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Study of RP-3500, Camonsertib, in Advanced Solid Tumors

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ClinicalTrials.gov Identifier: NCT04497116
Recruitment Status : Recruiting
First Posted : August 4, 2020
Last Update Posted : February 9, 2023
Sponsor:
Collaborator:
Roche Pharma AG
Information provided by (Responsible Party):
Repare Therapeutics

Study Description
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Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Advanced Solid Tumor Drug: RP-3500 (camonsertib) Drug: Talazoparib Drug: Gemcitabine Injection Phase 1 Phase 2

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
  • Examine biomarker responses and establish a correlation with RP-3500 (camonsertib) exposure and clinical outcomes.

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 Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 451 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: Dose Escalation, expansion and phase 2
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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)
Actual Study Start Date : July 22, 2020
Estimated Primary Completion Date : January 30, 2024
Estimated Study Completion Date : March 30, 2024

Resource links provided by the National Library of Medicine


Arms and Interventions
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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: RP-3500 (camonsertib)
Oral ATR inhibitor

Drug: Talazoparib
Oral PARP inhibitor

Drug: Gemcitabine Injection
Gemcitabine


Outcome Measures
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Primary Outcome Measures :
  1. To define the Maximum Tolerated Dose (MTD) which will then be used to inform and determine the Recommended Phase 2 Dose (RP2D) and schedule alone or in combination with talazoparib or gemcitabine [ Time Frame: Up to 90 days after last administration of study intervention ]
  2. Frequency of Dose limiting Toxicities (DLTs) [ Time Frame: At the end of cycle 1 (each cycle is 21 days or 28 days) ]
  3. Safety and tolerability [ Time Frame: Up to 90 days after last administration of study intervention ]
    Grade and frequency of adverse events and serious adverse events


Secondary Outcome Measures :
  1. 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. [ Time Frame: About 1 year ]
    Overall response rate

  2. 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) [ Time Frame: About 1 year ]
    Objective response rate (ORR)

  3. Assess CR+PR+SD (≥ 4 months) based on RECIST v1.1, confirmed CA-125 response by GCIG criteria, or PSA response based on PCWG3 [ Time Frame: About 1 year ]
    Clinical Benefit Rate

  4. 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). [ Time Frame: About 1 year ]
    Duration of response (DOR)

  5. Characterize the pharmacokinetic profile of RP-3500 (camonsertib) [ Time Frame: Through Study Day 152 ]
    Area-under-the-curve (AUC 0-inf)

  6. Peak plasma concentration [ Time Frame: Through Study Day 152 ]
    Cmax

  7. To assess PK parameters of RP-3500 (camonsertib) monotherapy in fasted and fed states [ Time Frame: Through Study Day 152 ]
    Comparison of geometric mean ratios (GMR)

  8. 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 [ Time Frame: Through Study Day -28 to Day 66 (each cycle is 21 days) ]
    Tumor tissue samples will be collected pre and post dosing


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 or urine) 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.

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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04497116


Contacts
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Contact: Gabriela Gomez, MD, MBA 857-340-5415 ggomez@reparerx.com

Locations
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United States, Illinois
Participating Site 1014 Recruiting
Chicago, Illinois, United States, 60611
United States, Massachusetts
Participating Site 1006 Recruiting
Boston, Massachusetts, United States, 02114
Participating Site 1002 Recruiting
Boston, Massachusetts, United States, 02215
United States, New York
Participating Site 1004 Recruiting
New York, New York, United States, 10065
United States, North Carolina
Participating Site 1005 Recruiting
Durham, North Carolina, United States, 27710
United States, Rhode Island
Participating Site 1007 Recruiting
Providence, Rhode Island, United States, 02903
United States, Tennessee
Participating Site 1003 Recruiting
Nashville, Tennessee, United States, 37203
United States, Texas
Participating Site 1001 Recruiting
Houston, Texas, United States, 77030
Canada, Ontario
Participating Site 2001 Recruiting
Toronto, Ontario, Canada, M5G 2M9
Denmark
Participating Site 4001 Recruiting
Copenhagen, DK, Denmark, 2100 Ø
United Kingdom
Participating Site 3003 Recruiting
London, United Kingdom, W1G 6AD
Participating Site 3001 Recruiting
Manchester, United Kingdom, M20 4BX
Participating Site 3002 Recruiting
Newcastle Upon Tyne, United Kingdom, NE7 7DN
Sponsors and Collaborators
Repare Therapeutics
Roche Pharma AG
Investigators
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Principal Investigator: Timothy A Yap, MBBS PhD FRCP M.D. Anderson Cancer Center
More Information
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Responsible Party: Repare Therapeutics
ClinicalTrials.gov Identifier: NCT04497116    
Other Study ID Numbers: RP-3500-01
2020-000301-87 ( EudraCT Number )
First Posted: August 4, 2020    Key Record Dates
Last Update Posted: February 9, 2023
Last Verified: February 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Repare Therapeutics:
Adult
Additional relevant MeSH terms:
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Neoplasms
Gemcitabine
Talazoparib
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
 Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Poly(ADP-ribose) Polymerase Inhibitors