Clinical Trials /

Study of RP-3500 in Advanced Solid Tumors

NCT04497116

Description:

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.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study of RP-3500 in Advanced Solid Tumors
  • 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)

Clinical Trial IDs

  • ORG STUDY ID: RP-3500-01
  • SECONDARY ID: 2020-000301-87
  • NCT ID: NCT04497116

Conditions

  • Advanced Solid Tumor, Adult

Interventions

DrugSynonymsArms
RP-3500Expansion cohorts with RP-3500
Talazoparib: oral PARP inhibitorRP-3500

Purpose

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.

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
    

Trial Arms

NameTypeDescriptionInterventions
RP-3500ExperimentalPhase 1: Multiple doses of RP-3500 for oral administration alone or in combination with a talazoparib
  • RP-3500
  • Talazoparib: oral PARP inhibitor
Expansion cohorts with RP-3500ExperimentalPhase 2: Expansion cohorts with RP-3500
  • RP-3500

Eligibility 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description:Grade and frequency of adverse events and serious adverse events

Secondary Outcome Measures

Measure: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
Safety Issue:
Description:Objective response rate (ORR)
Measure: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
Safety Issue:
Description:Duration of response (DOR)
Measure:Characterize the pharmacokinetic profile of RP-3500
Time Frame:Through Study Day 152
Safety Issue:
Description:Area-under-the-curve (AUC 0-inf)
Measure:Peak plasma concentration
Time Frame:Through Study Day 152
Safety Issue:
Description:Cmax
Measure:To assess PK parameters of RP-3500 monotherapy in fasted and fed states
Time Frame:Through Study Day 152
Safety Issue:
Description:Comparison of geometric mean ratios (GMR)
Measure: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)
Safety Issue:
Description:Tumor tissue samples will be collected pre and post dosing

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Repare Therapeutics

Last Updated

July 29, 2020