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

Synopsis  RP-6303-03 Protocol Version 3.0  
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CLINICAL STUDY SYNOPSIS 
 
Title: 
Phase 1 Study of the PKMYT1 Inhibitor RP-6306 in Combination 
With FOLFIRI for the Treatment of Advanced Solid Tumors 
(MINOTAUR Study) 
Protocol Number: 
RP-6306-03 
Study treatment Names: 
RP-6306, FOLFIRI 
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 Protocol: 
26 October 2022 
Version of Protocol: 
3.0 
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. 
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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Eligible patients must have a CRC, GI, esophageal or other solid tumor harboring a CCNE1 
amplification, deleterious mutation in FBXW7 or other genetic alterations with mechanistic rationale 
agreed upon by the Sponsor and the Investigator and, in the opinion of the Investigator, are candidates 
for FOLFIRI treatment. These genomic alterations are hypothesized to be synthetic lethal with 
RP-6306 and in nonclinical mouse models were shown to be markedly sensitive to single-agent RP-
6306 and the combination of RP-6306 and irinotecan. 
The study will follow a Bayesian optimal interval (BOIN) design to identify the MTD (dose level and 
dosing schedule for Module 1a and, if necessary, Module 1b) of RP-6306 and FOLFIRI. Backfill 
cohorts with specific molecular alterations or cancer types will be enrolled to further evaluate the PK, 
pharmacodynamic and mechanism of action 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 CCNE1 amplification, deleterious mutations (eg, hotspot, truncating, splice site, or 
frameshift) in FBXW7, 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 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. 
 
 
Patients will continue treatment with RP-6306 and FOLFIRI until disease progression by Response 
Evaluation Criteria in Solid Tumors (RECIST) v1.1, adverse event (AE), Investigator decision, 
withdrawal of consent, protocol noncompliance, 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 that the participating patient would 
derive clinical benefit with continued treatment. 

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Figure A:  
Dose Finding Schema 
 
CCNE1=Cyclin E1; CRC=colorectal; FBXW7=F-box and WD repeat domain containing 7; 
GI=gastrointestinal; QD=once daily; RP2D=recommended Phase 2 dose. 
Note: Additional schedules may be tested based on safety, tolerability, and drug exposure data 
generated in Modules 1a and 1b. 
General Study Conduct: 
Study evaluations and procedures will occur as outlined in the Schedules of Assessments (refer to 
Section 12.1). The study will consist of a Screening Period (Day -28 to Day -1) to determine eligibility, 
a Treatment Period (14-day cycles), an End-of-Treatment (EOT) Period (occurring within 7 days after 
the last dose of study treatment), a Safety Follow-up Period (occurring 30 days ±2 weeks after the last 
dose of study treatment for all patients who are not cleared at the EOT visit, including patients with 
ongoing Grade ≥2 drug-related toxicities at the EOT visit), and a Survival Follow-up (every 3 months 
±2 weeks for up to 12 months). The End of Study is defined as the date of the last visit (including all 
follow-up visits up to 12 months) of the last patient in the study. Patients will be followed for survival 
up to 12 months after EOT unless the patient withdraws consent to the study, the study is terminated, 
the patient dies or is lost to follow-up (LTFU). 
Safety: 
Safety and tolerability will be reported by the Investigator and evaluated by the Medical Monitor, 
Safety Officer, and SRC throughout the study. Assessments will include AEs, TEAEs, serious adverse 
events (SAEs), treatment discontinuations or dose modifications due to AEs, DLTs, changes in Eastern 

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Cooperative Oncology Group (ECOG) performance status, changes in clinical laboratory results 
(hematology, chemistry, and urinalysis), vital signs, observations during physical examination (PE), 
ECGs, and others. All treatment-related AEs should be followed until resolution or documented 
Investigator decision stating that further improvement is not expected. 
Efficacy: 
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. 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 as Screening tumor assessments, if they are of diagnostic quality and could be 
evaluated by a study center radiologist. Subsequent post-baseline tumor assessments will be performed 
following RECIST v1.1 guidelines, preferably in study center, but outside evaluation, if assessed by 
study radiologist, are acceptable. Response will be assessed by the study Investigator; however, all 
scans will be retained for a blinded independent central review, if deemed necessary. 
For follow-up tumor assessments, CT/MRI scans of all sites of known disease 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). Thereafter, tumor assessments will be performed every 9 weeks 
(±7 days). Per RECIST v1.1, complete response (CR) or partial response (PR) should be confirmed; 
tumor imaging for confirmation of response must be performed at least 4 weeks after the first 
indication of response, ideally at the next scheduled tumor assessment. 
Tumor assessment should occur according to study schedule regardless of whether study treatment 
therapy is interrupted. If a patient discontinues treatment for a reason other than disease progression, 
withdrawal of study consent, or death, scans should continue at the specified intervals until progression 
is confirmed or until the start of subsequent anticancer treatment. 
Efficacy will be reported as ORR, best overall response rate, CBR, DOR, and best percent change in 
tumor size from baseline per RECIST v1.1. Available data for PFS at 6 months and OS at 12 months 
will also be reported.  
Laboratory Assessments: 
Blood samples will be collected throughout the study to closely monitor safety parameters and 
characterize the PK profile of RP-6306, irinotecan, and irinotecan’s active metabolite (SN-38) when 
co-administered. 
Patients being monitored for circulating tumor markers, such as cancer antigen 125, prostate-specific 
antigen, carcinoembryonic antigen, 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 on Day 1 of each subsequent 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 

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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 safely performed, the patient may still be 
eligible with Sponsor approval. Approval must be documented during Screening. Please refer to 
Laboratory Manual for details on tumor sample requirements, collection, preparation, storage, and 
shipping procedures. 
 
 
 
 
 
 
 
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 FOLFIRI. Details are outlined in the Informed Consent Form (ICF). 
Dose Finding: 
This study aims to identify the RP2D and preferred dosing schedule of RP-6306 in combination with 
FOLFIRI. The DLT evaluation period will consist of 2 cycles (28 days) of treatment. Initially, 
RP-6306 will be given on a continuous, once daily (QD) schedule (Module 1a) with dose escalation 
and de-escalation decisions guided by the BOIN drug combination criteria. If necessary, an intermittent 
dosing schedule (Module 1b) of 3 consecutive days on / 4 consecutive days off may be explored, and 
Module 1a may be terminated or proceed concurrently with Module 1b. Escalation/de-escalation will 
proceed independently as guided by the BOIN drug combination criteria. If both modules are run 
concurrently, patients will be enrolled into either Module 1a or 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 1 with up to 2 patients receiving 40 mg QD, oral RP-6306 in 
combination with 180 mg/m2 IV irinotecan given over 30 to 90 minutes, 400 mg/m2 IV leucovorin 
given over 30 to 90 minutes with irinotecan, and 400 mg/m2 IV fluorouracil bolus after leucovorin, 
then 2400 mg/m2 IV continuous IV of fluorouracil over 46 hours (Days 1 and 2) of each 14-day cycle. 

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This dose of RP-6306 was chosen based on the observed tolerability and PK of RP-6306 monotherapy 
in the MYTHIC study. If Dose Level 1 is tolerated, the dose of RP-6306 will be escalated to 120 mg 
and the dose of irinotecan will be maintained at 180 mg/m2 daily (Dose level 2). In addition, patients 
treated at Dose Level 1 will be eligible to receive RP-6306 at 120 mg QD, if Dose Level 2 has 
completed the DLT evaluation period and if agreed upon by the SRC. If Dose Level 1 is not tolerated, 
the dose of irinotecan will be de-escalated to 150 mg/m2 and RP-6306 will be maintained at 40 mg 
daily (Dose level 1D). 
After Dose Level 2, dose escalation of RP-6306 will proceed to the next higher dose level following 
BOIN criteria and dose escalation and de-escalation rules as follows: 
• 
Dose escalation will progress with N≥2 patients 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 2 14-day treatment cycles. 
• 
For de-escalation at Level R and thereafter, 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. In 
addition to decreasing the daily dose level of RP-6306, de-escalation can involve a reduced 
frequency of dosing (eg, 3 consecutive days on / 4 consecutive days off or 1 week on / 1 week 
off). 
• 
Dose escalation of RP-6306 will follow the BOIN criteria as guided by the SRC. RP-6306 can 
continue with increases of 20% to 50% (R+1).  
Intrapatient dose escalation may progress in subsequent patients once the next dose level is cleared by 
the SRC and the treating physician and the patient agrees that intrapatient dose escalation is desired. 
Module 1b: 
If tolerability of continuous RP-6306 with FOLFIRI is limiting, Module 1b will be initiated if agreed 
upon by the SRC. 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 FOLFIRI. When Module 1b is initiated, 
the starting dose of RP-6306 and FOLFIRI will be the same as the highest total daily dose evaluated in 
Module 1a and will be given to a cohort of N≥2 patients. To allow better dose and schedule exploration 
early in the development, additional schedules may be evaluated that involve intermittent dosing 
(eg, 2 consecutive days on / 5 consecutive days off or 1 week on / 1 week off) depending on observed 
toxicities. The dose of RP-6306 or FOLFIRI will be increased or decreased per BOIN criteria 
independently of Module 1a until an MTD is established. Dose escalation decisions will be discussed 
with the SRC after at least 2 evaluable patients completing the first 2 14-day treatment cycles and 
based on the emerging safety and tolerability profile, and clinical PK/pharmacodynamic data across the 
entire patient population in Modules 1a and 1b. 
In the event Modules 1a and 1b are explored concurrently, the Medical Monitor and SRC will prioritize 
slot allocation for each module. The highest dose level of RP-6306 in this study will not exceed the 
MTD of RP-6306 monotherapy identified in the MYTHIC study for a given schedule. The totality of 
safety, PK, pharmacodynamic, and preliminary efficacy data will be used to select a preferred RP2D 
and schedule for RP-6306 and FOLFIRI. 

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If anti-tumor activity is observed at a dose level that is lower than the current dose level being explored 
(after escalation has proceeded to a higher dose level), additional patients (N≤6), preferably with the 
same tumor/genomic alteration, may be enrolled at the lower dose level to further confirm safety and 
efficacy at that dose level. The relevant DLTs from the backfill cohorts will be included in the MTD 
and RP2D determination by the SRC. Additionally, intrapatient dose escalations for patients at a lower 
dose level will be allowed at the discretion of the Investigator, and with Sponsor approval and guidance 
by the SRC, if the higher dose level was deemed safe by the SRC. 
Figure B: 
Module 1a and 1b Escalation Schema 
 
BOIN=Bayesian optimal interval; DLT=dose-limiting toxicity; MTD=maximum tolerated dose; 
QD=once daily. 

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If Dose Level 1 is not tolerated in Module 1a, Dose Level 1D will be explored. At Dose Level 1D, 
RP-6306 will be given at 40 mg daily on a continuous schedule and irinotecan in the FOLFIRI regimen 
will be reduced to 150 mg/m2 over 30 to 90 minutes on Day 1 of each 14-day cycle. If Dose Level 1D 
is tolerated and deemed safe by the SRC, irinotecan will be maintained at 150 mg/m2, and escalation of 
RP-6306 will proceed in increments of 50% to 100% in a continuous schedule. If Dose Level 1D is not 
tolerated, Dose Level 2D will be explored. At Dose Level 2D, RP-6306 will be given at 40 mg daily on 
a continuous schedule and irinotecan in the FOLFIRI regimen will be reduced to 120 mg/m2 over 30 to 
90 minutes on Day 1 of each 14-day cycle. If Dose Level 2D is tolerated and deemed safe by the SRC, 
irinotecan will be maintained at 120 mg/m2 and escalation of RP-6306 will proceed in increments of 
50% to 100% in a continuous schedule. If dose level 2D is not tolerated, dose Level 3D will be 
explored, in which the bolus of fluorouracil will be eliminated from the regimen. 
Based on the outcome of RP-6306 PK evaluation in the initial dose levels and emerging PK data in the 
MYTHIC (RP-6306-01) monotherapy study, a consideration for a twice daily (BID; same total daily 
dose as QD) RP-6306 administration will be discussed with the SRC. The decision to initiate BID 
dosing will be based on observed patient outcomes (eg, absence of toxicities, tumor response, or other 
pharmacologic activity) and PK parameters such as, but not limited to, elimination half-life (t½) is 
<12 hours or the Cmax:Cmin ratio >10 (where Cmin is the minimum observed plasma concentration within 
the dosing interval). The same dose escalation/de-escalation criteria will apply for BID dosing cohorts. 
If BID dosing is initiated, the SRC can elect to continue enrolling patients on a daily dosing arm or 
cease enrollment on this arm based on the data collected. 
Maximum Tolerated Dose: 
The BOIN design will be employed to find the MTD of continuous RP-6306 (Module 1a) and, if 
necessary, intermittent RP-6306 (Module 1b) in combination with FOLFIRI. The target toxicity rate is 
25%. The maximum sample size will be 80 patients for dose finding in Modules 1a and 1b combined. 
DLTs occurring within the first 28-days (2 cycles) will be used to direct MTD finding. 
The BOIN design uses the following criteria, optimized to minimize the probability of incorrect dose 
assignment, to guide dose escalation/de-escalation: 
• 
If the observed DLT rate at the current dose is ≤0.197 (<20%), escalate the dose to 1 of the 
2 next higher dose levels (ie, 1 level increase of RP-6306 or 1 level increase of FOLFIRI). 
• 
If the observed DLT rate at the current dose is ≥0.298 (≥30%), de-escalate the dose to 1 of the 
2 next lower dose levels (ie, 1 level decrease of RP-6306 or 1 level decrease of FOLFIRI). 
• 
Otherwise, stay at the current dose. 
With the BOIN design, re-escalation after de-escalation is allowed and it is possible to escalate back to 
a dose level previously declared nontolerated. Prior to re-escalating to a previously nontolerated dose, 
an intermediate dose level may be explored. The final decision regarding degree of re-escalation will 
be determined by the SRC based on the totality of the safety and PK data. 
For the purpose of overdose control, doses j and higher levels will be eliminated from further 
consideration if Pr(pj > 0.25 | data) > 0.95 and at least 3 evaluable patients have been treated at dose 
level j, where pj is the true DLT rate of dose level j, j = 1, …, 5. This posterior probability is evaluated 
based on the beta-binomial model yj | pj ~ binomial(pj) with pj ~ uniform(0, 1), where yj is the number 
of patients experienced DLT at dose level j. When the lowest dose is eliminated, stop the trial for 

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safety. When the lowest dose is eliminated, stop the trial for safety. The above dose escalation/de-
escalation and elimination rule can be equivalently presented in Table B, which will be used to conduct 
the trial. 
Table B provides information on the different dose decisions based on number of evaluable patients 
and the number of DLTs reported. Note, more than 6 patients may be exposed at a dose level to better 
define the MTD. 
Table B:  
Dose Escalation/De-escalation Rules for the BOIN Design 
Action 
Number of Evaluable Patients at Current Dose Level 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
↑ if number 
of DLT ≤ 
0 
0 
0 
0 
0 
1 
1 
1 
1 
1 
2 
2 
Stay current 
dose if 
number of 
DLT = 
NA 
NA 
NA 
1 
1 
NA 
2 
2 
2 
2 
3 
3 
↓ if number 
of DLT ≥ 
1 
1 
1 
2 
2 
2 
3 
3 
3 
3 
4 
4 
Elim if 
number of 
DLT ≥ 
NA 
NA 
3 
3 
3 
4 
4 
4 
5 
5 
6 
6 
BOIN = Bayesian optimal interval; ↑ = increase, ↓ = decrease, DLT = dose-limiting toxicity, 
Elim=eliminate, NA = not applicable, dose cannot be eliminated until at least 3 patients have been 
treated 
Note: Number 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.  
Dose finding starts at Dose Level 1. The steps to implement the BOIN design are described as follows: 
1. Patients in the first cohort are treated at Dose Level 1. Dose decisions will depend on 2 or more 
evaluable patients completing the first 2 14-day treatment cycles. 
2. To assign a dose to the next cohort of patients, conduct dose escalation/de-escalation according 
to the rule displayed in Table B. When using Table B, please note the following: 
a. “Eliminate” means eliminate the current and higher doses from the trial to prevent treating 
any future patients at these doses because they are overly toxic. 
b. When we eliminate a dose, automatically de-escalate the dose to the next lower level. 
When the lowest dose is eliminated, stop the trial for safety. In this case, no dose should be 
selected as the MTD. 
c. If none of the actions (i.e., escalation, de-escalation or elimination) is triggered, treat the 
new patients at the current dose. 
 

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d. 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 trial for safety. 
e. 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 is reached or stop the 
trial early if the number of evaluable patients treated at the current dose ≥9 and the decision 
according to Table B is to stay at the current dose. 
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 30% 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 FOLFIRI 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. 
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 2 cycles (28 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 (a TEAE is any event that was not present prior to the initiation 
of study treatment or any event that worsens in either intensity or frequency following exposure to 
study treatment and for up to 30 days following the last dose of study treatment) 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 if granulocyte colony-stimulating factor or 
granulocyte macrophage colony-stimulating factor is given at any time 
• 
Febrile neutropenia (defined as absolute neutrophil count [ANC] <1000/mm3 with a single 
temperature of 38.3ºC [101℉] or a sustained temperature of 38ºC [100.4℉] for >1 hour) 
• 
Grade 4 thrombocytopenia or Grade 3 thrombocytopenia associated with Grade ≥2 
bleeding 
• 
Grade 4 anemia or Grade 3 anemia requiring red blood cell (RBC) transfusion per local 
hospital guidelines 
Note: The use of transfusions and hematopoietic growth factors, including thrombopoietin 
analogues, will be part of the DLT definition if such intervention is required. 

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Treatment-related Nonhematologic TEAEs: 
• 
Grade ≥3 nausea/vomiting/diarrhea that lasts >3 days despite optimal supportive care 
• 
Any Grade 3 treatment-related TEAE of >24-hour duration 
• 
Any Grade 4 treatment-related TEAE of any duration 
TEAEs That Will Not Be Considered a DLT Include the Following: 
• 
Grade ≥3 nonhematologic 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 2 cycles and is considered drug-related by the Investigator 
• 
Grade ≥3 nausea/vomiting/diarrhea that has not been treated with optimal supportive care 
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 
initial 28 days of the study. Minimum safety requirements will be met if, during the first 2 cycles of 
treatment, the patient receives at least 75% of planned total doses of RP-6306 and 100% of the planned 
dose of FOLFIRI, completes all required safety evaluations per Schedule of Assessments, and is 
observed at least until 28 days following the first dose of study treatment. 
If a patient withdraws from treatment during the first 2 cycles 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 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 CRC, GI, or esophageal cancer(s) and 
radiographic evidence of progressing disease or any solid tumor with eligible molecular 
alterations (see criterion 6) that in the opinion of the Investigator are suitable for therapy with 
FOLFIRI regimen. Patients will be eligible if they have received no more than 3 prior 
treatment regimens, excluding adjuvant treatment. If the Investigator considers the patient a 

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candidate for FOLFIRI as initial treatment of newly diagnosed, metastatic, or advanced 
disease, the patient is eligible. 
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 safely 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 (nonequivocal) as determined by tumor or plasma NGS or FISH 
b. FBXW7 deleterious mutations (eg, hotspot, truncating, splice site, frameshift) 
identified by either tumor or plasma NGS test 
c. Other genetic alterations with mechanistic rationale agreed upon by the Sponsor and 
the Investigator, determined by a tumor NGS test 
Note: For all patients, an anonymized/redacted Molecular Pathology or other report(s) 
describing CCNE1, FBXW7 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: 
a. GFR ≥60 mL/min/1.73 m2 using the Chronic Kidney Disease Epidemiology 
Collaboration (CKD-EPI) equation or calculated creatinine clearance ≥60 mL/min 
using Cockcroft-Gault equation (or by 24-hour urine collection). 
b. Total bilirubin ≤1.5 × upper limit of normal (ULN) 
c. Aspartate aminotransferase and alanine aminotransferase ≤3.0 × ULN or ≤5.0 × ULN 
in the case of presence of liver metastases 
10. Acceptable hematologic function at Screening: 
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/mm3 
d. Platelet count ≥100,000 cells/mm3 
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 study treatment 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 include hysterectomy, bilateral salpingectomy, and bilateral 

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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 at least as conservative as Clinical Trial Facilitation Group recommendations during 
their 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 14 days prior to the start of study 
treatments, 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 
≤21 days, a minimum of 10 days between termination of the prior treatment and administration 
of RP-6306 and FOLFIRI 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. Prior treatment with a PKMYT1 inhibitor or Wee1-like protein kinase (WEE1) inhibitor at any 
time, or irinotecan-based therapy given as an immediate prior therapy. 
4. Patients who are pregnant or breastfeeding. 
5. Known sensitivity to any of the ingredients of the study treatment. 
6. Patient who are unable to swallow oral medications. 
7. Life-threatening illness, medical condition, active uncontrolled infection, or organ system 
dysfunction (such as ascites, coagulopathy, or encephalopathy), or other reasons that, 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 for at least 4 weeks prior to the first dose of study treatment and any neurologic 
symptoms are controlled and stable), patients have no evidence of new or enlarged brain 
metastases, and patients are clinically stable and off steroids for at least 7 days prior to study 
treatment. 
10. Uncontrolled hypertension (systolic blood pressure [BP] ≥160 mmHg; diastolic 
BP ≥100 mmHg) despite adequate treatment prior to first dose of study treatment. 

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11. 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, 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’s 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: 
e. Unstable angina pectoris 
f. Congestive heart failure 
g. Acute myocardial infarction 
h. Conduction abnormality not controlled with pacemaker or medication 
i. 
Significant ventricular or supraventricular arrhythmias (patients with chronic 
rate-controlled atrial fibrillation in the absence of other cardiac abnormalities are 
eligible) 
j. 
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 ≥1 minute apart at study entry. 
15. Current treatment with medications that are well-known to prolong the QT interval 
(Appendix 2). 
16. Psychological, familial, sociological, or geographical conditions that do not permit compliance 
with the protocol and/or follow-up procedures outlined in the protocol. 
17. Patients who are receiving strong cytochrome P450 (CYP) 3A inhibitors or inducers within 
14 days prior to first dose of study treatment (see prohibited concomitant medications in 
Appendix 3). 

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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 after an overnight fast of at least 
8 hours. Food and drink will be withheld for at least 1 hour after administration of RP-6306. Patients 
will be initially instructed to take their dose at approximately the same time in the morning. RP-6306 
will be taken QD, on a continuous schedule in each 14-day cycle. If a BID dosing schedule is 
evaluated, the dose will be approximately an even split and should be taken 12 hours apart with food 
and drink withheld for at least 2 hours prior to and 1 hour post administration of the evening dose. If 
tolerability of RP-6306 is limited by continuous dosing, an intermittent dosing schedule of 
3 consecutive days on / 4 consecutive days off may be explored as guided by the SRC and should 
follow the administration recommendations of the continuous schedule. 
Irinotecan, leucovorin, and fluorouracil will be supplied as commercially available single-use vials. 
Initially, irinotecan will be administered IV at 180 mg/m2 (100% of the approved dose level) given 
over 30 to 90 minutes on Day 1 of each 14-day cycle. Leucovorin will be administered concomitantly 
with irinotecan IV at 400 mg/m2 (100% of approved leucovorin dose) given over 30 to 90 minutes on 
Day 1 of each 14-day cycle. Upon completion of the leucovorin infusion, a 400 mg/m2 bolus of 
fluorouracil IV and then a 2400 mg/m2 continuous infusion of fluorouracil (100% of approved 
fluorouracil dose) over 46 hours (Days 1 and 2 of each 14-day cycle) will be administered. 
On Day 1 of each cycle, RP-6306 should be taken 15 minutes to 1 hour prior to the start of irinotecan 
and leucovorin. 
During dose finding, intrapatient dose escalations are allowed at the discretion of the Investigator and 
with Sponsor approval. The dose of RP-6306 and/or irinotecan in the FOLFIRI regimen may be 
escalated to a higher dose level 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 and carefully 
monitored by the Investigator, Sponsor, and SRC. 
Duration of Treatment: 
Patients will continue treatment until disease progression by RECIST v1.1, AE, Investigator decision, 
withdrawal of consent, protocol noncompliance, 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 as agreed upon by the Sponsor) every 3 months 
(±2 weeks) up to 12 months unless the patient withdraws consent to the study, the study is terminated, 
the patient dies or is LTFU. 
Safety: 
All AEs/SAEs in enrolled patients must be recorded regardless of the relationship of the AE/SAE 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 treatment 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 12 months after the last dose of investigational product (IP) or until LTFU, patient withdrawal of 
consent, or whenever the investigator becomes aware thereafter. 

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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; abnormal laboratory values have normalized, stabilized, 
or returned to baseline and there is a satisfactory explanation for the changes observed; withdrawal of 
consent; or the patient is LTFU or has died. Any AE that occurs beyond the reporting period that the 
Investigator assesses as at least possibly related to RP-6306 and/or FOLFIRI should be reported to 
Repare Therapeutics. 
Tolerability and safety will be evaluated by assessment of AEs, TEAEs, SAEs, DLTs, concomitant 
medications, PEs, vital signs, clinical safety laboratory evaluations (hematology, chemistry, and 
urinalysis), ECOG performance status, ECGs, and exposure (including dose interruptions and 
modification). 
Concomitant Medications: 
Unless contraindicated, patients may receive atropine 0.25 to 1 mg IV/subcutaneous for cholinergic 
adverse effects (eg, early diarrhea). Diarrhea should be managed aggressively according to institutional 
guidelines and may include use of loperamide 4 mg at onset of diarrhea, then 2 mg every 2 hours until 
the patient is diarrhea-free for 12 hours. This may be combined with diphenoxylate/atropine if not 
adequately controlled with loperamide alone. 
Patients with ileus, fever, or febrile neutropenia should receive antibiotics. 
It is recommended that patients receive premedication with antiemetic agents according to institutional 
guidelines. A common antiemetic regimen includes 10 mg of dexamethasone given in conjunction with 
another type of antiemetic agent, such as a 5-HT3 blocker (eg, oral ondansetron or granisetron). 
Physicians should also consider providing patients with an additional antiemetic regimen 
(eg, prochlorperazine) for subsequent use, as needed. 
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 drugs are prohibited. 

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Statistical Methods: 
Detailed methodology for summary and statistical analyses will be documented in the Statistical 
Analysis Plan. 
Sample Size Calculation: 
The maximum total sample size for this study is 104 patients. The maximum sample size for the Dose 
Finding Phase is 36 evaluable patients per Module (72 patients total if an intermittent dosing schedule 
is initiated). 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 initial 28 days (2 cycles) of the study. Minimum safety requirements will be met if, during 
the first 2 cycles of treatment, the patient receives at least 75% of planned total doses of RP-6306 for 
the evaluated schedule, 100% of planned doses of FOLFIRI, completes all required safety evaluations 
per Schedule of Assessments, and are observed at least until Day 28 since the first dose of study 
treatment. Thus, the possible total number per Module may be slightly higher at 40 patients 
(approximately +10%, 80 total patients). Depending on the toxicity profile of the combination and the 
number of dose levels required to establish the MTD/RP2D, the actual study sample size may vary. 
Approximately an additional 24 patients will be planned for backfill cohorts. 
Analysis Populations 
The following analysis populations will be used: 
• 
DLT Evaluable Population for dose decisions will be as defined above. 
• 
The Safety Population, used for the assessment of overall safety and tolerability, will 
consist of all patients who receive at least one dose of study treatment. Patients will be 
assessed for safety based on the dose level in which they were enrolled. 
• 
The Efficacy Population, used for the assessment of efficacy, will consist of all 
patients who have measurable disease, are exposed to at least one dose of study 
treatment, and have local confirmation of their genomic alterations. 
• 
The PK Population, used for the assessment of PK endpoints, will consist of all 
patients who have sufficient RP-6306, irinotecan, or SN-38 plasma concentration data 
recorded to derive PK endpoints. 
Efficacy Analysis: 
Approximately 24 additional patients will be enrolled in backfill cohorts (N≤8 per cohort) to further 
evaluate the safety/tolerability profile in specific patient populations (eg, specific cancer types or 
patients that are high-risk for toxicities),
 
 
The efficacy analysis will be summarized by dose combination and data from the backfill cohorts will 
be pooled with patients from the Dose Finding Phase that were treated at the RP2D (a minimum of 
6 patients are expected to be treated at the RP2D during dose finding) when applicable. 
Each cohort will be evaluated for ORR, best overall response rate, CBR, DOR, changes in tumor size, 
PFS at 6 months, and any available OS at 12 months. 

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Safety Analysis: 
Toxicity will be summarized by grade and type. All AEs will be listed, including the verbatim 
description, system organ class, and preferred term. 
Incidence of TEAEs, treatment-related TEAEs, TEAEs leading to death, SAEs, treatment-related 
SAEs, TEAEs leading to study treatment discontinuation or interruption, and TEAEs leading to dose 
modifications will be recorded. Clinically relevant laboratory abnormalities (ie, laboratory 
abnormalities that result in treatment modification or require intervention) will be recorded as AEs. 
TEAEs will be further summarized by severity (according to NCI CTCAE version 5.0). Changes in 
clinical laboratory parameters (eg, hematology, chemistry, urinalysis, etc.), CTCAE graded laboratory 
toxicities, vital signs, ECOG performance status, PEs, and usage of concomitant medications and 
procedures will be summarized. 
PK Analysis: 
PK parameters for RP-6306, irinotecan, and SN-38 will be calculated using noncompartmental analysis 
or other modeling methods as well as using a population PK model: AUC0-last, Cmax, and Tmax, and other 
parameters as appropriate. 
 
 
 
 
 
 
 
 
 
 
 
. 

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APPENDIX 1. CONTRACEPTIVE GUIDELINES 
Women of childbearing potential, who are sexually active, must agree to the use of the following 
highly effective form 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). 
 
 
 

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APPENDIX 2. CONCOMITANT MEDICATIONS ASSOCIATED WITH A 
RISK OF QTC INTERVAL PROLONGATION AND/OR 
TORSADES DE POINTES 
RP-6306 have not demonstrated adverse effects on QT prolongation in studies to date, however 
caution is advised when administering RP-6306 with any drug that may prolong QT. 
A vast number of medications prolong the QT interval. They are preferably classified based on 
the degree of QT prolongation they induce. This is specifically medication dependent. For 
example, many commonly used medications, such as diphenhydramine and azithromycin, exhibit 
QT-prolonging effects. However, the degree of QT prolongation is not severe enough to warrant 
caution in healthy patients. These medications bind to the human ether-related gene (hERG) 
channels and reduce electrical conduction through the potassium ion channels. This results in 
delayed repolarization of the heart.  
Caution is advised when combining QT-prolonging medications or when using these 
medications in patients with electrolyte abnormalities. Below is a list of potential medications 
that may prolong QT interval. Patients receiving medications classified as “know risk” should be 
excluded. Please reach out to the Medical Monitor prior to enrolling any patient on RP-6306 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-Sanchez 2017 
 
 

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APPENDIX 3. 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 3A.  
 
Strong CYP3A Inducers 
Inducers 
Therapeutic Class 
Rifampin 
Antibiotics 
Mitotane 
Other antineoplastics 
Avasimibe 
Other antilipemics 
Rifapentine 
Antibiotics 

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Inducers 
Therapeutic Class 
Apalutamide 
Antiandrogens 
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 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 3A; HCV=hepatitis C virus; HIV=human immunodeficiency virus. 

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APPENDIX 4. RESPONSE EVALUATION CRITERIA IN SOLID 
TUMORS, VERSION 1.1 
Evaluation of Target Lesions 
CR: Disappearance of all target lesions (TLs). Any pathological lymph nodes (whether target or 
nontarget) must have reduction in short axis to <10 mm. 
PR: At least a 30% decrease in the sum of the diameters of TLs, taking as reference the baseline 
sum diameters. 
PD: At least a 20% increase in the sum of the diameters of TLs, taking as reference the smallest 
sum on study (this includes the baseline sum if that is the smallest on study). In addition to the 
relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. 
(Note: the appearance of one or more new lesions is also considered progressions). 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
Evaluation of NonTLs 
CR: Disappearance of all nonTLs and normalization of tumor marker level. All lymph nodes 
must be nonpathological in size (<10 mm short axis). 
Note: If tumor markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response. 
NonCR/NonPD: Persistence of one or more nonTLs and/or maintenance of tumor marker level 
above the normal limits. 
PD: Appearance of one or more new lesions and/or unequivocal progression of existing nonTLs. 
Unequivocal progression should not normally trump TL status. It must be representative of 
overall disease status change, not a single lesion increase. 
Although a clear progression of “nontarget” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or Principal Investigator). 
Evaluation of Best Objective Response 
The best objective response (BOR) is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for PD the smallest measurements 
recorded since the treatment started). The patient’s best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
 
 

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For Patients With Measurable Disease (ie, Target Disease) 
Target Lesions Nontarget Lesions 
New Lesions 
Overall 
Response 
Best Overall Response 
When Confirmation Is 
Requireda 
CR 
CR 
No 
CR 
>4 wks confirmationb 
CR 
NonCR/nonPD 
No 
PR 
>4 wks confirmationb 
CR 
Not evaluated 
No 
PR 
PR 
NonCR/nonPD/ not 
evaluated 
No 
PR 
SD 
NonCR/nonPD/  
not evaluated 
No 
SD 
Documented at least once 
8 wks from first dose of 
study treatmentb 
PD 
Any 
Yes or No 
PD 
No prior SD, PR, or CR 
Any 
PDc 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR=complete response; PD=progressive disease; PR=partial response; RECIST=Response Evaluation Criteria in 
Solid Tumors; SD=stable disease. 
a 
See RECIST v1.1 manuscript for further details on what is evidence of a new lesion (Eisenhauer 2009). 
b 
Only for nonrandomized studies with response as primary endpoint. 
c 
In exceptional circumstances, unequivocal progression in nontarget lesions may be accepted as disease 
progression. 
Note: Patients with a global deterioration of health status requiring discontinuation of treatment without objective 
evidence of disease progression at that time should be reported as “symptomatic deterioration.” Every effort 
should be made to document the objective progression even after discontinuation of treatment. 
For Patients With Nonmeasurable Disease (ie, Nontarget Disease) 
Nontarget Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
NonCR/nonPD 
No 
NonCR/nonPDa 
Not all evaluated 
No 
Not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
CR=complete response; PD=progressive disease; SD=stable disease. 
a 
“NonCR/nonPD” is preferred over SD for nontarget disease since SD is increasingly used as an endpoint for 
assessment of efficacy in some studies so to assign this category when no lesions can be measured is not 
advised. 
 
 

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APPENDIX 5. EASTERN COOPERATIVE ONCOLOGY GROUP 
PERFORMANCE STATUS 
Source: Oken 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. SIMULATED OPERATING CHARACTERISTICS OF 
DOSE ESCALATION DESIGN 
Table 22 shows the operating characteristics of the proposed design for this study with 
5 scenarios involving various numbers and locations for the MTDs, based on 5000 simulations 
using the BOIN Design Desktop Program. The computer simulations allow operating 
characteristics of the design to be estimated, such as the expected proportion of patients who will 
be either under- or over-dosed, how accurately the true MTD will be identified and how many 
patients are expected to be exposed to each dose level. The proportion of patients over-dosed, 
defined as receiving a dose that had a true dose-limiting toxicity rate of >30%, ranged between 
15.6% and 28.5% across all assumed dose-toxicity models. The operating characteristics also 
shows that the design selects one of the true MTD(s), if any, with high probability and allocates 
more patients to the dose levels with the dose-limiting toxicity rate closest to the target of 0.25. 
Table 1: 
Operating Characteristics of the Drug Combination BOIN design 
  
Dose Level 
Number of 
Patients 
% Early 
Stopping 
  
1 
2 
3 
4 
5 
6 
Scenario 2 
True DLT Rate 
0.12 
0.25 
0.42 
0.46 
0.51 
0.55 
21.6 
0.2 
Selection % 
24.8 
62.4 
11.1 
1.5 
0.1 
0.0 
% Pts Treated 
27.2 
47.9 
20.3 
3.8 
0.7 
0.1 
Scenario 3 
True DLT Rate 
0.04 
0.12 
0.25 
0.43 
0.53 
0.63 
24.1 
0.0 
Selection % 
1.2 
30.9 
57.2 
10.0 
0.6 
0.0 
% Pts Treated 
7.6 
36.2 
37.8 
15.5 
2.7 
0.3 
Scenario 4 
True DLT Rate 
0.02 
0.05 
0.08 
0.10 
0.25 
0.40 
28.5 
0.0 
Selection % 
0.1 
3.7 
8.3 
22.0 
52.0 
13.9 
% Pts Treated 
1.9 
15.6 
17.5 
25.5 
27.7 
11.7 
Scenario 5 

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True DLT Rate 
0.02 
0.04 
0.06 
0.09 
0.11 
0.25 
27.9 
0.0 
Selection % 
0.1 
2.0 
4.4 
9.5 
24.2 
59.9 
% Pts Treated 
1.5 
14.4 
16.5 
18.0 
25.1 
24.5 
BOIN=Bayesian optimal interval; DLT=dose-limiting toxicity; Pts=patients. 

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Appendix 7. 
STUDY CONDUCT IN UNFORESEEN 
CIRCUMSTANCES  
This appendix may be utilized by clinical trial sites during unforeseen circumstances that would result in 
increased risk associated with completion of the protocol conduct for study patients, such as during 
natural disasters (floods, tornadoes, earthquakes, hurricanes) or acts of people (e.g., acts of terrorism, 
riots, strikes, wars), and pandemics (e.g., COVID-19).  These measures may be implemented if allowed 
by applicable country laws and regulations.  These optional measures are put in place to preserve the risk-
benefit for study participation.  Measures should be documented by the site and reported by the Sponsor 
in the CSR.  
This appendix describes possible adaptations to:  
1. Consent Process  
2. Investigational Medicinal Product Shipment   
3. Patient Visits  
4. Trial Assessments  
5. Sample Collection  
6. AE Reporting  
7. Protocol Deviations  
 
Topic Requiring 
Adaptation  
Section  
Description  
Consent Process  
Inclusion Criteria  
Exclusion Criteria  
Original consent to enter the study must be performed in 
person at the clinical site.  
Written Informed Consent  
If original consent to enter the study has been obtained, 
subsequent remote consent is allowable for patients 
unwilling or unable to come to study site.  Alternative 
consents, in line with local/institutional guidelines, include 
such as usage of electronic signatures, faxing the signed 
consent forms, online consenting, oral consenting if the 
consent is obtained through audio/video communication 
through different applications, such as Skype.  The specific 
consent process and the patient’s consent should be 
documented in the patient’s chart.  The patient should re-
sign the consent once able to visit the clinic.  

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Study Drug Shipment  
All safety assessments 
must be carried out at the 
clinical trial site prior to 
the first treatment cycle 
and study drug being 
dispensed to the patient for 
the first time  
Study Drug Shipping, Labeling 
and Storage  
If potential border closures, flight restrictions and 
disruption affecting couriers, are observed during the 
enrollment of patients, this may cause delays in the 
shipment of the medication and customs clearance. The 
Sponsor will continue to monitor the impact of the 
unforeseen circumstances on the shipment of study 
medication as sites are evaluated for activation and/or 
additional IP shipments. If there are expected delays with 
medication importation or shipments, sites will be advised 
of the risk to screening and enrollment may be put on hold 
until the importation risks are mitigated, and medication 
supply can be provided to sites.   
Alternative shipment methods, including providing study 
medication directly to study participants may be 
considered.  
Patient Visits  
Screening and Day 1 of 
Cycle 1 must be conducted 
in person at the clinical 
trial site  
Schedule of Assessments and 
Pharmacokinetic Sampling  
If the Investigator believes that travel to the study site for a 
study assessment would place the study patient at increased 
risk relative to the benefit of the in person assessment, the 
assessment can be conducted remotely through 
telemedicine (phone, Skype, etc.) by a trained clinician on 
the study team with the exception of the visits/assessments 
specified in the Schedule of Assessments.  These can be 
billed as a visit while conducting standard assessments and 
to identify adverse events and ensure continuous medical 
care and oversight for this trial.).  Visit changes will be 
considered a Protocol Deviation related to the unforeseen 
circumstances, such as COVID19, and should be 
documented by study standard procedures.  
Changes in study visit schedules, missed visits, or patient 
discontinuations due to unforeseen circumstances may lead 
to missing information. Sites are being advised to capture 
specific information in the case report form that explains 
the basis of the missing data, including the relationship to 
the unforeseen circumstance for missing protocol-specified 
information (e.g., from missed study visits or study 
discontinuations due to COVID-19).  

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Study Assessments 
(including imaging and 
laboratory assessments)  
 
All safety assessments 
must be carried out at the 
clinical trial site prior to 
the first treatment cycle 
and study drug being 
dispensed to the patient for 
the first time  
Schedule of Assessments and 
Pharmacokinetic Sampling  
Laboratory assessment can be completed locally and sent to 
the study site, taking into consideration study drug may get 
sent for more than 1 cycle worth, that safety labs must be 
reviewed by an Investigator to verify if the patient is fit for 
treatment continuation.  Communication pathway should be 
agreed to with local office, including when to expect 
results, prior to completion of the assessment.  
• 
Imaging assessment and protocol-
mandated tumor samples or malignant fluid 
collection should be conducted as soon as they are 
considered safe and feasible; out of window 
assessments are preferable to a missed 
assessment.  Visit changes will be considered a 
Protocol Deviation related to the unforeseen 
circumstances, such as COVID-19, and should be 
documented by study standard 
procedures.  Performing an out of window imaging 
assessment is preferable to missing the assessment 
entirely.  
AE Reporting  
Collecting and Recording 
Adverse Events  
If physical visits are reduced or postponed, the 
Investigators will continue collecting AEs from the patient 
through alternative means, e.g., by phone calls or 
telemedicine visits, as appropriate.  
Protocol Deviations  
Protocol Deviations  
Protocol deviations (e.g., out of visit windows, etc.) should 
be captured per the usual study/institutional requirements.  

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Appendix 8. 
COUNTRY-SPECIFIC SUPPLEMENTS 
United Kingdom (UK) 
The following language apply to sites in the UK only. 
Additional clarifications for contraceptive guidance for male participants who take RP-6306 or 
5-FU (fluorouracil) are as follows: 
1. Men must use a condom and partners who are WOCBP should be advised to use a highly 
effective contraception methods throughout the study and for 6 months after the last dose of 
study treatment.  
2. Men should also be advised about cryopreservation of sperm prior to treatment because of 
the possibility of infertility due to therapy with study drug.