 
power and a one-sided type I error of 5%. The probability of early termination under the 
null is 60%. A case report of RCC patients pre-treated with PD-1/PD-L1 inhibitors who 
then went on to receive a different PD-1 inhibitor has shown progressive disease as best 
response to therapy to subsequent PD-1 agent (69). There remains insufficient 
prospective data regarding the efficacy of immune checkpoint inhibitors (monotherapy or 
combination strategy) after progression through a prior immune checkpoint inhibitor 
therapy. Thus, since patients in Cohort 1 are refractory to PD-1/PD-L1 inhibitors, a 5% null 
rate was selected for this study. 


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As of October 2021, the cohort is now closed. The PI, Co-PI, and study team met 
to review and discuss study compliance, adverse events, toxicities, and overall 
response experienced by the first 10 patients enrolled in Cohort 1 on 10/11/2021. 
Patients were treated with talazoparib 1 mg PO daily and Avelumab 800mg IV Q2 
weeks. All patients met the minimum dose exposure criterion as specified in the 
protocol (at least 50% of drug in the first cycle) and therefore all were considered 
evaluable for primary endpoint. All patients had follow-up evaluation by imaging, 
and if the imaging was performed prior to scheduled scan per protocol it was due 
to concern for early progressive disease. Upon summary review, no patients 
achieved an objective response per iRECIST criteria, and therefore the efficacy 
threshold was notmet to advance to stage 2 per protocol. Therefore, we have 
decided to close Cohort 1 as per study design. 
 
14.2 
Cohort 2 Enrollment and Statistical Plan 
Cohort 2 includes rare sub-types of RCC including FH- and SDH-deficient RCCs and renal 
medullary carcinoma (RMC). Given the rarity of these cancers and considering limited 
historical data, the sample size for this cohort is not based on a formal delineation of a null 
and alternative hypothesis. All analyses of ORR, PFS and OS will be descriptive. It is 
feasible that we will accrue 15 patients in Cohort 2 in a reasonable timeframe. The 
maximum 90% exact confidence interval half-width for ORR in a sample size of 15 is 0.23. 
If we observe 1 response, the response rate and 90% exact confidence interval is as 
follows: 6.7% with 90% CI of (.34%, 27.93%). 
For both cohorts, ORR will be estimated with a 90% confidence interval. PFS and OS will 
be estimated using Kaplan-Meier methods. Safety and tolerability will be summarized 
descriptively as frequencies. Compliance will be summarized by the calculating the 
amount of dose received over the study period. 
14.3 
Sample Size/Accrual Rate 
The total planned size of cohorts 1 (29 patients total) and cohort 2 (15 patients). The 
anticipated accrual time for both cohorts at MSKCC is 3 years. This is based on the historic 
accrual patterns that are seen in early and large scale clear cell RCC clinical trials, that 
would account for the majority of cohort 1 enrollment. Cohort 2 consists of a rare subtype 
of RCC, and therefore estimation is more challenging regarding accrual patterns. In prior 
study of non-clear cell RCC, by which FH- and SDH- loss would be accounted for, 34 
patients were accrued within 3 years at the MSK Manhattan site. Therefore, we expect 
accrual to this cohort to also be reasonably completed in this timeframe as well. 
Patients are evaluable for the primary endpoint if they have received at least 50% of the 
planned doses for each agent during Cycle 1. Patients who have taken less than 50% of 
the planned doses during Cycle 1 will be replaced for the primary endpoint, but will be 
evaluated in all safety and correlative analyses. Patients who have taken at least 50% of 


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the planned dose but do not have a second tumor scan due to toxicity will be counted as 
a failure for the primary analyses on efficacy. Note, given unpublished data on this drug, 
we anticipate inevaluability and the number of patients not receiving a second scan to be 
a rare if not unobserved event. 
14.4 
Exploratory Analyses 
Exploratory analyses of biomarkers for response to therapy will be performed in 
accordance to studies set forth in the protocol’s laboratory manual (Appendix 6). Analyses 
will be separated by cohort given distinct genomic differences, and all analyses will be 
descriptive and graphical as noted below. Biomarker data will include baseline and on- 
treatment/end of treatment assessments of changes to biomarker data including, but not 
limited to, centrally assessed defects. Measures are detailed in section 12.3. 
For all continuous measurements used in biomarker analysis, summary statistics (i.e. the 
mean, standard deviation, median, percent of coefficient of variation, and 
minimum/maximum levels) will be calculated at baseline and on treatment/end of 
treatment time points, as appropriate based on patient’s available samples. Change from 
baseline measurements will be calculated. 
For discrete measurement biomarkers (e.g., tumor marker status), frequencies and 
percentages of categorical biomarker measures will be determined at baseline and on 
treatment/post treatment time points, as appropriate; shift tables may also be provided. 
Data from biomarker assays will be analyzed using graphical methods. Specifically, we 
will graphically examine the relationship between the biomarkers and measures of 
efficacy, such as ORR and progression free survival. If the data allow, these relationships 
will be tested using a Fisher’s exact test, a Wilcoxon test, or a log-rank test as appropriate. 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION 
PROCEDURES 
15.1 
Research Participant Registration 
 
Confirm eligibility as defined in the section entitled Inclusion/Exclusion Criteria. 
Obtain informed consent, by following procedures defined in section entitled 
Informed Consent Procedures. During the registration process registering 
individuals will be required to complete a protocol specific Eligibility Checklist. The 
individual signing the Eligibility Checklist is confirming whether or not the 
participant is eligible to enroll in the study. Study staff are responsible for ensuring 
that all institutional requirements necessary to enroll a participant to the study have 
been completed. See related Clinical Research Policy and Procedure #401 
(Protocol Participant Registration). 
15.2 
Randomization 
 
N/A. No randomization in this study. 
16. 0 
DATA MANAGEMENT ISSUES 


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A Clinical Research Coordinator (CRC) will be assigned to this research protocol. The 
responsibilities of the CRC include data collection, abstraction and entry, aid in adverse 
reporting, sponsor communication, audit preparation, and generation of registration 
reports. The data collected for this study will be entered into a secure database 
(Medidata). The principal investigator will maintain ultimate responsibility for the clinical 
trial. 
16.1 
Quality Assurance 
Weekly registration reports will be generated to monitor for patient accrual and 
completeness in registration data. Routine data quality reports will also be generated to 
assess missing data and inconsistencies. Accrual rates and the extent and accuracy of 
evaluations and follow-up will be monitored periodically throughout the study duration. 
Potential issues will be brought to the attention of the study team for discussion and action 
at protocol related meetings. Random sample data quality and protocol compliance audits 
will the conducted by the study team. 
16.2 
Data and Safety Monitoring 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center 
were approved by the National Cancer Institute in September 2001. The plans address 
the new policies set forth by the NCI in the document entitled “Policy of the National 
Cancer Institute for Data and Safety Monitoring of Clinical Trials” which can be found at: 
http://cancertrials.nci.nih.gov/researchers/dsm/index.html. The DMS Plans at MSKCC 
were established and are monitored by the Clinical Research Administration. The MSKCC 
Data and Safety Monitoring Plans can be found on the MSKCC Intranet at: 
http://mskweb2.mskcc.org/irb/index.htm There are several different mechanisms by which 
clinical trials are monitored for data, safety and quality. There are institutional processes 
in place for quality assurance (e.g. Protocol monitoring, compliance and data verification 
audits, therapeutic response, and staff education on clinical research QA) and 
departmental procedures for quality control, plus there are two institutional committees 
that are responsible for monitoring the activities of our clinical trials programs. The 
committees: Data and Safety Monitoring Committee (DSMC) for Phase I and II clinical 
trials, and the Data and Safety Monitoring Board (DSMB) for Phase III clinical trials, report 
to the Center’s Research Council and Institutional Review Board. 
During the protocol development and review process, each protocol will be assessed for 
its level of risk and degree of monitoring required. Every type of protocol (e.g. NIH 
sponsored, in-house sponsored, industrial sponsored, NCI cooperative group, etc.) will be 
addressed and the monitoring procedures will be established at the time of protocol 
activation. 
16.3 
Study Treatment Accountability 
The primary investigator and study team will maintain accurate records of receipt of all 
study treatment including dates of receipt. In addition, accurate records will be kept 


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regarding the date, lot number, and how much study treatment is dispensed and used by 
each subject in the study. Reasons for deviation from the expected dispensing regimen 
must also be recorded. At completion of the study, to satisfy regulatory requirements 
regarding drug accountability, all unused study treatment will be reconciled and destroyed 
according to applicable state, federal, and local regulations. 
16.4 
Conditions for Protocol Modification 
Protocol modifications including amendments may be made and will be prepared, 
reviewed and approved by representatives of the investigator. Protocol modifications or 
amendments must be reviewed by Pfizer prior to implementation. 
All protocol modification must be submitted to the IRB for information and approval in 
accordance with local requirements and to regulatory agencies if required. Approval must 
be obtained before any changes can be implemented, except for changes necessary to 
eliminate an immediate hazard to study subjects or those that involve only logistical or 
administrative aspects of the trial (i.e. change in telephone number). 
16.5 
Conditions for Termination of Study 
At any time, the study may be terminated by MSKCC or Pfizer. Should this be necessary, 
Pfizer and MSKCC will arrange the procedures on an individual study basis after review 
and consultation. Adequate consideration is given for the protection of the subject’s 
interest. Upon study termination, MSKCC shall cease enrolling subjects into the study, 
and shall discontinue study conduct as soon as medically practicable. 
17. 0 
PROTECTION OF HUMAN SUBJECTS 
 
Prior to the enrollment of each patient, the risks, benefits and objectives of the study will 
be reviewed with the participant, including a discussion of the possible toxicities and side 
effects. Alternative, non-protocol, treatment options will be discussed with the patient. It 
will be reviewed that participation in this clinical trial is voluntary and that the patient may 
withdraw consent at any time. The study is designed with careful safety monitoring for 
toxicity including physician visits. Specific guidelines for symptom management are in 
place to protect the study participant. 
Human Subjects Involvement and Characteristics: All patients at MSKCC who meet the 
inclusion criteria will be eligible. Up to 44 patients will be enrolled on study. Patients 
eligible will be 18 years of age or older with an ECOG 0-2. Both men and women and 
members of all ethnic groups are eligible for this trial. Pregnant and breast-feeding 
women are excluded from this study. This protocol does not include children because 
this disease does not occur or occurs rarely in participants under 18 years. This 
statement is based on exclusion 4b of the NIH Policy and Guidelines on the Inclusion of 
Children as Participants in Research Involving Human Subjects. 
Consent process: All patients at MSKCC who meet the inclusion criteria will be eligible. 
Participation in the trial is voluntary. All patients will be required to sign a statement of 


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informed consent, which must conform to IRB guidelines. The informed consent 
procedure is described in Section 18.0. 
Possible Toxicities/Side-Effects: There are risks associated with treatment as described in 
Section 11.0; however, patients screened for enrollment will be deemed appropriate for 
treatment independent of this study. 
Benefits: There is a potential benefit to society, in that a successful study could lead to a 
larger phase II or III trial which would improve our understanding of the treatment of these 
diseases and potentially extend survival for patients with RCC. Participation in this study 
may not provide any benefit to the individual participant, and may or may not provide 
information which will ultimately benefit others. 
Costs: The patient will be responsible for all costs related to treatment and complications 
of treatment. Costs to the patient (third party insurer) will include administration of 
avelumab, hospitalizations, routine blood tests and diagnostic studies, office visits, 
baseline EKG and doctor’s fees. However, Pfizer will provide a supply of talazoparib and 
avelumab at no cost to the patient. Patients will not be charged for correlative research 
work that is included in this trial. Patients will be responsible for the costs of standard 
medical care, including complications of treatment. Non-billable tests include the tests 
performed for research purposes. 
Incentives: No incentives will be offered to patients/subjects for study participation. 
 
Alternatives: The alternative to this trial would be treatment with standard cytotoxic 
chemotherapy, immunotherapy or participation in alternative clinical trial. 
 
Confidentiality: Every effort will be made to maintain patient confidentiality. Research 
and hospital records are confidential. Patients’ names and any other identifying 
information will not be used in reports or publications resulting from this study. Other 
authorized agencies and appropriate internal personnel (e.g. qualified monitors from 
MSKCC) and external personnel, the FDA, and/or other governmental agencies) may 
review patient records as required. 
Patient safety: Patients are monitored by physicians and oncology nurses who are very 
familiar with clinical trials. In the case of an adverse reaction, immediate medical 
attention is available. In the evenings and weekends, we have a 24-hour urgent care 
facility for outpatients. The PI or co-PI will also be available at all times to organize any 
necessary intervention. 
Monitoring of data to ensure safety: This study is to be monitored by the institutional IRB. 
This incorporates an independent data and safety monitoring committee established by 
arrangement with the National Cancer Institute. The analysis of safety will include all 
patients. Adverse events, including all toxic effects of treatment, will be tabulated 
individually, and summarized by severity and causality. 
 
17.1 
Privacy 


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MSK’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure 
of protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB). 
All parties will ensure protection of patient personal data and will not include patient 
names, or other identifiable data in any reports, publications or other disclosures, except 
if required by law. The investigator will maintain a confidential list of patients who 
participated in this study, linking each patient’s numerical code to his or her actual identity. 
The consent indicates that individualized de identified information collected for the 
purposes of this study may be shared with other qualified researchers. Only researchers 
who have received approval from MSK will be allowed to access this information which 
will not include protected health information, such as the participant’s name, except for 
dates. It is also stated in the Research Authorization that their research data may be 
shared with others at the time of study publication. 
 
The consent indicates that samples and genetic information collected may be shared with 
other qualified researchers and placed in online databases. An example of an online 
database is the NIH dbGAP database, which is monitored by the National Institutes of 
Health, and may be made accessible to investigators approved by the U.S. government. 
Such information will not include identifying information such as name. It is also stated in 
the Research Authorization that research data (e.g. genomic sequence) may be shared 
with regulators. The requirements for submission of genotype/phenotype data into the NIH 
dbGAP or any other public database will be followed as per the IRB SOP for Genomic 
Data Sharing. 
 
17.2 
Serious Adverse Event (SAE) Reporting 
An adverse event is considered serious if it results in ANY of the following outcomes: 
• 
Death 
• 
A life-threatening adverse event 
• 
An adverse event that results in inpatient hospitalization or prolongation of 
existing hospitalization 
• 
A persistent or significant incapacity or substantialdisruption of the ability to 
conduct normal life functions 
• 
A congenital anomaly/birth defect 
• 
Important Medical Events (IME) that may not result in death, be life 
threatening, or require hospitalization may be considered serious when, 
based upon medical judgment, they may jeopardize the patient or participant 
and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition 
Note: Hospital admission for a planned procedure/disease treatment is not considered 
an SAE. 


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SAE reporting is required as soon as the participant starts investigational 
treatment/intervention. SAE reporting is required for 30-days after the participant’s last 
investigational treatment/intervention. Any event that occur after the 30 -day period that is 
unexpected and at least possibly related to protocol treatment must be reported . 
 
Please note: Any SAE that occurs prior to the start of investigational 
treatment/intervention and is related to a screening test or procedure (i.e., a screening 
biopsy) must be reported. 
All SAEs must be submitted in PIMS. If an SAE requires submission to the HRPP office 
per IRB SOP RR-408 ‘Reporting of Serious Adverse Events’, the SAE report must be 
submitted within 5 calendar days of the event. All other SAEs must be submitted within 
30 calendar days of the event. 
The report should contain the following information: 
 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
The grade of the event 
• 
Relationship of the adverse event to the treatment(s) 
• 
If the AE was expected 
• 
Detailed text that includes the following 
o An explanation of how the AE was handled 
o A description of the participant’s condition 
o Indication if the participant remains on the study 
• If an amendment will need to be made to the protocol and/or consent form 
• If the SAE is an Unanticipated Problem 
For IND/IDE protocols: 
The SAE report should be completed as per above instructions. If appropriate, the 
report will be forwarded to the FDA by the IND Office 
 
Any overdose or study drug administration error that results in SAE even if it does not 
meet the criteria for definition of SAE. 
 
17.2.1 SAE Reporting to Pfizer 
All serious adverse events that occur after the patients’ written consent to participate in 
the study through 28 days of discontinuation of dosing must be reported to Pfizer, whether 
related or not related to the study drug. If applicable, SAEs must be collected that relate 
to any later protocol specific procedures. 
 
Following the subject’s written consent in the study, all SAEs, whether related or not 
related to study drug, are collected including those thought to be associated with protocol 
specific procedures. The investigator should report any SAE occurring after these time 


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periods, which is believed to be related to study drug or protocol-specified procedure. An 
SAE report must be completed for any event where doubt exists regarding its seriousness. 
SAEs that occur after completion of the reporting time as defined above are reportable to 
Pfizer if the Investigator suspects a causal relationship between the Pfizer product and the 
SAE. 
The time frame for reporting an SAE to Pfizer is immediately upon awareness if the SAE 
is fatal or life-threatening (i.e. causes an immediate risk of death), regardless of the 
available information extent, or within 24 hours of first awareness of the SAE if the SAE is 
not fatal or life-threatening. 
The following reportable events must be submitted to Pfizer within 24 hours (or 
immediately for death or life-threatening events) using the provided Investigator-Initiated 
Research Serious Adverse Event Form (IIR SAE) with the Pfizer Reportable Events Fax 
Cover Sheet with each SAE submission. 
• 
Serious Adverse Events 
• 
Exposure during Pregnancy or Breastfeeding (even if not associated with adverse 
event) 
• 
Occupational Exposure (even if not associated with an adverse event) 
• 
Potential drug-induced liver injury (Hy’s Law cases): These events are considered 
important medical events and should be reported as SAEs. 
When new, updated, or corrected information about a previously reported SAE is obtained, 
a follow-up report should be submitted to Pfizer on a new SAE Report Form (or other 
agreed reporting method) that includes the data that are new or revised from the previous 
report. Follow-up information should never be added to a previously submitted report form. 
Ensure that any new events included on a follow-up report are marked as serious and a 
causality assessment is provided for each of them. 
An occupational exposure is an exposure to a Pfizer product for human use because of 
one's occupation. An occupational exposure is reportable regardless of whether there is 
an associated SAE. An exposure during breastfeeding occurs if an infant or child may 
have been exposed through breast milk to the Pfizer product during breastfeeding by a 
female taking the Pfizer product. Exposure during breastfeeding is reportable to Pfizer 
regardless of whether there is an associated SAE in the infant or child. Exposure During 
Pregnancy occurs when a fetus (from pre-embryo to birth) may have been exposed at any 
time during pregnancy to a Pfizer product (or blinded therapy). 
Contact information for submission of reportable events to Pfizer: 
Fax: Pfizer U.S. Clinical Trial Department, Fax 1-866-997-8322 or 
E-mail: USA.AEReporting@pfizer.com, specifying: 
• 
PROTOCOL: 
• 
SUBJECT: 


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• 
SITE/PI 
• 
SAE/ONSET 
 
MSK will provide Pfizer a redact internal serious adverse event (SAE) form. 
18.0 
INFORMED CONSENT PROCEDURES 
Before protocol-specified procedures are carried out, consenting professionals will explain 
full details of the protocol and study procedures as well as the risks involved to participants 
prior to their inclusion in the study. Participants will also be informed that they are free to 
withdraw from the study at any time. All participants must sign an IRB/PB-approved 
consent form indicating their consent to participate. This consent form meets the 
requirements of the Code of Federal Regulations and the Institutional Review 
Board/Privacy Board of this Center. The consent form will include the following: 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of 
supportive care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and 
to withdraw from participation at any time. 
Before any protocol-specific procedures can be carried out, the consenting professional 
will fully explain the aspects of patient privacy concerning research specific information. 
In addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
Each participant and consenting professional will sign the consent form. The participant 
must receive a copy of the signed informed consent form. 
19.0 
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Inhibitor Combinations. Cancer Research, (2018). 
51. 
A. Zehir et al., Mutational landscape of metastatic cancer revealed from prospective 
clinical sequencing of 10,000 patients. Nat Med 23, 703-713 (2017). 
52. 
M. D. Hellmann et al., Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor 
Mutational Burden. New England Journal of Medicine 378, 2093-2104 (2018). 
53. 
N. A. Rizvi et al., Cancer immunology. Mutational landscape determines sensitivity to 
PD-1 blockade in non-small cell lung cancer. Science (New York, N.Y.) 348, 124-128 
(2015). 
54. 
L. Ding et al., PARP Inhibition Elicits STING-Dependent Antitumor Immunity in Brca1- 
Deficient Ovarian Cancer. Cell Reports 25, 2972-2980.e2975 (2018). 
55. 
S. Jiao et al., PARP Inhibitor Upregulates PD-L1 Expression and Enhances Cancer- 
Associated Immunosuppression. Clinical Cancer Research 23, 3711-3720 (2017). 
56. 
M. Friedlander et al., A phase 1b study of the anti-PD-1 monoclonal antibody BGB-A317 
(A317) in combination with the PARP inhibitor BGB-290 (290) in advanced solid tumors. 
Journal of Clinical Oncology 36, 48-48 (2018). 
57. 
Y. Shen et al., BMN 673, a Novel and Highly Potent PARP1/2 Inhibitor for the Treatment 
of Human Cancers with DNA Repair Deficiency. Clinical Cancer Research 19, 5003 
(2013). 
58. 
G. Hamilton, B. Rath, Avelumab: combining immune checkpoint inhibition and antibody- 
dependent cytotoxicity. Expert Opin Biol Ther 17, 515-523 (2017). 
59. 
C. R. Heery et al., Avelumab for metastatic or locally advanced previously treated solid 
tumours (JAVELIN Solid Tumor): a phase 1a, multicohort, dose-escalation trial. The 
Lancet Oncology 18, 587-598 (2017). 
60. 
H. L. Kaufman et al., Avelumab in patients with chemotherapy-refractory metastatic 
Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. Lancet 
Oncol 17, 1374-1385 (2016). 
61. 
S. P. D’Angelo, J. Russell, C. Lebbé, et al., Efficacy and safety of first-line avelumab 
treatment in patients with stage iv metastatic merkel cell carcinoma: A preplanned 
interim analysis of a clinical trial. JAMA Oncology 4, e180077 (2018). 
62. 
T. A. Yap et al., 1241TiPJAVELIN PARP medley: A phase Ib/II study of avelumab (anti– 
PD-L1) plus talazoparib in locally advanced or metastatic solid tumors. Annals of 
Oncology 29, (2018). 
63. 
M. R. Patel et al., Avelumab in metastatic urothelial carcinoma after platinum failure 
(JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, 
phase 1 trial. The Lancet Oncology 19, 51-64 (2018). 
64. 
U. N. Vaishampayan et al., 877PFirst-line (1L) or second-line (2L) avelumab 
monotherapy in patients (pts) with advanced renal cell carcinoma (aRCC) enrolled in the 
phase Ib JAVELIN solid tumor trial. Annals of Oncology 29, mdy283.086-mdy283.086 
(2018). 
65. 
R. J. Motzer et al., LBA6_PRJAVELIN renal 101: A randomized, phase III study of 
avelumab + axitinib vs sunitinib as first-line treatment of advanced renal cell carcinoma 
(aRCC). Annals of Oncology 29, mdy424.036-mdy424.036 (2018). 
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T. K. Choueiri et al., Preliminary results for avelumab plus axitinib as first-line therapy in 
patients with advanced clear-cell renal-cell carcinoma (JAVELIN Renal 100): an open- 


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label, dose-finding and dose-expansion, phase 1b trial. Lancet Oncol 19, 451-460 
(2018). 
67. 
K. Kelly et al., Safety profile of avelumab in patients with advanced solid tumors: A 
pooled analysis of data from the phase 1 JAVELIN solid tumor and phase 2 JAVELIN 
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L. Seymour et al., iRECIST: guidelines for response criteria for use in trials testing 
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(2017). 


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20.0 
APPENDICES 
 
Appendix 1: Eastern Cooperative Oncology Group (ECOG) Performance Status Chart 
Appendix 2: iRECIST and RECIST v1.1. Guidelines 
Appendix 3: Avelumab Infusion Related Events and Management 
Appendix 4: Avelumab Immune Related Adverse Events and Management 
Appendix 5: Talazoparib Medication Interactions 
Appendix 6: Correlative Lab Manual 


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Appendix 1: Eastern Cooperative Oncology Group (ECOG) Performance Status Chart 
 
Description 
Grade 
Fully active, able to carry on all pre-disease performance without restriction 
0 
Restricted in physically strenuous activity, but ambulatory and able carry out light or 
sedentary nature (i.e. light house work, office work) 
1 
Ambulatory and capable of all self-care, but unable to carry out work activities. Up 
and about more than 50% of waking hours 
2 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours 
3 
Completely disabled, cannot carry on self-care. Totally confined to bed or chair 
4 
Death 
5 


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Appendix 2: iRECIST and RECIST v1.1 Guidelines. 
iRECIST and RECIST: The following criteria will apply to target and non-target lesions, adapted 
from Seymour et al. (68): 
1. Previously irradiated lesions: Lesions that are previously irradiated will not be considered 
measurable unless progression is documented radiographically previously or if a biopsy 
confirms persistence of disease ≥ 90 days following completion of therapy. 
2. Malignant Lymph Nodes: Lymph nodes are considered pathologically enlarged and 
measurable if >15 mm in short axis when assessed by CT scan. At baseline and in follow- 
up, only the short-axis will be used in measurement. 
3. Measurable disease, other: Visceral lesions are considered measurable if the longest 
diameter measures >10mm. 
4. Non-measurable disease: Lesions that include small lesions (longest diameter <10 mm) 
or pathological lymph nodes with <15 mm in short axis will be considered non-measurable. 
Bone lesions without extraosseous component, leptomeningeal disease, malignant 
ascites, pleural/pericardial effusion, lymphangitic disease, inflammatory breast disease is 
not considered measurable. 
5. Target Lesions: Up to five selected measurable lesions (maximum of 2 lesions per organ), 
will be identified as target lesions by the study radiologist to represent relevant distribution 
of disease burden and will be measured and recorded at baseline. Target lesions should 
be reproducibly measured in follow up. It may be the case that the largest lesions do not 
lend themselves to reproducibility, at which point next largest lesions should then be 
selected. A sum of the diameters of the longest for non-nodal lesions and short-axis for 
nodal lesions should then be used for the target lesion calculation and the sum of 
diameters should be used for baseline. The baseline sum will be used as a reference to 
further characterize any objective tumor response. 
6. Non-Target Lesions: All other lesions or sites of disease including measurable lesions 
over the 5 target lesions chosen should be identified as non-target lesions and should be 
recorded at baseline. Measurement of these lesions is not required, but the presence, 
absence, or unequivocal progression of these should be noted during follow-up imaging. 
7. Cystic Lesions: Cystic lesions that meet requirements for radiographic simple cysts should 
not be considered malignant. Cystic lesions that are thought to represent metastases can 
be considered measurable if they meet the above criteria. 
8. Clinical lesions: clinical lesions will only be considered measurable when they are 
superficial (i.e. skin nodules, palpable lymph nodes), and >10 mm in diameter when 
assessed using calipers. In the case of skin lesions, documentation by color photography 
including ruler to estimate size of lesion is required if used for follow-up. 
 
In contrast to RECIST v1.1 guidelines, iRECIST guidelines: 
1. Require confirmation of both progression and response by imaging at least 4 weeks from 
the date first documented 
2. Does not necessarily score the appearance of new lesions as progressive disease if the 
sum of the lesion diameters of target lesions (minimum of 10 mm/lesion, maximum of 5 


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target lesions, maximum of 2 per organ), and measurable new lesions does not increase 
by ≥ 20%. 
 
The same method of assessment and technique should then be used to characterize each 
identified and reported target lesion(s) at baseline and throughout the study. Response 
assessment is defined then by the following: 
 
Target Lesions: 
1. 
Complete Response (iCR): Disappearance of all target lesions. Any pathological lymph 
nodes must have a reduction in short axis to <10 mm. 
2. 
Partial Response (iPR): At least 30% decline in the sum of diameters of target lesions as 
compared to the reference baseline sum of diameters. 
3. 
Unconfirmed Progressive Disease (iUPD): At least 20% increase in the sum of diameters 
of target lesions compared to the reference of the smallest sum of the study (this includes 
the baseline sum if that is the smallest on the study). In addition to the relative increase of 
20%, sum must demonstrate an absolute increase of at least 5 mm. This will need to be 
confirmed with imaging for iCPD assessment to be performed 4 weeks (± 7 days) later. 
4. 
Stable Disease (iSD): Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, compared to reference of the smallest sum of diameters while on study. 
5. 
Confirmed Progressive Disease (iCPD): If further increase in tumor burden, compared to 
the last assessment, is seen as evidenced by one or more of the following: 
• 
if new lesions were previously identified and they have increased in size (≥5 mm in 
sum of measures for new lesion target or any increase for new lesion non-target) or 
number; if no change is seen in new lesions (size or number) from last timepoint, 
assignment remains iUPD 
• 
Further increase in the size of non-target disease (does not need to meet RECIST 
1.1 criteria for unequivocal progression) 
• 
Further increase in the sum of measures ≥5 mm; otherwise assignment remains iUPD 
• 
Further increase in previously identified target lesion iUPD in sum of measures >5 
mm or non-target lesion iUPD (previous assessment need not have shown 
unequivocal progression) OR 
• 
Further increase in previously identified target lesion iUPD sum of measures ≥5 mm, 
previously identified non-target lesion iUPD (does not need to be unequivocal), or an 
increase in the size or number of new lesions previously identified 
• 
Further increase in the size or number of new lesions previously identified 
 
Non-Target Lesions: 
1. Complete Response: Disappearance of all non-target lesions. All lymph nodes must be non- 
pathological in size <10 mm 
2. Non-CR / Non- PD: Persistence of one or more non-target lesions 
3. Unconfirmed Progressive Disease (iUPD)*: Appearance of one of more new lesions and/or 
unequivocal progression of existing non-target lesions. Unequivocal progression should be 
representative of overall disease status changes and not single lesions increases. 


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For RECIST guidelines, see below: 
https://ctep.cancer.gov/protocolDevelopment/docs/recist_guideline.pdf 
 
RECIST v1.1 Response Criteria 
Target Lesions 
Complete 
Response 
(CR) 
Disappearance of all target lesions. Any pathological lymph nodes must have a 
reduction in short axis to <10 mm. 
Partial 
Response (PR) 
At least 30% decline in the sum of diameters of target lesions as compared to the 
reference baseline sum of diameters. 
Stable Disease 
(SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, 
compared to reference of the smallest sum of diameters while on study 
Progressive 
Disease (PD) 
At least a 20% increase in the sum of diameters of target lesions, taking as reference 
the smallest sum on study (this includes the baseline sum if that is the smallest on 
study). In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. 
Note: the appearance of one or more new lesions is also considered progression. 
Non-Target Lesions 
Complete 
Response 
Disappearance of all non-target lesions. All lymph nodes must be non-pathological in 
size <10 mm in short axis. 
Non-CR / Non- 
PD 
Persistence of one or more non-target lesions and/or maintenance of tumor marker 
levels above the normal limits. 
Progressive 
Disease (PD) 
Unequivocal progression of existing non-target lesions. 
Note: the appearance of one or more new lesions is also considered progression. 


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Appendix 3: Avelumab Infusion Related Events and Management 
 
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. 
• 
Next scheduled infusion can be re- 
attempted at original rate, per treating 
investigator’s discretion. 
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 
• 
Next scheduled infusion should be 
initiated at 50% of original rate. Added 
premedication should be considered. 
Grade 3 or Grade 4 – severe or 
life-threatening 
• 
Grade 3: Prolonged (for example, not 
rapidly responsive to symptomatic 
medication and/or brief interruption of 
infusion); recurrence of symptoms 
following initial improvement; 
hospitalization indicated for clinical 
sequelae. 
• 
Grade 4: Life-threatening consequences; 
urgent intervention indicated. 
• 
Stop the avelumab infusion immediately 
and disconnect infusion tubing from the 
patient. 
• 
Patients must be withdrawn immediately 
from avelumab treatment and should not 
receive any further avelumab treatment. 


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Appendix 4: Avelumab Immune Related Adverse Events and Management 
 
Gastrointestinal irAEs 
Severity of Diarrhea/Colitis 
(NCI-CTCAE v5) 
Initial Management 
Follow-up Management 
Grade 1 
• 
Diarrhea: <4 
stools/day over 
Baseline 
• 
Colitis: asymptomatic 
• 
Continue avelumab therapy 
• 
Symptomatic treatment (eg, 
loperamide). 
• 
Close monitoring for 
worsening symptoms 
• 
Educate patient to report 
worsening immediately 
• 
If worsens, treat as 
Grade 2, 3 or 4 
Grade 2 
• 
Diarrhea: 4 to 6 stools 
per day over Baseline; 
IV fluids indicated <24 
hours; not interfering 
with ADL 
• 
Colitis: abdominal 
pain; blood in stool 
• 
Withhold avelumab therapy 
• 
Symptomatic treatment. 
• 
If improves to Grade ≤1, 
resume avelumab therapy 
• 
If persists >5-7 days or 
recurs, treat as Grade 3 or 
4. 
Grade 3 to 4 
• 
Diarrhea (Grade 3): 
≥7 stools per day over 
Baseline; 
incontinence; IV fluids 
≥24 h; interfering with 
ADL 
• 
Colitis (Grade 3): 
severe abdominal 
pain, medical 
intervention indicated, 
peritoneal signs 
• 
Grade 4: 
life-threatening, 
perforation 
• 
Withhold avelumab for Grade 3 
• 
Permanently discontinue avelumab 
for Grade 4 or recurrent Grade 3 
• 
1.0 - 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 5 mg/kg (if no 
contraindication). Note: 
infliximab should not be 
used in cases of 
perforation or sepsis 
Dermatological irAEs 
Grade of Rash 
PFS(NCI-CTCAE v5) 
Initial Management 
Follow-up Management 


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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 Grade 3 
• 
Consider skin biopsy 
• 
Consider dermatology consult 
• 
Consider 1.0 - 2.0 mg/kg/day 
prednisone or equivalent 
• 
Consider addition of prophylactic 
antibiotics for opportunistic 
infections. 
• 
If improves to Grade ≤1, 
taper steroids over at least 
1 month; resume 
avelumab therapy 
following steroids taper (for 
initial Grade 3) 
Pulmonary irAEs 
Grade of Pneumonitis 
(NCI-CTCAE v5) 
Initial Management 
Follow-up Management 
Grade 1 
Radiographic changes 
only 
• 
Consider withholding avelumab 
therapy 
• 
Monitor for symptoms every 2 - 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 
• 
Consider pulmonary and infectious 
disease consults 
• 
Monitor symptoms daily; consider 
hospitalization 
• 
1.0 - 2.0 mg/kg/day prednisone or 
equivalent 
• 
Consider Add prophylactic 
antibiotics for opportunistic 
infections 
• 
Consider bronchoscopy, lung 
biopsy. 
• 
Re-assess every 1 to 3 
days 
• 
When symptoms return to 
Grade ≤1, taper steroids 
over at least 1 month, and 
then resume avelumab 
therapy following steroids 
taper 
• 
If not improving after 
2 weeks or worsening, 
treat as Grade 3 to 4. 


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Grade 3 to 4 
• 
Grade 3: Severe new 
symptoms; 
New/worsening 
hypoxia; 
• 
Grade 4: 
Life-threatening 
• 
Permanently discontinue avelumab 
therapy 
• 
Hospitalize 
• 
Consider pulmonary and infectious 
Disease consults. 
• 
1.0 - 2.0 mg/kg/day prednisone or 
equivalent 
• 
Consider addition of prophylactic 
antibiotics for opportunistic 
infections 
• 
Consider bronchoscopy, lung 
biopsy 
• 
If improves to Grade ≤1, 
taper steroids over at least 
1 month 
• 
If not improving after 
48 hours or worsening, 
add additional 
immunosuppression (for 
example, infliximab, 
cyclophosphamide, IV 
immunoglobulin, or 
mycophenolate mofetil) 


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Hepatic irAEs 
Grade of Liver Test 
Elevation 
(NCI-CTCAE v5) 
Initial Management 
Follow-up Management 
Grade 1 
• 
AST or ALT >ULN - 
3.0 x ULN if baseline 
was normal; 1.5 - 3.0 x 
baseline if baseline 
was abnormal 
• 
And/or total bilirubin 
>ULN - 1.5 x ULN if 
baseline was normal; 
> 1.0 - 1.5 x baseline if 
baseline was 
abnormal 
• 
Continue avelumab therapy. 
• 
Continue liver function 
monitoring 
• 
If worsens, treat as 
Grade 2 or 3 to 4. 
Grade 2 
• 
>3.0 - 5.0 x ULN if 
baseline was 
normal; >3.0 - 5.0 x 
baseline if baseline 
was abnormal 
• 
and/or total bilirubin 
>1.5 - 3.0 x ULN if 
baseline was 
normal; >1.5 - 3.0 x 
baseline if baseline 
was abnormal 
• 
Withhold avelumab therapy 
• 
Increase frequency of monitoring 
to every 3 days. 
• 
If returns to Grade ≤1, 
resume routine monitoring; 
resume avelumab therapy 
• 
If elevation persists >5 to 
7 days or worsens, treat as 
Grade 3 to 4. 
Grade 3 to 4 
>5.0 x ULN if baseline was 
normal; >5.0 - 20.0 x 
baseline if baseline was 
abnormal and/or total 
bilirubin >3.0 x ULN if 
baseline was normal; >3.0 
x baseline if baseline was 
abnormal 
• 
Permanently discontinue 
avelumab therapy 
• 
Increase frequency of monitoring 
to every 1 to 2 days 
• 
1.0 - 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 
v5) 
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 
• 
Add prophylactic antibiotics for 
opportunistic infections 
• 
Consider renal biopsy 
• 
1.0-2.0 mg/kg/day prednisone or 
equivalent. 
• 
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 
• 
Add prophylactic antibiotics for 
opportunistic infections 
• 
Consider renal biopsy 
• 
Nephrology consultation. 
• 
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 
arrhythmia management 
• 
Cardiology consult to establish 
etiology and rule-out 
immune-mediated myocarditis 
• 
Guideline based supportive 
treatment as per cardiology 
consult* 
• 
Consider myocardial biopsy if 
recommended per cardiology 
consult 
• 
If symptoms improve and 
immune-mediated etiology 
is ruled out, re-start 
avelumab therapy 
• 
If symptoms do not 
improve/worsen, viral 
myocarditis is excluded, 
and immune-mediated 
etiology is suspected or 
confirmed following 
cardiology consult, 
manage as 
immune-mediated 
myocarditis 
Immune-mediated 
myocarditis 
• 
Permanently discontinue avelumab 
• 
Guideline based supportive 
treatment as appropriate as per 
cardiology consult* 
• 
1.0-2.0 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). 


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*Local guidelines, or e.g., ESC or AHA guidelines ESC guidelines website: 
https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines 
AHA guidelines website: 
http://professional.heart.org/professional/GuidelinesStatements/searchresults.jsp?q=&y=&t=1001 
Endocrine irAEs 
Endocrine Disorder 
Initial Management 
Follow-up Management 
Grade 1 or Grade 2 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I 
diabetes mellitus) 
• 
Continue avelumab therapy 
• 
Consider 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) 
• 
Continue hormone 
replacement/suppression 
and monitoring of 
endocrine function as 
appropriate. 
Grade 3 or Grade 4 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I 
diabetes mellitus) 
• 
Withhold avelumab therapy 
• 
Consider hospitalization 
• 
Consider 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 


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• 
Hypopituitarism 
• 
Hypophysitis 
(secondary 
endocrinopathies) 
If secondary thyroid and/or adrenal 
insufficiency is confirmed (i.e., 
subnormal serum FT4 with 
inappropriately low TSH and/or low 
serum cortisol with inappropriately low 
ACTH): 
• 
Consider referral 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 
• 
Consider pituitary MRI and visual 
field examination as indicated 
If hypophysitis confirmed: 
• 
Continue avelumab if mild 
symptoms with normal MRI. 
Repeat the MRI in 1 month 
• 
Withhold avelumab if moderate, 
severe or life-threatening 
symptoms of hypophysitis and/or 
abnormal MRI 
• 
Consider hospitalization. Initiate 
corticosteroids (1 to 2 mg/kg/day 
prednisone or equivalent) followed 
by corticosteroids taper during at 
least 1 month 
• 
Consider addition of prophylactic 
antibiotics for opportunistic 
infections. 
• 
Resume avelumab once 
symptoms and hormone 
tests improve to Grade ≤1 
(with or without hormone 
replacement) 
• 
In addition, for 
hypophysitis with 
abnormal MRI, resume 
avelumab only once 
shrinkage of the pituitary 
gland on MRI/CT scan is 
documented 
• 
Continue hormone 
replacement/suppression 
therapy as appropriate 
Other irAEs (not described above) 
Grade of other irAEs 
(NCI-CTCAE v5) 
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 - 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. 


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Recurrence of same 
Grade 3 irAEs 
• 
Permanently discontinue avelumab 
therapy 
• 
1.0 - 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 - 2.0 mg/kg/day prednisone or 
equivalent and/or other 
immunosuppressant as needed 
• 
Add prophylactic antibiotics for 
opportunistic infections 
• 
Specialty consult. 
• 
If improves to Grade ≤1, 
taper steroids over at least 
1 month. 
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=aadrenocorticotropic hormone; ADL=activities of daily living; ALT=alanine 
aminotransferase; AST=aspartate aminotransferase; BNP=B-type natriuretic peptide; 
CK-MB=creatinine 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. 


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Appendix 5: Prohibited Potent P-gp Inhibitors 
 
Amiodarone 
Carvedilol 
Clarithromycin 
Cobicistat 
Dronedarone 
Erythromycin 
Glecaprevir/pibrentasvir 
Indinavir 
Itraconazole 
Ketoconazole 
Lapatinib 
Lopinavir 
Propafenone 
Quinidine 
Ranolazine 
Ritonavir 
Saquinavir 
Sofosbuvir/velpatasvir/voxilaprevir 
Telaprevir 
Tipranavir 
Valspodar 
Verapamil 


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Appendix 6: Correlative Laboratory Manual 
Tissue Specimen Collection and Storage 
Time Points: Pre-treatment (optionally at screening), and during study period 
 
Tumor Specimens: 
• 
Fresh Tumor Biopsy: Tumor biopsies may be obtained for patients upon entry into clinical 
study during screening period, as well as while on-treatment. Tumor specimen may 
include nephrectomy or metastatic site specimen and should include 4 core biopsy 
specimens. On the date of biopsy, part of the specimen will be transported to the Chan 
Lab. Two core biopsies will be utilized for RNA/DNA extraction, 1 core biopsy will be snap 
frozen, and 1 core biopsy will be formalin fixed and paraffin embedded. Portions of tumors 
and normal tissue can then be prepared for further storage and analysis per laboratory 
guidelines. This will include placement of portions of tissue in aliquoted conical tubes in 
RPMI solution in TPS. The snap frozen specimens may be then stored for future 
investigation, including micro- and microdissection as well as for DNA/RNA extraction, and 
ultimately stored at -80ºC. 
• 
Archival Tissue: If available, 1-2 paraffin embedded tissue blocks containing formalin-fixed 
tumor slides will be requested. Paraffin blocks may then be processed according to 
standard institutional protocol, with final preparation of 20 unstained slides for available 
analysis. 
• 
All specimens will be delivered with the attached specimen submission form. All tissue will 
then be stored at the Hakimi Lab at IPOP, MSKCC Zuckerman Research Center (417 
East 68th Street, New York, NY). 
 
Peripheral Blood Sample Collection and Storage 
Time Points: C1D1, C2D1, C3D1, , End of Treatment 
 
Materials and Collection: 
Materials§ 
C1D1* 
C2D1 & 
C3D1 
End of Treatment* 
Vacutainer 
CPT Tubes 
(8mL/each 
tube) 
X (3 tubes) 
X (2 tube) 
X (3 tubes) 
Streck BCT 
Tube 
(10mL/each 
tube) 
X (1 tube) 
X (1 tube) 
X (1 tube) 
EDTA Tube 
(6cc/each 
tube) 
X (1 tube) 
X (1 tube) 
X (1 tubes) 
Table 1: Peripheral Blood Sample Schedule 


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*All blood draws should occur prior to avelumab administration. Collections may occur ±7 days of 
specified time point. 
**An additional two blood draws at different time points beyond those listed is permitted when 
feasible based upon clinical / immunological findings 
§Changes to these methods may be adapted depending upon the most recent, generally accepted 
protocols. 
 
 
Preparation: 
Vacutainer CPT Tubes: The BD Vacutainer CPT Tube (Catalog: 362761), or equivalent, will be 
used. For collection, standard phlebotomy will fill tubes with 8 mL of blood, with attempt to obtain 
full 8 mL during collection attempt. The tube will then be inverted several times after collection to 
ensure adequate mixing. The patient’s name, MRN, adhesive stickers will be attached to the tube. 
The date/time will be noted on the collection requisition form. The RSA will then deliver all 
specimens to Hakimi Lab at IPOP, MSKCC Zuckerman Research Center (417 East 68th Street, 
New York, NY). 
Streck Tubes: The Streck Cell-Free DNA BCT tube (Streck Catalog No 218961), or equivalent, 
will be used. For collection, standard phlebotomy will fill each tube with 10 mL of blood, with 
attempt to obtain full 10 mL during collection attempt. The tube should be inverted several times 
after collection. The patient’s name, MRN should be documented on adhesive stickers to each 
tube. The date/time will be noted on the requisition form, and the tubes will be placed in a 
biohazard bag at room temperature. The RSA will then deliver all specimens to Hakimi Lab at 
IPOP, MSKCC Zuckerman Research Center (417 East 68th Street, New York, NY). 
EDTA Tubes: The BD lavender tube (BD Catalog: 367863) will be used. For collection, standard 
phlebotomy will fill each tube with 6 mL of blood, with attempt to obtain full 6 mL during collection 
attempt. The tube should be inverted several times after collection. The patient’s name, MRN 
should be documented on adhesive stickers to each tube. The date/time will be noted on the 
requisition form, and the tubes will be placed in a biohazard bag at room temperature. The RSA 
will then deliver all specimens to Hakimi Lab at IPOP, MSKCC Zuckerman Research Center (417 
East 68th Street, New York, NY). Samples may then be stored at -80ºC per standard practice 
procedure for future analysis. 
 
 
 
 
Data Entry for Specimen Collection 
MSKCC RSA and/or Chan laboratory personnel will collect information into a secured database 
once samples are collected and transported. If a sample is not fully collected, the reasoning for 
incomplete or partial collection should be documented into the database as well for accurate 
records. 
RNA/DNA Preparation Methodology 


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Tumor samples will be prepared with the AllPrep DNA/RNA/Protein Mini Kit from Qiagen (CAT: 
80004). Samples then will be used include fresh snap frozen core biopsies, biopsies preserved in 
RNAlater, or alternatively paraffin embedded core biopsies. When samples are in paraffin 
embedded, the RNeasy FFPE Kit and QIAamp DNA FFPE Tissue Kit will be used. Changes to 
the RNA/DNA preparation methodology may be adapted depending upon the most recent, 
generally accepted protocols. 
Tumor Exome Sequencing and matched normal DNA from blood 
Whole exome sequencing will be carried out using the Illumina Hiseq 2100 according to Nextera 
Rapid Capture kit (Cat # FC-140-1000) protocol with using 50 ng of genomic DNA as input. 
Nextera Rapid Capture kit targets 214,405 coding exons offering comprehensive coverage of 
human exomes with target size of 37 Mb. Changes to the methods for exome sequencing may 
be adapted depending upon the most recent, generally accepted protocols. 
DNA Damage Responses will then be characterized using homologous recombination deficiency 
(HRD) assays which encompass multiple parameters. This may include loss of heterozygosity 
scoring (LOH), large scale transition scoring (LST), and telomeric allelic imbalance scoring (TAI). 
Transcriptome Sequencing of Tumor RNA 
Messenger RNA is isolated from Total RNA using the Life Technology Dynabeads mRNA Direct 
Microkit (Cat# 61021). The isolation relies on base pairing between the poly (A) residue at the 3’ 
end of most mRNA, and the oligo (dt) 25 residues covalently coupled to the surface of the 
Dynabeads. Other RNA species lacking a poly (A) tail do not hybridize to the bead and are readily 
washed away. Briefly, 1 ug of RNA is heat denatured at 70°C and 50 ul of lysis/binding buffer 
and beads are added to bind the mRNA to the beads. Two rounds of mRNA isolation are 
performed and finally mRNA is eluted in 10 ul of nuclease free water. The resulting isolated 
mRNA contains low ribosomal RNA content, which allows for most accurate measurement of 
coding transcripts. 
The mRNA is subsequently converted to representative cDNA libraries for strand-specific RNA 
sequencing on the Ion Torrent Personal Genome Machine (PGM) system using the Life 
Technology Ion Total RNA –Seq kit (Cat #4475936). Briefly, 1-500 ng of mRNA is fragmented 
with RNAse III enzyme and purified using beads. The size of the fragmented RNA is assessed 
on the Agilent 2100 Bioanalyzer. The fragmented RNA is hybridized and ligated with Ion adapters 
and subsequently reverse transcribed using SuperScript III to generate single stranded cDNA 
copies of the fragmented RNA molecule. Library generation uses a magnetic bead-based, size 
selection process, to enrich library fragments with 200-bp length. Complementary DNA library 
is subsequently amplified using Ion PCR primers, and Platinum PCR High Fidelity enzyme as 
per the protocol. The size and yield of the resultant amplified cDNA library size is determined on 
the Agilent High sensitivity DNA Bioanalyzer chip. 
The library dilution factor is determined for the template preparation. Template preparation is 
carried out on OneTouch Emulsion PCR system using the Life Technology Ion PGM Template 
OT2 200 kit (Cat #4480285). OneTouch uses membrane passages and microfluidics to create 


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bulk emulsion of DNA library in oil and performs an in situ thermocycling PCR to produce template 
beads. The template beads are enriched on OneTouch ES using streptavidin beads to bind to 
biotinylated, properly adapted library fragments. This emulsion PCR and enrichment yields a 
sequencing template bead population where 95% of beads carry the template. The template 
beads are deposited on to the sequencing chip and sequenced on PGM using the Ion PGM 
Sequencing 200 Kit (Cat # 4482006) from Life Technologies. Changes to these methods may be 
adapted depending upon the most recent, generally accepted protocols. 
Specific Pathways of interest that will be included for analysis include DDR pathways: BRCA1, 
BRCA2, 
PARP1, 
ATM, 
ATR, 
RAD51C, 
BAP1, 
PALB2, 
MRE11, 
BARD1/BRIP1, 
RAD50/51/51B/51D, ERCC2, ERCC3, ERCC4, ERCC5, MMR genes, POLE, FANCC, FANCA, 
BLM, CHEK1, CHEK2, RB1, ATRX, as well as others. 
Somatic Mutation Identification and Verification 
Matched tumor and normal exome sequencing reads will be mapped to the human reference 
genomic using Bowtie2. Non-uniquely mapped reads are then discarded, and calculation of 
mismatch statistics for each position is performed for both samples. The aligned reads are then 
trimmed at the 5’ and 3’ end at the points where the mismatch rate goes above 1% based 
on this analysis. To reduce bias introduced through PCR amplification during library preparation, 
multiple reads with alignments starting at the same genomic location with their consensus are 
replaced. MuTect, which is one of the methods used in the TCGA project to call somatic 
mutations, is then used to predict somatic variants single nucleotide variants (SNVs) from 
matched tumor and normal aligned reads. Haplotype inference over called SNV genotypes is 
performed using the RefHap Single Individual Haplotyping algorithm that uses read evidence to 
phase blocks of proximal SNVs. 
RNA-Seq reads are mapped on a diploid human transcript library derived from the NCBI CCDS 
(http://www.ncbi.nlm.nih.gov/CCDS/CcdsBrowse.cgi) 
annotations. 
Expressed 
genes 
are 
identified by inferring gene expression levels from the RNA-Seq aligned reads, using IsoEM. 
IsoEM is an accurate EM algorithm that makes use of information such as insert size, quality 
scores, and read pairing, if available, to handle read mapping ambiguities. Epitope prediction 
is done for somatic SNVs that appear in expressed genes, according to FPKM (Fragment 
per Kilobase Per Million reads) values predicted by IsoEM. 
After the candidate neo-epitope peptides are selected, the SNVs encoding these peptides will 
be verified by reverse-transcriptase PCR followed by DNA sequencing. Two sets of primers are 
synthesized for each SNV with the second set of primers as nested primers. RNA will be extract 
from each tumor sample using Qiagen RNAeasy Mini Kit. The first primer set will be used to 
synthesize cDNA samples from RNA samples. The cDNA will be used as template for reverse 
transcriptase PCR reaction using the second set of primers. The PCR product will be purified 
using QIAquick PCR Purification Kit. Purified PCR product and the second primer set will be used 
to Genewiz to sequence verify the SNVs called by high throughput sequencing analysis. Changes 
to these methods may be adapted depending upon the most recent, generally accepted protocols. 
Neo-Antigen Prediction 


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For each somatic SNV in the expressed gene, reference and mutated peptide sequences are 
then generated based on the two inferred haplotypes for each CCDS transcript. Generated amino 
acid sequences are then processed using the NetMHC epitope prediction program and scored 
using an Artificial Neural Network (ANN) algorithm, for the patients’ identified HLA alleles. The 
Differential Agretopic Index (DAI), which is the difference between the NetMHC score for the 
mutated peptide and its un-mutated wild type counterpart, is calculated for each peptide, by 
subtracting the wild type score from the mutant score. Epitopes based on DAI will be ranked. 
Multiple mutational antigen prediction scores (Net MHC, DAI, pathogen-associated sequences) 
may be compared in an exploratory fashion and each will be tested against response rates. 
Changes to these methods may be adapted depending upon the most recent, generally accepted 
protocols. 
MSK-IMPACT Analysis 
MSK-IMPACT will be performed according to the institutional protocol. This assay analyzes a 
pre-defined set of cancer susceptibility genes which are captured and sequenced on an Illumina 
HiSeqTM. Tumor mutational burden will be calculated using the total number of non-synonymous 
mutations divided by the total genomic target region for which mutations are reported. TMB will 
be reported as an estimate / mB of DNA. Copy number assessment will be used to determine 
gene amplification or deletion (amplification defined as >2-fold change, deletion defined as <2- 
fold change). Degree of copy number change is influenced by tumor purity and content. Changes 
to these methods may be adapted depending upon the most recent, generally accepted protocols. 
Immune Infiltrate Analysis 
The immune infiltrate analysis will be performed using several techniques, including IHC, 
immunofluorescence, flow cytometry and/or computational approaches (deconvolution) based 
upon RNA sequencing data analysis. Matrix type analysis will be performed including 
CIBERSORT and single-sample gene expression set analysis (ssGSEA). Populations of cells 
analyzed may include, but will not be limited to CD4, CD8, Treg populations, B cells, MDSC, 
monocytes, and dendritic cells and expression of biologically relevant/phenotypic markers thereof. 
Standard established institutional protocols will be applied. Changes to these methods may be 
adapted depending upon the most recent, generally accepted protocols. 
Peripheral blood analysis 
Peripheral blood analysis will be performed using flow cytometry, and/or computational 
approaches including immune deconvolution based upon RNA sequencing data analysis. 
Populations of cells that may be characterized include, but are not limited to, CD4, CD8, Treg 
populations, B cells, MDSC, monocytes, and dendritic cells and expression of biologically 
relevant/phenotypic markers thereof. Standard established institutional protocols will be applied. 
Changes to these methods may be adapted depending upon the most recent, generally accepted 
protocols. 
Peripheral blood analysis will also include analysis for circulating tumor DNA (ctDNA). Tumor 
DNA will be extracted using QIAamp circulating nucleic acid kit, and libraries will then be prepared 


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using previously described and captured gene specific DNA probes. This may include gene sets 
as described by MSK-ACCESS, as well as targeted amplification for select genes of interest in 
RCC. Changes to these methods may be adapted depending upon the most recent, generally 
accepted protocols. 
Metabolomic Profiling 
Tissue samples will be identified for metabolite changes with metabolite identification and 
quantification. Snap frozen core biopsy samples will be incubated and prepared to precipitate 
polar metabolite proteins for mass spectrometer analysis per standard procedures. Non-targeted 
gas and liquid chromatography coupled with mass spectrometer (LC/MS) analyses will then be 
performed, with lower limit of quantitation of 100 ng/g of tumor. Metabolites of interes t may 
include, but is not limited to, specific TCA cycle metabolites: fumarate, succinate, malate, alpha- 
ketoglutarate, citrate, isocitrate, malate, fumarate, glutamine, glutamate, ATP, 2-HG, aspartic 
acid, asparagine, orotic acid. Changes to these methods may be adapted depending upon the 
most recent, generally accepted protocols.