Phase 1b/2 Study of ATR InhibiTor RP-3500 and PARP Inhibitor Combinations in Patients With Molecularly Selected Cancers (ATTACC)
Phase: PHASE1
Conditions: Advanced Solid Tumor, Adult
Sponsor: Repare Therapeutics

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CLINICAL STUDY PROTOCOL SYNOPSIS 
Title: 
Phase 1b/2 Study of ATR InhibiTor RP-3500 and PARP 
Inhibitor Combinations in Patients with Molecularly Selected 
Cancers (ATTACC) 
 
Protocol Number: 
RP-3500-03 
Study Drug Names: 
RP-3500, niraparib, olaparib 
Development Phase: 
1b/2 
Sponsor: 
Repare Therapeutics 
7210 Frederick-Banting 
Suite 100 
St-Laurent, Quebec, H4S 
2A1 Canada 
101 Main Street 
16th Floor, Suite 1650 
Cambridge, MA 02142   
USA 
Medical Monitor: 
Gabriela Gomez, M.D., M.B.A. 
Indication: 
Advanced solid tumors 
IND Number: 
146,280 
Date of Protocol: 
Date of Amendment 1: 
Date of Amendment 2: 
Date of Amendment 3: 
Date of Amendment 4: 
Date of Amendment 5: 
11 February 2021 
19 February 2021 
17 March 2021 
1 April 2021 
7 April 2021 
17 December 2021 
Date of Amendment 6: 
21 September 2022 
Date of Amendment 7: 
15 February 2023 
Version of Protocol: 
8.0 
GCP Statement: 
This study is to be performed in full compliance with International Council for 
Harmonization (ICH) of Technical Requirements for Pharmaceuticals for Human 
Use and all applicable local Good Clinical Practice (GCP) guidelines and 
regulations. All required study documentation will be archived as required by 
regulatory authorities. 
NCT#:    NCT04972110

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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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Dose Finding Study 
The study will begin with accelerated titration by enrolling 1 patient at Dose Level 1 in each arm (RP-
3500 in combination with niraparib or olaparib), to minimize the exposure of patients to sub-
therapeutic doses. RP-3500 and the PARPi will be administered together weekly, following a 
concomitant 3 consecutive days on and 4 consecutive days off dosing schedule (3/4 schedule) in 21-
day cycles. Administration of RP-3500 and the PARPi may follow an intermittent weekly schedule (eg, 
2 weeks on/1 week off, 1 week on/1 week off, 1 week on/2 weeks off) with a cycle length of 21 or 
28 days. Niraparib or olaparib administered in combination with RP-3500 may also follow a 2 
consecutive days on and 5 consecutive days off dosing schedule (2/5 schedule). Patient enrollment to 
receive RP-3500 in combination with niraparib or olaparib will be guided by the SSC.  
In the absence of Grade ≥2 drug-related toxicity in Cycle 1, dose escalation will progress to the next 
dose level, with a cohort size of 1 (Dose Level Table and Dose Finding Schema). If Grade ≥2 drug-
related toxicity is observed at any time during Cycle 1, up to 2 additional evaluable patients will be 
enrolled at that dose level to further assess safety and tolerability. Cohorts of at least 3 patients will be 
evaluated thereafter.  
The starting doses will be RP-3500 50 mg orally (PO) once daily (QD) plus niraparib 100 mg PO QD 
or olaparib 150 mg PO BID. Olaparib may be administered QD as long as the total daily dose does not 
exceed the BID dose for the respective dose level. All drugs will be given on Days 1-3, 8-10, and 15-17 
of each 21-day cycle for the 3 weeks on 3/4 dosing schedule; on Days 1-2, 8-9, and 15-16 of each 
21-day cycle for the 3 weeks on 2/5 dosing schedule; on Days 1-2 and 8-9 of each 21-day cycle for the 
2 weeks on/1 week off 2/5 dosing schedule; on Days 1-3 of each 21-day cycle for the 1 week on/2 
weeks off 3/4 dosing schedule; or on Days 1-3 and 15-17 of each 28-day schedule for the 1 week on/1 
week off 3/4 dosing schedule. Dosing and scheduling details are presented in the tables below.  
RP-3500 as monotherapy is currently being evaluated in a Phase 1 first-in-human study 
(NCT04497116). A RP2D dose for RP-3500 was established at 160 mg 3 days on/4 days off 
administered weekly, with dose de-escalation schedules proposed as 120 mg on the same schedule of 
160 mg administered 3 days on/4 days off and 2 weeks on/1 week off. As of 12 July 2021, 85 patients 
have been accrued into the study, and 79 patients have been treated with monotherapy of RP-3500 in 
doses ranging from 5 mg to 160 mg QD and 40 mg to 80 mg BID, given on a 5 consecutive days on/2 
consecutive days off or 3 days on/4 days off schedule. Further updates to the clinical safety data in the 
RP-3500-01 study can be found in the Investigator Brochure (IB). 
The initial dose of 50 mg QD for RP-3500 for 3 days (3/4 dosing schedule) was chosen based on the 
observed tolerability of RP-3500 monotherapy given at 160 mg QD on a 3/4 dosing schedule.  
 
 
 
 
 
 
 
 
 

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Phase 1 Dose Finding Study Schema For Arm 1  
 
 
Phase 1 Dose Finding Study Schema For Arm 2  
 
 

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In the absence of toxicity, dose escalation will follow Dose Levels Tables below as agreed by SSC. 
Niraparib and olaparib escalations will progress independently. 
 
Phase 1 Dose Levels and Schedules for RP-3500 + Niraparib (Arm 1) 
Dose 
Level 
21-Day Cycles 
28-Day Cycle 
Schedule: 3 weeks 
on 
Dosing: 3 days 
on/4 days off  
Schedule: 3 weeks 
on 
Dosing: 2 days 
on/5 days off  
Schedule: 2 
weeks on/1 week 
off 
Dosing: 2 days 
on/5 days off  
Schedule: 1 week 
on/2 weeks off 
Dosing: 3 days 
on/4 days off  
Schedule: 1 week 
on/1 week off 
Dosing: 3 days 
on/4 days off 
1   
RP-3500 50 mg 
QD 
Niraparib 100 mg 
QD  
RP-3500 50 mg 
QD 
Niraparib 100 mg 
QD  
RP-3500 50 mg 
QD 
Niraparib 100 mg 
QD  
RP-3500 50 mg 
QD 
Niraparib 100 mg 
QD  
RP-3500 50 mg 
QD  
Niraparib 100 mg 
QD  
2 
RP-3500 80 mg 
QD 
Niraparib 100 mg 
QD  
RP-3500 80 mg 
QD  
Niraparib 100 mg 
QD  
RP-3500 80 mg 
QD  
Niraparib 100 mg 
QD  
RP-3500 80 mg 
QD  
Niraparib 100 mg 
QD  
RP-3500 80 mg 
QD  
Niraparib 100 mg 
QD  

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3 
RP-3500 80 mg 
QD  
Niraparib 200 mg 
QD  
RP-3500 80 mg 
QD  
Niraparib 200 mg 
QD  
RP-3500 80 mg 
QD  
Niraparib 200 mg 
QD  
RP-3500 80 mg 
QD  
Niraparib 200 mg 
QD  
RP-3500 80 mg 
QD  
Niraparib 200 mg 
QD  
3a 
RP-3500 120 mg 
QD  
Niraparib 100 mg 
QD  
RP-3500 120 mg 
QD  
Niraparib 100 mg 
QD 
RP-3500 120 mg 
QD  
Niraparib 100 mg 
QD 
RP-3500 120 mg 
QD  
Niraparib 100 mg 
QD  
RP-3500 120 mg 
QD  
Niraparib 100 mg 
QD  
4 
RP-3500 120 mg 
QD 
Niraparib 200 mg 
QD 
RP-3500 120 mg 
QD  
Niraparib 200 mg 
QD 
RP-3500 120 mg 
QD  
Niraparib 200 mg 
QD 
RP-3500 120 mg 
QD 
Niraparib 200 mg 
QD  
RP-3500 120 mg 
QD 
Niraparib 200 mg 
QD  
Abbreviation: BID = twice daily; QD = once daily 
 
 
Phase 1 Dose Levels and Schedules for RP-3500 + Olaparib (Arm 2) 
Dose 
Level 
21-Day Cycles 
28-Day Cycle 
Schedule: 3 
weeks on 
Dosing: 3 days 
on/4 days off 
Schedule: 3 
weeks on 
Dosing: 2 days 
on/5 days off 
Schedule: 2 weeks 
on/1 week off 
Dosing: 2 days 
on/5 days off  
Schedule: 1 week 
on/2 weeks off 
Dosing: 3 days 
on/4 days off  
Schedule: 1 week 
on/1 week off 
Dosing: 3 days 
on/4 days off  
-1 
RP-3500 50 mg 
QD  
Olaparib 100 mg 
BID  
RP-3500 50 mg 
QD  
Olaparib 100 mg 
BID  
RP-3500 50 mg 
QD  
Olaparib 100 mg 
BID  
RP-3500 50 mg 
QD  
Olaparib 100 mg 
BID  
RP-3500 50 mg 
QD  
Olaparib 100 mg 
BID  
1   
RP-3500 50 mg 
QD  
Olaparib 150 mg 
BID  
RP-3500 50 mg 
QD  
Olaparib 150 mg 
BID  
RP-3500 50 mg 
QD  
Olaparib 150 mg 
BID  
RP-3500 50 mg 
QD  
Olaparib 150 mg 
BID  
RP-3500 50 mg 
QD  
Olaparib 150 mg 
BID  
1a 
RP-3500 80 mg 
QD  
Olaparib 100 mg 
BID  
RP-3500 80 mg 
QD  
Olaparib 100 mg 
BID  
RP-3500 80 mg 
QD  
Olaparib 100 mg 
BID  
RP-3500 80 mg 
QD  
Olaparib 100 mg 
BID  
RP-3500 80 mg 
QD  
Olaparib 100 mg 
BID  
2 
RP-3500 80 mg 
QD  
Olaparib 150 mg 
BID  
RP-3500 80 mg 
QD  
Olaparib 150 mg 
BID  
RP-3500 80 mg 
QD  
Olaparib 150 mg 
BID  
RP-3500 80 mg 
QD  
Olaparib 150 mg 
BID  
RP-3500 80 mg 
QD  
Olaparib 150 mg 
BID  
2a 
RP-3500 120 mg 
QD  
Olaparib 100 mg 
BID  
RP-3500 120 mg 
QD  
Olaparib 100 mg 
BID  
RP-3500 120 mg 
QD  
Olaparib 100 mg 
BID  
RP-3500 120 mg 
QD  
Olaparib 100 mg 
BID  
RP-3500 120 mg 
QD  
Olaparib 100 mg 
BID  
3 
RP-3500 80 mg 
QD  
Olaparib 300 mg 
BID  
RP-3500 80 mg 
QD  
Olaparib 300 mg 
BID  
RP-3500 80 mg 
QD  
Olaparib 300 mg 
BID  
RP-3500 80 mg 
QD  
Olaparib 300 mg 
BID 
RP-3500 80 mg 
QD  
Olaparib 300 mg 
BID  

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3a 
RP-3500 120 mg 
QD  
Olaparib 150 mg 
BID  
RP-3500 120 mg 
QD  
Olaparib 150 mg 
BID  
RP-3500 120 mg 
QD  
Olaparib 150 mg 
BID  
RP-3500 120 mg 
QD  
Olaparib 150 mg 
BID  
RP-3500 120 mg 
QD  
Olaparib 150 mg 
BID  
3b 
RP-3500 120 mg 
QD  
Olaparib 200 mg 
BID  
RP-3500 120 mg 
QD  
Olaparib 200 mg 
BID  
RP-3500 120 mg 
QD  
Olaparib 200 mg 
BID  
RP-3500 120 mg 
QD  
Olaparib 200 mg 
BID  
RP-3500 120 mg 
QD 
Olaparib 200 mg 
BID  
3c 
RP-3500 120 mg 
QD  
Olaparib 250 mg 
BID  
RP-3500 120 mg 
QD  
Olaparib 250 mg 
BID  
RP-3500 120 mg 
QD  
Olaparib 250 mg 
BID  
RP-3500 120 mg 
QD  
Olaparib 250 mg 
BID  
RP-3500 120 mg 
QD  
Olaparib 250 mg 
BID  
4 
RP-3500 120 mg 
QD  
Olaparib 300 mg 
BID  
RP-3500 120 mg 
QD  
Olaparib 300 mg 
BID  
RP-3500 120 mg 
QD  
Olaparib 300 mg 
BID  
RP-3500 120 mg 
QD  
Olaparib 300 mg 
BID  
RP-3500 120 mg 
QD 
Olaparib 300 mg 
BID  
Abbreviation: BID = twice daily; QD = once daily 
Olaparib may be administered QD as long as the total daily dose does not exceed the BID dose for the respective 
dose level. 
 
If no DLT is observed at the highest proposed doses (Dose Level 4), 1 additional escalation of RP-3500 
will be permitted by up to 50% of the last daily dose given.  
Initially, dose finding will start with RP-3500 QD administration but a BID schedule could be explored 
if significant toxicity is observed. 
Intra-patient dose escalations will be allowed at the discretion of the investigator and with sponsor 
approval. 
Dose-Limiting Toxicity Criteria: 
Toxicity will be assessed with the guidance of 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, meets the pre-defined criteria for 
DLT, 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 adverse events (AEs): 
 
Grade 4 neutropenia lasting at least 7 days 
 
Febrile neutropenia (defined as absolute neutrophil count <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 

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General Study Conduct: 
The study will consist of a patient Pre-screening Period (within 6 months from time of screening/main 
informed consent form [ICF] signature, to confirm eligibility of genetic mutation), Screening Period 
(Day -28 to Day -1, to determine overall study eligibility per inclusion/exclusion criteria), Treatment 
Period (21-day cycles or 28-day cycles), and 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 the patient 
discontinued due to a treatment-related toxicity). If a patient is removed from the study due to a 
treatment-related toxicity, an additional safety follow-up visit will occur within 30 days (+14 days) 
after the last dose of study drug. Survival Follow-up will be conducted every 3 months ± 2 weeks until 
the end of the study unless the patient withdraws consent to the study or the study is terminated prior to 
the 12-month follow-up period.  
Study Procedures: 
Study procedures will occur as outlined in the Schedule of Assessments (SOA). Safety and tolerability 
will be followed by the Medical Monitor and evaluated by the SSC throughout the study. Assessments 
conducted throughout the treatment period will include treatment-emergent adverse events (TEAEs), 
serious adverse events (SAEs), treatment discontinuations or dose reductions due to AEs, DLTs, 
changes in Eastern Cooperative Oncology Group (ECOG) performance status, changes in clinical 
laboratory results (hematology and chemistry), vital sign measurements, observations during physical 
examination (PE), electrocardiograms (ECGs), and others.  
Tumor Assessments: 

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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. For patients with prostate cancer, radionuclide bone 
scans will also be required at baseline as per the Prostate Cancer Working Group 3 (PCWG3) criteria 
(Appendix 3). 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 (Appendix 2), and PCWG3 criteria for 
patients with prostate cancer (Appendix 3), or Gynecological Cancer Intergroup (GCIG) definitions for 
response and progression in patients with ovarian cancer (Appendix 4). Response will be assessed by 
the Investigator. 
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 will be performed every 9 weeks 
(±7 days). Per RECIST v1.1, CR or PR should be confirmed; tumor imaging for confirmation of 
response must be performed at least 4 weeks after the first indication of response but may be done at 
the next scheduled assessment. 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 ±7 days thereafter). 
For patients with prostate cancer and bone lesions at baseline, follow-up radionuclide bone scans will 
be required at the same frequency as the RECIST assessments for assessment of progression of bone 
disease as per PCWG3. For PD as defined by PCWG3 as a result of new bone lesions, progression 
should be confirmed on a subsequent bone scan. For patients with prostate cancer and non-measurable 
disease only, bone scans should be performed at baseline and as clinically indicated. 
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 study consent, 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.  
Laboratory Assessments:  
Blood samples will be collected throughout the study to closely monitor safety parameters and 
characterize the pharmacokinetic (PK) profile of RP-3500 and niraparib or olaparib when administered 
in combination. Patients with cancers being monitored by specific circulating tumor biomarkers, 
including but not limited to cancer antigen 125 (CA-125) or prostate-specific antigen (PSA), will 
continue to have these laboratory assessments performed during Screening or prior to first dose on 
Cycle 1 Day 1 and at least once per cycle while on study and at EOT. For all patients with prostate 
cancer, 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 criteria (Appendix 3). For patients with ovarian cancer, CA-
125 measurement will also be mandatory at baseline and on Day 1 of each cycle (through and 
including EOT) as part of the evaluation of response per the GCIG criteria (Appendix 4).  
Blood samples for the analysis of ctDNA will be obtained pre-treatment, throughout treatment, and at 
EOT.  
Tumor Tissue: 

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All patients must provide a tumor tissue sample either archival or fresh biopsy during the Screening 
Period. It is recommended that the tumor tissue sample has been collected within 24 months of signing 
the screening/main informed consent. The most recent archival tumor tissue sample available is 
preferred and the tumor cell content must be confirmed by center pathologist at >30% prior to 
shipping. The tumor sample, along with the confirmation of cellularity, must be shipped to the central 
laboratory prior to Cycle 1/Day 1+7 days. If available, the sponsor will also request archival material 
from the primary tumor- this is optional and not required for enrollment. 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. Bone tissue is not acceptable 
for tumor tissue submission because bone biopsies require a decalcification step that will interfere with 
downstream processing of the sample. 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. An optional tumor biopsy will also be requested at disease progression. 
Eligibility:  
Inclusion Criteria: 
Patients must meet all of the inclusion criteria listed below to be eligible for participation in the study: 
1. Written informed consent, according to local guidelines, signed and dated by the participating 
patient or legal guardian prior to the performance of any study-specific procedures, sampling, 
or analyses. Patients with impaired decision-making capacity must have a close caregiver or 
legally authorized representative (LAR) present. 
2. Male or female patient ≥18 years of age at the time of signature of the ICF. 
3. Ability to comply with the protocol and study procedures detailed in the Schedule of 
Assessments. 
4. Patient must have locally advanced or metastatic solid tumor that has progressed or was non-
responsive or intolerant to available therapies and for which no standard or available curative 
therapy exists, or in the opinion of the investigator, is not a candidate for, or would be unlikely 
to tolerate or derive significant clinical benefit from, appropriate standard of care therapy, or if 
the patient declines standard-of-care therapy. Documented counselling by center investigator 
on benefits/risks of standard-of-care therapy is required for enrolled patients who decline 
standard-of-care therapy.  
5. ECOG performance status of 0 or 1. 
6. Patients must have evaluable disease per RECIST v1.1. For patients with prostate cancer or 
ovarian cancer that have non-measurable disease, PCWG3 criteria (radionuclide bone scan and 
PSA, refer to Appendix 3) or GCIG criteria (CA-125, refer to Appendix 4) will be used 
respectively to assess anti-tumor activity.  
7. Tumor, germline, or plasma DNA analysis for all patients must be performed in a CLIA 
accredited laboratory (or equivalent), confirmed by PODS and must meet one of the following 
biomarker requirements: 
a. Deleterious ATM, CDK12, PALB2, RAD51B, RAD51C, or RAD51D mutation or other 
genes decided upon between the sponsor and investigators. Justification and 
agreement between investigator and sponsor will be documented. 
b. ATM confirmed by liquid biopsy: liquid biopsy results will only be accepted for 
patients with ATM, if the ATM VAF is > 25%. However, an ATM VAF of < 25% can 

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be accepted if the ctDNA test is performed in parallel with testing of a matched whole 
blood sample to confirm that the alteration is tumor derived.  
c. Deleterious BRCA1 or BRCA2 mutation. Patients must have the following:   
i. Presence of a deleterious or suspected deleterious germline or somatic BRCA1 
or BRCA2 mutation.  
ii. For patients with ovarian or pancreatic cancer previously treated with 
platinum-based therapy, platinum sensitivity as measured by at least 6 months 
of platinum-free interval (PFI) must be documented.  PFI can occur at any 
time of the disease course, including immediately prior to trial enrollment.  
d. Loss of tumor ribonuclease H2 (RNASEH2) by one of the following methods: 
i. RNASEH2 immunohistochemistry (IHC) loss  
ii. RNASEH2A or RNASEH2B homozygous loss determined by NGS 
iii. RNASEH2A loss of heterozygosity (LOH) or RNASEH2B LOH and IHC loss 
Note: The sponsor will provide a separate guidance document for molecular 
eligibility.  
8. Provision of archival tumor tissue sample (or if adequate tumor tissue is not available, 
provision of a fresh biopsy if there is a lesion that can be safely biopsied). Sample must be 
shipped to the sponsor’s central laboratory by Cycle 1/Day 1+7 days. It is recommended that 
the tumor tissue sample has been collected within 24 months of signing the screening/main 
informed consent. If a fresh biopsy was provided during pre-screening, then a biopsy during 
screening is not required. Bone tissue is not acceptable for tumor tissue submission because 
bone biopsies require a decalcification step that will interfere with downstream processing of 
the sample. 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. 
9. Life expectancy ≥12 weeks after the start of the treatment according to the investigator’s 
judgment. 
10. Acceptable hematologic function at Screening: 
a. No red blood cell or platelet transfusions or growth factors within 14 days of the first 
dose and stable platelet/hemoglobin levels, based on investigator judgement 
b. Absolute neutrophil count ≥1500/µL 
c. Hemoglobin ≥10.0 g/dL  
d. Platelets ≥120,000/µL 
11. Acceptable organ function at Screening, as evidenced by the following laboratory data: 
a. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3.0 × upper 
limit of normal (ULN). 
b. Either glomerular filtration rate (GFR) ≥ 60 mL/min/1.73 m² using the Chronic Kidney 
Disease Epidemiology Collaboration (CKD-EPI) equation, or calculated creatinine 
clearance (CrCl) ≥60 mL/min using Cockcroft-Gault equation (or by 24-hour urine 
collection).  
c. Total bilirubin ≤1.5 × ULN or <3.0 × ULN if known Gilbert’s disease.   
12. Negative pregnancy test (serum) for women of childbearing potential (WOCBP) at Screening.   
a. WOCBP is defined as fertile, following menarche and until becoming post-
menopausal unless permanently sterile. WOCBP and their partners must agree to use a 

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highly effective form of contraception as detailed in Appendix 1 throughout their 
participation during study treatment and for 6 months after the last dose of study drugs. 
b. 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 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. 
c. Female patients must refrain from donating eggs during their participation in the study 
and for 6 months following last dose of study drug.  
13. 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 during their participation in the study and for 6 months 
following last dose of 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.  
14. Ability to swallow and retain oral medications. 
 
Exclusion Criteria: 
Patients who meet any of the following criteria will be excluded from the study: 
1. Tumors that have a deleterious mutation in BRCA1 or BRCA2 gene that were treated with 
PARPi and progressed during treatment without any evidence of prior response are non-
eligible for the study. Patients who had stable disease (SD), partial response (PR) or complete 
response (CR) evaluation while being treated with PARPi treatment and/or subsequently 
progressed, are still considered eligible for the study.   
2. Prior therapy with an ATRi or DNA-dependent protein kinase (DNA-PK) inhibitor. 
3. Chemotherapy, small molecule anticancer or biologic anticancer therapy given within 10 days 
or 5 half-lives (whichever is shorter) prior to the first dose of study treatment. 
4. Use of radiotherapy (except for palliative reasons) within 7 days prior to study treatment 
initiation. 
5. No other anticancer therapy (chemotherapy, immunotherapy, hormonal anticancer therapy, 
biological therapy, lanreotide/octreotide for NET/NECs, or other novel agent) is to be 
permitted while the patient is receiving study treatment. For patients with breast or prostate 
cancer continuation of long-term luteinizing hormone-releasing hormone (LHRH), 
gonadotrophin releasing hormone (GnRH), or previously prescribed receptor activator of 
nuclear factor kappa-B ligand (RANKL) inhibitor are allowed if these medications were 
prescribed for at least 4 months before study entry. Bisphosphonates are allowed if prescribed 
at least 28 days prior to enrollment.  
6. Major surgical procedures ≤28 days prior to study treatment initiation, or minor surgical 
procedures ≤7 days prior to study treatment initiation. Patients must have recovered from any 
of the effects of any major surgery. No waiting period is required following implanted/port-a-
cath placement or other central venous access placement. 

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7. Persistent Grade >1 toxicity from prior cancer therapy (except alopecia, anorexia, or toxicity 
that is stable and poses no significant risk to the participant). Grade 2 peripheral neuropathy 
after documented treatment with taxanes and/or platinum-based therapy is allowed. 
8. Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, or non-
malignant systemic disease. Examples include but are not limited to uncontrolled ventricular 
arrhythmia, uncontrolled major seizure disorder, unstable spinal cord compression, superior 
vena cava syndrome, or extensive interstitial bilateral lung disease on high resolution 
computed tomography scan. 
9. Moderate or severe hepatic impairment (ie, Child-Pugh class B or C). 
10. Known malignant central nervous system disease other than neurologically stable, treated brain 
metastases – defined as metastasis having no evidence of progression or hemorrhage for at 
least 4 weeks after treatment (including brain radiotherapy). Must be off any systemic 
corticosteroids for the treatment of symptomatic brain metastases for at least 14 days prior to 
enrollment, however a short course of treatment with steroids during palliative radiation is 
allowed. 
11. Uncontrolled hypertension (systolic blood pressure [BP] ≥160 mmHg; diastolic BP 
≥100 mmHg) despite adequate treatment prior to first dose of treatment. 
12. Patients with either previous or current myelodysplastic syndrome (MDS)/acute myeloid 
leukemia (AML) or features suggestive of MDS/AML. 
13. Any of the following cardiac diseases currently or within the last 3 months prior to study 
treatment initiation as defined by the New York Heart Association ≥Class 2: 
a. Unstable angina pectoris 
b. Congestive heart failure 
c. Acute myocardial infarction 
d. Conduction abnormality not controlled with pacemaker or medication 
e. Significant ventricular or supraventricular arrhythmias  
(NOTE: Patients with chronic rate-controlled atrial fibrillation in the absence of other 
cardiac abnormalities are eligible.) 
14. History of Torsades de pointes (TdP) unless all risk factors that contributed to TdP have been 
corrected. 
15. Mean resting QT interval corrected for heart rate using Fridericia’s formula (QTcF) 
>450 msec/male patients and >470 msec/female patients (as calculated per institutional 
standards) obtained from triplicate ECG ≥1 minute apart at study entry. Please review 
Appendix 6 for reference of concomitant medications associated with a risk of QTc interval 
prolongation. 
16. Active, uncontrolled bacterial, fungal, or viral infection, including hepatitis B virus, hepatitis C 
virus, known human immunodeficiency virus (HIV), or acquired immunodeficiency syndrome 
(AIDS) related illness. In equivocal cases, patients whose viral load is negative, may be 
eligible. HIV seropositive patients who are healthy and low risk for AIDS-related outcomes 
could be considered eligible. Eligibility criteria for HIV positive patients should be evaluated 
and discussed with the sponsor medical monitor and will be based on current and past CD4 and 
T-cell counts, history (if any) of AIDS defining conditions (eg, opportunistic infections), and 
status of HIV treatment. 
17. Presence of other known active invasive cancers. 
18. Female patients must refrain from nursing/breastfeeding during their participation in the study 
and for 30 days following last dose of study drug. 

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19. Patients who are receiving moderate or strong cytochrome P450 (CYP) 3A inhibitors or 
inducers, P-glycoprotein (P-gp) inhibitors and/or breast cancer resistant protein (BCRP) 
inhibitors within 14 days prior to first dose of study drug. Please review Appendix 7. 
20. Any known hypersensitivity or contraindication to the components of the study drugs RP-
3500, niraparib, and olaparib. 
21. Psychological, familial, sociological, or geographical conditions that do not permit compliance 
with the study protocol and/or follow-up procedures outlined in the protocol. 
Investigational Product, Dosage, and Mode of Administration: 
All drugs will be self-administered and taken together according to the following schedules:  
 
3 weeks on - 3 days on/4 days off schedule  
o Taken on Days 1-3, 8-10, and 15-17 of each 21-day cycle 
 
 
3 weeks on - 2 days on/5 days off schedule  
o Taken on Days 1-2, 8-9, and 15-16 of each 21-day cycle 
 
 
2 weeks on/1 week off – 2 days on/5 days off  
o Taken on Days 1-2 and 8-9 of each 21-day cycle 
 
 
1 week on/2 weeks off - 3 days on/4 days off  
o Taken on Days 1-3 of each 21-day cycle 
 
 
1 week on/1 week off - 3 days on/4 days off  
o Taken on Days 1-3 and 15-17 of each 28-day cycle 
RP-3500 and niraparib will be administered QD, whereas olaparib will be administered BID. Olaparib 
may be administered QD as long as the total daily dose does not exceed the BID dose for the respective 
dose level. 
Patients should take their drugs with 240 mL (~8 oz) of water and take their morning (RP-3500 and 
either niraparib or olaparib) and evening dose (olaparib BID only) approximately 12 hours apart. 
Patients will be instructed to take their drugs at approximately the same time each day. Patients must 
swallow and not chew all capsules/tablets.  
The starting dose levels for the two treatment combinations will be RP-3500 50 mg PO QD plus 
niraparib 100 mg PO QD or olaparib 150 mg PO BID. Olaparib may be administered QD as long as the 
total daily dose does not exceed the BID dose. A BID dosing schedule for RP-3500 may be explored if 
significant toxicity is observed with QD dosing.  
RP-3500 will be supplied as immediate-release solid dosage form for oral administration. Niraparib 
will be supplied as immediate-release hard capsules for oral administration of 100 mg strength. 
Olaparib will be supplied as immediate-release tablets for oral administration in 100 mg or 150 mg 
strengths.  
Dose interruptions and dose reduction to manage toxicities are allowed and will be carefully monitored 
by the SSC.  
Duration of Treatment:  
Treatment will continue until disease progression by RECIST v1.1 criteria, and PCWG3 or GCIG 
criteria (for patients with prostate and ovarian cancer), intolerability to study drug, risk to patient as 

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 
If the observed DLT rate at the current dose is ൑0.197 (<20%), escalate the dose to the 
next higher dose level. 
 
If the observed DLT rate at the current dose is ൒0.298 (>30%), de-escalate the dose to the 
next lower dose level. 
 
Otherwise, stay at the current dose. 
For each treatment combination, dose finding starts at Dose Level 1. The steps to implement the BOIN 
design are described as follows: 
1. 
Perform accelerated titration as follows: treat the first patient at Dose Level 1. If no Grade ≥2 
drug-related toxicity is observed, escalate the dose to the next higher level. Continue this one-
patient-per-dose dose escalation process until a Grade ≥2 drug-related toxicity is observed during 
Cycle 1, or the highest dose level is reached, and then treat up to 2 additional patients at that dose 
level. Hereafter, cohorts of at least 3 patients will be evaluated, as described in Steps 2 and 3. 
2. 
To assign a dose to the next cohort of patients, conduct dose escalation/de-escalation according to 
the rule displayed in the Dose Escalation/De-Escalation Rules Table below.  
3. 
Repeat Step 2 until the maximum sample size of 30 patients is reached within the specific PARPi 
combination in Phase 1, or if the number of patients treated at the current dose reaches 9 and the 
decision according to the Dose Escalation/De-Escalation Rules Table (below) is to stay at the 
current dose or a decision is made by the SSC to stop. 
Dose Escalation/De-Escalation Rule for the BOIN Design 
 
Number of Patients Treated at Current Dose 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Escalate if # of DLT ≤ 
0 
0 
0 
0 
0 
1 
1 
1 
1 
Stay at current dose 
NA 
NA 
NA 
1 
1 
NA 
2 
2 
2 
Deescalate if # of DLT ≥ 
1 
1 
1 
2 
2 
2 
3 
3 
3 
Eliminate if # of DLT ≥ 
NA 
NA 
3 
3 
3 
4 
4 
4 
5 
Abbreviations: BOIN = Bayesian optimal interval; DLT = dose-limiting toxicity 
Note: # of DLT is the number of patients with at least 1 DLT. When none of the actions (ie, escalate, de-escalate 
or eliminate) is triggered, stay at the current dose for treating the next cohort of patients. “NA” means that a dose 
cannot be eliminated before treating 3 patients. 
After the study is completed, the dose for which the isotonic estimate of the toxicity rate is closest to 
and no higher than the target toxicity rate of 25% will be selected as the MTD. This computation can 
be implemented by the shiny app “BOIN” available at http://www.trialdesign.org. The RP2D for each 
combination will be based on discussion between the investigators and the sponsor and will be either 
the established MTD or a dose lower than MTD based on the totality of the safety and tolerability. 
In the event that operational/practical circumstances result in an over-enrollment (ie, n>3) or under-
enrollment (ie, n=2) for a BOIN cohort, the next dose level decision would be based on the actual 
number of patients exposed in the cohort and the BOIN criteria. 
The recommended Phase 2 dose maybe lower than the MTD.  
 
Efficacy Analysis: 
After the MTDs/RP2Ds of the treatment combinations are established from dose escalation and backfill 
cohorts, 
at the RP2D dose (
 

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2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
SYNOPSIS ...................................................................................................................3 
2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............24 
Appendix 1. CONTRACEPTIVE GUIDELINES ......................................................................25 
Appendix 2. RESPONSE EVALUATION CRITERIA IN SOLID TUMORS, Version 
1.1 ...............................................................................................................................26 
Appendix 3. RESPONSE EVALUATION BASED ON PROSTATE CANCER 
WORKING GROUP 3 CRITERIA ............................................................................28 
Appendix 4. GYNECOLOGICAL CANCER INTERGROUP DEFINITIONS FOR 
RESPONSE AND PROGRESSION IN PATIENTS WITH OVARIAN 
CANCER ....................................................................................................................30 
Appendix 5. EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE 
STATUS .....................................................................................................................33 
Appendix 6. CONCOMITANT MEDICATIONS ASSOCIATED WITH A RISK OF 
QTc INTERVAL PROLONGATION AND/OR TORSADES DE POINTES ..........34 
Appendix 7. STRONG CYP3A INHIBITORS AND INDUCERS, P-GP 
INHIBITORS, AND BCRP INHIBITORS ................................................................36 
 
 
 
 

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APPENDIX 1. CONTRACEPTIVE GUIDELINES  
Patients of childbearing potential 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 
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 5. EASTERN COOPERATIVE ONCOLOGY GROUP 
PERFORMANCE STATUS 
Source: Oken et al., 1982 
 
 
 
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 

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APPENDIX 6. CONCOMITANT MEDICATIONS ASSOCIATED 
WITH A RISK OF QTC INTERVAL PROLONGATION 
AND/OR TORSADES DE POINTES  
RP-3500, Olaparib, and niraparib have not demonstrated adverse effects on QT-prolongation in 
studies to date; however, caution is advised when administering RP-3500, olaparib, and niraparib 
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 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 “known risk” should 
be excluded. Please contact the sponsor 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 7. STRONG CYP3A INHIBITORS AND INDUCERS, 
P-GP INHIBITORS, AND BCRP INHIBITORS 
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 
 
Strong CYP3A Inducers 
Inducers 
Therapeutic class 
Rifampin 
Antibiotics 
Mitotane 
Other Antineoplastics 
Avasimibe 
Other Antilipemics 
Rifapentine 
Antibiotics 
Apalutamide 
Antiandrogens 
Ivosidenib 
Cancer Treatments 
Phenytoin 
Anticonvulsants 

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Inducers 
Therapeutic class 
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