Study of RP-3500, Camonsertib, in Advanced Solid Tumors (TRESR)

Phase 1/2a Study of the Safety, Pharmacokinetics, Pharmacodynamics and Preliminary Clinical Activity of RP-3500 Alone or in Combination With Talazoparib or Gemcitabine in Advanced Solid Tumors With ATR Inhibitor Sensitizing Mutations (TRESR Study)

The primary purpose of this study is to define the maximum tolerated dose (MTD) and determine a recommended Phase 2 dose (RP2D) and schedule of orally-administered RP-3500 (camonsertib) alone or in combination with talazoparib, a PARP inhibitor, or Gemcitabine in patients with advanced solid tumors with ATR inhibitor-sensitizing mutations. This study will also evaluate the safety and tolerability of RP-3500 (camonsertib) alone or in combination with talazoparib or gemcitabine, examine both the pharmacokinetics (PK)and pharmacodynamics (PD)and investigate its anti-tumor activity in solid tumors.

Study Overview

• Status: Completed
• Conditions: Advanced Solid Tumor
• Intervention / Treatment: Drug: Talazoparib; Drug: Gemcitabine Injection; Drug: RP-3500 (camonsertib)

Detailed Description

This is a first-in-human, Phase 1/2a, multi-center, open-label, dose-escalation and expansion study to:

• Evaluate the safety profile and MTD of RP-3500 (camonsertib) when administered orally, alone and in combination with talazoparib or gemcitabine, to establish the dose and schedule recommended for the Phase 2
• Characterize the PK profile of RP-3500 (camonsertib) alone or in combination with talazoparib or gemcitabine
• Identify anti-tumor activity associated with RP-3500 (camonsertib) given alone or in combination with talazoparib or gemcitabine

The initial cohorts will test RP-3500 (camonsertib) as monotherapy. Additional cohorts will enroll with RP-3500 (camonsertib) in combination with talazoparib or gemcitabine.

After the RP2D and schedule is determined, expansion cohort(s) for RP-3500 (camonsertib) will be enrolled to study the anti-tumor effect, and further examine the safety and PK of RP-3500 (camonsertib) at the RP2D

• Study Type: Interventional
• Enrollment (Actual): 276
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • #2001, Princess Margaret Cancer Centre
• Denmark
  • DK
    • Copenhagen, DK, Denmark, 2100 Ø
      • #4001, Copenhagen University Hospital Rigshospitalet - Blegdamsvej
• United Kingdom
  • London, United Kingdom, W1G 6AD
    • #3003, Sarah Cannon Research Institute
  • Manchester, United Kingdom, M20 4BX
    • #3001, The Christie NHS Foundation Trust
  • Newcastle upon Tyne, United Kingdom, NE7 7DN
    • #3002, Freeman Hospital Newcastle
• United States
  • Illinois
    • Chicago, Illinois, United States, 60611
      • #1014, Northwestern University
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • #1006, Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02215
      • #1002, Dana Farber Cancer Institute
  • New York
    • New York, New York, United States, 10065
      • #1004, Memorial Sloan Kettering Cancer Institute
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • #1005, Duke Cancer Institute
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • #1007, Rhode Island Hospital
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • #1003, Sarah Cannon Research Institute
  • Texas
    • Houston, Texas, United States, 77030
      • #1001, The University of Texas M.D. Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Written informed consent, according to local guidelines, signed and dated by the patient or legal guardian prior to the performance of any study-specific procedures, sampling, or analyses.
• Male or female and ≥ 18 years-of-age at the time of signature of the consent.
• Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1.
• Histologically confirmed solid tumors resistant or refractory to standard treatment and/or patients who are intolerant to standard therapy.
• Measurable disease as per RECIST v1.1
• Existing biomarker profile (tumor tissue or plasma) reported from a local test obtained in a certified lab per institutional guidelines:
• Available tumor tissue
• Ability to comply with the protocol and study procedures detailed in the Schedule of Assessments.
• Ability to swallow and retain oral medications.
• Acceptable organ function at screening
• Acceptable blood counts at screening
• Negative pregnancy test (serum) for females of childbearing potential at Screening and prior to first study drug.
• Resolution of all toxicities of prior treatment or surgery.
• Male patients with female partners of childbearing potential and females of childbearing potential must follow a contraception method (oral contraceptives allowed) during their participation in the study and for at least 6 months following last dose of study drug. Male patients must also refrain from donating sperm during their participation in the study and for 6 months following last dose of study drug.
• Life expectancy ≥12 weeks after the start of the treatment according to the investigator's judgment.
• Module 1c only: Ability to consume a high-fat meal and fast for 12 hours.

Exclusion Criteria:

• Chemotherapy, small molecule anticancer or biologic anticancer therapy given within 14 days prior to first dose of study drug.
• History or current condition (such as transfusion dependent anemia or thrombocytopenia), 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.
• Prior therapy with an ATR or DNA-dependent protein kinase (DNA-PK) inhibitor.
• Known hypersensitivity to any of the ingredients of RP-3500 (camonsertib).
• Life-threatening illness, medical condition, active uncontrolled infection, or organ system dysfunction or other reasons which, in the investigator's opinion, could compromise the patient's safety.
• Uncontrolled, symptomatic brain metastases.
• Uncontrolled high blood pressure
• Patients with active, uncontrolled bacterial, fungal, or viral infection, including hepatitis B virus (HBV), hepatitis C virus (HCV), known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) related illness.
• Moderate or severe hepatic impairment (ie, Child-Pugh class B or C).
• History or presence of an abnormal ECG that is clinically significant in the investigator's opinion.
• History of ventricular dysrhythmias or risk factors such as structural heart disease, coronary heart disease (clinically significant electrolyte abnormalities or family history of sudden unexplained death or long QT syndrome
• Current treatment with medications that are well-known to prolong the QT interval
• History of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) diagnosis
• Module 3 only: Known sensitivity to any of the ingredients of talazoparib.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: RP-3500 (camonsertib) alone; Phase 1: Multiple doses of RP-3500 (camonsertib) for oral administration alone	Drug: RP-3500 (camonsertib); Oral ATR inhibitor
Experimental: Expansion cohorts with RP-3500 (camonsertib); Phase 2: Expansion cohorts with RP-3500 (camonsertib)	Drug: RP-3500 (camonsertib); Oral ATR inhibitor
Experimental: RP-3500 (camonsertib) with Talazoparib or Gemcitabine; Phase 1: Multiple doses of RP-3500 (camonsertib) for oral administration in combination with talazoparib or gemcitabine	Drug: Talazoparib; Oral PARP inhibitor; Drug: Gemcitabine Injection; Gemcitabine; Drug: RP-3500 (camonsertib); Oral ATR inhibitor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frequency of Treatment-Related Adverse Event of CTCAE Grade 3 and Above	Treatment-emergent adverse events (TEAEs) are those events that occur or worsen on or after the first dose of study drug up through 30 days post the last dose (or cross over to a different module) or the start of subsequent anticancer therapy. AEs are considered related to treatment if the relationship to camonsertib or the other combination drug (in the study regimen) is "Related" (include unknown relationship) as indicated on the AE eCRF page based on investigator's assessment.	Start of treatment to 30 days post last dose, up to 1 year
Frequency of Dose Limiting Toxicity (DLT)	Toxicity were assessed using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. A toxicity was considered dose-limiting if it occurred during the first cycle and was deemed at least possibly related to study treatment. If multiple toxicities occurred, the most severe toxicity was used in the assessment. The DLT Evaluable population consists of patients who received at least 80% of planned total doses of camonsertib , 80% of planned total doses of camonsertib and talazoparib, or 80% of planned total doses of camonsertib and 100% of gemcitabine; complete all required safety evaluations and are observed through the end of Cycle 1; or patients who experience a DLT qualifying event in the first cycle of treatment.	Either 21 days or 28 days (1 cycle) from the initiation of the study treatment.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assess preliminary anti-tumor activity with Overall Response Rate in patients with eligible advanced solid tumors by CT/MRI Response evaluation criteria in solid tumors (RECIST 1.1) or confirmed response in CA-125 or PSA per GCIG or PSWG criteria.	Overall response rate	About 1 year
Assess preliminary anti-tumor activity with Overall Response Rate in patients with eligible advanced solid tumors by CT/MRI Response evaluation criteria in solid tumors (RECIST 1.1)	Objective response rate (ORR)	About 1 year
Assess CR+PR+SD (≥ 4 months) based on RECIST v1.1, confirmed CA-125 response by GCIG criteria, or PSA response based on PCWG3	Clinical Benefit Rate	About 1 year
Assess preliminary anti-tumor activity with Duration of Response (DOR) in patients with eligible advanced solid tumors by CT/MRI Response evaluation criteria in solid tumors (RECIST 1.1).	Duration of response (DOR)	About 1 year
Peak plasma concentration	Cmax	Through Study Day 152
Pharmacodynamic biomarkers of DNA damage (e.g. gH2AX) will be measured by immunohistochemistry and the percentage of positive cells will be compared between the pre and post treatment biopsies to evaluate target engagement	Tumor tissue samples will be collected pre and post dosing	Through Study Day -28 to Day 66 (each cycle is 21 days)
Characterize the pharmacokinetic profile of RP-3500 (camonsertib)	Area-under-the-curve (AUC 0-inf)	Through Study Day 152
To assess PK parameters of RP-3500 (camonsertib) monotherapy in fasted and fed states	Comparison of geometric mean ratios (GMR)	Through Study Day 152

Collaborators and Investigators

• Sponsor: Repare Therapeutics
• Collaborators: Roche Pharma AG
• Investigators: Principal Investigator: Timothy A Yap, MBBS PhD FRCP, M.D. Anderson Cancer Center

Publications and helpful links

General Publications

• Fontana E, Rosen E, Lee EK, Hojgaard M, Mettu NB, Lheureux S, Carneiro BA, Cote GM, Carter L, Plummer R, Mahalingam D, Fretland AJ, Schonhoft JD, Silverman IM, Wainszelbaum M, Xu Y, Ulanet D, Koehler M, Yap TA. Ataxia telangiectasia and Rad3-related (ATR) inhibitor camonsertib dose optimization in patients with biomarker-selected advanced solid tumors (TRESR study). J Natl Cancer Inst. 2024 Sep 1;116(9):1439-1449. doi: 10.1093/jnci/djae098.
• Yap TA, Fontana E, Lee EK, Spigel DR, Hojgaard M, Lheureux S, Mettu NB, Carneiro BA, Carter L, Plummer R, Cote GM, Meric-Bernstam F, O'Connell J, Schonhoft JD, Wainszelbaum M, Fretland AJ, Manley P, Xu Y, Ulanet D, Rimkunas V, Zinda M, Koehler M, Silverman IM, Reis-Filho JS, Rosen E. Camonsertib in DNA damage response-deficient advanced solid tumors: phase 1 trial results. Nat Med. 2023 Jun;29(6):1400-1411. doi: 10.1038/s41591-023-02399-0. Epub 2023 Jun 5.

Study record dates

Study Major Dates

• Study Start (Actual): July 22, 2020
• Primary Completion (Actual): June 13, 2025
• Study Completion (Actual): June 13, 2025

Study Registration Dates

• First Submitted: July 21, 2020
• First Submitted That Met QC Criteria: July 29, 2020
• First Posted (Actual): August 4, 2020

Study Record Updates

• Last Update Posted (Estimated): October 21, 2025
• Last Update Submitted That Met QC Criteria: October 7, 2025
• Last Verified: October 1, 2025

More Information

Terms related to this study

• Keywords: Adult
• Additional Relevant MeSH Terms: Neoplasms; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Gemcitabine; talazoparib
• Other Study ID Numbers: RP-3500-01; 2020-000301-87 (EudraCT Number)

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