Clinical trial NCT05147350
Conditions: Advanced Solid Tumor
Sponsor: Repare Therapeutics
Start date: 2022-08-09; Completion date: 2025-02-12
Enrollment: 38 participants; Allocation: NA; Intervention model: SEQUENTIAL

Brief summary:
The primary purpose of this study is to assess the safety and tolerability of RP-6306 with FOLFIRI in patients with eligible advanced solid tumors, determine the maximum tolerated dose (MTD), identify a recommended phase 2 dose (RP2D) and preferred schedule, and assess preliminary anti-tumor activity.

Detailed description:
To assess the safety and tolerability of RP-6306 in combination with FOLFIRI 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.

Arms: arm 1: RP-6306 will be administered as oral capsules Multiple dose levels of RP-6306 (oral) and FOLFIRI (IV)
Interventions: intervention 1: RP-6306 (oral PKMYT1 inhibitor)
Intervention descriptions: intervention 1: RP-6306 (Oral) in combination with FOLFIRI (IV)

Protocol documents:
Prot_000.pdf: 
Synopsis  RP-6303-03 Protocol Version 3.0  
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Page 1 of 37 
 
 
 
 
 
 
 
 
 
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. 
 

SAP_001.pdf: 
 
 
Statistical Analysis Plan 
Study Code 
RP-6306-03 
Edition 
Number 
Version 1.0 
Date 
29 Jul 2024 
 
 
 
Phase 1 Study of the PKMYT1 Inhibitor RP-6306 in Combination With 
FOLFIRI for the Treatment of Advanced Solid Tumors (MINOTAUR 
Study) 
Statistical Analysis Plan for RP-6306-03 
 


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Phase 1 Study of the PKMYT1 Inhibitor RP-6306 in Combination With 
FOLFIRI for the Treatment of Advanced Solid Tumors (MINOTAUR Study) 
 
 


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ......................................................................................................... 5 
1. 
INTRODUCTION ....................................................................................................... 8 
2. 
STUDY OBJECTIVES AND ENDPOINTS ............................................................... 8 
2.1. 
Module 1 Objectives and Endpoints ............................................................................ 8 
2.2. 
Analysis Endpoints ...................................................................................................... 9 
2.2.1. 
Safety Endpoints ........................................................................................................ 10 
2.2.2. 
Efficacy Endpoints ..................................................................................................... 10 
2.2.3. 
Pharmacokinetics ....................................................................................................... 11 
3. 
INVESTIGATIONAL PLAN .................................................................................... 11 
3.1. 
Overall Study Design and Plan .................................................................................. 11 
3.2. 
Schedule of Assessments ........................................................................................... 12 
3.2.1. 
Dose and Schedule Finding........................................................................................ 13 
3.2.2. 
Maximum Tolerated Dose ......................................................................................... 18 
3.3. 
Sample Size Considerations ....................................................................................... 21 
4. 
ANALYSIS POPULATIONS .................................................................................... 21 
4.1. 
DLT Evaluable Population ......................................................................................... 21 
4.2. 
Efficacy Population .................................................................................................... 21 
4.3. 
Safety Population ....................................................................................................... 21 
4.4. 
Pharmacokinetic Population ...................................................................................... 21 
5. 
DATA AND ANALYSIS CONSIDERATIONS ....................................................... 22 
5.1. 
General Principles ...................................................................................................... 22 
5.2. 
Study Day and Analysis Visit .................................................................................... 22 
5.2.1. 
Analysis Visit ............................................................................................................. 22 
5.3. 
Handling of Missing Data .......................................................................................... 23 
5.3.1. 
Missing/Partial Dates in Adverse Events ................................................................... 23 
5.3.2. 
Missing/Partial Dates in Concomitant Medication .................................................... 24 
5.3.3. 
Missing/Partial Dates during Screening Visit or Prior to Study Treatment ............... 25 
5.3.4. 
Missing/Partial Dates in Post-study Anticancer Therapy .......................................... 25 
5.3.5. 
Missing/Partial Last Dose Date.................................................................................. 26 
5.3.6. 
Relationship and Severity Imputation Rules for Adverse Events .............................. 26 
6. 
DISPOSITION, DEVIATIONS AND PATIENT CHARACTERISTIC DATA ...... 27 
6.1. 
Protocol Deviations .................................................................................................... 27 
6.2. 
Demographic and Baseline Characteristics................................................................ 28 


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6.3. 
Genotype and Mutation Status at Enrollment ............................................................ 28 
6.4. 
Disease Characteristics .............................................................................................. 28 
6.5. 
Medical History.......................................................................................................... 28 
6.6. 
Prior and Concomitant Medications .......................................................................... 29 
7. 
SAFETY AND EXPOSURE DATA ......................................................................... 29 
7.1. 
Adverse Events .......................................................................................................... 30 
7.2. 
Treatment Exposure ................................................................................................... 31 
7.3. 
Laboratory Evaluations .............................................................................................. 33 
7.4. 
Vital Signs and Abnormalities ................................................................................... 34 
7.5. 
12-lead ECG ............................................................................................................... 35 
7.6. 
Physical Examination and ECOG Performance Status .............................................. 36 
8. 
EFFICACY DATA .................................................................................................... 36 
8.1. 
Derivation of Efficacy Endpoints .............................................................................. 36 
8.1.1. 
Best Percentage Change in Tumor Size ..................................................................... 36 
8.1.2. 
Objective Response Rate (ORR) ................................................................................ 36 
8.1.3. 
Best Overall Response Rate ....................................................................................... 36 
8.1.4. 
Clinical Benefit Rate (CBR) ...................................................................................... 37 
8.1.5. 
Duration of Response (DOR) ..................................................................................... 37 
8.1.6. 
Categorization of Best Tumor Response ................................................................... 37 
8.1.7. 
Change in Tumor Size ................................................................................................ 38 
8.1.8. 
Progression Free Survival (PFS) ................................................................................ 38 
8.2. 
Efficacy Analysis Methods ........................................................................................ 39 
9. 
PHARMACOKINETIC (PK) PARAMETERS DATA ............................................. 40 
9.1. 
Population PK/PD Modelling .................................................................................... 42 
11. 
INTERIM ANALYSIS .............................................................................................. 42 
12. 
REFERENCES........................................................................................................... 43 
APPENDIX 1. DEFINITION OF DOSE LIMITING TOXICITY (DLT) ................................ 44 
APPENDIX 2. GYNECOLOGICAL CANCER INTERGROUP DEFINITIONS FOR 
RESPONSE AND PROGRESSION IN PATIENTS WITH OVARIAN 
CANCER ................................................................................................................... 45 
APPENDIX 3. RESPONSE EVALUATION CRITERIA IN SOLID TUMORS, 
VERSION 1.1 ............................................................................................................ 47 


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LIST OF ABBREVIATIONS 
Abbreviation or 
special term 
Explanation 
AE 
Adverse Event 
ADaM 
Analysis Data Model 
ALT 
Alanine Aminotransferase 
ALP 
Alkaline Phosphatase 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Curve  
AUC0-8 
Area under the plasma concentration-time curve from time 0 to 8 hours post dose 
AUC0-12 
Area under the plasma concentration-time curve from time 0 to 12 hours post dose 
AUC0-inf 
Area under the plasma concentration-time curve from time 0 to infinite time 
AUC0-last 
Area under the plasma concentration-time curve from time 0 to t (“t” being the longest 
time interval evaluable in all periods) 
AUCss 
Area under the plasma concentration-time curve at steady-state 
BID 
Twice daily 
BOIN 
Bayesian Optimal Interval 
BP 
Blood Pressure 
BUN  
Blood Urea Nitrogen 
CBR 
Clinical Benefit Rate 
CCNE1 
Cyclin E1 
CDISC 
Clinical Data Interchange Standards Consortium 
CDK 
Cyclin-dependent kinase 
CDK1 
Cyclin-dependent kinase 1 
CDK2 
Cyclin-dependent kinase 2 
CI 
Confidence Interval 
Cmax 
Maximum observed plasma Concentration 
Cmin 
Minimum observed plasma concentration 
CR 
Complete Response 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
Circulating Tumor DNA 
DBP 
Diastolic Blood Pressure 
DCO 
Data Cut off 


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Abbreviation or 
special term 
Explanation 
DLT 
Dose Limiting Toxicity 
DNA 
Deoxyribonucleic Acid 
DOR 
Duration of Response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EOT 
End-of-Treatment 
FBXW7 
F-box and WD repeat domain containing 7 
FDA 
Food and Drug Administration 
FISH 
Fluorescent in situ hybridization 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte Colony Stimulating Factor 
GI 
Gastrointestinal 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IHC 
Immunohistochemistry 
LTFU 
Lost to Follow-up 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximal Tolerated Dose 
NCA 
Non-compartmental Analysis 
NCI 
National Cancer Institute 
NE 
Not Evaluable 
NGS 
Next-Generation Sequencing 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PD 
Progressive Disease  
PE 
Physical Exam 
PET 
Positron Emission Tomography 
PFS 
Progression Free Survival 
PK 
Pharmacokinetics 
PKMYT1 
Membrane-associated tyrosine- and threonine-specific Cdc2-inhibitory kinase 
PODS 
Precision Oncology Decision Support 
PPP2R1A 
Protein phosphatase 2 scaffold subunit A 
PR 
Partial Response 


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Abbreviation or 
special term 
Explanation 
PSA 
Prostate-Specific Antigen 
PT 
Preferred Term 
QD 
Once daily 
QT 
ECG interval measured from the onset of the QRS complex to the end of the T wave 
QTc 
QT interval corrected for heart rate 
QTcF 
Fridericia formula for corrected QT interval 
RBC 
Red Blood Cells 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
Recommended Phase 2 Dose 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
SDTM 
Study Data Tabulation Model 
SOC 
System Organ Class 
SRC 
Safety Review Committee 
TEAE 
Treatment Emergent Adverse Event 
t½ 
Terminal Elimination Half-Life 
TL 
Target Lesions 
Tmax 
Time to Maximum observed plasma concentration 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cells 
WHO 
World Health Organization 
 


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1. 
INTRODUCTION 
This statistical analysis plan (SAP) prospectively describes the planned analyses for the study  Protocol 
RP-6306-03 “Phase 1 Study of the PKMYT1 Inhibitor RP-6306 in Combination With FOLFIRI for the 
Treatment of Advanced Solid Tumors (MINOTAUR Study)” Version 3.0, which was issued on 26 
October 2022. The SAP is in full conformity with the most current version of Good Clinical Practices 
(GCP), the FDA and ICH Guidelines for clinical trials. It contains definitions of analysis populations, 
derived variables, and statistical methods for the analysis of efficacy and safety. In addition, the datasets 
generated for this study will be compliant with the latest version of the CDISC standards for the SDTM 
and ADaM datasets. 
This SAP mainly covers the primary and secondary objectives of the study. Analyses for some of the 
exploratory objectives will be addressed outside the SAP, where additional analysis plans may be 
developed to address these objectives. In addition, population pharmacokinetics (PK) and 
PK/pharmacodynamic modelling will be addressed outside of the SAP.  
The purpose of this SAP is to ensure the credibility of the study findings by pre-specifying the statistical 
approaches to the analysis of study data prior to database lock. This SAP will be finalized and approved 
prior to the clinical database lock.   
2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Module 1 Objectives and Endpoints 
Primary Objectives 
Primary Endpoints 
To assess the safety and tolerability of RP-6306 in 
combination with FOLFIRI 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 the 
recommended Phase 2 dose (RP2D) and schedule of RP-
6306 in combination with FOLFIRI 
Dose-limiting toxicities (DLTs) 
Secondary Objectives 
Secondary Endpoints 
To assess the preliminary efficacy of RP-6306 in 
combination with FOLFIRI in patients with molecularly 
selected, advanced solid tumors 
Best percent change in tumor size from baseline, objective 
response rate (ORR), best overall response rate, duration of 
response (DOR), clinical benefit rate (CBR), and 
progression-free survival (PFS) at 6 months 
To assess PK parameters of RP-6306 in combination with 
FOLFIRI 
Plasma concentrations of RP-6306, irinotecan, and SN-38 
with calculation of maximum observed plasma 
concentration within the dosing interval (Cmax), time to 
maximum observed plasma concentration (Tmax), area under 
the plasma concentration-time curve from time 0 to t (“t” 
being the longest time interval evaluable in all periods) 
(AUC0-last), and other parameters as appropriate 




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2.2.1. 
Safety Endpoints 
• DLTs  
• Incidence of TEAEs, treatment related TEAEs, TEAEs leading to death, serious adverse 
events (SAEs), treatment related SAEs, TEAEs leading to study drug discontinuation, TEAEs 
leading to dose modifications (interruptions or reductions)  
• Changes in clinical laboratory parameters (hematology, chemistry, urinalysis), CTCAE 
graded laboratory toxicities, vital signs, Eastern  Cooperative Oncology Group (ECOG) 
performance status, ECG parameters including QTc, physical exams (PEs) and usage of 
concomitant medications 
2.2.2. 
Efficacy Endpoints 
Best percentage change in tumor size: defined as the largest decrease or smallest increase (in the 
absence of a decrease) in the sum of diameters of the target lesions (TLs) prior to progression or last 
evaluable assessment in the absence of progression. 
• Objective response rate (ORR): defined as the proportion of patients with confirmed best 
overall response of complete response (CR) or partial response (PR) (i.e., 2 subsequent 
responses of either CR or PR at least 4 weeks apart) according to RECIST v1.1.  
• Best overall response rate: defined as the proportion of patients with confirmed or 
unconfirmed response of CR or PR based on best overall response by investigators across all 
visits. Unconfirmed CR or PR will be defined as those patients with CR or PR only reported 
once in overall tumor assessment form by the Investigators according to RECIST 1.1.   
• Clinical benefit rate (CBR):  defined as the proportion of patients with a best overall 
response of CR or PR according to RECIST v1.1 based on Investigator’s assessment, or 
duration on treatment of at least 16 weeks without evidence of progression.  
Duration of response (DOR, applicable only to patients with confirmed CR or PR): defined as the 
time interval between the date of the earliest qualifying response (CR or PR) and the date of disease 
progression or death for any cause, whichever occurs earlier.  
For patients who are alive without disease progression following response, DOR will be censored on the 
date of last evaluable tumor assessment.  
• Progression-free survival (PFS): defined as the time from the first day of study treatment 
administration (Day 1) to disease progression as defined by RECIST v1.1 or death from any 
cause.     
− Patients who are alive and free from disease progression will be censored at the date of 
their last tumor assessment.    
− Any patient who dies in the absence of progression, and the death is >12 weeks after the 
last evaluable tumor assessment, will be censored for PFS at the date of their last 
evaluable tumor assessment. More details are provided in Section 8.1.9 and Table 8.  
Detailed derivation of the endpoints can be found in Section 36. 




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Figure 1: 
Module 1 Study 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. 
 
3.2. 
Schedule of Assessments 
The study will consist of a Screening Period (Day -28 to Day -1) to determine eligibility, Treatment 
Period (14-day cycles), End-of-Treatment (EOT) Period (occurring within 7 days after the last dose of 
study treatment), and a Safety Follow-up Period (occurring 30 days ±2 weeks after the last dose of study 
treatment for all patients not cleared at the EOT visit, including patients with ongoing Grade ≥2 drug-
related toxicities at the EOT visit (Figure 2). 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). 
 
Figure 2: 
Study Conduct 
    


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AE=adverse event; C1D1=Cycle1 Day 1; ctDNA=circulating tumor deoxyribonucleic acid; ECG=electrocardiogram; 
EOT=End-of-Treatment; FU=Follow-up; PD=progressive disease; PK=pharmacokinetic; RP2D=recommended Phase 2 
dose. 
The start of the study is defined as the date when the first patient in the whole study signs an informed 
consent form (ICF). 
The end of the study is defined as the date of the last visit (including all follow-up visits) of the last 
patient in the whole study. 
See protocol for full details on the schedule of assessments. 
The key procedures required in this study include: 
• Tumor assessments (based on CT, PET, and/or MRI scan) according to RECIST v1.1 or as 
clinically indicated (see Appendix 4 of the protocol) 
• PK samples throughout the study 
• Baseline, on-treatment, and EOT blood samples 
• Reporting all AEs occurring from the administration of the first dose of RP-6306 and 
FOLFIRI 
• Paired biopsies 
• ECG 
A cycle of treatment is 2 weeks (14 calendar days).  
3.2.1. 
Dose and Schedule Finding  
This study aims to identify the RP2D and preferred dosing schedule of RP-6306 in combination with 
FOLFIRI. RP-6306 will be given on a continuous QD schedule (Module 1a) and intermittent schedule 


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(Module 1b) as outlined below. 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.  
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 3 and Table 1 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). 
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 


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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. 
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 3:  
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. 
3.2.2. 
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%. 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. 
Table 2: 
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 


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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 2. 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.  
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.  
2. 
To assign a dose to the next cohort of patients, conduct dose escalation/de-escalation according to 
the rule displayed in Table 2. When using Table 2, 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 for the 
corresponding module 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 the dose that at or 
lower than the MTD based on the totality of the safety, PK, pharmacodynamics, and preliminary 
efficacy. 
 
 
 
 


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3.3. 
Sample Size Considerations 
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 (Section 11.1 of the protocol). 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 (Section 12.1 of the protocol), 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. 
4. 
ANALYSIS POPULATIONS 
4.1. 
 DLT Evaluable Population 
DLT Evaluable Population will consist of patients who have met the minimum safety evaluation 
requirements of the study and/or who experience a DLT at any time during the first two cycles (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 for the evaluated schedule, 100% of 
planned doses of FOLFIRI, completes all required safety evaluations per the Schedule of Assessments 
(refer to Section 12.1 of the protocol), and is observed at least until Day 28 since the first dose of study 
treatment. 
4.2. 
Efficacy Population  
The Efficacy Population, used for the assessment of efficacy, will consist of all patients who receive at 
least 1 dose of study treatment and had at least 1 post‑baseline tumor assessment based on RECIST v1.1 
or without post-baseline tumor assessment but discontinued the treatment due to clinical progression or 
death prior to any post-baseline tumor assessment, and have local confirmation of their genomic 
alterations.  
4.3. 
Safety Population 
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 are enrolled. 
4.4. 
Pharmacokinetic Population 
The Pharmacokinetic Population, used for the assessment of PK endpoints, will consist of all patients 
who have sufficient RP-6306, irinotecan and/or SN-38 PK concentration data recorded to derive PK 
endpoints. 
For all analysis populations, patients will be presented by the initial dose received. 


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5. 
DATA AND ANALYSIS CONSIDERATIONS 
5.1. 
General Principles 
All demography and safety data will be presented by the safety population, except for the DLT reporting 
which will be based on the DLT evaluable population. Assessment of anti-tumor activity will be based 
on the Efficacy Population and PK data will be presented by the PK Population. 
Most of the analyses will be descriptive in nature. Unless stated otherwise, continuous variables will be 
summarized using descriptive statistics (number of patients, mean, standard deviation, median, lower and 
upper quartile, minimum and maximum values) and the number and percentage of patients will be used 
for categorical variables. In general, missing data will be considered as missing and will not be imputed. 
Unless stated otherwise, percentages will be calculated out of the number of patients in the relevant 
analysis population. 
Baseline will be the last assessment of the variable under consideration prior to first dose of RP-6306. 
Unless stated otherwise, safety and efficacy data will be presented by assigned dose/schedule. 
After determination of RP2D dose(s), safety and efficacy data may also be summarized by grouping dose 
levels based on RP2D and clinical relevance.  
All DLT rates will be summarized by the assigned initial dose levels.  
Summary statistics will be presented to the following degree of precision unless otherwise specified: 
Degree of Precision 
Mean, Geometric mean, Median, Quartiles, 
Confidence limit boundaries 
One more decimal digit than the raw data. 
Standard deviation, Standard error 
Up to 2 more than the raw data  
Minimum, Maximum 
The same decimal digit as the raw data. 
Percentage 
One decimal place. A percentage of 100% will be reported as 100%. 
Percentages of zero will be reported as 0. 
5.2. 
Study Day and Analysis Visit 
Study Day will be calculated from the reference start date (defined as the date of first dose of study 
drug), and will be used to show start/stop day of assessments/events:  
Study Day = (date of assessments/events - reference start date) if event/assessment is prior to the 
reference start;   
Study Day = (date of assessments/events - reference start date + 1) if event/assessment is on or after the 
reference start. 
There is no Study Day 0. 
5.2.1. 
Analysis Visit  
Baseline value will be the latest non-missing result obtained on or before the first dose of study 
treatment. The nominal visits will be used as analysis visits for the purpose of summarizing data over 
scheduled visit. If visits are clearly defined, no windowing algorithm will be used.  


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All recorded data will be included in the listings. 
5.3. 
Handling of Missing Data 
There will be no imputation of incomplete or missing data other than the dates mentioned below. No 
imputation will be performed for missing data elements for by-patient listings. However, the imputation 
will be implemented for summary tabulations, when applicable.  
5.3.1. 
Missing/Partial Dates in Adverse Events 
 
Missing Data Imputation for Adverse Event Start Dates 
If the stop date is non-missing and the imputed start date is after the stop date, the stop date will be used 
as the start date. 
(1) Missing day only 
• If the month and year are the same as the month and year of the first dose date, the first dose 
date will be used. 
• If the month and year are before the month and year of the first dose date, the last day of the 
month will be assigned to the missing day. 
• If the month and year are after the month and year of the first dose date, the first day of the 
month will be assigned to the missing day. 
(2) Missing day and month 
• If the year is the same as the year of the first dose date, the first dose date will be used. 
• If the year is prior to the year of the first dose date, December 31 will be assigned to the 
missing fields. 
• If the year is after the year of the first dose date, January 1st will be assigned to the missing 
fields. 
(3) Missing day, month, and year (or only year) 
• The first dose date will be used. 
 
Missing Data Imputation for Missing Adverse Event Stop Date 
If the start date is non-missing and the imputed stop date is before the start date, the start date will be 
used. If the death date is available and the imputed stop date is after the death date, the death date will be 
used. 
(1) Missing day only 
• The last day of the month will be assigned as the missing day. 
(2) Missing day and month 
• December 31 will be assigned to the missing fields. 
(3) Missing day, month, and year (or only year) 


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• The event will be regarded as ongoing. 
 
5.3.2. 
Missing/Partial Dates in Concomitant Medication 
 
Missing Data Imputation for Concomitant Medication Start Dates 
If the stop date is non-missing and the imputed start date is after the stop date, the stop date will be used 
as the start date. 
(1). Missing day only 
• If the month and year are the same as the month and year of the first dose date, the first dose 
date will be used. 
• If the month and year are before the month and year of the first dose date, the last day of the 
month will be assigned to the missing day. 
• If the month and year are after the month and year of the first dose date, the first day of the 
month will be assigned to the missing day. 
(2). Missing day and month  
• If the year is the same as the year of the first dose date, the first dose date will be used. 
• If the year is prior to the year of the first dose date, December 31 will be assigned to the 
missing fields. 
• If the year is after the year of the first dose date, January 1st will be assigned to the missing 
fields. 
(3). Missing day, month, and year (or only year) 
• Do not impute. 
 
Missing Data Imputation for Missing Concomitant Medication Stop Date 
If the start date is non-missing and the imputed stop date is before the start date, the start date will be 
used. If the death date is available and the imputed stop date is after the death date, the death date will be 
used. 
(4) Missing day only 
• The last day of the month will be assigned as the missing day. 
(5) Missing day and month 
• December 31 will be assigned to the missing fields. 
(6) Missing day, month, and year 
• Do not impute. 
 


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5.3.3. 
Missing/Partial Dates during Screening Visit or Prior to Study Treatment 
The following rules apply to dates recorded during the screening visits (e.g., prior therapies/medications, 
initial diagnosis): 
(1) Missing day only 
• The first day of the month will be used if the year and the month are the same as those for the 
first dose of study drug. Otherwise, the 15th will be used.  
(2) Missing day and month 
• If the year is the same as the year of the first dose of study drug, the 15th of January will be 
used unless it is later than the first dose, in which case the date of the first of January will be 
used. 
• If the year is not the same as the year of the first dose of study drug, the date of the first of 
July will be used, unless other data indicates that the date is earlier. 
(3) Missing day, month, and year 
• No imputation will be applied. 
If the imputed date is later than the first dose, then the date of the first dose will be used. 
5.3.4. 
Missing/Partial Dates in Post-study Anticancer Therapy 
 
Post-study therapy/radiotherapy start date: 
If the stop date is non-missing and the imputed start date is after the stop date, the stop date will be used 
as the start date. 
• If year is missing (or completely missing), do not impute. 
• If year is present and month and day are missing: 
− If year is the same as the year of last dose date, impute as the last dose date + 1. 
− If year is greater than the year of last dose date, impute as January 1st. 
• If year and day are present and month is missing: 
− If year is the same as the year of last dose date, and day is not greater than the day of last 
dose date, impute the month as the month of last dose date + 1.  
− If year or day is greater than the year or day of last dose date, impute the month as the 
month of last dose date. 
• If year and month are present and day is missing: 
− If year and month are the same as the year and month of last dose date, impute as last dose 
date + 1. 
− If year or month is greater than the year or month of last dose date, impute day as first day 
of the month. 
 


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Post-study therapy/radiotherapy end date: 
If the start date is non-missing and the imputed stop date is before the start date, the start date will be 
used. If the death date is available and the imputed stop date is after the death date, the death date will be 
used. 
• If year is missing (or completely missing), do not impute. 
• If (year is present and month and day are missing) or (year and day are present and month 
is missing, impute as December 31st. 
• If year and month are present and day is missing, impute day as last day of the month. 
• If the imputed end date is earlier than the observed/imputed post-study therapy/radiotherapy 
start date, the end date will be imputed as the same as the start date. 
 
5.3.5. 
Missing/Partial Last Dose Date 
Missing/incomplete last dose date from the treatment discontinuation page will be imputed as follows: 
1. 
Missing day only 
• If the treatment discontinuation reason is death, the death date will be used. 
Else if the last available dosing date from dosing data matches the partial last dose date from the 
treatment discontinuation page, the last available dosing date will be used. 
• Else the first day of the month will be used. 
(2) Missing day and month 
• If the treatment discontinuation reason is death, the death date will be used. 
• Else if the last available dosing date from dosing data matches the partial last dose date from 
the treatment discontinuation page, the last available dosing date will be used. 
• Else January 1st will be used. 
(3) Missing day, month and year 
• If the treatment discontinuation reason is death, the death date will be used. 
• Else the last available dosing date will be used. 
The imputed last dose date will be compared to the available study discontinuation date and the data cut 
off date. Then the earliest date will be used. 
 
5.3.6. 
Relationship and Severity Imputation Rules for Adverse Events 
Imputation will not be made for data listings and datasets. Missing severity and relationship will not be 
imputed. All AEs are expected to have non-missing severity (to toxicity grade) and relationship at the 
time of database lock.  


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6. 
DISPOSITION, DEVIATIONS AND PATIENT CHARACTERISTIC 
DATA 
An overall patient disposition summary will be presented for all subjects to show the number of unique 
patients who entered the study. 
In addition, patient disposition will be presented by Module 1a or 1b and by dose/schedule with 
percentages based on the safety population. The following information will be presented for disposition: 
• Included in each analysis population (DLT evaluation, safety, Efficacy and PK) 
• Ongoing/discontinued study treatment at the data cut off 
− Including reasons for discontinuation of treatment as per the eCRF 
• Ongoing/withdrawn/completion from study at the data cut off 
− Including reasons for study termination as per the eCRF 
Disposition data will be listed for all patients and will include patient status, date of discontinuation from 
treatment, date of withdrawal from study and reason for treatment discontinuation and study withdrawal. 
In addition, the number and percentage of subjects by country and site will be summarized. 
6.1. 
Protocol Deviations 
There is no per protocol analysis population defined for this study, therefore patients will not be excluded 
from the data analysis and reporting based on deviations. 
Any important deviations discovered during the trial either through the data collected on eCRFs or 
monitoring visits/reports will be listed and summarized. Deviation data may be exported into the 
database via third party data such as an excel file used by study monitors to track deviations (e.g., 
deviations collected via the clinical study management system, CTMS). 
The following deviations will be considered important deviations: 
• Patients who entered the study but did not fulfil the entry criteria. 
• Treatment deviations such as wrong treatment received or incorrect dose during the study. 
Note, treatment delays or changes due to AE management are not considered  treatment 
deviations. A review of relevant data may be required to confirm all important deviations in 
this category. 
• Patients who received a prohibited concomitant treatment, including prohibited anti- cancer 
treatments. 
If a patient has a delay in treatment or misses cycles due to the impact of COVID-19, their eligibility for 
inclusion in the analysis will be decided on a case-by-case basis prior to database lock. 
Following review of all reported deviations and associated data and prior to database lock, other 
important deviation categories may be added. Only important deviations will be listed and summarized if 
appropriate.  If the number of important deviations are few (<=5 patients), only listing will be provided.   


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6.2. 
Demographic and Baseline Characteristics 
Demographics will be summarized by Module 1a or 1b and dose schedule for the safety population. 
Baseline demographic will include age at informed consent, age group (<65 and ≥65 years),  gender, race, 
ethnicity, height (cm), weight (kg), BMI (kg/m2). Baseline characteristics will include primary tumor 
type and ECOG status.  
6.3. 
Genotype and Mutation Status at Enrollment 
The genes and mutation status of patients based on local test at enrollment will be listed and summarized. 
If a patient tests positive for more than one mutation/gene, the patient will be listed under the mixture of 
mutation/gene category for the baseline summary.  
6.4. 
Disease Characteristics 
The following disease characteristics will be summarized based on the Safety Population: 
Disease History: 
• Time since initial diagnosis (in years) 
• Time since presentation of metastatic disease  
• Primary tumor type 
• Histology and grade of disease at diagnosis 
 
Prior Anti-Cancer Therapy: 
• Number of prior lines of treatment 
• Prior irinotecan use 
• Prior use of platinum containing regimen   
• Information on last prior anticancer therapy: 
− Reason for administration (adjuvant, neoadjuvant, advanced/metastatic, etc.) 
− Best response   
− Disease progression (yes, no) 
− Time since end of last treatment in months 
− Duration of last treatment 
− Reason for end of regimen 
6.5. 
Medical History 
Medical history will be coded using the latest version of Medical Dictionary for Regulatory Activities 
(MedDRA) and will be summarized for the Safety Population, using System Organ Class (SOC) and 
preferred term (PT). The table will include the number and percentage of subjects and will be sorted in 
alphabetical order by SOC and PT. A subject will only be counted once within a class. A listing of 


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medical and surgical history will also be provided. In particular, cancer related medical history will be 
summarized by SOC and PT. 
6.6. 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the World Health Organization (WHO) Drug 
Dictionary. The number and percentage of patients will be tabulated by WHO drug generic term for the 
Safety Population.  
All prior and concomitant procedures (including transfusions) will be recorded from the Screening 
through to the EOT visit. 
Prior medications will include medications which started prior to the date of first dose of study treatment. 
A summary table will present the numbers and percentages of patients who received prior therapy, 
including prior systemic anticancer therapy, prior radiation, prior surgery, and best response to the prior 
therapy, if known. Concomitant medications will include medications which started or were ongoing at 
the date of first dose of study treatment through to 30 days after the last dose of study treatment, or to the 
start of subsequent anticancer therapy, whichever occurs first. For Concomitant medications (including 
transfusions), 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. 
The number of patients with a transfusion, reason for transfusion and type of transfusion will be provided 
in a listing.  
Details of prohibited concomitant medications are provided in the protocol. To determine prohibited 
medications programmatically, a coded list of all prohibited medications will be provided by clinical 
team. Listings of prior and concomitant medications will display a flag for prohibited medications. This 
information will be used to identify protocol deviations. 
7. 
SAFETY AND EXPOSURE DATA 
Safety and tolerability will be assessed in terms of AEs, TEAEs, SAEs, DLTs, concomitant medications, 
PEs, vital sign measurements, clinical safety laboratory evaluations (hematology, serum chemistry, and 
urinalysis), ECOG performance scores, and ECGs including QTc. 
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 28 days, it is deemed to be related to treatment and it meets the 
criteria defined in Appendix 1. The DLT Evaluable Population will be used as the analysis set during 
dose escalation to make dose decisions in determining the MTD. By-subject listings will be provided for 
DLTs (Cycle 2) using DLT Evaluable Population. 
DLTs will be identified from the AE eCRF where the AE is selected as a DLT. All AEs reported as 
DLTs on the eCRF will be included even if they were not considered DLTs by the Safety Review 
Committee (SRC) during the study reviews.  
The MTD for this study will be defined as the highest dose with the toxicity probability (DLT rate) 
<25%. The BOIN drug combination design will be employed to find the MTD of continuous RP-6306 
(Module 1a) or intermittent RP-6306 (Module 1b) in combination with FOLFIRI. Module 1a and 1b will 
be evaluated separately based on target toxicity rate is 25%. Simulations confirm that with this study 
design, defining the MTD this way is equivalent to using an isotonic regression with a descending pooled 


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adjacent violators algorithm, which is the recommended method in the publication for BOIN study 
designs (Yuan et al., 2016). 
7.1. 
Adverse Events 
Adverse events (AEs) will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
version 26.0 or more recent version (at the time of database lock) and graded according to NCI-CTCAE 
version 5. All laboratory test results will be classified for toxicity grade according to the NCI-CTCAE 
version 5 criteria. 
DLTs will be listed and summarized based on the DLT Evaluable Population.  
Treatment emergent adverse events (TEAEs) are those events that occur or worsen on or after the first 
dose of study drug up through 30 days post the last dose. Those events occurred after start of subsequent 
anticancer therapy will be excluded.    
An overview summary table of the number and percentage of patients in each of the categories listed 
below will be presented. This summary will be presented based on all patients in the study (overall 
summary to summarize unique patients) and then repeated split by module 1a or 1b and dose/schedule 
(see Section 5.1 for general presentation format). 
• All TEAEs 
• Treatment related TEAEs (related to either study drug) 
• DLTs 
• TEAEs with ≥ CTCAE Grade 3 
• Treatment-related TEAEs with ≥ CTCAE Grade 3 (related to either study drug) 
• Serious TEAEs 
• Treatment-related serious TEAEs (related to either study drug) 
• TEAEs with outcome of death 
• TEAEs leading to discontinuation of study treatment 
• TEAEs leading to dose modification (i.e., dose reduced or dose interrupted) of study treatment 
TEAEs will be summarized by system organ class (SOC), preferred term (PT), and by NCI CTCAE 
toxicity grade (where applicable). For summary tables, an AE that occurs more than once within a SOC 
and/or PT for the same patient will be counted only once using the worst NCI toxicity grade experienced. 
Number and percentage of participants with TEAEs will also be presented by PT only. This summary 
will be sorted in decreasing order of frequency based on overall safety population. 
For the summary tables related to toxicity grades, if there are two or more TEAEs (or AEs) with same 
SOC or PT and different toxicity CTCAE grades for the same subject, only the maximum toxicity grade 
of AE be counted. 
Data listing will be provided for all TEAEs, TEAEs with ≥ CTCAE Grade 3 and serious TEAEs. 


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An AE table of most frequently occurring TEAEs, showing all events in at least 5% of patients, will be 
summarized by preferred term, by decreasing frequency based on all patients. This cut-off may be 
modified after review of the data.  
TEAEs with outcome of death, leading to discontinuation of study treatment or leading to dose reduction, 
dose interruption or discontinuation of study treatment will be summarized by preferred term. 
Corresponding listings will be provided.  If the number of occurrences is low (e.g., when ≤ 5 patients 
involved), only listing will be provided. If necessary, tabulated by preferred term depending on the 
number of TEAEs reported for those categories. 
For patients who have a dose modification, all AEs (due to drug or otherwise) will be assigned to the 
initial dose group for summarizing. Any AE occurring before the first dose of study treatment will be 
included in the data listings but will not be included in the summary tables of AEs.  
Summary tables will include only treatment-emergent adverse events (TEAEs). Non-TEAEs will be 
listed but will not be included in the summaries. Note that those events with onset after start of 
subsequent anticancer therapy will be excluded from the TEAE summary. 
Pooled rash will include preferred terms of Rash Maculo-popular, Pruritis, Rash, Skin Exfoliation, 
Erythema, Dermatitis Contact, Eczema, Flushing, Rash Erythematous, and Rash Pruritic.   
A listing of all deaths and causes of deaths will be provided. 
 
7.2. 
Treatment Exposure 
Exposure will be derived for RP-6306 and FOLFIRI respectively. 
Duration of Exposure for each drug RP6306 and FOLFIRI will be defined as the duration between the 
first and last doses of respective study drug 
• Duration of RP6306 exposure = last dose date - first dose date + 1. 
• Duration of FOLFIRI exposure = last infusion date - first infusion date + 14,  due to 2 week 
infusion cycle 
 
Overall duration of treatment for the study regimen is defined as Date of Treatment Discontinuation 
(from EOT page in the CRF) – first dose date +1. If treatment is still ongoing, use cut off date. If Date of 
Treatment Discontinuation is not collected, use the duration of exposure calculated above (take the 
longer of the either drugs).. 
The last dose date will be obtained from the end of treatment (EOT) CRF page for each study drug. 
Number of days dosed will be derived as the number of days a patient received a dose of each study drug 
(i.e., excludes off treatment days and any missed doses). 
 
Dose intensity for RP-6306 will be derived as: 
Dose intensity = (total dose received/total planned dose)*100%  


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Total dose received (mg) for RP6306 is the sum of total doses (mg) received. If a patient had a dose 
reduction/change during treatment, then the total dose received will be calculated for each actual dose 
received and then summed to give the total dose received. 
Total dose received: ∑
 number of days dosed at dose 𝑥𝑥𝑖𝑖∗𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑥𝑥𝑖𝑖 
𝑘𝑘
𝑖𝑖=0
 
for i = 1 to k where i represents the number of dose levels received and k = number of distinct dose levels 
Total planned dose for RP6306 will be derived as initial assigned dose a patient will receive without any 
interruptions or reductions based on the time-period between the date of first dose and date of last dose 
after excluding days when dosing information is not available, accounting for the number of treatment 
days per week. This is assuming the days without dosing information is missing at random. 
A dose interruption will be defined as a planned interruption where a decision is made to interrupt the 
dose temporarily, usually due to AE reason. Dose interruptions will be captured on the eCRF. 
A dose reduction is any reduction prescribed by PI in dose/schedule compared to the initial dose. 
Patients who do not have an end of treatment date in the eCRF at the time of analysis and reporting will 
be considered ongoing treatment. For deriving exposure, ongoing patients will be assumed to be ongoing 
at the date of the data cut off and therefore the data cutoff date will be used to derive exposure. 
Exposure for RP6306 will be listed and summarized by the Safety Population and presented by module 
1a and 1b and dose/schedule. 
The following will be presented for RP-6306 (if applicable) 
• Duration of exposure (days) 
• Number and % of patients with at least 1 cycle, with at least 2 cycles...etc (up to at least 5 
cycles). 
• Number of cycles treated (completed) 
• Total dose received (mg) 
• Dose intensity based on initial planned dose (%)    
• Number and % of patients with at least one dose interruption reported in dosing log by 
considering only those incidences when AE is indicated as a reason 
− Further broken down by number with 1, 2 or ≥ 3 interruptions 
• Number and % of patients with at least one dose reduction (include dose reduction as a result 
of schedule change with less dose intensity) reported in dosing log considering only those 
incidences when AE is indicated as a reason 
− Further broken down by number with 1, 2 or ≥ 3 reductions 
• Number of patients with any dose escalation per protocol  
Patients with both an interruption and reduction will be included in both the interruption and  reduction 
summaries.  
The following will be presented for FOLFIRI. 
• Duration of exposure (days) 


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• Number of infusions received  
7.3. 
Laboratory Evaluations 
All laboratory data recorded in the eCRF will be listed. Out-of-reference range values will be flagged as 
high (H) or low (L) in the listings. The results in standard unit will be used in the summary tables. 
Box plots for percent changes from baseline over time for lab parameters will be produced by for all 
treated patients, based on the safety population and the number of patients with data at the relevant 
timepoints from selected lab tests. Sample size for each timepoint will be displayed. Summary tables of 
actual and change from baseline from all the numerical lab tests will be provided. 
Selected laboratory assessments (hemoglobin, neutrophils, white blood cells [WBC], platelets, ALT, 
AST, BUN, total bilirubin, and creatinine) will be also presented in shift tables showing baseline grade 
vs. maximum grade on study for lab assessment with CTCAE grading, based on all post-baseline data 
including unscheduled assessments. The denominator for each on-treatment maximum grade is the total 
number of patients in the corresponding row for baseline grade (i.e., the baseline row totals). The shift 
from baseline to worst value will be summarized. 
For lab assessments which do not have CTCAE grading these will be categorized as low/normal/high 
based on reference ranges and shift tables will present baseline versus worst value on study. 
If worst criteria could be a low or a high value or an increase or decrease (i.e., in both directions) then 
shift tables should be split to show shift from baseline to worst low/decrease value and then repeated for 
worst high/increase value. For example, CTCAE grade criteria is given for both lymphocytes count 
increased and lymphocyte count decreased. 
Table 3: 
Clinical Safety Laboratory Analytes from the Protocol 
Hematology 
Serum Chemistry 
Urinalysis 
• White blood cell count with 
differential (including at 
minimum: neutrophils, 
basophils, eosinophils, 
lymphocytes, monocytes) 
• RBC count 
• Hemoglobin 
• Hematocrit 
• Platelet count 
• Albumin 
• Alkaline phosphatase 
• ALT 
• AST 
• BUN and/or urea 
• Calcium 
• Chloride 
• Creatinine 
• Glucose 
• Lactate dehydrogenase 
• Phosphate or phosphorus 
• Potassium 
• Sodium 
• Magnesium 
• Total bilirubin 
• Specific gravity 
• Leukocyte esterase 
• Ketones 
• Protein 
• Glucose 
• Nitrite 
• Occult blood 
• Microscopy (if clinically 
indicated) 
• 
pH 


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Hematology 
Serum Chemistry 
Urinalysis 
• Direct bilirubin 
• Total protein 
• Uric acid 
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen 
 
Post-baseline liver function tests including unscheduled assessments will be summarized in the following 
categories in Safety Population. Corresponding listing will be produced to assess clinical relevance of 
these events (some maybe due to underlying disease): 
• AST > 3 × ULN or 3 × Baseline (if baseline value is >ULN) 
• ALT > 3 × ULN or 3 × Baseline (if baseline value is >ULN) 
• ALP > 3 × ULN or 3 × Baseline (if baseline value is >ULN) 
• Total bilirubin > 2 × ULN 
 
7.4. 
Vital Signs and Abnormalities 
Descriptive statistics of pulse/heart rate, blood pressure (systolic and diastolic) (sitting/semi- recumbent), 
weight, and body temperature values will be summarized at baseline and post baseline visits, and 
changes from baseline will be summarized for post baseline visits based on the Safety Population. A 
separate listing will include all the vital sign measurements, including those from the unscheduled visits.   
The following post-baseline vital signs will be summarized based on the Safety Population: 
• Maximum post-baseline in SBP: 
− No increase 
− Increase < 20 mmHg 
− Increase ≥ 20 mmHg 
− 
≥ 160 mmHg and increase ≥ 20 mmHg 
• Maximum post-baseline in DBP: 
− No increase 
− Increase < 20 mmHg 
− Increase ≥ 20 mmHg 
− 
≥ 100 mmHg and increase ≥ 20 mmHg 
For the number of subjects meeting each category for the post-baseline results or for the change from, the 
numerator is the number of subjects with meeting the criterion at any post-baseline including the 
unscheduled, and the denominator is the number of subjects with normal baseline and at least one post 
baseline assessment including unscheduled visits in the Safety Population.  


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A listing for patients with any post-baseline potentially clinically significant changes listed above will be 
also presented. 
Box plots for percent changes from baseline over time will be produced by combining module 1a and 1b 
based on the Safety Population and the number of patients with data at the relevant timepoints. 
 
7.5. 
12-lead ECG 
Descriptive statistics (n, mean, SD, median, minimum, and maximum) of ECG parameters, including PR 
interval, RR interval, QRS duration, QT interval, and QTcF interval (Fridericia’s corrections) will be 
presented for baseline, each post-baseline visit, and change from baseline to each post baseline visit for 
Safety Population. All measurements, including those during unscheduled visits, will be provided in data 
listings, but only the scheduled measurements will be included in the by-visit summary. The average of 
triplicate 12-lead ECG results will be used for descriptive statistics. 
Overall ECG interpretation category (normal, abnormal NCS (not clinically significant), abnormal CS 
(clinically significant), and not evaluable) is collected in the CRF at baseline and each scheduled 
post-baseline visit. Shifts in ECG interpretation at baseline to worst post baseline will be presented. For 
triplicate 12-lead ECG results collected at a visit, the average of triplicate 12-lead ECG results will be 
used as the interpretation at baseline as well as post-baseline.  
The QTcF will be categorized into the following categories. 
• QTc interval >450 msec and ≤480 msec 
• QTc interval >480 msec and ≤500 msec 
• QTc interval >500 msec 
The change from baseline in QTcF will also be categorized separately as follows: 
•  QTc interval increases from baseline by >30 msec and ≤60 msec 
•  QTc interval increases from baseline by >60 msec 
For the number of subjects meeting each category for the post-baseline results, the numerator is the 
number of subjects with meeting the criterion at any post-baseline including unscheduled visits and the 
denominator is the number of subjects with normal baseline and at least one post baseline assessment 
including unscheduled visits in the Safety Population. For the number of subjects meeting each category 
for the change at post-baseline from baseline, the numerator is the number of subjects with meeting the 
criterion at post-baseline and the denominator is the number of subjects with baseline and at least one 
post baseline assessment in the Safety Population.  
Box plots for absolute and pchange from baseline for QTcF will be produced by combining module 
based on the Safety Population and the number of patients with data at the relevant timepoints. All ECG 
parameters will be listed in a data listing. All ECG tables and listings will be reported on the safety 
analysis set.   
A separate analysis on correlation between exposure and QTc will be performed as part of the population 
PK/ER analysis (outside the scope of this SAP).   


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7.6. 
 Physical Examination and ECOG Performance Status 
Abnormalities identified from physical examination will be listed for the safety analysis set. 
Shift table of baseline ECOG performance to worst post-baseline status will be summarized as the 
number and % of patients in each ECOG category based on the Safety Population.  
Any change in PE findings assessed as clinically significant should be recorded as an AE or SAE. 
8. 
EFFICACY DATA 
The efficacy analysis will be summarized by dose combination. 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. 
Efficacy data will be summarized using the Efficacy Population. 
8.1. 
Derivation of Efficacy Endpoints 
8.1.1. 
Best Percentage Change in Tumor Size 
Best percentage change in tumor size is defined as the largest decrease or smallest increase (in the 
absence of a decrease) in the sum of diameters of the TLs prior to progression or last evaluable 
assessment in the absence of progression.  
• If a patient receives another anti-cancer therapy prior to progression, then data up until the 
least evaluable TL assessment prior to the start of subsequent therapy will be included 
• If a patient does not have any evaluable post-treatment TL assessments to allow a derivation 
of best percentage change from baseline, they will be excluded from analysis 
8.1.2. 
Objective Response Rate (ORR) 
Objective Response Rate (ORR) is defined as the proportion of patients with a confirmed response of CR 
or PR (i.e., 2 visit responses of either CR or PR at least 4 weeks apart) according to RECIST v1.1 
criteria. This analysis will be limited to patients with measurable disease.   
• Response will be assessed based on all evaluable assessments up to and including progression 
per RECIST v1.1. Responses occurring following subsequent anti-cancer therapy will be 
excluded from the assessment of ORR but will be included in the listing. 
8.1.3. 
Best Overall Response Rate 
Best Overall Response Rate is defined as the proportion of patients with confirmed or unconfirmed 
response of CR or PR based on best overall response by investigators across all visits. Unconfirmed CR 
or PR will be defined as those patients with CR or PR only reported once in overall tumor assessment 
form by the Investigators according to RECIST 1.1. 
Note that the unconfirmed CR or PR (assessed by investigator) is added as a response criterion in 
addition to protocol defined confirmed CR or PR, to identify signal of anti-tumor activity for the 
treatment. 


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8.1.4. 
Clinical Benefit Rate (CBR) 
CBR is defined as the proportion of patients with a best overall response of CR or PR according to 
RECIST v1.1 based on Investigator’s assessment or duration on treatment of at least 16 weeks without 
evidence of progression. 
CBR will be defined for patients in efficacy population only.  
8.1.5. 
Duration of Response (DOR) 
Duration of Response (DOR) will be derived for patients with a confirmed CR or PR only. DOR is 
defined as the time from the date of the earliest qualifying response (CR or PR) to the date of disease 
progression or death for any cause, whichever occurs earlier. Note, the end of response should coincide 
with the date of progression or death from any cause used for the PFS endpoint. 
Given responses are required to be confirmed, the date of earliest qualifying response is the latest date 
for the visit where the initial overall visit assessment of CR/PR was observed rather than the 
confirmation visit assessment. 
For patients who are alive without disease progression following response, DOR will be censored on the 
date of the last evaluable tumor assessment, last follow-up for disease progression, or data cut-off date, 
whichever occurs first. Handling of death without PD will be similar to PFS.   
Table 4 gives the details rules of defining censoring/event for DOR. 
Table 4: 
Censoring rule for Duration of Response (DOR) based on radiographical tumor 
assessment or death 
Situation 
Date of Censoring or 
Date of Event 
DOR (weeks) 
Censor 
Documented disease 
progression (PD) before 
data cutoff date 
Date of first PD 
(Date of first PD – Date of first PR/CR + 1)/7 
0 
No PD, but death date 
before data cutoff date, 
or death date within 12 
weeks after last adequate 
tumor assessment 
Date of death  
(Date of death – Date of first PR/CR + 1)/7 
0 
No PD and no death 
before data cutoff date, 
or death date beyond 12 
weeks after last adequate 
tumor assessment 
Date of last adequate 
tumor assessmenta before 
data cutoff  
(Date of last adequate tumor assessmenta – Date 
of first PR/CR + 1)/7 
1 
a Adequate disease assessment is defined as a response assessment other than “not assessed” or “not evaluable.”  
 
8.1.6. 
Categorization of Best Tumor Response  
For supportive information, the following confirmed best response categories will be derived for all 
patients with at least one post-baseline tumor assessment: 
• Complete Response (CR): 2 visit responses of CR at least 4 weeks apart. 
• Partial Response (PR): 2 visit responses of PR at least 4 weeks apart. 


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• Stable Disease (SD): If not confirmed CR/PR, at least one visit response of SD (or better i.e., 
unconfirmed CR/PR) recorded at least 6 weeks after the date of first dose of study drug. 
− To allow for the protocol window of ± 7 days, an overall assessment of SD on or after day 
35 (i.e., 5 weeks) will be regarded as stable disease. 
• Progressive Disease (PD): If not CR/PR/SD, and with at least one response of disease 
progression 
• Not-Evaluable (NE): No evidence of CR, PR, SD, or PD. Either by default or the only visit 
response recorded is ‘NE’. 
8.1.7. 
Change in Tumor Size 
The percent change in target lesions (TL) size compared to baseline will be derived at each visit as: 
• Percent change in TL at Visit X = [(Visit X TL sum of diameters – Baseline TL sum of 
diameters)/Baseline TL sum of diameters] *100 
The best percent change will be derived as the largest decrease or smallest increase (in the absence of a 
decrease) up to and including progression or last evaluable assessment in the absence of progression. If a 
patient receives another anti-cancer therapy prior to progression, then data up until the last evaluable TL 
assessment prior to the start of subsequent therapy will be included.   
Note that only TLs matched with baseline will be used for calculation of percent change.  
8.1.8. 
Progression Free Survival (PFS) 
Progression-Free Survival (PFS) is defined as the time from the first day of study drug administration 
(Day 1) to disease progression as defined by RECIST v1.1 criteria or death from any cause.  
TL, NTL and new lesion assessments may be performed on different dates. The following rules will be 
applied for determine progression and censoring dates: 
Date of progression will be determined based on the earliest of the dates of the component that triggered 
the progression. For example, if progression was due to a new lesion only then the date of the new 
lesions would be used. If progression was due to TLs and a new lesion, then the earliest of the TL and 
new lesion dates would be used. 
Patients who are alive and free from disease progression will be censored at the date of their last 
evaluable tumor assessment prior to or equal to the data cut off date. 
Any patient who dies in the absence of progression after 2 or more missed assessments will be censored 
at the date of their last radiographic tumor assessment. Specifically, if the death date is >12 weeks from 
the last tumor assessment, the death date will not be used for the calculation of PFS. 
If a patient has no baseline tumor assessment/no post dose tumor assessments then they will be censored 
at 0 days for PFS, unless they died within 12 weeks from the date of first dose (and also before cut-off), 
in which case their death date will be used as a PFS event. 
Table 5 gives the details rules of defining censoring/event for PFS. 
PFS at 6 months will be reported based on KM methods as the number and % of patients estimated to be 
progression free at 6 months. 


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Table 5: 
Censoring Rule for time-to-event analyses (PFS) based on radiographical tumor 
assessment or death 
Situation 
Date of Censoring or Date of 
Event 
Censor 
Documented disease progression (PD) before data cutoff 
Date of first PD 
0  
No PD, but death date is within 12 weeks from the last adequate post-
baseline assessmenta 
Date of death  
 
0 
No PD, no post-baseline assessment, and death date is within 12 
weeks from the date of first dose 
Date of death 
0 
No PD, no post-baseline assessmenta, and death date > 12 weeks from 
the date of first dose 
Date of the first dose 
1 
No PD, no post-baseline assessmenta, and no death  
Date of the first dose 
1 
No PD, Death date > 12 weeks from the last adequate post-baseline 
assessmenta (e.g., 2 or more consecutive missed scheduled disease 
status assessments and the gap > 12 weeks) 
Date of last adequate tumor 
assessmenta    
1 
No PD or death, but with last adequate assessmenta before data cut off  Date of last adequate tumor 
assessmenta   
1 
a Adequate disease assessment is defined as a response assessment other than “not assessed” or “not evaluable.”  
 
This Censoring Rule is used for the data after implementation of data cut off. 
 
8.2. 
Efficacy Analysis Methods 
For overall response rate, ORR, and CBR, the number and percentage of patients along with an exact 
binomial 95% confidence interval (CI), using the Clopper-Pearson method, will be presented. 
In general, summary of all efficacy endpoints will be provided by dose level separately for Module 1a 
and 1b patients.  
The assessment of tumor efficacy will be based on the measurements recorded by the investigator. 
A summary of the best objective response will be presented which will include the number and 
percentage of patients with a best response of CR, PR, SD, PD and NE. 
Time-to-event endpoints (PFS) will be analyzed using the KM method and results will be summarized 
by the 25th, 50th and 75th percentiles, if estimable, with associated 2-sided 95% CIs. KM plots will be 
provided. For PFS, the number (%) of patients with an event and the number (%) of patients censored 
will also be presented. The rate of PFS at 16 weeks and 24 weeks will be derived from the corresponding 
Kaplan-Meier curves. The KM analyses for DOR may be replaced by descriptive summary of median, 
and quartiles with individual listing for responders if total confirmed responders are few and less than 5 
patients.   


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Maximum reduction in tumor size will be summarized by n, mean, standard deviation, median, 25th 
quartile and 75th quartile, minimum and maximum. The spider plots displaying change in tumor size over 
time for each patient will also be provided for each module and dose/schedule group as described above. 
In addition, waterfall plots showing the best percentage change from baseline (largest decrease or smallest 
increase in the absence of a decrease) in the sum of the TL sizes will be produced for each module by 
dose/schedule group indicating each patient’ best objective response. 
Swimmer plots will be produced for each module and dose/schedule group to show the duration of study 
treatment per patient with indicators for timing of response, progression or death, where applicable. 
9. 
PHARMACOKINETIC (PK) PARAMETERS DATA 
All PK data will be presented based on the Pharmacokinetic Population and presented by module 1a or 
1b and dose/schedule.  
PK parameters for RP-6306, irinotecan and SN-38 will be calculated using noncompartmental analysis 
(NCA) or population PK modeling. In summaries of raw concentration data, plasma concentration that 
falls below the lower limit of quantitation (BLQ) will be treated as zero in data tabulation. In individual 
PK parameter estimation, BLQ plasma concentrations will be treated as zero if the value preceded Tmax. 
BLQ plasma concentrations will be treated as missing if the value occurs after Tmax. All BLQ 
concentration values will be listed as reported. 
PK concentrations and parameters will be listed for all patients in the PK population.  
Individual patient and mean plasma concentration-time profiles will be plotted on linear and semi-
logarithmic scales for each cohort and dose/schedule. 
The following summary statistics will be presented for AUC0-last, Cmax, Tmax, terminal elimination rate 
constant (Kel), and terminal elimination half-life (t½) for RP-6306, irinotecan and SN-38. AUC0-8h, 
AUC0-24h (for QD dosing), AUC0--12h (for BID dosing) will be calculated for RP-6306 only.  Other 
parameters maybe calculated to support the development of RP-6306. The PK parameters will be 
calculated using Phoenix WinNonlin version 8.3 or higher (Certara USA, Inc., Princeton, NJ) or other 


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appropriate software as appropriate. Default reporting in text and tables is 3 significant figures except for 
time related parameters (t1/2, and Tmax). Time related parameters will be reported to two decimal places. 
PK parameters for RP-6306, irinotecan and SN-38 will be derived using non-compartmental methods 
from the concentration--time profiles as follows: 
Table 6: 
Derivation of Pharmacokinetic Parameters Prior to Analysis 
Parameter 
Definition 
Method of Determination 
Cmax 
Maximum observed concentration within the 
dosing interval 
Observed directly from data 
tmax 
Time to Cmax 
Observed directly from data as time of first 
occurrence 
AUC0-last  
Area under the plasma concentration-time curve 
from time 0 to t (“t” being the longest time interval 
evaluable in all periods) 
Linear up/Log down method 
AUC0-8h 
Area under the plasma concentration-time curve 
from time 0 to 8 hours post dose 
Linear up/Log down trapezoidal method 
AUC0-12h 
Area under the plasma concentration-time curve 
from time 0 to 12 hours post dose 
Linear up/Log down trapezoidal method 
AUC0-24h 
Area under the plasma concentration-time curve 
from time 0 to 24 hours post dose 
Linear up/Log down trapezoidal method 
t½ 
Elimination half-life 
Ln (2)/kel, where kel is the terminal phase rate 
constant calculated by a linear regression of the 
log-linear concentration-time curve 
PK parameters will not be calculated for profiles with less than three quantifiable concentrations. Actual 
PK sampling times will be used in the derivation of PK parameters. 
For PK parameters on the respective cycles and days appropriate to a given dose and schedule, the 
following will be calculated: 
• The geometric mean (gmean, calculated as exp [μ], where μ is the mean of the data on a 
logarithmic scale). 
• Coefficient of variation (CV, calculated as CV =100*SD/mean], where SD is the standard 
deviation of the untransformed data).]). 
• Geometric Coefficient of Variation calculated using log transformed data (Geom CV) 
• Arithmetic mean calculated using untransformed data. 
• Standard Deviation (SD) calculated using untransformed data. 
• Minimum. 
• Median. 
• Maximum. 
• Number of observations (n). 


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Tmax will be summarized as median, minimum, maximum and number of observations (n).  -For summary 
statistics and summary plots by sampling time, the nominal PK sampling time will be used, for individual 
patient plots by time, the actual PK sampling time will be used. 
Given that no formal hypothesis testing is being undertaken for this module, no statistical  inference will 
be made. 
 
9.1. 
Population PK/PD Modelling 
The population PK/PD and exposure-response analyses will be developed and reported separately from 
the CSR. Exploratory analysis of the population PK and biomarker changes may also be performed and 
also reported separately from the CSR. In addition, population PK and PK/PD modelling will be 
addressed outside of the SAP.  
11. 
INTERIM ANALYSIS 
No interim analysis is planned for this study. 


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12. 
REFERENCES 
Eisenhauer EA, Therasse P, Bogaerts J, Schwart LH, Ford R, Dancey J, Arbuck S, et al. New response 
evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer. 2009; 
45(2):228-47. 
Liu S, Yuan Y. Bayesian optimal interval designs for phase I clinical trials. Appl Statist. 
2015;64(3):507-523. 
Yuan Y, Hess KR, Hilsenbeck SG, Gilbert MR. Bayesian Optimal Interval Design: A Simple and 
Well-Performing Design for Phase I Oncology Trials. Clin Cancer Res. 2016;22(17):4291-301 
 


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APPENDIX 1. DEFINITION OF DOSE LIMITING TOXICITY (DLT) 
DLTs are defined as follows: 
Hematologic AEs: 
• Grade 4 neutropenia lasting at least 7 days or if G-CSF or GM-CSF is given at any time  
• Febrile neutropenia (defined as absolute neutrophil count [ANC] < 1000/ mm3 with a single 
temperature of ≥38.3○C[101○F] or a sustained temperature of ≥38○C[100.4○F] 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.  
Non-hematologic AEs: 
 
• 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  
 
The following events will not be considered a DLT: 
• 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 
 
 
 
 
 


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APPENDIX 2. GYNECOLOGICAL CANCER INTERGROUP 
DEFINITIONS FOR RESPONSE AND PROGRESSION IN PATIENTS 
WITH OVARIAN CANCER  
For patients with ovarian cancer with elevated CA-125 levels, response evaluation will include cancer 
antigen 125 (CA-125) in addition to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 
criteria as per Gynecological Cancer Intergroup (GCIG) criteria [Rustin 2011]. 
Definition of Response by CA-125 
• A ≥50% reduction in CA-125 levels from a pretreatment sample. The response must be 
confirmed and maintained for at least 3 weeks (note that GCIG recommends maintenance for 
at least 28 days; Patients can be evaluated for a CA-125 response only if they have a 
pretreatment sample that is at least twice the upper limit of the reference range and within two 
weeks before starting treatment. 
• Intervening samples and the confirmatory sample must be less than or equal to the previous 
sample (within an assay variability of 10%). 
• The date when the CA-125 level is first reduced by 50% is the date of the CA-125 response. 
•  A CA-125 complete response can occur if CA-125 levels fall to within the reference range.  
Definition of Progression by CA-125  
• For patients with elevated CA-125 pre-treatment that normalizes or for patients with CA-125 
in the normal range at baseline: CA-125 at least 2 times the upper limit of the reference range 
on 2 occasions at least 1 week apart.  
• For patients with elevated CA-125 pre-treatment which never normalizes: CA-125 at least 
2 times the nadir value on 2 occasions at least 1 week apart.  
• Progressive disease (PD) by objective change in tumor size should always take precedence 
over changes in CA-125 should it occur first. If measurable disease is reducing in size but the 
CA-125 suggests progression the patient should remain on treatment.  
• CA-125 progression will be assigned the date of the first measurement that meets the above 
criteria.  
Note: CA-125 progression in the absence of radiographic or other clinical evidence of progression will 
not be sufficient criteria for treatment discontinuation in this study.  
Patients are not evaluable by CA-125 if they have received mouse antibodies (unless the assay used has 
been shown not to be influenced by human antimouse antibody) or if there has been medical and/or 
surgical interference with their peritoneum or pleura during the previous 28 days.  
Evaluation of Best Overall Response by Combined CA-125 and RECIST 1.1 Criteria  
• If patients have a CA-125 response but have PD by RECIST within 28 days of the CA-125 
response, they will be classified as PD. 
• Patients whose best response by RECIST is stable disease (SD) but who have a CA-125 
response will be classified as CA-125 responders  


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• For a patient to be classified as a complete responder according to RECIST, CA-125 levels 
must be within the normal range  
For Patient with Measurable Disease 
 
For Patients without Measurable Disease 
 
Reference:  Rustin GJS, Vergote I, Elizabeth E, Pujade-Laurane E, Quinn M, Thigpen T, et al; 
Gynecological Cancer Intergroup. Definitions for response and progression in ovarian cancer clinical 
trials incorporating RECIST 1.1 and CA 125 agreed by the Gynecological Cancer Intergroup (GCIG). Int 
J Gynecol Cancer. 2011; 21(2):419-2 
 


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APPENDIX 3. RESPONSE EVALUATION CRITERIA IN SOLID 
TUMORS, VERSION 1.1 
Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether 
target or non-target) must have reduction in short axis to <10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as 
reference the baseline sum diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking 
as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In 
addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 
5 mm. (Note: the appearance of one or more new lesions is also considered progressions). 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
PD, taking as reference the smallest sum diameters while on study. 
 
Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor marker 
level. All lymph nodes must be non-pathological in size (<10 mm short axis). 
Note: If tumor markers are initially above the upper normal limit, they must normalize for a patient to be 
considered in complete clinical response. 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker 
level above the normal limits. 
PD: Appearance of one or more new lesions and/or unequivocal progression of existing non-target 
lesions. Unequivocal progression should not normally trump target lesion status. It must be 
representative of overall disease status change, not a single lesion increase. 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the treating 
physician should prevail in such circumstances, and the progression status should be confirmed at a later 
time by the review panel (or principal investigator). 
 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for PD the smallest measurements recorded since the 
treatment started). The patient’s best response assignment will depend on the achievement of both 
measurement and confirmation criteria. 
 
 


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For Patients with Measurable Disease (i.e., Target Disease) 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-PD/not 
evaluated 
No 
SD 
Documented at least once 8 
wks. from first dose of study 
medication** 
PD 
Any 
Yes or No 
PD 
No prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Abbreviations: CR = complete response; PD = progressive disease; PR = partial response; RECIST = Response Evaluation 
Criteria in Solid Tumors; SD = stable disease.  
*  
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion (Eisenhauer 2009). 
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease progression. 
Note: Patients with a global deterioration of health status requiring discontinuation of treatment without objective evidence of 
disease progression at that time should be reported as “symptomatic deterioration.” Every effort should be made to document 
the objective progression even after discontinuation of treatment. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
Abbreviations: CR = complete response; PD = progressive disease; SD = stable disease. 
*Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used as an endpoint for 
assessment of efficacy in some trials so to assign this category when no lesions can be measured is not advised. 
 
Reference:  Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumors: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45(2): 228–247.