A Study of RP-3500 in Combination With Standard Radiation Therapy in People With Solid Tumor Cancer

RP-3500 (ATRi) + External Beam Radiotherapy (EBRT) for the Palliative Treatment of Metastatic Disease

The purpose of this study is to test the safety of the study drug, RP-3500 when given in combination with palliative external beam radiotherapy (EBRT) to people who have metastatic solid tumor cancer with a mutation of the ATM gene. The study researchers will do tests to find the highest dose of RP3500 that causes few or mild side effects.

Study Overview

• Status: Active, not recruiting
• Conditions: Solid Tumor; Metastatic Cancer
• Intervention / Treatment: Radiation: External Beam Radiotherapy (EBRT); Drug: RP-3500

• Study Type: Interventional
• Enrollment (Actual): 49
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • New Jersey
    • Basking Ridge, New Jersey, United States, 07920
      • Memorial Sloan Kettering Basking Ridge (Limited Protocol Activites)
    • Middletown, New Jersey, United States, 07748
      • Memorial Sloan Kettering Monmouth (All Protocol Activities)
    • Montvale, New Jersey, United States, 07645
      • Memorial Sloan Kettering Bergen (Limited Protocol Activities)
  • New York
    • Commack, New York, United States, 11725
      • Memorial Sloan Kettering Cancer Center at Suffolk-Commack (All Protocol Activities)
    • Harrison, New York, United States, 10604
      • Memorial Sloan Kettering Westchester (All Protocol Activities)
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center (All Protocol Activities)
    • Uniondale, New York, United States, 11553
      • Memorial Sloan Kettering Nassau (Limited Protocol Activities)

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Histologically confirmed malignancy with at least one metastatic lesion amenable to radiotherapy. Bone, visceral, and soft tissue are eligible.

• Mutation in ATM (deleterious or VUS; somatic or germline; monoallelic or biallelic)

  • Note: Homozygous Deletion in the ATM gene will also be allowed
• ECOG performance status 0-2 or KPS equivalent
• Age ≥18 years
• Expected survival greater than 6 months
• Participant or Legally Authorized Representative (LAR) able to provide written informed consent
• Patients of reproductive potential must agree to practice an effective contraceptive method
• Ability to swallow capsules and retain oral medications

• Acceptable organ function at Screening, as evidenced by the following laboratory data:

  1. Serum creatinine ≤1.5 × upper limit of normal (ULN) or calculated creatinine clearance ≥60 mL/min using the Cockcroft-Gault equation or by 24-hour urine collection
  2. Total bilirubin ≤1.5 × ULN or <3.0 × ULN if known Gilbert's disease
  3. Serum albumin ≥2.5 g/dL
  4. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × ULN unless liver metastases are present and thought to be a reason for AST/ALT elevation, in which case they must be ≤5 × ULN

• Acceptable hematologic function at Screening:

  1. No red blood cell or platelet transfusions or growth factors within 7 days of the first dose of RP-3500
  2. Hemoglobin ≥9.5 g/dL
  3. ANC ≥1700 cells/mm^3
  4. Platelet count ≥130,000 cells/mm^3
• Resolution of all toxicities of prior therapy or surgical procedures to baseline or Grade 1 (except for neuropathy, hypothyroidism requiring medication and alopecia can be resolved to Grade ≤2)
• Negative pregnancy test (serum or urine) for women of childbearing potential (WOCBP) at Screening and prior to first study drug. Non-WOCBP is defined as 1) adequate time of amenorrhea for > 12 months plus adequate FSH level or 2) surgically or anatomically infertile
• Male patients with female partners of childbearing potential and WOCBP must follow a contraception method (oral contraceptives allowed) at least as conservative as Clinical Trial Facilitation Group (CTFG) recommendations during their participation in the study. WOCBP must follow the recommendations until 6 months following last dose of study drug and male patients must follow the recommendations for 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:

• Previous radiotherapy to the intended treatment site
• Prior therapy with an ATR or DNA-dependent protein kinase (DNA-PK) inhibitor
• Serious medical co-morbidities precluding radiotherapy
• Pregnant or breast-feeding women
• No other concurrent systemic therapy during the entire duration of protocol treatment. Patients can have other systemic treatments up until the start of protocol treatment. Patients can also have other systemic treatments after the completion of protocol treatments
• Known hypersensitivity to any of the ingredients of RP-3500
• Uncontrolled hypertension (systolic blood pressure [BP] ≥160 mmHg; diastolic BP ≥100 mmHg) despite adequate treatment prior to first dose of RP-3500
• 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. In equivocal cases, patients whose viral load is negative, may be eligible. HIV seropositive patients who are healthy and low risk for AIDS related outcomes could be considered eligible. Eligibility criteria for HIV positive patients should be evaluated and discussed, and will be based on current and past CD4 and T-cell counts, history (if any) of AIDS-defining conditions (eg, opportunistic infections), and status of HIV treatment
• 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, including complete left bundle branch block, second- or third-degree heart block, or recent history of myocardial infarction that in the opinion of the investigator will pose an increased risk of rhythm abnormalities
• History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias such as structural heart disease (eg, severe left ventricular systolic dysfunction, left ventricular hypertrophy), coronary heart disease (symptomatic or with ischemia demonstrated by diagnostic testing), clinically significant electrolyte abnormalities (eg, hypokalemia, hypomagnesemia, hypocalcemia), or family history of sudden unexplained death or long QT syndrome
• Current treatment with medications that are well-known to prolong the QT interval
• Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol and/or follow-up procedures outlined in the protocol
• Patients who are receiving strong CYP3A inhibitors or inducers, P-gp inhibitors and/or BCRP inhibitors
• Patients with germline homozygous ATM mutations

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: RP-3500 in Combination With Standard Radiation Therapy; Patients with metastatic cancers with identified mutations in ATM will be enrolled. All patients will receive a standard palliative RT (4Gy x 5 fractions) on Days 1-5 in combination with RP-3500 on Days 1-5. In the first phase of the study, a 3+3 study design will be used to identify a safe dose of RP-3500 (starting at 80 mg QD) in combination with palliative RT.	Radiation: External Beam Radiotherapy (EBRT); Palliative radiation therapy (4Gy x 5 fractions) to a metastatic site on Days 1-5; Drug: RP-3500; RP-3500 on Days 1-5.
Experimental: Pilot subcohort; The primary objective is to assess 6 month local control rate of patients of new metastatic lesions with pathogenic ATM who haves received prior RP-3500 and palliative RT.	Radiation: External Beam Radiotherapy (EBRT); Palliative radiation therapy (4Gy x 5 fractions) to a metastatic site on Days 1-5; Drug: RP-3500; RP-3500 on Days 1-5.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase I - Safety and Tolerability of RP-3500 in combination with radiation therapy	by assessing the grade and frequency of adverse events and serious adverse events. A dose limiting toxicity (DLT) will be graded according to NCI CTCAE v5.0.	2 years
Phase II - Assess 6 month local control rate of patients with pathogenic ATM who received RP-3500 and palliative RT	Imaging per discretion of treating physician, and may include PET, CT and MRI imaging.	2 years

Collaborators and Investigators

• Sponsor: Memorial Sloan Kettering Cancer Center
• Collaborators: Repare Therapeutics
• Investigators: Principal Investigator: Nancy Lee, MD, Memorial Sloan Kettering Cancer Center

Publications and helpful links

Helpful Links

• Memorial Sloan Kettering Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): September 30, 2022
• Primary Completion (Estimated): September 30, 2026
• Study Completion (Estimated): September 30, 2026

Study Registration Dates

• First Submitted: September 30, 2022
• First Submitted That Met QC Criteria: September 30, 2022
• First Posted (Actual): October 4, 2022

Study Record Updates

• Last Update Posted (Estimated): December 17, 2025
• Last Update Submitted That Met QC Criteria: December 11, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: Palliative treatment; RP-3500 (ATRi); External Beam Radiotherapy (EBRT); 22-222
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Neoplastic Processes; Pathological Conditions, Signs and Symptoms; Neoplasm Metastasis
• Other Study ID Numbers: 22-222

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Memorial Sloan Kettering Cancer Center supports the international committee of medical journal editors (ICMJE) and the ethical obligation of responsible sharing of data from clinical trials. The protocol summary, a statistical summary, and informed consent form will be made available on clinicaltrials.gov when required as a condition of Federal awards, other agreements supporting the research and/or as otherwise required. Requests for deidentified individual participant data can be made beginning 12 months after publication and for up to 36 months post publication. Deidentified individual participant data reported in the manuscript will be shared under the terms of a Data Use Agreement and may only be used for approved proposals. Requests may be made to: crdatashare@mskcc.org.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No