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

Advanced Solid Tumor Clinical Trial

— MYTHIC  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04855656
• Other study ID #: RP-6306-01
• Status: Recruiting
• Phase: Phase 1
• Start date: April 30, 2021
• Est. completion date: December 31, 2026

Study information

• Verified date: April 2024
• Source: Repare Therapeutics
• Contact: Nathan Hawkey, MD, MBA
• Phone: +1 (857) 340-5402
• Email: clininfo[@]reparerx.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 364
• Est. completion date: December 31, 2026
• Est. primary completion date: June 30, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Advanced Solid Tumor
• Neoplasms

Intervention

Drug:
• RP-6306
Oral PKMYT1 Inhibitor
• RP-3500
Oral ATR Inhibitor
• Debio0123
Oral WEE1 Inhibitor

Locations

Country	Name	City	State
Canada	Participating site # 2002	Toronto	Ontario
Canada	Participating site #2001	Toronto	Ontario
Denmark	Participating Site #4001	Copenhagen
United States	Participating site # 1002	Boston	Massachusetts
United States	Participating Site, # 1027	Charlottesville	Virginia
United States	Participating Site # 1001	Houston	Texas
United States	Participating Site # 1012	New Haven	Connecticut
United States	Participating Site # 1004	New York	New York
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 # 1030	Providence	Rhode Island
United States	Participating site #1011	Saint Louis	Missouri
United States	Participating Site #1013	Salt Lake City	Utah

Sponsors (2)

Lead Sponsor	Collaborator
Repare Therapeutics	Debiopharm International SA

Countries where clinical trial is conducted

United States,  Canada,  Denmark, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Assessed by treatment-emergent adverse events (TEAEs), physical examinations (PEs), safety laboratory assessments, electrocardiograms (ECGs), and vital sign measurements	Up to 90 days after last administration of study intervention
Primary	To define the MTD of RP-6306 monotherapy, and determine a recommended Phase 2 dose (RP2D) and preferred schedule	Assessed by the incidence of Dose-limiting toxicities (DLTs) and the incidence and severity of cumulative safety data	Up to 90 days after last administration of study intervention
Primary	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	Assessed by the incidence of dose-limiting toxicities (DLTs) and the incidence and severity of cumulative safety data	Up to 90 days after last administration of study intervention
Primary	The relative bioavailability of RP-6306 capsule formulation as compared to RP-6306 tablet formulation in the fasted state	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.	Time 0 (time of dosing) to 72 hours post-dose for each treatment condition
Primary	The effect of food on the PK of tablet formulation of RP-6306 when administered in fed conditions compared to administration under fasted conditions	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.	Time 0 (time of dosing) to 72 hours post-dose for each treatment condition
Primary	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	Assessed by DLTs, TEAEs, safety laboratory assessments, the incidence of DLTs and the incidence and severity of cumulative safety data	Up to 90 days after last administration of study intervention
Secondary	The plasma concentrations of RP-6306 monotherapy (capsule formulation) in the fasted and fed states	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	Up to 90 days after last administration of study intervention
Secondary	To assess the relationship between pharmacodynamic biomarkers and PK of RP-6306 at different dose levels and/or schedules	Assessed by evaluation of biomarkers in pre- and on-treatment biopsies, and circulating tumor DNA (ctDNA) dynamics during treatment	Up to 90 days after last administration of study intervention
Secondary	The plasma concentrations of RP-6306 and RP-3500 when dosed in combination	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	Up to 90 days after last administration of study intervention
Secondary	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	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).	Through Study Completion, an average of 1 year
Secondary	To assess the safety and anti-tumor effects of RP-6306 capsule + RP-3500	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	Through Study Completion, an average of 1 year
Secondary	To further characterize the PK of RP-6306 tablets and assess preliminary anti-tumor	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	Through Study Completion, an average of 1 year