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Study of RP-3500 in Advanced Solid Tumors

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04497116
Recruitment Status : Recruiting
First Posted : August 4, 2020
Last Update Posted : August 4, 2020
Sponsor:
Information provided by (Responsible Party):
Repare Therapeutics

Brief Summary:
The primary purpose of this study is to study the maximum tolerated dose (MTD) of orally-administered RP-3500 alone or in combination with talazoparib, a PARP inhibitor, in patients with advanced solid tumors with ATR inhibitor-sensitizing mutations. This study will also evaluate the safety and tolerability of RP-3500 alone or in combination with talazoparib, 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, Adult Drug: RP-3500 Drug: Talazoparib: oral PARP inhibitor Phase 1 Phase 2

Detailed Description:

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

  • Evaluate the safety profile and MTD of RP-3500 when administered orally, alone and in combination with talazoparib, to establish the dose and schedule recommended for the Phase 2
  • Characterize the PK profile of RP-3500 alone or in combination with talazoparib
  • Identify anti-tumor activity associated with RP-3500 given alone or in combination with talazoparib
  • Examine biomarker responses and establish a correlation with RP-3500 treatment.

The initial cohorts will test RP-3500 as monotherapy. Additional cohorts will be enrolled with RP-3500 in combination with a PARP inhibitor.

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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 239 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 in Advanced Solid Tumors With ATR Inhibitor Sensitizing Mutations (TRESR Study)
Actual Study Start Date : July 22, 2020
Estimated Primary Completion Date : May 30, 2022
Estimated Study Completion Date : July 30, 2022

Arm Intervention/treatment
Experimental: RP-3500

Phase 1:

Multiple doses of RP-3500 for oral administration alone or in combination with a talazoparib

Drug: RP-3500
Oral ATR inhibitor

Drug: Talazoparib: oral PARP inhibitor
Talazoparib: oral PARP inhibitor

Experimental: Expansion cohorts with RP-3500

Phase 2:

Expansion cohorts with RP-3500

Drug: RP-3500
Oral ATR inhibitor




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 [ 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) ]
  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 (ORR) in patients with eligible advanced solid tumors by CT/MRI Response evaluation criteria in solid tumors (RECIST 1.1). [ Time Frame: Through Study completion, an average of 1 year ]
    Objective response rate (ORR)

  2. 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: Through Study completion, an average of 1 year ]
    Duration of response (DOR)

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

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

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

  6. 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



Information from the National Library of Medicine

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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 ICF.
  • 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 or willingness to have a biopsy performed to obtain 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 women of childbearing potential at Screening and prior to first study drug. Women who are not of childbearing potential is defined as 1) adequate time with absence of menses (period) or 2) documented infertility.
  • Resolution of all toxicities of prior treatment or surgery.
  • Male patients with female partners of childbearing potential and women of childbearing potential must follow a contraception method (oral contraceptives allowed) during their participation in the study and for at least 4 months following last dose of study drug. Male patients must also refrain from donating sperm during their participation in the study and for 4 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.
  • 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

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: Peter Manley, MD, MPH 857-322-5553 pmanley@reparerx.com

Locations
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United States, Texas
The University of Texas M.D. Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Sandra Montez, RN    713-745-6274    smontez@mdanderson.org   
Principal Investigator: Timothy A Yap, MBBS PhD FRCP         
Sponsors and Collaborators
Repare Therapeutics
Investigators
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Principal Investigator: Timothy A Yap, MBBS PhD FRCP M.D. Anderson Cancer Center
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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: August 4, 2020
Last Verified: July 2020
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
Additional relevant MeSH terms:
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Neoplasms
Talazoparib
Poly(ADP-ribose) Polymerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents