Study of RP-6306 Alone or in Combination With RP-3500 or Debio 0123 in Patients With Advanced Solid Tumors

Phase 1

Recruiting

• Conditions: Advanced Solid Tumor
• Interventions: Drug: RP-6306; Drug: RP-3500; Drug: Debio0123

• Registration Number: NCT04855656
• Lead Sponsor: Repare Therapeutics

Brief Summary

The primary purpose of this study is to assess the safety and tolerability of RP-6306 alone and in combination with RP-3500 or in combination with Debio 0123 in patients with eligible advanced solid tumors, determine the maximum tolerated dose (MTD) and assess preliminary anti-tumor activity.

Detailed Description

Phase 1/1b, multi-center, open-label, dose-escalation study to:

* Evaluate the safety profile and MTD of RP-6306 alone and in combination with RP-3500 or in combination with Debio 0123 when administered orally to establish the recommended Phase 2 dose and schedule

* Characterize the PK and pharmacodynamics of RP-6306 alone and in combination with RP-3500 or in combination with Debio 0123

* Assess preliminary anti-tumor activity associated with RP-6306 alone and in combination with RP-3500 or in combination with Debio 0123

Study Timeline

• Study First Submitted: 2021-04-09
• Study First Submitted QC: 2021-04-19
• Study First Posted: 2021-04-22
• Study Start: 2021-04-30
• Status Verified: 2024-04
• Last Update Submitted: 2024-04-10
• Last Update Posted: 2024-04-15
• Primary Completion: 2026-06-30
• Study Completion: 2026-12-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 364

Inclusion Criteria

• Male or female and ≥12 years-of-age at the time of informed consent.
• Lansky performance status ≥50% for patients ≤16 years of age, or ECOG score of 0, 1, (or 2 for module 1) for patients >16 years of age.
• Locally advanced or metastatic resistant or refractory solid tumors.
• Patients <18 years of age must weigh at least 40 kg.
• Submission of available tumor tissue at screening or willingness to have a biopsy performed if safe and feasible
• Next generation sequencing (NGS) report obtained in a CLIA-certified or equivalent laboratory demonstrating eligible tumor biomarker.
• CCNE1 amplification (non-equivocal) as determined by either a tumor or plasma NGS test, or FISH
• FBXW7 deleterious mutations identified by either a tumor or plasma NGS test
• PPP2R1A deleterious mutations identified by either a tumor or plasma NGS test
• Measurable disease as per RECIST v1.1. For certain modules, patients with prostate cancer or ovarian cancer that have non-measurable disease but have elevated tumor markers (PSA or CA-125, respectively) can also be eligible
• Ability to swallow and retain oral medications.
• Acceptable hematologic and organ function at screening.
• Negative pregnancy test (serum) for women of childbearing potential (WOCBP) at Screening.
• Resolution of all toxicities of prior therapy or surgical procedures.
• Any prior radiation must have been completed at least 7 days prior to the start of study drugs, and patients must have recovered from any acute adverse effects prior to the start of study treatment.

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Exclusion Criteria

• Chemotherapy or small molecule antineoplastic agent given within 21 days or <5 half-lives, whichever is shorter, prior to first dose of study drug.
• History or current condition, 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.
• Patients who are pregnant or breastfeeding.
• Life-threatening illness, medical condition, active uncontrolled infection, or organ system dysfunction or other reasons which, in the investigator's opinion, could compromise the participating patient's safety.
• Major surgery within 4 weeks prior to first dose of RP-6306.
• Uncontrolled, symptomatic brain metastases.
• Uncontrolled hypertension.
• Certain prior anti-cancer therapy
• Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol and/or follow-up procedures outlined in the protocol.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Phase 1: RP-6306 in combination with RP-3500, Dose Escalation Study	RP-6306	Patients receive RP-6306 with RP-3500 orally until disease progression, unacceptable toxicity, or investigator/patient decision. Dose escalation will proceed until a maximum tolerated dose is identified.
Phase 1: RP-6306 in combination with RP-3500, Dose Escalation Study	RP-3500	Patients receive RP-6306 with RP-3500 orally until disease progression, unacceptable toxicity, or investigator/patient decision. Dose escalation will proceed until a maximum tolerated dose is identified.
Phase 1: RP-6306 in combination with Debio 0123, Dose Escalation Study	RP-6306	Patients receive RP-6306 with Debio 0123 orally until disease progression, unacceptable toxicity, or investigator/patient decision. Dose escalation will proceed until a maximum tolerated dose is identified.
Phase 1: RP-6306 Single-Agent, Dose Escalation and Food-effect Study	RP-6306	Patients receive RP-6306 orally until disease progression, unacceptable toxicity, or investigator/patient decision. Dose escalation will proceed until a maximum tolerated dose is identified.
Phase 1: RP-6306 in combination with Debio 0123, Dose Escalation Study	Debio0123	Patients receive RP-6306 with Debio 0123 orally until disease progression, unacceptable toxicity, or investigator/patient decision. Dose escalation will proceed until a maximum tolerated dose is identified.

Primary Outcome Measures

Name	Time	Method
To define the MTD of RP-6306 in combination with RP-3500 or in combination with Debio 0123, and determine a recommended Phase 2 dose (RP2D) and preferred schedule	Up to 90 days after last administration of study intervention	Assessed by the incidence of dose-limiting toxicities (DLTs) and the incidence and severity of cumulative safety data
The relative bioavailability of RP-6306 capsule formulation as compared to RP-6306 tablet formulation in the fasted state	Time 0 (time of dosing) to 72 hours post-dose for each treatment condition	Assessed by the plasma concentrations of RP-6306 with calculation of pharmacokinetic (PK) parameters including maximum observed plasma concentration (Cmax), time to maximum observed plasma concentration (Tmax), area under the plasma concentration-time curve (AUC) , for both formulations in the fasted state.
To assess the safety and tolerability of RP-6306 tablets in combination with RP-3500, confirm the MTD of RP-6306 tablets in combination with RP-3500, and determine a RP2D and preferred schedule	Up to 90 days after last administration of study intervention	Assessed by DLTs, TEAEs, safety laboratory assessments, the incidence of DLTs and the incidence and severity of cumulative safety data
Safety and Tolerability of RP-6306 either in monotherapy or in combination with RP-3500 or with Debio 0123 in patients with eligible advanced solid tumors	Up to 90 days after last administration of study intervention	Assessed by treatment-emergent adverse events (TEAEs), physical examinations (PEs), safety laboratory assessments, electrocardiograms (ECGs), and vital sign measurements
To define the MTD of RP-6306 monotherapy, and determine a recommended Phase 2 dose (RP2D) and preferred schedule	Up to 90 days after last administration of study intervention	Assessed by the incidence of Dose-limiting toxicities (DLTs) and the incidence and severity of cumulative safety data
The effect of food on the PK of tablet formulation of RP-6306 when administered in fed conditions compared to administration under fasted conditions	Time 0 (time of dosing) to 72 hours post-dose for each treatment condition	Assessed by the plasma concentrations of RP-6306 with calculation of the ratio of PK parameters (e.g., Cmax and AUC) between the tablet formulation under fasted and fed state.

Secondary Outcome Measures

Name	Time	Method
The plasma concentrations of RP-6306 and RP-3500 when dosed in combination	Up to 90 days after last administration of study intervention	Assessed by the plasma concentrations of RP-6306 and RP-3500 with calculation of maximum observed plasma concentration (Cmax), time to maximum observed plasma concentration (Tmax), minimum observed plasma concentration (Cmin), area under the plasma concentration-time curve (AUC), elimination half-life (t1/2), and other parameters as appropriate for each analyte
The plasma concentrations of RP-6306 monotherapy (capsule formulation) in the fasted and fed states	Up to 90 days after last administration of study intervention	Assessed by the plasma concentrations of RP-6306 with calculation of maximum observed plasma concentration (Cmax), time to maximum observed plasma concentration (Tmax), minimum observed plasma concentration (Cmin), area under the plasma concentration-time curve (AUC), elimination half-life (t1/2), and other parameters as appropriate
To assess the relationship between pharmacodynamic biomarkers and PK of RP-6306 at different dose levels and/or schedules	Up to 90 days after last administration of study intervention	Assessed by evaluation of biomarkers in pre- and on-treatment biopsies, and circulating tumor DNA (ctDNA) dynamics during treatment
To assess the safety and anti-tumor effects of RP-6306 capsule + RP-3500	Through Study Completion, an average of 1 year	As measure by TEAEs, safety laboratory assessments, Best percent change in tumor size from baseline, ORR, overall response rate, DOR, CBR, tumor marker response, PFS
To assess preliminary anti-tumor activity achieved with RP-6306 monotherapy, RP-6306 in combination with RP-3500 or RP-6306 in combination with Debio 0123	Through Study Completion, an average of 1 year	Measured by best percent change in tumor size from baseline, objective response rate (ORR), overall response rate, tumor marker response, duration of response (DOR), clinical benefit rate (CBR), progression-free survival (PFS).
To further characterize the PK of RP-6306 tablets and assess preliminary anti-tumor	Through Study Completion, an average of 1 year	Measured by Plasma concentrations of RP-6306 with calculation of Cmax, Tmax, AUC, elimination t1/2, and other PK parameters as appropriate, Best percent change in tumor size from baseline, ORR, overall response rate, DOR, CBR, tumor marker response, PFS

Trial Locations

Locations (14)

Participating Site #4001; 🇩🇰 Copenhagen, Denmark

Participating Site # 1004; 🇺🇸 New York, New York, United States

Participating Site # 1001; 🇺🇸 Houston, Texas, United States

Participating site #2001; 🇨🇦 Toronto, Ontario, Canada

Participating site # 1002; 🇺🇸 Boston, Massachusetts, United States

Participating site #1011; 🇺🇸 Saint Louis, Missouri, United States

Participating Site # 1008; 🇺🇸 New York, New York, United States

Participating Site # 1010; 🇺🇸 Philadelphia, Pennsylvania, United States

Participating Site # 1007; 🇺🇸 Providence, Rhode Island, United States

Participating Site, # 1027; 🇺🇸 Charlottesville, Virginia, United States

Participating Site # 1030; 🇺🇸 Providence, Rhode Island, United States

Participating Site # 1012; 🇺🇸 New Haven, Connecticut, United States

Participating Site #1013; 🇺🇸 Salt Lake City, Utah, United States

Participating site # 2002; 🇨🇦 Toronto, Ontario, Canada