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

• ClinicalTrials.gov Identifier: NCT04855656
• Recruitment Status: Recruiting
• First Posted: April 22, 2021
• Last Update Posted: April 15, 2024
• Sponsor: Repare Therapeutics
• Collaborator: Debiopharm International SA
• Information provided by (Responsible Party): Repare Therapeutics

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Advanced Solid Tumor	Drug: RP-6306; Drug: RP-3500; Drug: Debio0123	Phase 1

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 364 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase 1/1b Study of the Safety, Pharmacokinetics, Pharmacodynamics and Preliminary Clinical Activity of RP-6306 Alone or in Combination With RP-3500 or Debio 0123 in Patients With Advanced Solid Tumors
• Actual Study Start Date: April 30, 2021
• Estimated Primary Completion Date: June 30, 2026
• Estimated Study Completion Date: December 31, 2026

Arms and Interventions

Arm	Intervention/treatment
Experimental: Phase 1: RP-6306 Single-Agent, Dose Escalation and Food-effect Study; 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.	Drug: RP-6306; Oral PKMYT1 Inhibitor
Experimental: Phase 1: RP-6306 in combination with RP-3500, Dose Escalation Study; 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.	Drug: RP-6306; Oral PKMYT1 Inhibitor; Drug: RP-3500; Oral ATR Inhibitor
Experimental: Phase 1: RP-6306 in combination with Debio 0123, Dose Escalation Study; 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.	Drug: RP-6306; Oral PKMYT1 Inhibitor; Drug: Debio0123; Oral WEE1 Inhibitor

Outcome Measures

Primary Outcome Measures :

1. 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 [ Time Frame: 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
2. To define the MTD of RP-6306 monotherapy, and determine a recommended Phase 2 dose (RP2D) and preferred schedule [ Time Frame: 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
3. 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 [ Time Frame: 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
4. The relative bioavailability of RP-6306 capsule formulation as compared to RP-6306 tablet formulation in the fasted state [ Time Frame: 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.
5. 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 Frame: 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.
6. 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 [ Time Frame: 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

Secondary Outcome Measures :

1. The plasma concentrations of RP-6306 monotherapy (capsule formulation) in the fasted and fed states [ Time Frame: 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
2. To assess the relationship between pharmacodynamic biomarkers and PK of RP-6306 at different dose levels and/or schedules [ Time Frame: 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
3. The plasma concentrations of RP-6306 and RP-3500 when dosed in combination [ Time Frame: 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
4. 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 [ Time Frame: 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).
5. To assess the safety and anti-tumor effects of RP-6306 capsule + RP-3500 [ Time Frame: 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
6. To further characterize the PK of RP-6306 tablets and assess preliminary anti-tumor [ Time Frame: 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

Eligibility Criteria

• Ages Eligible for Study: 12 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

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.

Contacts and Locations

Contacts

Contact: Nathan Hawkey, MD, MBA; +1 (857) 340-5402; clininfo@reparerx.com

Locations

United States, Connecticut

Participating Site # 1012; Recruiting

New Haven, Connecticut, United States, 06520

United States, Massachusetts

Participating site # 1002; Recruiting

Boston, Massachusetts, United States, 02215

United States, Missouri

Participating site #1011; Recruiting

Saint Louis, Missouri, United States, 63130

United States, New York

Participating Site # 1008; Recruiting

New York, New York, United States, 10032

Participating Site # 1004; Recruiting

New York, New York, United States, 10065

United States, Pennsylvania

Participating Site # 1010; Active, not recruiting

Philadelphia, Pennsylvania, United States, 19104

United States, Rhode Island

Participating Site # 1007; Recruiting

Providence, Rhode Island, United States, 02903

Participating Site # 1030; Recruiting

Providence, Rhode Island, United States, 02903

United States, Texas

Participating Site # 1001; Recruiting

Houston, Texas, United States, 77030

United States, Utah

Participating Site #1013; Recruiting

Salt Lake City, Utah, United States, 84112

United States, Virginia

Participating Site, # 1027; Recruiting

Charlottesville, Virginia, United States, 22903

Canada, Ontario

Participating site # 2002; Recruiting

Toronto, Ontario, Canada, M5G 1X8

Participating site #2001; Recruiting

Toronto, Ontario, Canada, M5G 2C1

Denmark

Participating Site #4001; Recruiting

Copenhagen, Denmark

Sponsors and Collaborators

Repare Therapeutics

Debiopharm International SA

More Information

• Responsible Party: Repare Therapeutics
• ClinicalTrials.gov Identifier: NCT04855656
• Other Study ID Numbers: RP-6306-01
• First Posted: April 22, 2021
• Last Update Posted: April 15, 2024
• Last Verified: April 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Neoplasms