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

Tracking Information

• First Submitted Date: April 9, 2021
• First Posted Date: April 22, 2021
• Last Update Posted Date: April 15, 2024
• Actual Study Start Date: April 30, 2021
• Estimated Primary Completion Date: June 30, 2026 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 10, 2024)

• 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
• 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
• 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
• 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.
• 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.
• 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

Original Primary Outcome Measures (submitted: April 19, 2021)

• Safety and Tolerability of RP-6306 in patients with advanced solid tumors as assessed by NCI CTCAE v5.0 [ Time Frame: Up to 90 days after last administration of study intervention ]
• 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 ]

Current Secondary Outcome Measures (submitted: April 10, 2024)

• 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
• 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
• 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
• 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).
• 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
• 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

Original Secondary Outcome Measures (submitted: April 19, 2021)

• To assess PK parameters of RP-6306 monotherapy in fasted and fed states [ Time Frame: through study completion, an average of 1 year ]
• To assess the relationship between pharmacodynamic biomarkers and PK of RP-6306 at different dose levels and/or schedules [ Time Frame: for the first 3 months on treatment ]
• To assess preliminary anti-tumor activity of RP-6306 monotherapy [ Time Frame: Through Study Completion, an average of 1 year ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study of RP-6306 Alone or in Combination With RP-3500 or Debio 0123 in Patients With Advanced Solid Tumors
• 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
• 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 Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Advanced Solid Tumor

Intervention

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

Study Arms

• 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.
  Intervention: Drug: RP-6306
• 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.
  Interventions:

  • Drug: RP-6306
  • Drug: RP-3500
• 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.
  Interventions:

  • Drug: RP-6306
  • Drug: Debio0123

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: April 10, 2024): 364
• Original Estimated Enrollment (submitted: April 19, 2021): 60
• Estimated Study Completion Date: December 31, 2026
• Estimated Primary Completion Date: June 30, 2026 (Final data collection date for primary outcome measure)

Eligibility 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 12 Years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

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

• Listed Location Countries: Canada, Denmark, United States

Administrative Information

• NCT Number: NCT04855656
• Other Study ID Numbers: RP-6306-01
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

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

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Repare Therapeutics
• Original Responsible Party: Same as current
• Current Study Sponsor: Repare Therapeutics
• Original Study Sponsor: Same as current
• Collaborators: Debiopharm International SA
• Investigators: Not Provided
• PRS Account: Repare Therapeutics
• Verification Date: April 2024