Phase 1 Trial of the Safety, Pharmacokinetics, Pharmacodynamics, and Preliminary Clinical Activity of RP-3467 Alone and in Combination With Olaparib in Participants With Advanced Solid Tumors (POLAR Trial)
Phase: PHASE1
Conditions: Advanced Solid Tumor
Sponsor: Repare Therapeutics

 
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Protocol Full Title: 
Phase 1 Trial of the Safety, Pharmacokinetics, Pharmacodynamics, and 
Preliminary Clinical Activity of RP-3467 Alone and in Combination with 
Olaparib in Participants with Advanced Solid Tumors (POLAR Trial) 
Sponsor 
Confidentiality 
Statement: 
This document is confidential. It contains proprietary information of Repare 
Therapeutics (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 trial. 
GCP Statement 
This trial 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 trial documentation will be archived as required 
by regulatory authorities. 
Protocol Number: 
RP-3467-01 
Version: 
2.0  
Amendment 
Number: 
1 
Amendment Scope: 
To accommodate requests from the Food and Drug Administration (FDA) 
Compound 
Number(s): 
RP-3467, olaparib 
Trial Phase: 
Phase 1 
Acronym: 
POLAR  
Short Title: 
Phase 1 Trial of RP-3467 Alone and in Combination with Olaparib in 
Participants with Advanced Solid Tumors 
Sponsor Name and 
Address: 
Repare Therapeutics  
7171 Frederick-Banting  
Building 2 
St-Laurent, Quebec, H4S 1Z9  
Canada 
Regulatory Agency 
Identifier Number(s): 
IND: 170556 
Sponsor Approval 
Date:  
17 July 2024 

 
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Overall Design 
Several key aspects of the trial design are summarized below. 
Intervention Model: 
N/A 
Population Type: 
Adult participants 
Control: 
None 
Population Diagnosis or 
Condition: 
Advanced solid tumors 
Active Comparator: 
N/A 
Population Age: 
Minimum: 18 years 
Maximum: N/A 
Trial Intervention 
Assignment Method: 
N/A 
Site Distribution: 
Multi-site and multi-regional 
Number of Arms: 2  
Blinding: Not applicable (no blinding) 
Number of Participants: Approximately 52 evaluable participants 
Trial Duration: Approximately 24 months  
This is a multicenter, open-label Phase 1 trial to investigate the safety
 
and preliminary efficacy of the Polθ inhibitor RP-3467 alone or in combination with the poly-
ADP ribose polymerase (PARP) inhibitor (PARPi) olaparib in adults with molecularly selected 
advanced solid tumors.  
This trial will enroll participants with breast, ovarian, prostate, or pancreatic cancers that harbor 
a deleterious alteration in BRCA1/2, PALB2, RAD51B/C/D or that have homologous 
recombination deficiency (HRD+). The estimated sample size for this trial will be approximately 
52 evaluable participants 
, including 
an estimated 36 participants in dose escalation and an estimated 16 participants in backfill 
cohorts. Dose finding will follow Bayesian Optimal Interval (BOIN) decision criteria for both 
the monotherapy (Arm 1) and combination (Arm 2) arms, which will occur in parallel, starting 

 
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For all participants, treatment will continue until radiographic disease progression, intolerability 
to trial intervention, risk to participant (including clinical progression) as determined by the 
Investigator and/or Sponsor, consent withdrawal, start of a non-trial anticancer treatment, major 
protocol noncompliance that would jeopardize participant safety and/or data interpretation as 
determined by the Sponsor, pregnancy, or death. For participants with progression based on 
tumor markers per GCIG or PCWG3 criteria, evidence of radiographic and/or other signs of 
clinical progression should be used in determining treatment decisions. Participants requiring 
more than 3 continuous weeks off planned trial treatment for any reason will be discontinued 
unless the Investigator in agreement with the Sponsor believes that the participant would derive 
clinical benefit with continued treatment. 
Participants are allowed to continue treatment after disease progression if the Investigator deems 
that it is in the participant’s best interest. Participants in Arm 1 will have the opportunity to 
continue treatment post-progression with the combination of RP-3467 and olaparib (up to the 
highest dose level of the combination deemed safe and tolerable and cleared by the SRC, but 
dependent on the participant’s overall tolerability of RP-3467 monotherapy). In all cases of 
treatment post-progression, the participant will be required to provide signed written consent 
agreeing to treatment after disease progression. 
 
Eligibility Criteria 
Inclusion Criteria:  
To be eligible to participate in this trial, an individual must meet all the following criteria: 
1. Written informed consent, according to local guidelines, signed and dated by the 
participant or legal guardian prior to the performance of any trial-specific procedures, 
sampling, or analyses. Participants with impaired decision-making capacity must have a 
close caregiver or legally authorized representative (LAR) present. 
2. Male or female participants ≥18 years of age at the time of signing the informed consent 
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
4. Participant must have one of the following that has progressed or was non-responsive to 
prior systemic therapy and for which no standard or available known therapeutic option 
exists: 

 
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a. locally advanced or metastatic epithelial ovarian cancer (including fallopian tube 
or primary peritoneal), or 
b. metastatic breast cancer, or 
c. metastatic castration-resistant prostate cancer (mCRPC), or  
d. pancreatic adenocarcinoma  
Participants are also eligible if the treating physician determines the participant is not a 
candidate for or would be unlikely to tolerate or derive significant clinical benefit from 
standard of care therapy, or if the participant declines standard-of-care therapy. 
Documented counselling by center Investigator on benefits/risks of standard-of-care 
therapy is required for enrolled participants who decline standard-of-care therapy. 
PARPi-naïve participants that would be eligible to receive a monotherapy PARPi per 
USPI label will also be eligible for treatment in Arm 2 after a safe and tolerable 
combination dose level (with 300 mg BID olaparib) has been established and agreed 
upon by the SRC. 
5. Measurable disease per RECIST v1.1  
Exception: Participants with non-measurable but evaluable disease (e.g., nontarget 
lesions only per RECIST v1.1 and/or elevated tumor markers for participants with 
prostate or ovarian cancer) and evidence of locally advanced or metastatic disease on 
imaging obtained during Screening, may be eligible if agreed upon by the Sponsor and 
Investigator.  
6. Existing biomarker profile reported from a local test obtained in a College of Pathology 
(CAP)/Clinical Laboratory Improvement Amendments (CLIA) certified lab (International 
Organization for Standardization [ISO] or equivalent): 
a. Pathogenic or likely pathogenic somatic or germline alteration in at least 1 of the 
following genes: BRCA1, BRCA2, PALB2, RAD51B/C/D 
And/or 
b. HRD+ (by Myriad MyChoice®CDx or FoundationOne®CDx tests) 
For all participants, an anonymized/redacted Molecular Pathology report should be 
submitted to the central annotation group during Pre-screening to confirm eligibility. For 
details on the pre-screening eligibility process, see the Molecular Eligibility Manual. 
7. Provision of archival tumor tissue, or if adequate archival tumor tissue is not available, 
provision of a fresh biopsy if there is a lesion that can be safely biopsied  

 
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Note: If adequate archived tumor tissue is not available and/or a fresh biopsy cannot be 
safely performed, the participant may still be eligible with prior Sponsor approval. 
8. Acceptable organ function at Screening, as evidenced by the following laboratory data: 
a. Creatinine clearance ≥ 60 mL/min calculated using Cockcroft-Gault equation or 
measured by 24-hour urine collection 
b. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 × 
upper limit of normal (ULN) or ≤ 5.0 × ULN if liver metastases present 
c. Total bilirubin ≤ 1.5 × ULN or < 3.0 × ULN if known Gilbert’s disease 
d. Albumin ≥ 2.5 g/dL 
9. Acceptable hematologic function at Screening: 
a. No red blood cell (RBC) or platelet transfusions or growth factors within 14 days 
of the first dose  
b. Absolute neutrophil count ≥ 1500/µL 
c. Hemoglobin ≥ 10.0 g/dL 
d. Platelets ≥ 120,000/µL 
10. 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, who are sexually active, and 
their partners must agree to use a highly effective form of contraception 
 
 throughout their participation in the trial and for 6 
months after the last dose of trial intervention. Female participants must refrain 
from donating eggs during their participation in the trial and for 6 months 
following last dose of trial intervention. 
b. Women are considered post-menopausal and not of childbearing potential if they 
have had no menses for 12 months without an alternative, potentially reversible 
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. 

 
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11. Male participants with female partners of childbearing potential must follow a 
contraception method at least as conservative as Clinical Trial Facilitation Group (CTFG) 
recommendations 
 during their participation in the trial 
for 3 months following last dose of trial intervention. Male participants must also refrain 
from donating sperm during their participation in the trial and for 3 months following last 
dose of trial intervention. 
12. Ability to comply with the protocol and trial procedures detailed in the Schedule of 
Activities 
13. Ability to swallow and retain whole, intact oral medications, without crushing or chewing 
14. Life expectancy ≥12 weeks after the start of the treatment according to the Investigator’s 
judgment 
Exclusion Criteria:  
An individual who meets any of the following criteria will be excluded from participation in this 
trial: 
1. History or current condition (such as transfusion-dependent anemia, thrombocytopenia, 
or chronic neutropenia) or laboratory abnormality that in the opinion of the Investigator 
or Sponsor might pose a significant risk to participant safety, confound the trial results, or 
interfere with participation for the full duration of the trial treatment 
2. Life-threatening illness, medical condition, active uncontrolled infection, or organ system 
dysfunction (such as coagulopathy or encephalopathy), or other reasons which, in the 
Investigator’s opinion, could compromise the participant’s safety, or interfere with or 
compromise the integrity of the trial outcomes 
3. Uncontrolled, symptomatic brain metastases. Participants with previously treated brain 
metastases may participate provided the metastases are stable (without evidence of 
progression by imaging within 4 weeks prior to the first dose of trial intervention and any 
neurologic symptoms are controlled and stable), they have no evidence of new or 
enlarged brain metastases, and they are clinically stable and off steroids for at least 7 days 
prior to trial treatment. Participants with leptomeningeal disease are excluded without 
exception. 
4. Presence of other known second malignancy with the exception of any cancer that has 
been in complete remission for ≥ 2 years, International Society of Urological Pathology 
(ISUP) Grade group 1 prostate cancer on active surveillance, non-muscle invasive 
bladder cancer, any carcinoma in-situ, or completely resected squamous and basal cell 
carcinomas of the skin 
5. Major surgical procedures ≤28 days prior to trial treatment initiation. Participants must 
have recovered from any of the effects of any major surgery. No waiting period is 

 
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required following central venous access placement, biopsy collection, or minor surgeries 
as long as the Investigator assesses the impact on trial participation. 
6. Active, uncontrolled bacterial, fungal, or viral infection, including hepatitis B virus 
(HBV), hepatitis C virus (HCV), known human immunodeficiency virus (HIV), or 
acquired immunodeficiency syndrome (AIDS)-related illness. In equivocal cases, 
participants with a negative viral load may be eligible. Eligibility criteria for HIV positive 
participants currently on highly active antiretroviral therapy should be evaluated and 
discussed with the Medical Monitor and will be based on current and past CD4 and T cell 
counts, history (if any) of AIDS‑defining conditions (e.g., opportunistic infections), and 
status of HIV treatment. Participants with previously treated HBV and HCV with 
negative viral load are eligible. 
7. Clinically significant vascular (both arterial and venous) and nonvascular cardiac 
conditions, active or within 6 months prior to enrollment, including: 
a. Arterial disease such as cerebral vascular accident/stroke (including transient 
ischemic attack), myocardial infarction, and unstable angina 
b. Venous diseases such as deep vein thrombosis and/or pulmonary embolism, 
central venous thrombosis (active or within 3 months prior to enrollment) 
c. Nonvascular cardiac disease such as congestive heart failure (New York Heart 
Association Classification Class ≥2) 
d. Conduction abnormality not controlled with pacemaker or medication 
e. Significant ventricular or supraventricular arrhythmias, including history of 
Torsades de pointes (TdP) unless all risk factors that contributed to TdP have 
been corrected. Participants with chronic rate-controlled atrial fibrillation/flutter 
in the absence of other cardiac abnormalities are eligible. 
f. Family history of sudden unexplained death or long electrocardiogram (ECG) 
interval measured from the onset of the QRS complex to the end of the T wave 
(QT syndrome) 
g. History of risk factors for QT prolongation or TdP (e.g., organic heart disease, 
congestive heart failure, hypokalemia, hypocalcemia, hypomagnesemia, 
congenital long QT syndrome, myocardial ischemia, or infarction) 
8. Mean resting QT interval corrected for heart rate (QTc) using the Fridericia formula 
(QTcF) >470 msec (as calculated per institutional standards) demonstrated by at least 2 
ECGs ≥1 minute apart at trial entry 

 
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9. Uncontrolled hypertension (systolic blood pressure [BP] ≥160 mmHg; diastolic BP ≥100 
mmHg) despite adequate treatment prior to first dose of treatment. Optimization of anti-
hypertensive regimen and re-Screening are permissible. 
10. Persistent Grade >1 non-hematological 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 anti-cancer 
therapies known to induce neuropathy is allowed. 
11. Participants with either previous or current myelodysplastic syndrome (MDS)/acute 
myeloid leukemia (AML) or features suggestive of MDS/AML 
12. Chemotherapy, small molecule, or biologic antineoplastic agent given within 21 days or 
< 5 half‑lives, whichever is shorter, and monoclonal antibodies given within 28 days or 
<5 half-lives, whichever is shorter, prior to first dose of trial intervention. For compounds 
for which 5 half‑lives is ≤ 21 days, a minimum of 10 days between termination of the 
prior treatment and administration of trial intervention is required. 
13. Other anticancer therapy (chemotherapy, immunotherapy, hormonal anticancer therapy, 
biological therapy, lanreotide/octreotide for neuroendocrine tumors 
(NETs)/neuroendocrine carcinomas (NECs), or other novel agent) administered while the 
participant is receiving trial intervention. For participants with breast or prostate cancer, 
continuation of long-term luteinizing hormone-releasing hormone 
(LHRH)/gonadotrophin-releasing hormone (GnRH) analogs are allowed if these 
medications were prescribed for at least 4 months before trial entry. Participants with 
prostate cancer without history of bilateral orchiectomy are required to be maintained on 
LHRH/GnRH analog and have serum testosterone < 50 ng/dL documented during 
Screening.  
14. Previously prescribed receptor activator of nuclear factor kappa-B ligand (RANKL) 
inhibitor and bisphosphonates must be prescribed at least 28 days prior to enrollment.  
15. Prior therapy with a Polθ inhibitor other than RP-3467 
16. For Arm 2 participants only: Discontinued treatment with any prior full-dose 
monotherapy PARPi regimen due to poor tolerability or has a history of intolerability to 
full dose PARPi (when given as monotherapy). 
17. Use of radiotherapy (except for palliative reasons) within 14 days prior to trial treatment 
initiation unless approved by Sponsor 
18. Current treatment with medications that are known to prolong the QT interval 
 
 

 
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19. Participants who are receiving moderate or strong CYP3A inhibitors or inducers and P-gp 
inhibitors within 14 days or 5 half-lives (whichever is longer) prior to first dose of trial 
intervention 
20. Gastrointestinal abnormalities which may significantly impact absorption of trial 
intervention(s), including: requirement for intravenous alimentation, prior surgical 
procedures affecting absorption including gastric resection/bypass or lap band, active 
inflammatory gastrointestinal disease, treatment for active peptic ulcer disease in the past 
6 months, and malabsorption syndromes 
21. Any known hypersensitivity or contraindication to the components of the trial 
interventions RP-3467 and/or olaparib (as applicable per Arm) 
22. Participants who are breastfeeding at Screening or planning to become pregnant (self or 
partner) at any time during trial participation 
23. Psychological, familial, sociological, or geographical conditions that do not permit 
compliance with the trial protocol and/or follow-up procedures outlined in the protocol 
Trial Interventions 
RP-3467 will be administered as immediate-release solid dosage form for oral self-
administration. Olaparib will be administered as immediate-release tablets for oral 
administration. 
Committees 
Independent Committees: SRC