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

Phase 1/1b Study of the Safety, Pharmacokinetics, Pharmacodynamics and Preliminary Clinical Activity of Lunresertib Alone or in Combination With RP-3500 or Debio 0123 in Patients With Advanced Solid Tumors

The primary purpose of this study is to assess the safety and tolerability of lunresertib 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.

Study Overview

• Status: Recruiting
• Conditions: Advanced Solid Tumor
• Intervention / Treatment: Drug: RP-3500; Drug: Debio0123; Drug: Lunresertib

Detailed Description

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

• Evaluate the safety profile and MTD of lunresertib 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 lunresertib alone and in combination with RP-3500 or in combination with Debio 0123
• Assess preliminary anti-tumor activity associated with lunresertib alone and in combination with RP-3500 or in combination with Debio 0123

This study was previously posted by Repare Therapeutics. In September 2025, sponsorship of the trial was transferred to Debiopharm International S.A

Expanded Access Status: There is no expanded access program available for the investigational products in this study at this time.

• Study Type: Interventional
• Enrollment (Estimated): 464
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Debiopharm International S.A; Phone Number: +41 21 321 01 11; Email: clinicaltrials@debiopharm.com

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • Completed
      • #2002, The Hospital for Sick Children
    • Toronto, Ontario, Canada, M5G 2C1
      • Recruiting
      • #2001, Princess Margaret Cancer Centre
  • Quebec
    • Montreal, Quebec, Canada, H4A 3J1
      • Completed
      • #2003, The Research Institute of the McGill University Health Centre
• Denmark
  • Copenhagen, Denmark
    • Recruiting
    • #4001, Rigshospitalet - Blegdamsvej
• United Kingdom
  • London, United Kingdom, W1G 6AD
    • Recruiting
    • #3003, Sarah Cannon Research Institute
• United States
  • California
    • Los Angeles, California, United States, 90095
      • Completed
      • # 1019, UCLA, Westwood Cancer Center
    • San Francisco, California, United States, 94158
      • Recruiting
      • #1025, University of California San Francisco
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Recruiting
      • #1012, Yale
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Recruiting
      • #1017, Mayo Clinic
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Recruiting
      • #1002, Dana Farber Cancer Institute
  • Michigan
    • Grand Rapids, Michigan, United States, 49503
      • Recruiting
      • #1023, START Midwest
  • Minnesota
    • Rochester, Minnesota, United States, 55902
      • Recruiting
      • #1016, Mayo Clinic
  • Missouri
    • St Louis, Missouri, United States, 63130
      • Recruiting
      • #1011, Washington University
  • New York
    • New Hyde Park, New York, United States, 11042
      • Recruiting
      • #1032, Northwell Health Cancer Institute
    • New York, New York, United States, 10065
      • Recruiting
      • #1004, Memorial Sloan Kettering Cancer Institute
    • New York, New York, United States, 10032
      • Completed
      • #1008, Columbia University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Completed
      • #1010, University of Pennsylvania
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Recruiting
      • #1007, Rhode Island Hospital
    • Providence, Rhode Island, United States, 02903
      • Recruiting
      • #1030, Women & Infants Hospital of Rhode Island
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • #1001, The University of Texas M.D. Anderson Cancer Center
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Recruiting
      • #1013, The University of Utah
  • Virginia
    • Charlottesville, Virginia, United States, 22903
      • Recruiting
      • #1027, University of Virginia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 8 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 lunresertib.
• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase 1: Lunresertib Single-Agent, Dose Escalation and Food-effect Study; Patients receive lunresertib orally until disease progression, unacceptable toxicity, or investigator/patient decision. Dose escalation will proceed until a maximum tolerated dose is identified.	Drug: Lunresertib; Oral PKMYT1 Inhibitor
Experimental: Phase 1: Lunresertib in combination with RP-3500, Dose Escalation Study; Patients receive lunresertib 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-3500; Oral ATR Inhibitor; Drug: Lunresertib; Oral PKMYT1 Inhibitor
Experimental: Phase 1: Lunresertib in combination with Debio 0123, Dose Escalation Study; Patients receive lunresertib 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: Debio0123; Oral WEE1 Inhibitor; Drug: Lunresertib; Oral PKMYT1 Inhibitor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and Tolerability of lunresertib 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
To define the MTD of lunresertib 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
To define the MTD of lunresertib 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
The relative bioavailability of lunresertib capsule formulation as compared to lunresertib tablet formulation in the fasted state	Assessed by the plasma concentrations of lunresertib 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
The effect of food on the PK of tablet formulation of lunresertib when administered in fed conditions compared to administration under fasted conditions	Assessed by the plasma concentrations of lunresertib 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
To assess the safety and tolerability of lunresertib tablets in combination with RP-3500, confirm the MTD of lunresertib 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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
The plasma concentrations of lunresertib monotherapy (capsule formulation) in the fasted and fed states	Assessed by the plasma concentrations of lunresertib 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
To assess the relationship between pharmacodynamic biomarkers and PK of lunresertib 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
The plasma concentrations of lunresertib and RP-3500 when dosed in combination	Assessed by the plasma concentrations of lunresertib 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
To assess preliminary anti-tumor activity achieved with lunresertib monotherapy, lunresertib in combination with RP-3500 or lunresertib 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
To assess the safety and anti-tumor effects of lunresertib 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
To further characterize the PK of lunresertib tablets and assess preliminary anti-tumor	Measured by Plasma concentrations of lunresertib 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

Collaborators and Investigators

• Sponsor: Debiopharm International SA
• Collaborators: Debiopharm International SA

Study record dates

Study Major Dates

• Study Start (Actual): April 30, 2021
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): June 1, 2028

Study Registration Dates

• First Submitted: April 9, 2021
• First Submitted That Met QC Criteria: April 19, 2021
• First Posted (Actual): April 22, 2021

Study Record Updates

• Last Update Posted (Actual): May 28, 2026
• Last Update Submitted That Met QC Criteria: May 26, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms
• Other Study ID Numbers: Debio 0123-106; RP-6306-01 (Other Identifier: Repare Therapeutics)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No