Phase 1/2a Study of the Safety, Pharmacokinetics, Pharmacodynamics and Preliminary Clinical Activity of RP-3500 Alone or in Combination With Talazoparib or Gemcitabine in Advanced Solid Tumors With ATR Inhibitor Sensitizing Mutations (TRESR Study)
Phase: PHASE1
Conditions: Advanced Solid Tumor
Sponsor: Repare Therapeutics

 
 
 
CLINICAL STUDY PROTOCOL SYNOPSIS 
Title: 
Phase 1/2a Study of the Safety, Pharmacokinetics, Pharmacodynamics 
and Preliminary Clinical Activity of RP-3500 Alone or in Combination 
with Talazoparib or Gemcitabine in Advanced Solid Tumors with ATR 
inhibitor Sensitizing Mutations (TRESR Study) 
Protocol Number: 
RP-3500-01 
Study Drug Names: 
RP-3500, talazoparib, gemcitabine 
Development Phase: 
1/2a 
Sponsor: 
Repare Therapeutics 
7171 Frederick-Banting 
Building 2 
St-Laurent, Quebec, H4S 1Z9 Canada 
Medical Monitor: 
Gabriela Gomez, MD, MBA 
Indication: 
Advanced solid tumors 
IND Number: 
146,280 
EudraCT Number: 
2020-000301-87 
Date of Original Protocol: 
12 March 2020 
Date of Amendment 1: 
13 July 2020 
Date of Amendment 2: 
19 November 2020 
Date of Amendment 3: 
20 May 2021 
Date of Amendment 4: 
17 August 2021 
Date of Amendment 4.1: 
26 October 2021 
Date of Amendment 5.0: 
12 November 2021 
Date of Amendment 6.0 
14 July 2022 
Date of Amendment 7.0 
21 June 2024 
Version of Protocol: 
8.0 
GCP Statement: 
This study is to be performed in full compliance with International Council 
for Harmonization of Technical Requirements for Pharmaceuticals for 
Human Use (ICH) and all applicable local Good Clinical Practice (GCP) 
guidelines and regulations. All required study documentation will be 
archived as required by regulatory authorities. 
Confidentiality Statement: 
This document is confidential. It contains proprietary information of Repare 
Therapeutics (the Sponsor). Any viewing or disclosure of such information 
that is not authorized in writing by the Sponsor is strictly prohibited. Such 
information may be used solely for the purpose of reviewing or performing 
this study. 

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1. 
SYNOPSIS 
Name of Sponsor/Company: Repare Therapeutics 
Name of Investigational Products: RP-3500, talazoparib, and gemcitabine 
Name of Active Ingredients: RP-3500, talazoparib, and gemcitabine 
Title of Study: Phase 1/2a Study of the Safety, Pharmacokinetics, Pharmacodynamics and Preliminary 
Clinical Activity of RP-3500 Alone or in Combination with Talazoparib or Gemcitabine in Advanced 
Solid Tumors with ATR inhibitor Sensitizing Mutations (TRESR study: Treatment Enabled by SNIPRx)  
Study Duration: Approximately 42 months  
Phase of Development: 1/2a 
Number of Patients (planned): Approximately 451 patients are planned to be enrolled in this study. 
Module 1 Objectives: 
Primary Objectives 
• 
To assess the safety and tolerability of RP-3500 in patients with eligible advanced solid 
tumors 
• 
To define the maximum tolerated dose (MTD) of RP-3500 monotherapy, and determine a 
recommended Phase 2 dose (RP2D) and schedule 
Secondary Objectives 
• 
To assess preliminary anti-tumor activity with RP-3500 in patients with eligible advanced 
solid tumors 
• 
To characterize the pharmacokinetics (PK) profile of RP-3500  
• 
To assess PK parameters of RP-3500 monotherapy in fasted and fed states 
• 
To assess the relationship between pharmacodynamic biomarkers and PK of RP-3500 in a 
subset of patients to aid in schedule decisions and assess the correlation with clinical 
outcomes 
• 
To evaluate the concordance between local and central methods for detecting ataxia 
telangiectasia-mutated and rad3-related inhibitor (ATRi) sensitizing biomarkers  
• 
To evaluate the impact of treatment with RP-3500 on QT/QTc interval  
 
 
 
 
 
 
 
 
 
 
 
 

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Module 2 Objectives: 
Primary Objectives 
• 
To assess anti-tumor activity of RP-3500 when administered to eligible patients at the RP2D 
and schedule evaluated in the following arms: 
− 
ARM 1: Estrogen receptor-positive/human epidermal growth factor receptor 2-negative 
(ER+/HER2-) breast, ampullary, pancreas, prostate, bile duct, and gastroesophageal 
junction tumors with likely pathogenic/pathogenic germline ataxia 
telangiectasia-mutated (ATM) mutations 
− 
ARM 2: Leiomyosarcoma tumors with ribonuclease H2 (RNASEH2) loss or 
deleterious/likely deleterious BRCA2 mutations 
− 
ARM 3: Tumors with other ATRi sensitizing biomarkers: ATRIP, CHTF8, FZR1, 
MRE11, NBN, RAD17, RAD50, RAD51B/C/D, REV3L, SETD2, and other genes agreed 
upon between the Sponsor and Investigator 
Secondary Objectives 
• 
To determine safety and tolerability of RP2D and schedule in the biomarker-defined patient 
subsets  
• 
To assess anti-tumor activity of RP-3500 in selected tumors with biallelic versus monoallelic 
alternations 
• 
To evaluate the preferred assay methods for defining how to select patients for ATRi 
sensitizing biomarkers for future studies  
• 
To evaluate the concordance between local and central methods for detecting ATRi 
sensitizing biomarkers.  
• 
To further characterize the PK profile of RP-3500  
 
 
 
 
 
 
 
 
Module 3 Objectives: 
Primary Objectives 
• 
To assess the safety and tolerability of RP-3500 and talazoparib combination in eligible 
patients with advanced solid tumors 
• 
To define the MTD of RP-3500 and talazoparib combination and determine RP2D and 
schedule 
Secondary Objectives 
• 
To assess preliminary anti-tumor activity of RP-3500 and talazoparib combination in eligible 
patients with advanced solid tumors 

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• 
To assess any PK interaction of RP-3500 and talazoparib when administered in combination 
• 
To determine the pharmacokinetic/pharmacodynamic (PK/PD) relationships of RP-3500 and 
talazoparib combination to confirm dose/schedule  
• 
To determine activity of RP-3500 and talazoparib combination in patients who progressed 
after RP-3500 alone  
 
 
 
Module 4 Objectives: 
Primary Objectives 
• 
To assess the safety and tolerability of RP-3500 and gemcitabine combination in eligible 
patients with advanced solid tumors 
• 
To define the MTD of RP-3500 and gemcitabine combination and determine RP2D and 
schedule 
Secondary Objectives 
• 
To assess preliminary anti-tumor activity of RP-3500 and gemcitabine combination in 
eligible patients with advanced solid tumors 
• 
To assess the PK of RP-3500 when administered in combination with gemcitabine 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Eligible patients will be enrolled into Module 1 (approximately 140 patients), RP-3500 monotherapy 
dose escalation, evaluating the safety, tolerability, PK, and food effect of RP-3500 administered using 2 
schedules. The study will continue with the initiation of Module 3 (up to 50 patients), RP-3500 and 
talazoparib combination, after a dose level that demonstrates pharmacologic activity is observed in 
Module 1a. Evidence of pharmacologic activity can include Grade ≥2 drug-related toxicity at any cycle, 
PK data demonstrating exposure levels predicted to be efficacious based on nonclinical studies, or other 
evidence of treatment-related activity as agreed on by the Safety Review Committee (SRC). Module 2 
enrollment will proceed once the RP-3500 monotherapy RP2D and recommended dosing schedule are 
determined in Module 1. Module 2 (approximately up to 191 additional patients) aims to explore the 
preliminary efficacy of RP-3500 in patients whose tumors harbor an ATRi sensitizing biomarker. Module 
2 will include 3 arms:  
• 
ARM 1: ER+/HER2- breast, ampullary, pancreas, prostate, bile duct or gastroesophageal 
junction tumors with likely pathogenic/pathogenic germline ATM (gATM) mutations 
• 
ARM 2: Leiomyosarcomas with either RNASEH2 loss or deleterious/likely deleterious 
BRCA2 mutations. As of Protocol Amendment 6.0, Module 2 Arm 2 has closed for 
enrollment.  
• 
ARM 3: Tumors with other ATRi sensitizing biomarkers: ATRIP, CHTF8, FZR1, MRE11, 
NBN, RAD17, RAD50, RAD51B/C/D, REV3L, SETD2, and other genes agreed upon between 
the Sponsor and Investigator 
Module 4 will evaluate the safety and tolerability of RP-3500 in combination with gemcitabine.  
 
As applicable per module or arm, patients will be enrolled based on local tumor mutation data or 
Sponsor-approved IHC data (for ATM or RNAseH2) generated in a College of Pathology (CAP)/Clinical 
Laboratory Improvement Amendments (CLIA)-certified laboratory (International Organization for 
Standardization [ISO] or equivalent) and collected following center-specific institutional guidelines. 
Sponsor-approved local next-generation sequencing (NGS) tests include Guardant360®, Caris, 
Foundation Medicine F1, MSK IMPACT, Oncomine™ V3, Qiagen Comprehensive, or other validated 
platforms. Germline test results will be accepted from Ambry, Invitae, Myriad, or other tests approved by 
the Sponsor. 
The Precision Oncology Decision Support (PODS) Group at the Khalifa Institute for Personalized Cancer 
Therapy (IPCT) at the University of Texas MD Anderson Cancer Center (United States [US]) will 
confirm molecular eligibility for the study prior to start of treatment by comparing NGS CLIA (or 
equivalent) reports with predefined, Sponsor-approved alterations to ensure NGS results provided by 
enrolling centers are annotated consistently across all participating centers. This review (uniformly 
reported by PODS within 72 hours of receiving the report by email) is done to ensure that the patient’s 
tumor molecular profile matches the study eligibility criteria and is uniformly assessed to allow 
consistent interpretation of data. 
The results of nonclinical studies together with early efficacy signals observed in Modules 1 through 5 
may support the development of additional study modules to further test RP-3500 in patients with tumors 
carrying specific genomic alterations, either in monotherapy or in combination with other treatment 
modalities. 
General Study Conduct: 

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Patient enrollment in Modules 1 through 5 will rely on institutional and Investigator support to identify 
candidates for RP-3500 therapy and to determine if a patient’s tumor is a potential molecular match 
based on local NGS or IHC data.  
The study will consist of a Pre-Screening Period (within 6 months from time of enrollment), Screening 
Period (Day -28 to Day -1, to determine eligibility), Treatment Period, an End-of-Treatment (EOT) 
Period (occurring within 30+7 days after the last dose of study drug or 7 days after the last dose of study 
drug if discontinued due to a treatment-related toxicity), and a Survival Follow-Up (3 months ± 2 weeks 
from the date of last dose). The treatment period will consist initially of 21-day treatment cycles. 
In Module 1a, RP-3500 will be administered initially to 1 patient per dose level once daily (QD) at a 
starting dose of 5 mg following a 5 consecutive days on and 2 consecutive days off schedule 
(5/2 schedule). When pharmacologic activity is observed, sufficient patients will be enrolled at that dose 
level to ensure that safety and tolerability are assessed in at least 2 evaluable patients before a decision 
for further escalation is made by the SRC. An alternative dosing schedule of 3 days on followed by 
4 days off (Module 1b, 3/4 schedule), may be initiated after the dose level that demonstrates 
pharmacologic activity in Module 1a is confirmed safe by the SRC. If Module 1b is initiated, the starting 
dose will be the same as the highest total daily dose being evaluated in Module 1a, administered twice 
daily (BID). Additional schedules may be evaluated that involve intermittent dosing per Module 1a or 1b, 
with scheduled weeks off to enable bone marrow recovery. 
The dose will be increased as appropriate for dose escalation in parallel in both schedule arms until MTD 
and RP2D are established. Dose escalation decisions will be based on the emerging safety and tolerability 
profile and clinical PK/PD data across the entire patient population in the study, presented, and discussed 
regularly at the SRC meetings.  
Patients in Module 1c (open only in one US center) will participate in a food-effect evaluation to assess 
potential differences in RP-3500 exposures and absorption following a standard high-fat meal (up to 
12 patients). Patients will receive a single dose of RP-3500 in the fed state on Day -3, followed by a 
single dose of RP-3500 in the fasted state on Day 1. Patients will continue on study following the dosing 
schedule of Module 1a (5/2) or Module 1b (3/4), at the highest evaluable dose level as agreed with the 
Investigator.  
At the time of Protocol Amendment 4, enrollment in Module 1c has been completed. The results 
demonstrated that administration of RP-3500 with a high-fat meal did not result in significant 
changes to RP-3500 PK that would be expected to impact tolerability or efficacy. Thus, for all 
patients enrolled as of Protocol Amendment 4, the fasting requirement for RP-3500 will be lifted. 
In Module 2, RP-3500 will be administered at a dose level of 160 mg QD on a 3/4 schedule, the RP2D 
and schedule for monotherapy as established in Module 1.  
In Module 3, the RP-3500 starting dose will be one dose level below the highest evaluated daily dose in 
Module 1a and given initially BID for 3 days only. Patients in Module 3 will initially receive continuous 
talazoparib at a starting dose of 0.5 mg QD administered orally and escalating BID doses of RP-3500 on 
days 5, 6 and 7 of every week. As of Protocol Amendment 4, intermittent weekly dosing schedules will 
be evaluated (eg, 1 week on/1 week off).   
In Module 4, RP-3500 will be administered QD at 3 different dose levels (80, 120, and 160 mg) initially 
in combination with 1000 mg/m2 gemcitabine. Gemcitabine will be administered on Days 1 and 8, and 
RP-3500 will be administered on Days 1 to 3 and 8 to 10 in a 21-day treatment cycle. Pending review of 
safety/tolerability data lower dose levels of gemcitabine and alternative dosing schedules may also be 
evaluated such as a 1 week on/1 week off dosing schedule of both drugs (this schedule will involve a 28-

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day treatment cycle). A Low Dose Gemcitabine (LDG) arm will also be evaluated involving Gemcitabine 
administration at doses of 100-300 mg/m2 (on Days 1 and 8)  in combination with RP-3500 at 120 mg 
QD on Days 1 to 2 and 8 to 9 (21-day treatment cycle). 
 
 
RP-3500, talazoparib, and gemcitabine dose adjustments and interruptions are allowed and will follow 
the recommendations provided in the corresponding sections. Treatment in all modules will continue 
until disease progression, intolerability of study drugs, Investigator decision, withdrawal of consent, 
protocol noncompliance or death. 
Study procedures: 
Study procedures will occur as outlined in the Schedules of Assessments for each module. Safety and 
tolerability will be followed by the Medical Monitor and evaluated by the SRC throughout the study. 
Assessments will include clinical and laboratory evaluations, information on adverse events (AEs), 
serious adverse events (SAEs), treatment-emergent adverse events (TEAEs), dose-limiting toxicities 
(DLTs), physical examinations (PEs), concomitant medications and procedures, vital signs, 
electrocardiograms (ECGs) and others.  
Tumor assessments: 
Patients must have a baseline tumor assessment by computed tomography (CT) or magnetic resonance 
imaging (MRI) scans of known sites of disease as clinically indicated. Positron emission tomography 
(PET)/CT may be used as clinically indicated. Additional radiological evaluation, such as diffusion 
weighted MRI (DW-MRI) or dynamic contrast enhanced MRI (DCE-MRI), may also be used to clarify 
observations with standard imaging. If the patient has had appropriate imaging scans (eg, routine clinical 
management) performed within 28 days prior to Cycle 1/Day 1, the results of those scans may be used if 
they are of diagnostic quality. Subsequent post-baseline tumor assessments will be performed following 
response evaluation criteria in solid tumors (RECIST) v1.1 guidelines. Response will be assessed by the 
Investigator. Radiological tests and other measurements used to evaluate efficacy should be stored at the 
site for up to 12 months after completion of the RP-3500-01 study for possible Independent Radiological 
Review assessment. If additional imaging is performed (eg, DCE-MRI), this should be continued to 
properly compare imaging sets. 
For follow-up tumor assessments, CT/MRI scans will be performed every 6 weeks (± 7 days) or sooner if 
clinically indicated, from start of treatment (Cycle 1/Day 1) for the first 3 assessments (first ~5 
months/22 weeks on treatment). Thereafter, tumor assessments must be performed every 9 weeks 
(± 7 days). Per RECIST v1.1, complete response (CR) or partial response (PR) should be confirmed; 
tumor imaging for confirmation of response must be performed at least 4 weeks after the first indication 
of response. The subsequent tumor imaging after the confirmation of response should be obtained per the 
original scheduled interval from the confirmatory scan (6 weeks ± 7 days during the first ~5 months of 
study treatment or every 9 weeks thereafter).  
For patients with prostate cancer enrolled in Module 2, radionuclide bone scans will also be required at 
baseline and subsequently at the same frequency as the RECIST tumor assessments as per the Prostate 
Cancer Working Group 3 (PCWG3) criteria (Appendix 9).  
 
 

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Tumor assessment should occur according to study schedule regardless of whether study drug therapy is 
interrupted. If a patient discontinues treatment for a reason other than disease progression, withdrawal of 
consent to study, lost to follow-up, or death, scans should continue at the specified intervals until 
progression is confirmed or until the start of subsequent anticancer treatment. In Modules 1, 2, 3, and 4, 
patients with progressive disease, who are clinically stable, may continue treatment after providing 
signed written consent, if the Investigator deems that it is in the patient’s best interest. The patient may 
continue receiving treatment in the absence of symptoms or signs indicating clinically significant disease 
progression: decline in performance status, and rapid disease progression or threat to vital organs 
requiring urgent medical intervention and significant, unacceptable, or irreversible drug-related toxicity. 
These patients will be categorized as “PD” and treated only if the investigational drug safety and 
tolerability is confirmed upon case presentation at SRC. 
Laboratory assessments: 
Blood samples will be collected in all modules to monitor safety and characterize the PK profile of 
RP-3500 when administered as a single agent and in combination with talazoparib or gemcitabine.  
 
 
If specific circulating tumor biomarkers including, but not limited to, cancer antigen 125 (CA-125) or 
prostate-specific antigen (PSA), are monitored as part of a patient’s standard of care to follow the course 
of their disease, this information will also be collected during Screening (or prior to the first dose on 
Cycle 1 Day 1) and at least once per cycle throughout treatment and at EOT or as per standard of care. 
For all patients with prostate cancer enrolled in Module 2 (and those without measurable disease enrolled 
in the other modules), PSA monitoring at baseline and on Day 1 of every cycle and at EOT will be 
mandatory as part of the evaluation of response per PCWG3 (Appendix 9). For patients with ovarian 
cancer enrolled in Module 2, CA-125 measurement will also be mandatory at baseline and on Day 1 of 
each cycle (through EOT) as part of the evaluation of response per the Gynecological Cancer Intergroup 
(GCIG) criteria. 
Blood samples for the analysis of 4β-hydroxycholesterol, a biomarker of CYP3A induction, and total 
cholesterol will be collected in patients in Module 1c. This analysis will be conducted at a single center 
in the US. 
Tumor tissue: 
To meet primary, secondary
 objectives, a recent archival tumor tissue sample with 
tumor cell content confirmed by center pathologist at >30% prior to shipping, must be provided. Sites 
should provide 20 unstained slides (5 μM), along with a hematoxylin and eosin (H&E) stained slide 
confirming >30% tumor content. The samples must be shipped to the central laboratory during the 
Screening Period through Cycle 1/Day 1 (+7 days). Patients who do not have archival tumor tissue that 
meets the specifications detailed in the Laboratory Manual should undergo a fresh tumor biopsy, prior to 
treatment, if it is considered safe to perform. If adequate archived tumor tissue is not available and/or a 
fresh biopsy cannot be safely performed, the patient may still be eligible with prior Sponsor approval. 
Please refer to Laboratory Manual for details on tumor sample requirements, collection, preparation, 
storage, and shipping procedures. 

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Safety assessments: 
AEs will be collected and recorded for each patient from the day of signing the ICF until 30 days after 
last study drug administration (or until the patient starts a new anticancer therapy, if sooner). Prior to 
receiving study drug, only AEs considered related to study procedures or SAEs need to be reported. 
Events that are not serious and not related to a study procedure that occur prior to receiving study drug 
are to be recorded as medical history. After receiving the first dose of study treatment, information about 
AEs and SAEs regardless of relationship to the study treatment are reported until 30 days after last study 
drug administration or until the patient starts a new anticancer therapy, whichever is earlier. Any SAEs 
that are assessed by the Investigator as related to study treatment should be reported indefinitely (ie, no 
end to the reporting period).  
All TEAEs and SAEs experienced by a patient will be monitored until the TEAE or SAE has resolved or 
returned to baseline or the Investigator has provided a rationale for the observed changes and/or has 
determined there is no expectation of further improvement, or until the patient is lost to follow-up or has 
died. 
Module 1: RP-3500 Single-Agent, Dose Escalation: 
Module 1 will be composed of 3 sub-modules:  
• 
Module 1a: 5 days on/2 days off dosing schedule 
• 
Module 1b: 3 days on/4 days off dosing schedule  
• 
Module 1c: Food-effect evaluation  
Module 1 Study Schema: 

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Module 1 dose escalation decisions will be governed by the Bayesian optimal interval (BOIN) design. 
Module 1a and Module 1b will proceed in parallel. Dose escalations will continue independently until the 
MTD or RP2D is determined for each schedule. 
Module 1 cycle duration and DLT observation periods will initially be 21 days (Cycle 1). Each dose 
escalation decision will be confirmed at the SRC review meeting at the end of each treatment cycle. Dose 
escalation decisions will be based on the emerging safety and tolerability profile across the entire patient 
population in the study. Clinical PK/PD data, if available, will contribute to the dose/schedule decisions. 
Intra-patient dose escalations will be allowed at the discretion of the Investigator and with Sponsor 
approval. 
Based on the mechanism of action of RP-3500, data from nonclinical animal testing and clinical data 
from other investigational ATRi agents, and preliminary clinical data from RP-3500, myelotoxicity is an 
anticipated toxicity and potential DLT following repeated RP-3500 administration. Periodic drug 
holidays may be required to allow for bone marrow recovery. Patients will be closely monitored during 
the study. Beyond the DLT period (Cycle 1), study drug interruptions will be allowed for up to 2 weeks. 
Dose interruptions and dose reductions will be carefully monitored by the SRC. In addition to the 
intermittent daily dosing schedules specified in Modules 1a and 1b, additional schedules including 
scheduled weeks off (eg, 2 weeks on/1 week off) will be evaluated with the aim to prevent myelotoxicity 
and avoid unscheduled dose holds, reductions, and transfusions. In the event that a 
3-weeks-on/1-week-off schedule is evaluated, the cycle length will be 28 days. The RP2D and schedule 
determination will be based on all available data at the conclusion of Module 1, including but not limited 
to, longer term tolerability of the repeated cycles, required therapy holidays and dose decreases or 

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transfusions, acute and chronic toxicities, and PK data.  
Blood samples will be collected throughout the study to closely monitor safety parameters. Blood 
samples will be collected prior to and after treatment to evaluate PK of RP-3500 in all Module 1 patients. 
Blood samples for the analysis of 4β-hydroxycholesterol, a biomarker of CYP3A induction, and total 
cholesterol will be collected in patients in Module 1c.  
 
 
 
 
 
 
 
Backfill cohorts (up to n=8 patients) at dose levels where the initial treatment effect was observed, may 
be employed based on agreement with the SRC to enable an earlier and better understanding of the 
variability in drug-related toxicity, clinical benefit, or PK. The objective of the backfill cohorts is to 
(1) aid in the assessment of possible anti-tumor activity in a subset of patients with a specific genomic 
abnormality or tumor type; (2) allow additional PK/PD evaluation and (3) further assessment of 
drug-related toxicities. Patients enrolled in the backfill cohorts will follow the SOA of the corresponding 
module and the assessment will be conducted accordingly. 
 
 
To avoid exposure of patients to sub-therapeutic doses, 
the backfill cohorts may only be initiated if there is evidence of biological activity (such as drug related 
toxicity) or there are data supporting the dose level is within the predicted therapeutic range (such as 
clinical benefit) or when the RP2D and schedule are established. 
 
 
Module 1a:  
Eligible patients in Module 1a will initially receive RP-3500 QD at a starting dose of 5 mg, at the 
5/2 dosing schedule. Dose escalation and de-escalation decisions will be based on the BOIN criteria and 
dose escalation and de-escalation rules as follows:  
• 
Dose escalation will progress with 1 patient per dose level with dose escalation increments of 
100% until pharmacologic activity is observed (level N in Dose Level Table presented 
below). At this point, sufficient patients will be enrolled at that dose level to ensure that 
safety and tolerability are assessed in at least 2 evaluable patients, before a decision for 
further escalation is made by the SRC.  
• 
Dose escalation will continue with increments of 20% to 70% (N+1), enrolling 3 to 
4 patients per cohort and dose decisions will depend on 2 or more evaluable patients 
completing the treatment cycle.  
• 
Non-compartmental analysis will be utilized to analyze the RP-3500 PK parameters 
throughout the dose escalation phase. If the median human PK exposure required for target 

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inhibition and efficacy at 24 hours in nonclinical models is exceeded, and pharmacologic 
activity is still not observed, the dose escalation increments will be reduced to 50% or less. 
Discretion taking into consideration the PK values and presence, or absence of tumor 
responses will contribute to the degree of dose escalation in the absence of safety signal.  
• 
If BOIN escalation criteria are met but Grade ≥3 drug-related toxicity (but not DLT) has 
been observed at the current or lower doses, escalation increments will be limited to 20-50%.  
• 
In the event of dose de-escalation, the next dose level will be at least 30% lower than the 
current dose (rounded down based on capsule strength) or de-escalated down to the highest 
previously tolerated dose based on review of the toxicity patterns by SRC. In addition to 
decreasing the daily dose level, dose de-escalation can involve a reduced frequency of dosing 
(eg, 2 weeks on/1 week off) at the same daily dose level.  
 
Dose Levels Table*:  
Dose Level 
5/2 Dose Schedule (Module 1a) 
3/4 Dose Schedule (Module 1b) 
Daily (mg) or % of 
previous dose increment 
Number of 
patients 
Daily (mg) or % of 
previous dose increment 
Number of 
patients 
1 ** 
5 mg 
1 
- 
- 
2 ** 
100% increment 
until level N 
1 
- 
- 
N 
(pharmacologic activity 
observed) 
Expand dose 
2+ 
- 
- 
N+1 
20-70 % increments 
or 
20-50% increment if 
Grade ≥3 drug-related 
toxicity 
3+ 
Same dose as 5/2 
schedule (Module 1a) for 
3 days only 
3+ 
N+2 
as above 
3+ 
20-70 % increments 
or 
20-50% increment if 
Grade ≥3 drug-related 
toxicity 
3+ 
N+3, etc. 
as above 
3+ 
as above 
3+ 
*Modules 1a and 1b schedules will progress independently. 
** Level 1 or 2 may be already level N if early pharmacologic activity is observed. 
Based on the outcome of PK evaluation in the initial dose levels (minimum of 3 dose levels), a 
consideration for BID) drug administration will be discussed with the SRC. The decision to dose BID 
will be based on patient outcomes (eg, absence of evidence of hematologic toxicity, tumor response, or 
other pharmacologic activity) and PK parameters such as, but not limited to, t½ <12 hours or a Cmax:Cmin 
ratio >10. The same dose escalation/de-escalation rules will apply for BID dosing cohorts. If BID dosing 
is initiated, the SRC can elect to continue enrolling patients on a daily dosing arm or cease enrollment on 
this arm based on the data collected. 
 

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Module 1b: 
Module 1b (3/4 schedule) may be initiated after a dose level that demonstrates pharmacologic activity in 
Module 1a is confirmed safe and tolerable by the SRC.  
Module 1b starting dose will be the highest daily dose being evaluated in Module 1a but administered 
only for 3 days each week. Initially, Module 1b will start with RP-3500 administered BID, but a QD 
schedule could be explored if significant toxicity is observed or PK data instructs. Module 1b will start 
with cohorts of 3 to 4 patients and dose increments as outlined in Dose Levels Table.  
Subsequent dose escalations will continue, enrolling 3 to 4 patients per cohort and dose decisions will 
depend on 2 or more evaluable patients completing the treatment cycle. Module 1b will follow the same 
safety rules and dose escalation and de-escalation described in Module 1a. 
Module 1c: (open only in one US center) 
Module 1c will evaluate the effect of food on the systemic exposure to RP-3500 following a single dose 
of RP-3500 administered under fed conditions, relative to a single dose of RP-3500 administered under 
fasted conditions when given to patients with advanced solid tumors.  
Module 1c will be initiated at a RP-3500 dose level approved by the SRC that has been determined safe 
and to have adequate pharmacologic activity. Up to 12 patients will be evaluated to generate data on the 
potential effects of food on RP-3500 exposures.  
On Day -3 and following an overnight fast, patients will be given a standard high-fat breakfast 
30 minutes prior to administration of a single dose of RP-3500. On Day 1, following an overnight fast, 
patients will receive the same RP-3500 dose in a fasted state. Patients will then continue on study 
following the dosing schedule of Module 1a (5/2) or Module 1b (3/4) at the highest evaluable dose level 
as agreed with the Investigator. If a BID dosing regimen is implemented, then BID dosing will be 
initiated on Day 2, following serial PK collections on Day 1. 
Module 2: RP-3500 Monotherapy to Establish Preliminary Efficacy in Patients with Tumors 
Carrying ATRi Sensitizing Mutations 
The purpose of the expansion cohorts in Module 2 is to better characterize the anti-tumor activity of 
RP-3500 at the RP2D and recommended schedule, when administered to patients with tumors assigned to 
pre-defined molecular subsets and to determine if the subsets warrant further development. Based on the 
results of Module 1, the selected RP2D for Module 2 is 160 mg QD, administered on a 3/4 schedule. 
Patients in Module 2 will be assigned into the following arms: 
• 
ARM 1: ER+/HER2- breast, ampullary, pancreas, prostate, bile duct, and gastroesophageal 
junction tumors with likely pathogenic/pathogenic gATM mutations  
• 
ARM 2: Leiomyosarcoma tumors with RNASEH2 loss or deleterious/likely deleterious 
BRCA2 mutations  
• 
ARM 3: Tumors with loss of other ATRi sensitizing biomarkers  
For Arm 1, patient enrollment will be based on local or central test results for pathogenic gATM 
mutations. For patients with ATM mutations identified by NGS in tumor or liquid biopsy samples 
without known germline mutation status, a blood sample will be collected for germline testing by either a 
local or a Sponsor-approved test to confirm the presence of a likely pathogenic/pathogenic gATM 
mutation prior to enrollment. The aim will be to enroll approximately 5 to 8 patients with each tumor 
type for a total of 42 patients initially. Up to 3 additional expansion cohorts (8 patients each) may be 

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The RP2D and schedule determination will be based on all available data at the conclusion of Module 3, 
including, but not limited to, longer term tolerability of the repeated cycles, required therapy holidays and 
dose decreases, transfusions, acute and chronic toxicities, and PK data of RP-3500 in combination with 
talazoparib. 
 
 
 
 
 
 
Backfill cohorts (up to n=8 patients) may be employed based on agreement with the SRC to enable an 
earlier and better understanding of the variability in drug combination-related toxicity, clinical benefit, or 
PK. The objectives of the backfill cohorts are to: (1) aid in the assessment of possible anti-tumor activity 
in a subset of patients with a specific genomic abnormality or tumor type, (2) allow additional PK/PD 
evaluation, and (3) further assess drug combination-related toxicities.
 
 
Module 3a: RP-3500 with Talazoparib Dose Escalation(s) 
Module 3a may begin after a dose level that demonstrates pharmacologic activity in Module 1a (Dose 
Levels Table, Level N). Initiation of Module 3a will be determined by the SRC and the RP-3500 starting 
dose will be one dose level below the highest evaluated daily dose in Module 1a but administered BID 
for 3 days only (Days 5, 6, and 7 of each week). Talazoparib will initially be administered continuously 
QD at a starting dose of 0.5 mg. As of Protocol Amendment 4, RP-3500 and talazoparib will be 
administered on an intermittent weekly schedule (eg, 1 week on/1 week off) at a talazoparib starting dose 
level of 0.25 mg. Additional schedules (eg. 1 week on/2 weeks off) will be tested as needed. 
Module 3 will start with RP-3500 BID administration, but a QD schedule could be explored if significant 
toxicity is observed or PK data instructs. 
Module 3 will start with cohorts of 3 to 4 patients.  
Dose escalation in Module 3a will continue as follows: 
• 
RP-3500 will be escalated at a 20-70% range. The escalation level will be determined upon 
discussion with SRC, with the actual increment based on evaluation of safety, tolerability, 
and PK/PD data from all patients in the study, capsule strength for down-rounding, and any 
other pertinent information.  
• 
If any patient experiences a Grade ≥3 drug-related toxicity that is not considered 
dose-limiting, RP-3500 dose escalation increments will be limited to 20-50% depending on 
the type and duration of the toxicity.  
• 
In the event of dose de-escalation, the next dose level will be at least 30% lower than the 
current dose (rounded down based on capsule strength) or de-escalated down to the highest 
previously tolerated dose based on review of the toxicity patterns by SRC. In addition to 
decreasing the daily dose level, dose de-escalation may also involve a reduction in the 

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number of weeks of dosing in a given cycle. 
• 
Once the RP2D for talazoparib 0.5 mg + RP-3500 is established, the talazoparib dose may be 
escalated to 0.75 mg QD with RP-3500 adjusted to at least 1 dose level below. Further 
escalation of talazoparib will progress only if the RP-3500 dose in the 0.5 mg talazoparib + 
RP-3500 combination is established at approximately 50% of Module 1b RP2D (3/4 
monotherapy) and if no significant, unacceptable, or irreversible toxicities, or DLTs are 
observed. This is to assure that a presumed meaningful RP-3500 dose (ie, 50% of the RP2D 
for monotherapy) is included in the combination. Consistently, further escalation to a 
maximum of 1 mg of talazoparib QD is only allowed if the RP-3500 RP2D dose in the 
0.75 mg talazoparib + RP-3500 dose level is established as approximately 50% of Module 1b 
RP2D (3/4 monotherapy). Prior to any increase in the dose of talazoparib, the SRC will 
review all the available safety data to ensure a dose escalation is safe and acceptable. 
• 
The dose of RP-3500 in Module 3 will not exceed the RP2D in Module 1b.  
In the event of drug interactions or unexpected PK findings additional PK/PD evaluation may be required 
to establish the most effective combination dose and schedule for RP-3500 and talazoparib.  
After the RP-3500 plus talazoparib RP2D and schedule are identified in Module 3, expansion cohorts in 
eligible patients (n=10-20) with tumor types/genotypes of specific interest based on observed clinical 
benefit, may be enrolled to confirm the safety and tolerability and further evaluate efficacy of the RP2D 
and schedule for the combination. 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
Module 4: RP-3500 and Gemcitabine Combination 
The primary objectives of Module 4 are to evaluate the safety and tolerability or RP-3500 when 
administered in combination with gemcitabine and to establish a safe and well-tolerated RP2D. 
Preliminary signs of efficacy will also be evaluated. Approximately 70 eligible patients will be enrolled. 
Eligible patients will initially receive 1000 mg/m2 intravenous (IV) gemcitabine on Days 1 and 8 and oral 
RP-3500 on Days 1 to 3 and 8 to 10 of a 21-day treatment cycle (2 weeks on/1 week off dosing schedule) 
in Arm 1. Three dose levels of RP-3500 will be evaluated, starting at 80 mg QD with escalations to 120 

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and 160 mg QD. A DL-1 of 800 mg/m2 gemcitabine or a DL-2 of 600 mg/m2 gemcitabine in combination 
with 80 mg RP-3500 may also be evaluated. Once a safe dose of gemcitabine in combination with 80 mg 
RP-3500 has been established, further escalation of RP-3500 (up to a maximum of 160 mg QD) may be 
pursued if recommended by the SRC.   
Due to the potential for strong synergy and selective enhancement of cytotoxicity in the appropriate 
tumor genetic backgrounds when combining low doses of gemcitabine with RP-3500, and in order to 
avoid dose-limiting neutropenia, a low dose gemcitabine (LDG) arm (Arm 2) evaluating a therapeutic 
daily dose level of RP-3500 (120 mg QD) in combination with low doses of gemcitabine (≤300 mg/m2) 
will also be evaluated. Consistent with preclinical study observations of comparable efficacy and better 
tolerability, RP-3500 will be administered on a 2 days on/5 days off schedule rather than a 3 days on/4 
days off schedule in the LDG arm. Eligible patients will initially receive gemcitabine on Days 1 and 8 in 
combination with 120 mg RP-3500 on Days 1 to 2 and 8 to 9 of a 21-day treatment cycle. Three dose 
levels of gemcitabine will be evaluated, starting at 100 mg/m2 with escalations to 200 and 300 mg/m2. A 
DL-1 with 80 mg RP-3500 in combination with 100 mg/m2 gemcitabine may also be evaluated. Once a 
safe dose level of gemcitabine in combination with RP-3500 on a 2 days on/5 days off schedule has been 
identified, a cohort evaluating that gemcitabine dose with RP-3500 on a 3 days on/4 days off schedule 
may be evaluated if recommended by the SRC.  
Additional dose combinations of gemcitabine and RP-3500 (gemcitabine doses between >100 to 500 
mg/m2, RP-3500 dose of up to 160 mg QD) may be tested as warranted by clinical safety/tolerability and 
efficacy data, as well as emerging nonclinical data, if approved in advance by the SRC. 
Due to expected overlapping hematologic toxicities of RP-3500 and gemcitabine, additional treatment 
schedules may also be evaluated, including reducing the consecutive days of RP-3500 dosing (treatment 
on D1-2 or D8-9) in Arm 1 or a 1 week on/1 week off schedule of both drugs (to enable bone marrow 
recovery in between gemcitabine doses) in Arms 1 and 2. In the event that a schedule of 1 week on/1 
week off is evaluated, the cycle length will be 28 days. The decision to evaluate these alternative 
treatment schedules will be driven by review of safety/tolerability data and will require SRC approval. 
All Module 4 dose escalation cohorts will enroll 3 to 4 patients per dose level and dose decisions will 
depend on 2 or more evaluable patients completing the treatment cycle. Dose escalation decisions will be 
governed by the BOIN design and confirmed at the SRC review meetings at the end of each DLT 
evaluation period.  

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Module 4 Study Schema: 
 
Dose Levels of RP-3500 + Gemcitabine 
Dose Level 
Cycle 
Arm 1 
-2* 
• 
RP-3500 80 mg QD (D1-3 and D8-10) 
• 
Gemcitabine 600 mg/m2 (D1 and D8) 
-1 
• 
RP-3500 80 mg QD (D1-3 and D8-10) 
• 
Gemcitabine 800 mg/m2 (D1 and D8) 
1 
(Starting dose level) 
• 
RP-3500 80 mg QD (D1-3 and D8-10) 
• 
Gemcitabine 1000 mg/m2 (D1 and D8) 
2 
• 
RP-3500 120 mg QD (D1-3 and D8-10) 
• 
Gemcitabine 1000 mg/m2 (D1 and D8) 
3 
• 
RP-3500 160 mg QD (D1-3 and D8-10) 
• 
Gemcitabine 1000 mg/m2 (D1 and D8) 
Arm 2 (Low Dose Gemcitabine) 
-1 
• 
RP-3500 80 mg QD (D1-2 and D8-9) 
• 
Gemcitabine 100 mg/m2 (D1 and D8) 
1 
 (Starting Dose Level) 
• 
RP-3500 120 mg QD (D1-2 and D8-9) 
• 
Gemcitabine 100 mg/m2 (D1 and D8) 
2 
• 
RP-3500 120 mg QD (D1-2 and D8-9) 
• 
Gemcitabine 200 mg/m2 (D1 and D8) 

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3 
• 
RP-3500 120 mg QD (D1-2 and D8-9) 
• 
Gemcitabine 300 mg/m2 (D1 and D8) 
* Additional lower dose levels of gemcitabine may be evaluated as warranted based on safety/tolerability data. Final 
decision to escalate or de-escalate will be made by the Safety Review Committee (SRC) based on the dose 
recommendation by the BOIN method, clinical assessment of toxicity profiles, and PK information observed thus 
far. 
In the event that the scheduled weeks of study drug holiday incorporated are insufficient for adequate 
recovery from hematologic toxicity, drug reduction and/or interruptions may be required. Beyond the 
DLT period (Cycle 1), dose reductions and up to 2 weeks study drug holiday will be allowed. Dose 
interruptions and dose reductions will be carefully monitored by the SRC. Final RP2D for the 
combination will be established with the SRC based on long-term observation of safety and tolerability 
of the combination beyond the initial DLT period. 
Blood samples will be collected throughout the study to monitor safety parameters. A limited set of blood 
samples will be collected prior to and after treatment to evaluate PK of RP-3500 in combination with 
gemcitabine.  
Backfill cohorts (up to 8 patients each) may be employed based on agreement with the SRC to: (1) aid in 
the assessment of possible anti-tumor activity in a subset of patients with a specific genomic abnormality 
or tumor type, and (2) further assess drug combination related toxicities.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  

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Dose-Limiting Toxicity Criteria (As Assessed During Module 1, Module 3, Module 4
 
 
Toxicity will be assessed using the National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) Version 5.0 unless otherwise specified. A toxicity will be considered dose-
limiting if it occurs during the first cycle and is deemed at least possibly related to study treatment. If 
multiple toxicities occur, the most severe toxicity will be used in the assessment. 
DLTs will be defined as follows: 
Treatment-related hematologic AEs: 
• 
Grade 4 neutropenia lasting at least 7 days (Module 4 only: or Grade 3 neutropenia which 
limits the administration of a scheduled gemcitabine dose) 
• 
Febrile neutropenia (defined as absolute neutrophil count [ANC] <1000/mm3 with a single 
temperature of ≥38.3ºC [101℉] or a sustained temperature of ≥38ºC [100.4 ℉] for >1 hour) 
• 
Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia associated with Grade ≥2 bleeding 
• 
Grade 4 anemia, or Grade 3 anemia requiring blood transfusion 
Treatment-related non-hematologic AEs:  
• 
Any Grade 3 of >24 hours duration  
• 
Any Grade 4 of any duration 
• 
Grade 4 vomiting/diarrhea of any duration that is refractory to supportive care 
• 
Exclusions: Grade 3 nausea/vomiting/diarrhea unless refractory to supportive care that lasts 
<3 days, and Grade ≥3 isolated laboratory abnormalities that respond to medical 
intervention. 

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a. Modules 1, 3, and 4 only: Note: If the patient has non-measurable disease but has an elevated 
tumor marker(s) (eg, PSA), patient enrollment may be discussed between the Investigator 
and the Sponsor to obtain formal approval. 
b. Module 2:  Note: a subset of patients with prostate cancer with non-measurable disease will 
be considered for enrollment if they have elevated PSA levels (>2 ng/mL) evaluable for 
response per PCWG3. 
 
6. Existing biomarker profile reported from a local test obtained in a CAP/CLIA, ISO or equivalent 
laboratory per institutional guidelines: 
• 
Modules 1, 3, 4
: 
− 
Documented and confirmed by central review of local NGS reports by PODS Group, 
deleterious or likely deleterious genomic alterations for at least 1 of the following genes: 
ATM, ATRIP, BRCA1, BRCA2, CDK12, CHTF8, FZR1, MRE11, NBN, PALB2, RAD17, 
RAD50, RAD51B/C/D, REV3L, RNAseH2A, RNAseH2B, SETD2, or other genes agreed 
upon between the Sponsor and Investigator. 
− 
Or documented complete loss of ATM or RNASEH2 protein expression by IHC.  
• 
Module 2 only: 
− 
ARM1: ER+/HER2- breast, ampullary, pancreas, prostate, bile duct, and 
gastroesophageal junction tumors with likely pathogenic/pathogenic gATM mutations 
− 
ARM 2: Leiomyosarcoma tumors with RNASEH2 loss or deleterious or likely 
deleterious BRCA2 mutations 
− 
ARM 3: Tumors with other ATRi sensitizing biomarkers: ATRIP, CHTF8, FZR1, 
MRE11, NBN, RAD17, RAD50, RAD51B/C/D, REV3L, SETD2, and other genes agreed 
upon between the Sponsor and Investigator 
 
 
 
 
Biomarker results must be reported by a CAP/CLIA or an ISO-accredited laboratory. Plasma or 
tumor tissue NGS results accepted for all genes except, ATM. Only tumor NGS or evidence of 
germline alterations are accepted for ATM. 
7. Provision of archival tumor tissue sample (or if adequate archival tumor tissue is not available, 
provision of a fresh biopsy if there is a lesion that can be safely biopsied). Note: If adequate 
archived tumor tissue is not available and/or a fresh biopsy cannot be safely performed, the 
patient may still be eligible with prior Sponsor approval.  
8. Ability to comply with the protocol and study procedures detailed in the Schedule of 
Assessments.  
9. Ability to swallow and retain oral medications. 
10. Acceptable organ function at Screening, as evidenced by the following laboratory data: 
a. Serum creatinine ≤1.5 × upper limit of normal (ULN) or calculated creatinine clearance 
≥60 mL/min using the Cockcroft-Gault equation or by 24-hour urine collection  

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b. Total bilirubin ≤1.5 × ULN or <3.0 × ULN if known Gilbert’s disease. 
c. Serum albumin ≥2.5 g/dL 
d. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × ULN unless 
liver metastases are present and thought to be a reason for AST/ALT elevation, in which case 
they must be ≤5 × ULN 
11. Acceptable hematologic function at Screening: 
a. No red blood cell or platelet transfusions or growth factors within:  
• 
Module 1: 7 days of the first dose of RP-3500 
• 
Modules 2, 3, 4 
: 14 days of first dose of study drug/s 
b. Hemoglobin:  
Module 1: ≥9.5 g/dL  
Modules 2, 3, 4 
: ≥10 g/dL 
c. ANC ≥1700 cells/mm3 
d. Platelet count ≥140,000 cells/mm3 
12. Negative pregnancy test for women of childbearing potential (WOCBP) at Screening (serum test 
only) and prior to the first dose of study drug. 
• 
WOCBP is defined as fertile, following menarche and until becoming post-menopausal 
unless permanently sterile. WOCBP, who are sexually active, and their partners must agree 
to use a highly effective form of contraception as detailed in Appendix 3 throughout their 
participation during study treatment and for 6 months (or 7 months for Module 3 patients) 
after the last dose of study drug(s).  
• 
Women are considered post-menopausal and not of childbearing potential if they have had 
no menses for 12 months without an alternative medical cause or are permanently sterile. 
Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral 
oophorectomy. A high follicle stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a postmenopausal state in women not using hormonal contraception 
or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, 
confirmation with more than one FSH measurement is required. 
13. Resolution of all toxicities of prior therapy or surgical procedures to baseline or Grade 1 (except 
for neuropathy, hypothyroidism requiring medication and alopecia which must have resolved to 

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Grade ≤2). Any prior radiation (with exceptions for palliative radiotherapy) must have been 
completed at least 7 days prior to the start of study drugs, and patients must have recovered from 
any acute adverse effects prior to the start of study treatment.  
14. Male patients with female partners of childbearing potential must follow a contraception method 
(oral contraceptives allowed) at least as conservative as Clinical Trial Facilitation Group (CTFG) 
recommendations (Appendix 3) during their participation in the study and for 6 months 
following last dose of study drug. Male patients must also refrain from donating sperm during 
their participation in the study and for 6 months following last dose of study drug. 
15. Life expectancy ≥12 weeks after the start of the treatment according to the Investigator’s 
judgment. 
Additional Inclusion Criteria for Module 1c: 
16. Ability to consume a high-fat meal and fast for 12 hours. 
 
 
 
  
Exclusion Criteria: 
1. Chemotherapy, small molecule anticancer or biologic anticancer therapy given within 14 days 
prior to first dose of study drug. For patients with breast or prostate cancer continuation of 
long-term luteinizing hormone-releasing hormone (LHRH) or gonadotrophin releasing hormone 
(GnRH) are allowed if these medications were prescribed for at least 4 months before trial entry.  
• 
Module 2 only: 
− 
Patients in Module 2 with ER+/HER2- breast cancer, if they are currently taking anti-
estrogen therapy, can remain on the same anti-estrogen therapy while on study. If a 
patient has been off anti-estrogen therapy for >28 days, they should not restart.   
2. History or current condition (such as transfusion-dependent anemia or thrombocytopenia), 
therapy, or laboratory abnormality that might confound the study results, or interfere with the 
patient’s participation for the full duration of the study treatment. 
3. Prior therapy with an ATR or DNA-dependent protein kinase (DNA-PK) inhibitor. 
a. Module 4 only: 
− 
Prior therapy with a gemcitabine-containing regimen as the most recent prior line of 
therapy (prior gemcitabine is allowed if there is at least one intervening therapy). 
4. Known hypersensitivity to any of the ingredients of RP-3500.  
5. Life-threatening illness, medical condition, active uncontrolled infection, or organ system 
dysfunction (such as coagulopathy, encephalopathy or ascites requiring drainage within 4 weeks 
prior to enrollment) or other reasons which, in the Investigator’s opinion, could compromise the 
patient’s safety, or interfere with or compromise the integrity of the study outcomes.  
6. Uncontrolled, symptomatic brain metastases. Patients with previously treated brain metastases 
may participate provided the metastases are stable (without evidence of progression by imaging 
for at least 4 weeks prior to the first dose of study drug and any neurologic symptoms are 

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Investigational Product, Dosage and Mode of Administration: 
Study drug administration instructions and a dosing diary will be provided to patients to support study 
drug home dosing. 
Twelve patients in Module 1c received a single dose of RP-3500 in a fed and fasted state to determine the 
need for a fasting requirement prior to RP-3500 administration in subsequent patients and in subsequent 
modules. At the time of Protocol Amendment 4, enrollment in Module 1c has been completed. The 
results demonstrated that administration of RP-3500 with a high-fat meal did not result in 
meaningful changes to RP-3500 PK that would be expected to impact tolerability or efficacy. Thus, 
for all patients enrolled on Protocol Amendment 4, the fasting requirement for RP-3500 will be 
lifted. 
In all modules, RP-3500 is to be orally self-administered with approximately 240 mL (~8 oz) of water. 
Patients will be initially instructed to take their RP-3500 dose in the morning at approximately the same 
time each day.   
In Module 1a, RP-3500 will be initially administered, QD, at a starting dose of 5 mg, then as appropriate 
for dose escalation level until RP2D is established. In Module 3 patients will initially receive 0.5 mg of 
talazoparib QD continuously throughout each 21-day treatment cycle, and RP-3500 will be orally 
administered BID on Days 5, 6, and 7 of every week. As of Protocol Amendment 4, RP-3500 and 
talazoparib will be administered on an intermittent weekly schedule (eg, 1 week on/1 week off).   
The results from initial PK/PD/efficacy data in Module 1 will instruct dosing levels and schedule for 
Modules 2, 4
. 
In Module 2, RP-3500 will be administered at a dose level of 160 mg QD (3/4), and the schedule and 
dose will follow dose modifications recommendations. 
In Module 4 Arm 1, gemcitabine will be administered initially at a dose of 1,000 mg/m2 IV on Days 1 
and 8 in combination with oral RP-3500 on a 3/4 (Days 1 to 3 and 8 to 10) schedule in a 21-day treatment 
cycle. In Arm 2 (LDG), gemcitabine will be administered at escalating doses from 100-300 mg/m2 on 
Days 1 and 8 in combination with RP-3500 on a 2/5 (Days 1 to 2 and 8 to 9) schedule (21-day treatment 
cycle). A 1 week on/1 week off schedule of both drugs may also be evaluated with either RP-3500 dosing 
schedule (3/4 or 2/5).  
 
 
The results of initial PK analysis and RP-3500 half-life from QD dosing will determine the subsequent 
recommendations for daily dosing frequency. If a BID dosing schedule is evaluated, the dose will be 50% 
of the highest QD dose currently being evaluated and should be taken approximately 12 hours apart. Any 
adjustments to the proposed schedule or mode of administration will be discussed and confirmed with 
SRC and protocol and ICF amended if required.  
Dose interruptions and dose reduction to manage toxicities are allowed and will be carefully monitored 
by the SRC. Beyond the DLT period (Cycle 1) dose reductions and up to 2 weeks study drug holiday will 
be allowed. Periodic drug holidays may be required to allow for bone marrow recovery. Patients will be 
monitored weekly during Cycle 1, on Day 1 and Day 15 from Cycle 2 through Cycle 4, at the start of 
each cycle and as required.  

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Duration of Treatment  
Treatment will continue until disease progression by RECIST v1.1 criteria or PCWG3 for patients with 
prostate cancer in Module 2 
, intolerability of study 
drug(s), Investigator decision, consent withdrawal, start of a non-study anticancer treatment, protocol 
noncompliance or death. Patients will have a Survival Follow-Up assessment that will be done via 
telephone (or standard method used by participating centers and agreed with Sponsor) 3 months (± 2 
weeks) following the last dose unless the patient withdraws consent to the study. In Modules 1 to 4, 
patients with progressive disease by RECIST v1.1 (or PCWG3 for patients with prostate cancer) criteria, 
who are clinically stable, may continue treatment after providing signed written consent, if the 
Investigator deems that it is in the patient’s best interest. The patient may continue receiving treatment in 
the absence of symptoms or signs indicating clinically significant disease progression; decline in 
performance status; rapid disease progression or threat to vital organs requiring urgent medical 
intervention and significant, unacceptable, or irreversible drug-related toxicity 
. These 
patients will be categorized as “PD” and treated only if the investigational drug safety and tolerability is 
confirmed upon case presentation at SRC. 
Endpoints: 
Safety: 
• 
DLTs 
• 
Incidence of TEAEs, treatment-related TEAEs, TEAEs leading to death, SAEs, 
treatment-related SAEs, TEAEs leading to study drug discontinuation, TEAEs leading to 
dose modifications, and TEAEs leading to study discontinuation summarized by system 
organ class (SOC) and MedDRA preferred term (PT). 
• 
Changes in clinical laboratory parameters (hematology, chemistry, urinalysis), CTCAE 
graded laboratory toxicities, vital signs, ECOG performance status, ECG parameters, PEs 
and usage of concomitant medications and procedures 
• 
4β-hydroxycholesterol, a biomarker of CYP3A induction, will be evaluated at a 
pharmacologically active dose level 
Efficacy: 
• 
Overall response rate: best response of CR or PR, based on Investigator’s assessment using 
RECIST v1.1 criteria, or response in CA-125 or PSA (for patients with prostate cancer 
without measurable disease) as per GCIG or PCWG3. 
• 
Objective response rate (ORR): confirmed best response of CR or PR, based on 
Investigator’s assessment using RECIST v1.1  
• 
Duration of objective response (DOR): based on Investigator’s assessment using RECIST 
v1.1  
• 
Clinical benefit rate: CR + PR + stable disease [SD] ≥4 months, based on Investigator’s 
assessment using RECIST v1.1, CA-125 response by GCIG criteria, or PSA response based 
on PCWG3 (for patients with prostate cancer without measurable disease).  
• 
Progression-free survival time (PFS) and rate of PFS at 6 months, based on Investigator’s 
assessment using RECIST v1.1  

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Pharmacokinetics: 
Blood samples will be drawn to determine RP-3500 and talazoparib PK parameters. Blood samples will 
be collected at the timepoints outlined in each module. Blood samples for the analysis of 4β-
hydroxycholesterol, a biomarker of CYP3A induction, and total cholesterol will be collected in patients 
in Module 1c. The PK of gemcitabine will not be assessed in this study. 
 
 
 
 
 
 
 
Statistical Methods 
Sample Size Calculation 
The maximum total number of patients exposed across Modules 1 to 4 will be 451. The maximum 
number of patients across Modules 1 and 3 will be 190. Modules 1 and 3 will depend on the number of 
dose escalations and include up to 8 patients enrolled in any of the backfill cohorts. The maximum 
number of patients included in the assessment of efficacy in Module 2 will be 191 (including expansion 
cohorts). This will consist of an initial total sample of 143 patients across 3 different arms and genotype 
subsets, followed by potentially up to 48 patients from 6 cohort expansions based on observation of 
efficacy in specific tumor types/genotypes. The number of patients enrolled in Module 4 will be 
approximately 70.
 
The planned sample size, and the success criteria for Arm 1 and Arm 2 of Module 2, based on the overall 
response rate (RECIST v1.1, GCIG, and PCWG3), is described in the table below. 
Module 2 Efficacy Cohort Success Criteria for Arm 1 and Arm 2 
Arm 
Total 
N 
Success 
Criteria for 
Overall 
Response Rate 
p0 
p1 
Futility n 
Futility Criteria 
Pet-p0 
1 
42 
≥8/42 (19%) 
0.10 
0.25 
14 
≤1/14 (7%) 
0.58 
2 
21 
≥5/21 (24%) 
0.10 
0.32 
11 
≤1/11 (9%) 
0.70 
n = number of patients required for assessment of futility; N = total number of patients required for the final 
analysis if futility criteria is not met; p0 = the null hypothesis for ORR, the minimal level of efficacy required; p1 
= the alternative hypothesis for ORR, the desired level of efficacy; Pet-p0 = probability of early termination with 
a true ORR of p0  
Success criteria are defined as the total number of responses required to reject the null hypotheses at the 
final analysis. The futility criteria are defined as the total number of responses that would lead to 
cessation of enrollment in that arm.  
All designs have 1-sided alpha of <5% and ≥80% power utilizing a 2-stage design. 
The number of patients in each arm was determined by hypothesized efficacy specific to each arm that 
would warrant further development. Based on the rejection of a null hypothesis for a minimal response 

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rate, arm-specific success criteria are defined in terms of the number of responses needed to be observed, 
from the required number of patients. Due to preliminary Module 1 results showing prolonged stable 
disease and slow declines in tumor size in patients with ATM mutant tumors, the futility criteria will also 
take into consideration of clinical benefit rate in determining whether the study should continue to fulfill 
enrollment with the target sample size. The final success criteria for the hypothesis testing may be 
adjusted to ensure the overall type I error is reasonably controlled. 
Sensitivity analyses will be performed to assess the effect of including Module 1 efficacy patients who 
met the eligibility criteria of Module 2. 
The initial planned sample size for Arm 3 is 80. Due to the heterogeneity of this patient population, no 
formal hypothesis testing will be performed for Arm 3 of Module 2. If a cohort expansion is added based 
on efficacy signal in specific tumor types/genotypes, only descriptive statistics will be provided for 
hypothesis generating purpose.   
Module 2 expansion cohorts with up to 8 patients per cohort may be enrolled. Therefore, the maximum 
number of patients will be 66 for Arm 1 (up to 3 expansion cohorts), 21 for Arm 2, and 104 for Arm 3 
(up to 3 expansion cohorts). No formal hypothesis testing will be performed at the conclusion of the 
expansion cohorts. 
The following analysis populations will be used: 
• 
The primary analysis population for dose decisions within Modules 1, 3, 4
 will be the 
DLT Evaluable Population consisting of patients who receive at least 80% of planned total 
doses of RP-3500 (Modules 1
), both RP-3500 and talazoparib (Module 3), or 80% of 
RP-3500 and 100% of gemcitabine (Module 4); complete all required safety evaluations and 
are observed through the end of Cycle 1; or patients who experience a DLT. This population 
will be applied to dose escalation decisions in Modules 1, 3, 4
. 
• 
The Efficacy Population used for the assessment of efficacy for Phase 2 module (Module 
2), will consist of all patients who received at least 1 dose of RP-3500, evaluable for 
response by RECIST v1.1 and/or GCIG CA-125 criteria or PCWG3 PSA criteria or 
discontinued early due to clinical progression or death prior to any post-baseline tumor 
assessment. The Efficacy Population used for the assessment of efficacy for Phase 1 modules 
(Modules 1, 3, 4
) will consist of all patients who receive at least 1 dose of RP-3500, 
are evaluable for post-baseline response by radiographic tumor assessment and/or tumor 
marker assessment by GCIG CA-125 criteria or PCWG3 PSA criteria. 
• 
The Safety Population, used for the assessment of overall safety and tolerability, will 
consist of all patients who receive at least one dose of RP-3500. 
• 
The Pharmacokinetic Population, used for the assessment of PK endpoints, will consist of 
all patients who have sufficient PK RP-3500 (and talazoparib where applicable) 
concentration data recorded to derive PK endpoints. 
The primary efficacy endpoint of overall response rate is defined as the proportion of patients with best 
response of CR or PR according to RECIST v1.1 criteria based on the Investigator’s assessment, 
 
 CA-125 response based on GCIG criteria, or PSA response based on PCWG3 (for 
patients with prostate cancer without measurable disease). For a tumor marker responder, there must also 
be no evidence of radiologic or clinical progression prior to or within 4 weeks of the initial response. 
Depending on responses seen, a central review of all images may also be performed by an independent 
reviewer as a sensitivity analysis. More details on the statistical analysis can be found in the Statistical 

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Section. 
Safety Analysis 
All AEs will be listed, including the verbatim description and MedDRA PT and system organ class 
(SOC). TEAEs are defined as those occurring after the first dose of study drug and within 30 days 
following the cessation of treatment or until start of new anticancer therapy, whichever is earlier. 
Incidence of TEAEs, treatment-related TEAEs, TEAEs leading to death, SAEs, treatment-related SAEs, 
TEAEs leading to study drug discontinuation, TEAEs leading to dose modifications, and TEAEs leading 
to study discontinuation will be evaluated by dose and schedule for each Module and pooled across 
Modules 1 and 2 where applicable for the Safety Population. 
TEAEs will be further summarized by severity (according to NCI CTCAE Version 5.0). Changes in 
clinical laboratory parameters (hematology, chemistry, urinalysis), CTCAE graded laboratory toxicities, 
vital signs, ECOG performance status, ECG parameters, physical examinations and usage of concomitant 
medications and procedures. In addition, DLTs will be summarized by schedule and Cycle 1 dose level in 
Modules 1, 3, 4
 for the DLT Evaluable Population. 
PK Analysis: 
PK parameters for RP-3500 and talazoparib (when applicable) will be calculated using non-
compartmental analysis or modeling methods as well as using a population PK model: area under the 
concentration-time curve (AUC) from time 0 to last quantifiable concentration (AUC0-last); AUC from 
time 0 to 8 hours post dose (AUC0-8); AUC from time 0 to infinity (AUC0-inf); maximum observed 
plasma concentration (Cmax); time to reach Cmax (tmax); and terminal elimination half-life (t1/2) will be 
calculated along with additional parameters as needed. 
The effect of food on exposure to RP-3500 will be assessed by a comparison of geometric mean ratios 
(GMR) and the 90% confidence intervals of AUC0-last, AUC0-inf and Cmax.  
The effect of gemcitabine or talazoparib on the PK of RP-3500 will be assessed as a co-variate in the 
population PK model where appropriate. 
 
 
 
 
 
 
 

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2. 
TABLE OF CONTENTS  
1. 
SYNOPSIS ...................................................................................................................2 
2. 
TABLE OF CONTENTS ...........................................................................................34 
APPENDIX 1. RESPONSE EVALUATION CRITERIA IN SOLID TUMORS, VERSION 
1.1  ............................................................................................................................35 
APPENDIX 3. CONTRACEPTIVE GUIDELINES ..................................................................37 
APPENDIX 4.  CONCOMITANT MEDICATIONS ASSOCIATED WITH A RISK OF 
QTC INTERVAL PROLONGATION AND/OR TORSADES DE POINTES .........38 
APPENDIX 5. STRONG CYP3A INHIBITORS AND INDUCERS, P-GP INHIBITORS, 
AND BCRP INHIBITORS .........................................................................................40 
APPENDIX 7. EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE 
STATUS .....................................................................................................................42 
APPENDIX 9. RESPONSE EVALUATION BASED ON PROSTATE CANCER 
WORKING GROUP 3 CRITERIA ............................................................................43 
APPENDIX 10. GYNECOLOGICAL CANCER INTERGROUP DEFINITIONS FOR 
RESPONSE AND PROGRESSION IN PATIENTS WITH OVARIAN 
CANCER ....................................................................................................................45 

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APPENDIX 1. 
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS, 
VERSION 1.1 
Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking 
as reference the baseline sum diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of the 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 
progressions). 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD, taking as reference the smallest sum diameters while on study. 
Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). 
Note: If tumor markers are initially above the upper normal limit, they must normalize for a patient to 
be considered in complete clinical response. 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression 
of existing non-target lesions. Unequivocal progression should not normally trump target lesion 
status. It must be representative of overall disease status change, not a single lesion increase. 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the treating 
physician should prevail in such circumstances, and the progression status should be confirmed at a 
later time by the review panel (or Principal Investigator). 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for PD the smallest measurements recorded since the 
treatment started). The patient’s best response assignment will depend on the achievement of both 
measurement and confirmation criteria. 
Table 1: 
For Patients with Measurable Disease (ie, Target Disease) 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Requireda 
CR 
CR 
No 
CR 
>4 wks. Confirmationb 
CR 
Non-CR/Non-PD 
No 
PR 
>4 wks. Confirmationb 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-PD/not 
evaluated 
No 
PR 

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Target Lesions 
Non-Target Lesions 
New Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Requireda 
SD 
Non-CR/Non-PD/not 
evaluated 
No 
SD 
Documented at least once 8 
wks. from first dose of study 
medicationb 
PD 
Any 
Yes or No 
PD 
No prior SD, PR, or CR 
Any 
PDc 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Abbreviations: CR = complete response; PD = progressive disease; PR = partial response; RECIST = Response 
Evaluation Criteria in Solid Tumors; SD = stable disease  
a See RECIST v1.1 manuscript for further details on what is evidence of a new lesion [Eisenhauer 2009]. 
b Only for non-randomized trials with response as primary endpoint. 
c In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease progression. 
Note: Patients with a global deterioration of health status requiring discontinuation of treatment without objective 
evidence of disease progression at that time should be reported as “symptomatic deterioration.” Every effort should be 
made to document the objective progression even after discontinuation of treatment. 
 
Table 2: 
For Patients with Non-Measurable Disease (ie, Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PDa 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
Abbreviations: CR = complete response; PD = progressive disease; SD = stable disease 
a Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used as an endpoint 
for assessment of efficacy in some trials so to assign this category when no lesions can be measured is not a

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APPENDIX 3. CONTRACEPTIVE GUIDELINES  
Patients of childbearing potential, who are sexually active, and their partners must agree to the 
use of a highly effective form of contraception throughout their participation during the study 
treatment and for 6 months (or 7 months for Module 3 female patients) after the last dose of 
study drug(s): 
• Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation: 
− Oral route 
− Intravaginal route 
− Transdermal route 
• Progestogen-only hormonal contraception associated with inhibition of ovulation: 
− Oral 
− Injectable 
− Implantable 
• Intrauterine device 
• Intrauterine hormone-releasing system 
• Bilateral tubal occlusion 
• Vasectomized partner 
• Sexual abstinence if it is the preferred and usual lifestyle of the patient 
Source: Clinical Trials Facilitation and Coordination Group (CTFG) 2014.  
 

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APPENDIX 4.  
CONCOMITANT MEDICATIONS ASSOCIATED WITH 
A RISK OF QTC INTERVAL PROLONGATION 
AND/OR TORSADES DE POINTES 
RP-3500 has not demonstrated adverse effects on QT-prolongation in studies to date, however 
caution is advised when administering RP-3500 with any drug that may prolong QT. 
A vast number of medications prolong the QT interval. They are preferably classified based on 
the degree of QT prolongation they induce. This is specifically medication dependent. For 
example, many commonly used medications, such as diphenhydramine and azithromycin, exhibit 
QT-prolonging effects. However, the degree of QT prolongation is not severe enough to warrant 
caution in healthy patients. These medications bind to the human ether-related gene (hERG) 
channels and reduce electrical conduction through the potassium ion channels. This results in 
delayed repolarization of the heart.  
Caution is advised when combining QT-prolonging medications or when using these 
medications in patients with electrolyte abnormalities. Below is a list of potential medications 
that may prolong QT interval. Patients receiving medications classified as “know risk” should be 
excluded. Please reach out to the Medical Monitor prior to enrolling any patient on RP-3500 or 
starting them on new medication while on study that you believe may prolong QT.  Additionally, 
consulting with your local pharmacist is advised. 

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Note:  Known risk of torsades de pointes (TdP): These drugs prolong the QT interval and are clearly associated with 
a known risk of TdP, even when taken as recommended and should be excluded. Possible risk of TdP: These drugs 
can cause QT prolongation but lack evidence for a risk of TdP when taken as recommended. Conditional risk of 
TdP: These drugs could cause TdP only under certain conditions, such as excessive dosing, electrolyte imbalance, 
and interacting with other drugs that can cause TdP. Alternatives: Drugs that at this point have not been linked to 
clinically significant QTc prolongation. (Please see http://crediblemeds.org for an exhaustive list.)  
Ondansetron is only prohibited if administered as a single intravenous dose of >16 mg. Oral administration is 
allowed. 
Source: Porta-Sánchez 2017 
 

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APPENDIX 5. STRONG CYP3A INHIBITORS AND INDUCERS, P-GP 
INHIBITORS, AND BCRP INHIBITORS 
Table 3: 
Strong CYP3A Inhibitors 
Inhibitor 
Therapeutic Class 
ritonavir 
Protease Inhibitors 
cobicistat (GS-9350) 
None 
ketoconazole 
Antifungals 
troleandomycin 
Antibiotics 
telaprevir 
Antivirals 
itraconazole 
Antifungals 
indinavir 
Protease Inhibitors 
voriconazole 
Antifungals 
mifepristone 
Antiprogestins 
clarithromycin 
Antibiotics 
posaconazole 
Antifungals 
telithromycin 
Antibiotics 
grapefruit juice  
Food Products 
ceritinib 
Kinase Inhibitors 
conivaptan 
Diuretics 
nefazodone 
Antidepressants 
nelfinavir 
Protease Inhibitors 
saquinavir 
Protease Inhibitors 
ribociclib 
Kinase Inhibitors 
idelalisib 
Kinase Inhibitors 
boceprevir 
Antivirals 
 
Table 4: 
Strong CYP3A Inducers 
Inducers 
Therapeutic class 
rifampin 
Antibiotics 
mitotane 
Other Antineoplastics 
avasimibe 
Other Antilipemics 
rifapentine 
Antibiotics 
apalutamide 
Antiandrogens 

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Inducers 
Therapeutic class 
ivosidenib 
Cancer Treatments 
phenytoin 
Anticonvulsants 
carbamazepine 
Anticonvulsants 
enzalutamide 
Antiandrogens 
St John's Wort extract 
Herbal Medications 
lumacaftor 
Cystic Fibrosis Treatments 
phenobarbital 
Anticonvulsants 
P-gp Inhibitors: 
amiodarone, carvedilol, clarithromycin, dronedarone, itraconazole, lapatinib, propafenone, 
quinidine, ranolazine, ritonavir, telaprevir, verapamil 
BCRP Inhibitors:  
curcumin, cyclosporine A, eltrombopag 
 

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APPENDIX 7. EASTERN COOPERATIVE ONCOLOGY GROUP 
PERFORMANCE STATUS 
Description 
Grade 
Fully active, able to carry on all pre-disease performance without restriction. 
0 
Restricted in physically strenuous activity, but ambulatory and able to carry out work of 
a light or sedentary nature, (ie, light housework, office work). 
1 
Ambulatory and capable of all self-care but unable to carry out any 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 any self-care. Totally confined to bed or chair. 
4 
Dead. 
5 
Source: Oken 1982 
 

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APPENDIX 9. RESPONSE EVALUATION BASED ON PROSTATE 
CANCER WORKING GROUP 3 CRITERIA 
The Response Evaluation Criteria in Solid Tumors (RECIST) guidelines (version 1.1) are 
outlined in Appendix 1 and will be utilized for evaluation of response in patients with prostate 
cancer with measurable and non-measurable disease involving soft tissue lesions. A modification 
from standard RECIST 1.1 is that bone lesions will not be recorded as target or non-target 
lesions for the assessment. 
In addition to RECIST 1.1, patients with prostate cancer will be evaluated by the Prostate Cancer 
Working Group (PCWG3) criteria for assessment of bone progression and prostate-specific 
antigen (PSA) response as described by Scher 2016. 
Bone Lesions 
The presence or absence of bone metastasis will be assessed at baseline by 99mTc-methylene 
diphosphonate radionuclide bone scintigraphy. The total number of bone lesions will be 
recorded. 
Assessment for progression: 
• A minimum of two or more new lesions compared with the baseline bone scan after 
the 12-week flare window. 
• If the new lesions occur within the first 12 weeks of treatment, assessment of 
progression requires a confirmatory scan performed 6 or more weeks later showing 
two additional new lesions compared with the first follow-up scan to rule out 
pseudoprogression (2+2 rule).  
• If at least two additional new lesions are seen on the next (confirmatory) scan 
performed after the 12-week flare window, the date of progression is the date of the 
first post-treatment scan, when the first two new lesions were documented. 
• Changes in intensity of uptake alone do not constitute either progression or 
regression. 
PSA 
For patients with nonmeasurable disease, PSA measurements will be used to assess response. To 
be evaluable for PSA response PSA levels must be >2 ng/mL at the most recent assessment and 
must be rising as determined by a sequence of increasing values at a minimum of 1-week apart 
prior to treatment start. 
Assessment for response: 
• Confirmed PSA response is defined as ≥ 50% reduction in PSA from baseline to 
lowest post-baseline PSA result, with a consecutive assessment conducted at least 
3 weeks later. 
Assessment for progression: 

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• PSA progression is defined as a PSA increase ≥25% and ≥2g/mL above the nadir (or 
baseline for patients who did not have a decline in PSA), confirmed by a second 
increasing value at least 3 weeks later. 
• A PSA rise within the first 12 weeks of therapy in the absence of evidence of 
confirmed radiologic progression will not be used as a criterion for progression. 
Reference 
Scher HI, Morris MJ, Stadler WM, Higano C, Basch E, Fizazi K, et al; Prostate Cancer Clinical 
Trials Working Group 3. Trial design and objectives for castration-resistant prostate cancer: 
updated recommendations from the Prostate Cancer Clinical Trials Working Group 3. J clin 
Oncol. 2016;34(12):1402-18. 

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APPENDIX 10. 
GYNECOLOGICAL CANCER INTERGROUP 
DEFINITIONS FOR RESPONSE AND PROGRESSION 
IN PATIENTS WITH OVARIAN CANCER 
For patients with ovarian cancer with elevated CA-125 levels, response evaluation will include 
cancer antigen 125 (CA-125) in addition to Response Evaluation Criteria in Solid Tumors 
(RECIST) v1.1 criteria as per Gynecological Cancer Intergroup (GCIG) criteria [Rustin 2011]. 
Definition of Response by CA-125 
• A ≥50% reduction in CA-125 levels from a pretreatment sample. The response must 
be confirmed and maintained for at least 3 weeks (note that GCIG recommends 
maintenance for at least 28 days; a modification was made based on the 3-week cycle 
length in this study). Patients can be evaluated for a CA-125 response only if they 
have a pretreatment sample that is at least twice the upper limit of the reference range 
and within two weeks before starting treatment. 
• Intervening samples and the confirmatory sample must be less than or equal to the 
previous sample (within an assay variability of 10%). 
• The date when the CA-125 level is first reduced by 50% is the date of the CA-125 
response. 
• A CA-125 complete response can occur if CA-125 levels fall to within the reference 
range. 
Definition of Progression by CA-125  
• For patients with elevated CA-125 pre-treatment that normalizes or for patients with 
CA-125 in the normal range at baseline: CA-125 at least 2 times the upper limit of the 
reference range on 2 occasions at least 1 week apart. 
• For patients with elevated CA-125 pre-treatment which never normalizes: CA-125 at 
least 2 times the nadir value on 2 occasions at least 1 week apart. 
• Progressive disease (PD) by objective change in tumor size should always take 
precedence over changes in CA-125 should it occur first. If measurable disease is 
reducing in size but the CA-125 suggests progression the patient should remain on 
treatment.  
• CA-125 progression will be assigned the date of the first measurement that meets the 
above criteria. 
Note: CA-125 progression in the absence of radiographic or other clinical evidence of 
progression will not be sufficient criteria for treatment discontinuation in this study. 
Patients are not evaluable by CA-125 if they have received mouse antibodies (unless the assay 
used has been shown not to be influenced by human antimouse antibody) or if there has been 
medical and/or surgical interference with their peritoneum or pleura during the previous 28 days. 

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Evaluation of Best Overall Response by Combined CA-125 and RECIST 1.1 Criteria 
• If patients have a CA-125 response but have PD by RECIST within 28 days of the 
CA-125 response, they will be classified as PD.  
• Patients whose best response by RECIST is stable disease (SD) but who have a 
CA-125 response will be classified as CA-125 responders 
• For a patient to be classified as a complete responder according to RECIST, CA-125 
levels must be within the normal range 
Table 1: 
For Patients with Measurable Disease 
 
 
Table 2: 
For Patients Without Measurable Disease 
 

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Reference 
Rustin GJS, Vergote I, Elizabeth E, Pujade-Laurane E, Quinn M, Thigpen T, et al; 
Gynecological Cancer Intergroup. Definitions for response and progression in ovarian cancer 
clinical trials incorporating RECIST 1.1 and CA 125 agreed by the Gynecological Cancer 
Intergroup (GCIG). Int J Gynecol Cancer. 2011; 21(2):419-2.