Phase 1 Study of the PKMYT1 Inhibitor RP-6306 in Combination With Gemcitabine for the Treatment of Advanced Solid Tumors (MAGNETIC Study)
Phase: PHASE1
Conditions: Adult Solid Tumor
Sponsor: Debiopharm International SA

Synopsis of Protocol RP-6306-02    Version 4.0 
Repare Therapeutics 
 
 
  
 
 
 
 
 
CLINICAL STUDY PROTOCOL 
 
Title: 
Phase 1 Study of the PKMYT1 Inhibitor RP-6306 in 
Combination with Gemcitabine for the Treatment of 
Advanced Solid Tumors (MAGNETIC Study) 
Protocol Number: 
RP-6306-02 
Study Drug Names: 
RP-6306, Gemcitabine 
Development Phase: 
1 
Sponsor: 
Repare Therapeutics 
7210 Frederick-Banting 
Suite 100 
St-Laurent, Quebec, 
H4S 2A1  
Canada 
101 Main Street 
Suite 1650 
Cambridge, MA 02142  
USA 
 
 
Indication: 
Advanced solid tumors 
IND Number: 
153,096 
Date of Original Protocol: 
12 July 2021 
Date of Amendment 1 
30 July 2021 
Date of Amendment 2 
26 October 2022 
Date of Amendment 3 
24 July 2023 
Version of Protocol: 
4.0 
GCP Statement: 
This study is to be performed in full compliance with International 
Council for Harmonisation (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. 

Synopsis of Protocol RP-6306-02    Version 4.0 
Repare Therapeutics 
 
 
Name of Sponsor/Company: Repare Therapeutics  
Name of Investigational Products: RP-6306, Gemcitabine 
Name of Active Ingredients: RP-6306, Gemcitabine 
Title of Study: Phase 1 Study of the PKMYT1 Inhibitor RP-6306 in Combination with Gemcitabine for the 
Treatment of Advanced Solid Tumors (MAGNETIC Study: PKMYT1 Inhibitor And GemcitabiNE 
Treatment In Cancer) 
Study Duration: Approximately 30 months  
Phase of Development: 1 
Number of Patients (planned): Approximately 150 evaluable patients are planned to be enrolled in this 
study. 
Objectives and Endpoints: 
 
Primary Objectives 
Primary Endpoints 
To assess the safety and tolerability of 
RP-6306 in combination with gemcitabine in 
patients with eligible, advanced solid tumors 
Incidence and severity of treatment-emergent adverse 
events (TEAEs), laboratory assessments, vital signs, 
electrocardiograms (ECGs), and use of concomitant 
medications  
To define the maximum tolerated dose 
(MTD) and recommended Phase 2 Dose 
(RP2D) and schedule of RP-6306 in 
combination with gemcitabine  
Dose-limiting toxicities (DLTs) 

Synopsis of Protocol RP-6306-02    Version 4.0 
Repare Therapeutics 

Synopsis of Protocol RP-6306-02    Version 4.0 
Repare Therapeutics 
 
Study Design: 
This is a multicenter, open-label, Phase 1 study to evaluate the safety and preliminary efficacy of 
RP-6306, a first-in-class, membrane-associated tyrosine- and threonine-specific Cdc2-inhibitory 
kinase (PKMYT1) inhibitor, given on a continuous or, if necessary, intermittent schedule in 
combination with gemcitabine for the treatment of patients with relapsed or refractory, advanced 
solid tumors (Figure A). Eligible patients must have a tumor harboring a CCNE1 amplification, a 
deleterious mutation in FBXW7 or PPP2R1A or other genetic alterations with mechanistic rationale 
agreed upon by the Sponsor and the Investigator. These genomic alterations are hypothesized to be 
synthetic lethal with RP-6306 and in preclinical mouse models were shown to be markedly sensitive 
to the combination of RP-6306 and gemcitabine. 
The study will follow a Bayesian optimal interval (BOIN) drug combination design to identify the 
MTD (dose level and dosing schedule for Module 1a, Module 1b, 
) of 
RP-6306 and gemcitabine. Backfill cohorts with specific molecular alterations or cancer types will 
be enrolled to further evaluate the PK, pharmacodynamic and mechanism of action of biomarkers, 
safety and tolerability, and preliminary efficacy of the combination, as agreed upon by the 
Investigators and Safety Review Committee (SRC). The totality of safety, PK, pharmacodynamic, 
and preliminary efficacy data from each module will be used to establish a preferred RP2D and 
schedule. 
All tumors will be profiled by local clinical tests validated in a College of Pathology (CAP)-, 
Clinical Laboratory Improvement Amendments (CLIA)-, or International Organization for 
Standardization (ISO)-certified laboratory to assure the eligibility of patients. Biomarker-positive 
tumors are defined as tumors that harbor either CCNE1 amplification, deleterious mutations (eg, 
hotspot, truncating, splice site, or frameshift) in FBXW7 or PPP2R1A, or other agreed upon genetic 
alterations. Patients will be enrolled based on local tumor or plasma NGS or FISH results for 
CCNE1 amplified tumors, and liquid biopsy or tumor NGS results for tumors that harbor FBXW7 
or PPP2R1A deleterious mutations. Tumor NGS reports are required for enrollment of patients with 
cancers harboring other mutations agreed upon by the Sponsor and the Investigator. 
Sponsor-approved NGS tests include but are not limited to Guardant360, TSO-500, F1 liquid, 
Foundation Medicine F1CDx, Caris, Tempus, Paradigm, MSK IMPACT, OncomineTM V3, 
OncoPanel, or Qiagen Comprehensive. Additional NGS tests may be utilized for study enrollment 
upon Sponsor approval. 
Molecular eligibility for the study will be centrally reviewed prior to the start of treatment to ensure 
NGS results are annotated consistently across all participating centers. Central review will re-
annotate genomic results and ensure they meet the predefined, Sponsor-approved criteria for 
eligibility. CCNE1 amplification results deemed “equivocal” will not be allowed. Mutations in 
FBXW7 or PPP2R1A that are considered “likely pathogenic” may be allowed upon Sponsor review 
and approval. 
Patients will continue treatment with RP-6306 and gemcitabine until disease progression by 
Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, adverse event (AE), Investigator 
decision, withdrawal of consent, protocol non-compliance, pregnancy, or death. Patients requiring 
more than 2 continuous weeks off of planned study treatment for any reason will be discontinued 
from treatment unless the Investigator (in agreement with the Sponsor) believes and documents that 
the participating patient would derive clinical benefit with continued treatment. 

Synopsis of Protocol RP-6306-02    Version 4.0 
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Laboratory Assessments: 
Blood samples will be collected throughout the study to closely monitor safety parameters and 
characterize the PK profile of RP-6306 in combination with gemcitabine.  
Patients being monitored for circulating tumor markers, such as cancer antigen 125 (CA-125), 
prostate-specific antigen (PSA), carcinoembryonic antigen (CEA), or any other tumor markers used 
for routine clinical evaluation, 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 treatment. 
Blood samples for the analysis of ctDNA will be obtained at Screening, throughout treatment, and 
at EOT. 
Tumor Tissue: 
Sites must confirm availability of a recent archived tumor tissue, either tumor block (preferred) or 
20 × 4 to 5 µm unstained slides, with verification of at least 30% tumor content and ship to the 
Sponsor’s central laboratory during Screening or Cycle 1 Day 1 (+7 days). If less than 20 slides are 
available, the Sponsor must be contacted to gain approval. If archived tumor tissue is not available 
or is of insufficient quantity or quality, a fresh tumor biopsy should be obtained prior to initiating 
treatment. If, in the opinion of the Investigator, a fresh biopsy cannot be performed, the patient may 
still be eligible with Sponsor approval. Approval must be documented during Screening. Please 
refer to the Laboratory Manual for details on tumor sample requirements, collection, preparation, 
storage, and shipping procedures. 
To fulfill secondary and exploratory endpoints, predose and on-treatment biopsies will be 
mandatory for patients with accessible lesions during dose escalation. Paired biopsies collected 
during dose escalation will be assayed to evaluate the degree of target engagement to aid in the 
selection of the RP2D and schedule. Biomarkers include, but are not limited to, a proximal target 
engagement biomarker phospho-cyclin-dependent-kinase 1 (CDK1) Thr14 and the distal proof-of-
principle biomarker γ-H2AX.  
Once the RP2D and schedule has been defined, 15 evaluable paired biopsies will be collected, and 
the Sponsor will notify the site when paired biopsies are no longer required. The paired biopsy must 
be deemed evaluable to support preplanned biomarker analyses, which means more than 15 
participants at the RP2D and schedule may be required to have paired biopsies in order to collect 15 
evaluable pairs. Target engagement will be correlated with efficacy and enrollment biomarkers 
CCNE1 amplification, or deleterious mutations (eg, hotspot, truncating, splice site, or frameshift) in 
FBXW7 and PPP2R1A or other agreed upon genetic alterations. To minimize risk, Investigators 
will preferably choose patients who have easily accessible tumors and in whom an outpatient 
procedure without general anesthesia is possible. If, in the opinion of the Investigator, biopsies 
cannot be performed, the patient may still be eligible to participate in the study with Sponsor 
approval. Approval must be documented during Screening.  
Remaining tumor tissue and tumor derivatives such as deoxyribonucleic acid (DNA) and 
ribonucleic acid (RNA) will be stored for future diagnostic development and to further understand 
response and resistance to RP-6306 and gemcitabine. Details are outlined in the Informed Consent 
Form (ICF). 
Dose Finding: 

Synopsis of Protocol RP-6306-02    Version 4.0 
Repare Therapeutics 
 
This study aims to identify the RP2D and preferred dosing schedule of RP-6306 in combination 
with gemcitabine. RP-6306 will be given on a continuous schedule (Modules 1a 
 and 
intermittent schedule (Modules 1b 
) as outlined below. Once triggered, Module 1b, 
 
 may proceed concurrently with Module 1a, and escalation and de-escalation will proceed 
independently as guided by the BOIN drug combination criteria. Patients will be enrolled into 
Modules 1a, 1b, 
based on available slot openings at the time of signing the ICF and 
allocated to a cohort by the Medical Monitor with guidance from the SRC.   
Module 1a: 
The study will start at Dose Level 1A with 1 patient receiving 40 mg of once daily (QD), oral RP-
6306 in combination with 800 mg/m2 intravenous (IV) gemcitabine given over 30 minutes on 
Days 1 and 8 of each 21-day cycle. This dose of RP-6306 was chosen based on the observed 
tolerability of RP-6306 monotherapy in the MYTHIC study.  
Dose escalation will proceed to the next higher dose level (Dose Level 2A) following BOIN criteria 
and dose escalation and de-escalation rules as follows: 
• Dose escalation will progress with increases of up to 100% RP-6306 until a DLT is 
observed (Level R in Figure B and Table A below). Dose decisions will depend on 2 or 
more evaluable patients completing the first 21-day treatment cycle. 
• After Level R, RP-6306 will be de-escalated per BOIN drug combination criteria. For 
de-escalation at Level R, the next dose level of RP-6306 will be ≥25% 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 the SRC. 
Gemcitabine can be de-escalated up to 25%. Only 1 drug in the combination will be de-
escalated at any time. In addition to decreasing the daily dose level of RP-6306, de-
escalation can involve a reduced frequency of dosing (eg, 5 days instead of planned 
7 days or 2 days of RP-6306 rather than 3 days at the same dose level). 
• After Level R, any dose escalation of RP-6306 or gemcitabine will follow the BOIN 
drug combination criteria as guided by the SRC. RP-6306 can continue with increases of 
20% to 50% (R+1#), and dose escalation of gemcitabine can continue to a maximum of 
1000 mg/m2. Only 1 drug in the combination will be escalated at any time. 
Module 1b: 
Module 1b will be initiated after the first DLT is observed in Module 1a. In Module 1b, an 
intermittent dosing schedule of RP-6306 given 3 consecutive days on / 4 consecutive days off will 
be tested in combination with gemcitabine if confirmed safe by the SRC. When Module 1b is 
initiated, the starting dose of RP-6306 and gemcitabine will be the same as the highest total daily 
dose evaluated in Module 1a and will be given to a cohort of N≥2.  

Synopsis of Protocol RP-6306-02    Version 4.0 
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Synopsis of Protocol RP-6306-02    Version 4.0 
Repare Therapeutics 
 
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 B). Please 
note the following: 
a. When the rule indicates dose escalation, initially only RP-6306 dose level is escalated. 
Escalation of gemcitabine level in addition to RP-6306 can occur after dose level R 
(Table A). After that, the decision to escalate gemcitabine or RP-6306 level will be 
based by which level is associated with a higher desirability score as provided in Table 
35 (Appendix 3). When these 2 dose level combinations have the same desirability score 
(eg, no patients have been dosed at either of these 2 higher dose levels), choose one at 
the discretion of the SRC. When the rule indicates dose de-escalation, de-escalate the 
dose to one of the 2 next lower dose levels (ie., 1 level decrease of RP-6306 or 1 level 
decrease of gemcitabine), whichever has the higher desirability score as provided in 
Table 35 (Appendix 3). When they have the same desirability score, choose one at the 
discretion of the SRC. 
b. “Eliminate” means eliminate the current and higher doses (ie, all combinations of higher 
dose of RP-6306 and gemcitabine) from the study to prevent treating any future patients 
at these doses because they are overly toxic. 
c. When dose is eliminated, automatically de-escalate the dose to 1 of the 2 lower dose 
levels (ie, 1 level decrease of RP-6306 or 1 level decrease of gemcitabine). When the 
lowest dose is eliminated, stop the study for safety. In this case, no dose should be 
selected as the MTD. 
d. If none of the actions (ie, escalation, de-escalation, or elimination) is triggered, treat the 
new patients at the current dose. 
e. If the current dose is the lowest dose and the rule indicates dose de-escalation, treat the 
new patients at the lowest dose unless the number of DLTs reaches the elimination 
boundary, at which point terminate the study for safety. 
f. If the current dose is the highest dose and the rule indicates dose escalation, treat the new 
patients at the highest dose. 
3. Repeat Step 2 until the maximum sample size of 36 evaluable patients (Module 1a, 1b) 
 
in the Dose Finding Phase is reached within each 
module, or transition if the number of evaluable patients treated at the current dose reaches 
≥9 and the decision according to the Dose Escalation/De-Escalation Rules Table (Table B) is 
to stay at the current dose or a decision is made by the SRC to stop. 
Dose decisions for escalation or de-escalation will depend on a minimum of 2 evaluable patients 
completing the first treatment cycle (Modules 1a and 1b: 21 days; 
). 
Ultimately, dose (de)escalation decisions will be made by the SRC, in agreement with the Sponsor, 
based on totality of data in all patients evaluated in the study at the time of (de)escalation decisions. 
After the study is completed, results from all DLT-evaluable patients including the relevant backfill 
cohorts will be included to assess the MTD. The dose for which the isotonic estimate of the toxicity 
rate is closest to and no higher than 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 RP-
6306 and gemcitabine 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, 
PK, pharmacodynamics, and preliminary efficacy. 

Synopsis of Protocol RP-6306-02    Version 4.0 
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Dose-Limiting Toxicity Criteria: 
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 (Modules 1a and 1b: 21 days; 
 
), meets the predefined 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. 
A DLT is defined as any of the TEAEs listed below that is not clearly and incontrovertibly due to 
disease progression or extraneous causes. 
DLTs will be defined as any of the following: 
Treatment-Related Hematologic TEAEs: 
• Grade 4 neutropenia lasting at least 7 days or Grade 4 neutropenia lasting < 7 days 
requiring the use of G-CSF  
• Febrile neutropenia (defined as absolute neutrophil count [ANC] <1000 cells/µL 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 red blood cell (RBC) transfusion per local 
hospital guidelines 
Treatment-Related Non-Hematologic TEAEs: 
• Any Grade 3 treatment-related TEAE of >24-hour duration 
• Any Grade 4 treatment-related TEAE of any duration 
Any toxicity, regardless of the NCI CTCAE grade, resulting in discontinuation, Cycle 1 dose 
reduction, or treatment with less than 75% of planned doses will be reviewed by the SRC and will 
be considered a DLT if the SRC determines the toxicity cannot be attributed to the patient’s 
underlying disease, other medical condition, or concomitant medications. Any death not clearly due 
to disease progression or extraneous causes are DLTs. 
TEAEs That Will Not Be Considered a DLT Include the Following: 
• Grade ≥3 non-hematologic laboratory abnormalities that are not considered clinically 
relevant in the opinion of the Investigator or respond to medical intervention 
• Grade 3 fatigue with duration <7 days and resolved to Grade ≤2, unless it recurs within 
the first cycle and is considered drug-related by the Investigator 
• Grade ≥3 nausea/vomiting/diarrhea that has not been treated with optimal supportive 
care  
• The use of red blood cell transfusion for anemia Grade <3 or the use of G-CSF for Grade 
<4 neutropenia based on institutional practice guidelines. 

Synopsis of Protocol RP-6306-02    Version 4.0 
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Determination of Dose-Limiting Toxicities: 
The population used for determination of DLTs will consist of patients who have met the minimum 
safety evaluation requirements of the study and/or who have experienced a DLT at any time during 
the first treatment cycle. Minimum safety requirements will be met if, during Cycle 1 of treatment, 
the patient receives at least 75% of planned total doses of RP-6306 for the evaluated schedule, 
100% of planned doses of gemcitabine, completes all required safety evaluations per Schedule of 
Assessments, and is observed at least until the end of the first treatment cycle. 
If a patient withdraws from treatment during Cycle 1 due to any reason other than DLT and does not 
meet the minimum requirements for inclusion in the DLT-determining population described above, 
that patient will be replaced. 
Diagnosis and Main Criteria for Inclusion: 
Inclusion Criteria: 
1. Written informed consent, according to local guidelines, signed and dated by the 
participating patient 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. Males or females ≥18 years old at the time of signature of the ICF. 
3. ECOG performance status of 0 or 1. 
4. All patients must have locally advanced or metastatic resistant or refractory solid tumors. 
Patients will be eligible only if standard or available curative therapy does not exist. 
5. A recent archival tumor tissue sample must be shipped to the Sponsor’s central laboratory. 
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 performed, the patient may still be eligible with prior Sponsor approval. 
6. All patient’s tumors must have evidence of at least one of the following as reported by a 
local CLIA-certified or equivalent (ex-United States [US]) laboratory: 
a. CCNE1 amplification (non-equivocal) as determined by tumor or plasma NGS or FISH 
b. FBXW7 and/or PPP2R1A deleterious mutations (eg, hotspot, truncating, splice site, or 
frameshift) identified by either tumor or plasma NGS test 
c. Other genetic alterations with mechanistic rationale agreed upon by the Sponsor and the 
Investigator, identified by a tumor NGS test 
Note: For all patients, an anonymized/redacted Molecular Pathology or other report(s) 
describing CCNE1, FBXW7, PPP2R1A or other genomic alterations should be submitted to 
the Sponsor or designee during Screening to confirm eligibility. 
7. Measurable disease as per RECIST v1.1. 
8. Ability to comply with the protocol and study procedures detailed in the Schedule of 
Assessments. 
9. Acceptable organ function at Screening, as evidenced by the following laboratory data: 

Synopsis of Protocol RP-6306-02    Version 4.0 
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a. Calculated creatinine clearance ≥60 mL/min using Cockcroft-Gault equation  
b. Total bilirubin ≤1.5 × upper limit of normal (ULN) or <3.0 × ULN if known Gilbert’s 
disease 
c. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3.0 × ULN or 
≤5.0 × ULN in the case of presence of liver metastases 
10. Acceptable hematologic function at Screening, defined as follows: 
a. No RBC or platelet transfusions or growth factors within 7 days of the first dose of 
treatment 
b. Hemoglobin ≥9.5 g/dL 
c. ANC ≥1500 cells/µL 
d. Platelet count ≥100 000 cells/µL 
11. Negative pregnancy test (serum) for women of childbearing potential (WOCBP) at 
Screening. 
a. WOCBP is defined as fertile, following menarche and until becoming postmenopausal, 
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 1 
throughout their participation during the study and for 6 months after the last dose of 
study treatment. 
b. Women are considered postmenopausal and not of childbearing potential if they have 
had no menses for 12 months without an alternative medical cause or permanent 
sterilization methods including 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 1 FSH measurement is required. 
12. 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 recommendations during their study participation and for 6 months after last dose of 
study treatment. Male patients must also refrain from donating sperm during their 
participation in the study and for 6 months after last dose of study treatment. 
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 Grade ≤2). 
14. Any prior radiation must have been completed at least 7 days prior to the start of study 
treatment, and patients must have recovered from any acute adverse effects prior to the start 
of study treatment. 
15. Life expectancy ≥12 weeks after the start of the treatment according to the Investigator’s 
judgment. 
Exclusion Criteria: 
1. Chemotherapy or small molecule antineoplastic agent given within 21 days or <5 half-lives, 
whichever is shorter, prior to first dose of study treatment. For drugs for which 5 half-lives is 

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≤21 days, a minimum of 10 days between termination of the prior treatment and 
administration of RP-6306 and gemcitabine treatment is required.  
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. Patients who are pregnant or breastfeeding. 
4. Known sensitivity to any of the ingredients of RP-6306 or gemcitabine. 
5. Patients who are unable to swallow oral medications. 
6. Prior treatment with a Wee1-like protein kinase (WEE1) inhibitor or PKMYT1 inhibitor. 
7. Life-threatening illness, medical condition, active uncontrolled infection, or organ system 
dysfunction (such as ascites, coagulopathy, or encephalopathy), or other reasons which, in 
the Investigator’s opinion, could compromise the participating patient’s safety, or interfere 
with or compromise the integrity of the study outcomes. 
8. Major surgery within 4 weeks prior to first dose of study treatment. 
9. Uncontrolled, symptomatic brain metastases. Patients 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 study treatment 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 
study treatment. 
10. Uncontrolled hypertension (systolic blood pressure [BP] ≥160 mmHg and diastolic 
BP ≥100 mmHg) despite adequate treatment prior to first dose of study treatment. 
11. Active, uncontrolled bacterial, fungal, or viral infection, including hepatitis B virus, 
hepatitis C virus (HCV), 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 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. 
12. Moderate or severe hepatic impairment (ie, Child-Pugh Class B or C). 
13. Any of the following cardiac diseases currently or within the last 6 months as defined by 
New York Heart Association (NYHA) ≥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 (patients with chronic 
rate-controlled atrial fibrillation in the absence of other cardiac abnormalities are 
eligible) 

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f. Clinically relevant electrolyte abnormalities (eg, hypokalemia, hypomagnesemia, 
hypocalcemia) or family history of sudden unexplained death or long ECG interval 
measured from the onset of the QRS complex to the end of the T wave (QT) syndrome 
14. Mean resting QT interval corrected for heart rate (QTc) interval using the Fridericia formula 
(QTcF) >450 msec/male and >470 msec/female (as calculated per institutional standards) 
obtained from 3 ECGs taken ≥1 minute apart at study entry. 
15. Psychological, familial, sociological, or geographical conditions that do not permit 
compliance with the protocol and/or follow-up procedures outlined in the protocol. 
16. Patients who are receiving strong cytochrome P450 (CYP) 3A inhibitors or inducers within 
14 days prior to first dose of study treatment (see Appendix 2). 
Investigational Product, Dosage, and Mode of Administration: 
RP-6306 will be supplied as immediate-release hard capsules for oral administration. RP-6306 will 
be orally self-administered with approximately 240 mL (~8 oz) of water. Patients taking RP-6306 at 
doses less than or equal to 120 mg (QD or BID) may take RP-6306 with a light meal, in avoidance 
of high fat food. For patients taking RP-6306 at doses >120 mg, a fast of 2 hours prior to and 1 hour 
after dosing is required. Patients will be initially instructed to take their dose at approximately the 
same time in the morning. RP-6306 will be taken once daily, on a continuous schedule in each 
cycle. If a BID dosing schedule is evaluated, the dose will be approximately an even split of the 
total daily dose and should be taken 12 (± 2) hours apart with food and drink withheld for at least 
2 hours prior to and 1 hour post administration of the evening dose. In addition, an intermittent 
dosing schedule of 3 consecutive days on / 4 consecutive days off will be explored as guided by the 
SRC and should follow the administration recommendations as the continuous schedule. 
Gemcitabine will be supplied as commercially available single-use vials for IV administration. 
Initially, gemcitabine will be administered IV at 800 mg/m2 and, if safe, escalated to a maximum of 
1000 mg/m2 given over approximately 30 minutes. RP-6306 should be taken approximately 15 
minutes to 1 hour prior to administration of gemcitabine. 
During dose finding, intra-patient dose escalations are allowed at the discretion of the Investigator 
and with Sponsor approval. The dose of RP-6306 and/or gemcitabine may be escalated to a higher 
dose cohort only after that dose level has been declared safe and tolerable by the SRC. Dose 
interruptions and dose reductions to manage toxicities will be allowed for both study treatments and 
carefully monitored by the Investigator, Sponsor, and SRC. 
Duration of Treatment and Follow-up: 
Patients will continue treatment until disease progression by RECIST v1.1, AE, Investigator 
decision, withdrawal of consent, protocol non-compliance, pregnancy, or death. After treatment 
discontinuation, patients will be followed for survival. Survival Follow-up assessments will be done 
via telephone (or standard method used by participating centers and agreed upon by the Sponsor), 
every 3 months (±2 weeks) until up to 6 months unless the patient withdraws consent to the study, 
the study is terminated, the patient dies or is lost to follow-up. 

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Safety: 
All AEs in enrolled patients must be recorded regardless of the relationship of the AE to the study 
treatment from the date of first dose of study treatment through 30 days after the last dose of study 
treatment, or the start of new anticancer therapy if earlier than 30 days. SAEs considered related to 
study treatment are to be reported until the end of the Survival Follow-up Period which is up to 6 
months after the last dose of investigational product (IP) or until lost to follow-up, patient 
withdrawal of consent, or whenever the investigator becomes aware thereafter. 
During the Screening Period, all AEs related to study procedures are to be captured from the time 
ICF is signed to the first dose of study treatment. AEs considered not related to study procedures 
occurring during the Screening Period are to be captured as medical history. 
All AEs experienced by a patient, irrespective of the suspected causality, will be monitored and 
recorded until the TEAE or SAE has resolved or stabilized, abnormal laboratory values have 
normalized, stabilized, or returned to baseline and there is a satisfactory explanation for the changes 
observed, until the patient is lost to follow-up (LTFU), the Investigator determines that no further 
improvement is expected, or the patient has died. Any AE that occurs beyond the reporting period 
that the Investigator assesses as related to RP-6306 and/or gemcitabine should be reported to Repare 
Therapeutics. 
Tolerability and safety will be evaluated by assessment of AEs, TEAEs, SAEs, DLTs, concomitant 
medications, PEs, vital sign measurements, clinical safety laboratory evaluations (hematology, 
serum or plasma chemistry, and urinalysis), ECOG performance status, ECGs, and exposure 
(including dose interruptions and modification). 
Concomitant Medications: 
Concomitant treatment and medication information will be collected from the time the patient signs 
the ICF until 30 days after their last dose of study treatment. The generic name of the drug (or trade 
name for combination drugs) must be specified along with the reason for use and duration of 
treatment. Additionally, all diagnostic, therapeutic, or surgical procedures, whether relating to 
malignancy or not, should be recorded in the electronic case report form (eCRF) including the date, 
indication, description of the procedure(s), and any clinical finding. 
Any changes in documented, permitted concomitant treatments already being taken at the beginning 
of the clinical study must be recorded in the eCRF, noting the type of medication, the duration, and 
indication.  
Prohibited Treatments: 
Other investigational or anticancer agents are prohibited. Prophylactic antiemetics or prophylaxis 
for neutropenia, anemia, or thrombocytopenia will not be routinely provided from study start. 
Statistical Methods: 
Detailed methodology for summary and statistical analyses will be documented in the Statistical 
Analysis Plan (SAP). 

Synopsis of Protocol RP-6306-02    Version 4.0 
Repare Therapeutics 
 
APPENDIX 1. CONTRACEPTIVE GUIDELINES 
Women of childbearing potential who are sexually active must agree to the use of the following 
highly effective forms of contraception throughout their participation during the study treatment 
and for 6 months after the last dose of study treatment(s): 
• 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 
Partners of male patients can take combined (estrogen- and progestogen-containing) hormonal 
contraception associated with inhibition of ovulation: 
• Oral route 
• Intravaginal route 
• Transdermal route 
Male patients with female partners of reproductive potential must use effective contraception 
during treatment and for 6 months following the final dose of study treatment (Clinical Trials 
Facilitation and Coordination Group 2014). 
 

Synopsis of Protocol RP-6306-02    Version 4.0 
Repare Therapeutics 
 
APPENDIX 2. STRONG CYP3A INHIBITORS AND INDUCERS 
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 
CYP3A=cytochrome P450 (CYP) 3A  
 
Strong CYP3A Inducers 
Inducers 
Therapeutic class 
Rifampin 
Antibiotics 
Mitotane 
Other Antineoplastics 
Avasimibe 
Other Antilipemics 
Rifapentine 
Antibiotics 
Apalutamide 
Antiandrogens 

Synopsis of Protocol RP-6306-02    Version 4.0 
Repare Therapeutics 
 
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 
CYP3A=cytochrome P450 (CYP) 3A  
 
Sensitive CYP3A Substrates 
Inducers 
Therapeutic class 
Saquinavir 
HIV antiviral 
Indavir 
HCV antiviral 
Maraviroc 
HIV antiviral 
Lopinavir 
HIV antiviral 
Tipranavir 
HIV antiviral 
Darunavir 
HIV antiviral 
Efavirenz 
HIV antiviral 
Nelfinavir 
HIV antiviral 
Boceprevir 
HCV antiviral 
Daclatasvir 
HCV antiviral 
Velpatasvir 
HCV antiviral 
Telaprevir 
HCV antiviral 
Nevirapine 
HIV antiviral 
Sofosbuvir 
HCV antiviral 
Rilpivirine 
HIV antiviral 
Ritonavir 
HCV antiviral 
Estradiol 
Oral contraceptive 
CYP3A=cytochrome P450 (CYP) 3A; HCV=hepatitis C virus; HIV=human immunodeficiency virus

Synopsis of Protocol RP-6306-02    Version 4.0 
Repare Therapeutics 
 
APPENDIX 3. DESIRABILITY SCORE TABLE FOR TRIAL CONDUCT 
Table 35 is used to determine the dose for escalation or de-escalation when the BOIN rule in 
Table 5 indicates to do so. Suppose that the current dose level is (j, k), then the 2 higher dose 
levels eligible for escalation are (j+1, k) and (j, k+1), provided they exist and have not been 
eliminated from the study. To escalate, look up the desirability score of these 2 doses from  
Table 35 based on the DLT data observed at them, and choose the one with the higher 
desirability score for treating the next cohort of patients. The desirability score is based on 
DLT data already observed at that dose combination. If patients have not been dosed at that 
level, the desirability score is assigned a value of 8. If these 2 doses have the same desirability 
scores, choose one at the discretion of the SRC. Given specific DLT data, the desirability score is 
defined as the rank of that outcome, among all possible DLT outcomes, in terms of the posterior 
probability that the true DLT rate is located within the “stay” interval [0.197, 0.298], 
i.e, Pr(0.197 < pjk ≤ 0.298 |data). Thus, choosing a dose with the highest desirability score is 
equivalent to choosing a dose with the highest posterior probability that the true DLT rate is 
located within the “stay” interval [0.197, 0.298]. Note that “E” indicates that the dose is too toxic 
and should be eliminated from the study. If both higher doses should be eliminated, then the 
study should stay at the current dose level. 
Likewise, to de-escalate, look up the desirability score of 2 lower dose levels, (j-1, k) and (j, k-1), 
provided they exist and have not been eliminated from the study. Then, choose the one with the 
higher desirability score for treating the next cohort of patients. 
Table 35: 
Desirability Score Table (ɸ=0.25) 
Num. 
eval. 
Num. 
DLTs 
 
Score 
 
Num. 
eval. 
Num. 
DLTs 
 
Score 
 
Num. 
eval. 
Num. 
DLTs 
 
Score 
0 
0 
8 
 
4 
≥3 
E 
 
7 
3 
18 
1 
0 
15 
 
5 
0 
9 
 
7 
≥4 
E 
1 
1 
3 
 
5 
1 
27 
 
8 
0 
4 
2 
0 
16 
 
5 
2 
19 
 
8 
1 
22 
2 
1 
14 
 
5 
≥3 
E 
 
8 
2 
31 
2 
2 
1 
 
6 
0 
7 
 
8 
3 
23 
3 
0 
12 
 
6 
1 
28 
 
8 
≥4 
E 
3 
1 
20 
 
6 
2 
26 
 
9 
0 
2 
3 
2 
6 
 
6 
3 
11 
 
9 
1 
21 
3 
≥3 
E 
 
6 
≥4 
E 
 
9 
2 
32 
4 
0 
10 
 
7 
0 
5 
 
9 
3 
29 
4 
1 
24 
 
7 
1 
25 
 
9 
4 
17 
4 
2 
13 
 
7 
2 
30 
 
9 
≥5 
E 
DLT=Dose-limiting toxicities; Eval.=evaluable; Num.=number. 
“E” indicates that the dose is too toxic and should be eliminated from the study 

Synopsis of Protocol RP-6306-02    Version 4.0 
Repare Therapeutics 
 
A hypothetical scenario is provided to demonstrate how to use the desirability score to guide the 
dose escalation/de-escalation decision by SRC. The starting dose level is RP-6306 40 mg and 
gemcitabine 800 mg/m2, hereafter referred as 40/800. 
Figure 10: 
Hypothetical Scenario of Dose Escalation 
 
 
40/800=RP-6306 40 mg + gemcitabine 800 mg/m2; 80/800=RP-6306 80 mg + gemcitabine 800 mg/m2; 
160/800 = RP-6306 160 mg + gemcitabine 800 mg/m2; 40/1000=RP-6306 40 mg + gemcitabine 1000 mg/m2; 
80/1000=RP-6306 80 mg + gemcitabine 1000 mg/m2; 160/1000=RP-6306 160 mg + gemcitabine 1000 mg/m2; 
DLT=dose-limiting toxicity; SRC=Safety Review Committee