Study of RP-3500 in Advanced Solid Tumors

Sponsor

Repare Therapeutics (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04497116

Collaborator

(none)

457

Enrollment

Locations

Arms

44.3

Anticipated Duration (Months)

35.2

Patients Per Site

0.8

Patients Per Site Per Month

Study Details

Study Description

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 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 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. An evaluation of safety and tolerability in children over 4 years old will be initiated.

Condition or Disease	Intervention/Treatment	Phase
Advanced Solid Tumor	Drug: RP-3500 Drug: Talazoparib Drug: Gemcitabine Injection [Gemzar]	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 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 alone or in combination with talazoparib or gemcitabine
Identify anti-tumor activity associated with RP-3500 given alone or in combination with talazoparib or gemcitabine
Examine biomarker responses and establish a correlation with RP-3500 exposure and clinical outcomes.
Evaluate the safety and tolerability of RP-3500 in pediatric patients with advanced solid tumors to establish the dose and schedule recommended for the Phase 2

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

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 and PK of RP-3500 at the RP2D

Study Design

Study Type:

Interventional

Anticipated Enrollment :

457 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Intervention Model Description:

Dose Escalation, expansion and phase 2Dose 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 :

Jul 22, 2020

Anticipated Primary Completion Date :

Jan 30, 2024

Anticipated Study Completion Date :

Mar 30, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: RP-3500 alone Phase 1: Multiple doses of RP-3500 for oral administration alone	Drug: RP-3500 Oral ATR inhibitor
Experimental: Expansion cohorts with RP-3500 Phase 2: Expansion cohorts with RP-3500	Drug: RP-3500 Oral ATR inhibitor
Experimental: RP-3500 with Talazoparib or Gemcitabine Phase 1: Multiple doses of RP-3500 for oral administration in combination with talazoparib or gemcitabine	Drug: RP-3500 Oral ATR inhibitor Drug: Talazoparib Oral PARP inhibitor Drug: Gemcitabine Injection [Gemzar] Gemcitabine
Experimental: RP-3500 in children Phase 1: Multiple doses of RP-3500 for oral administration alone given in children	Drug: RP-3500 Oral ATR inhibitor

Outcome Measures

Primary Outcome Measures

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 [Up to 90 days after last administration of study intervention]
Frequency of Dose limiting Toxicities (DLTs) [At the end of cycle 1 (each cycle is 21 days or 28 days)]
Safety and tolerability [Up to 90 days after last administration of study intervention]
Grade and frequency of adverse events and serious adverse events

Secondary Outcome Measures

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. [About 1 year]
Overall response rate
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) [About 1 year]
Objective response rate (ORR)
Assess CR+PR+SD (≥ 4 months) based on RECIST v1.1, confirmed CA-125 response by GCIG criteria, or PSA response based on PCWG3 [About 1 year]
Clinical Benefit Rate
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). [About 1 year]
Duration of response (DOR)
Characterize the pharmacokinetic profile of RP-3500 [Through Study Day 152]
Area-under-the-curve (AUC 0-inf)
Peak plasma concentration [Through Study Day 152]
Cmax
To assess PK parameters of RP-3500 monotherapy in fasted and fed states [Through Study Day 152]
Comparison of geometric mean ratios (GMR)
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 [Through Study Day -28 to Day 66 (each cycle is 21 days)]
Tumor tissue samples will be collected pre and post dosing

Eligibility Criteria

Criteria

Ages Eligible for Study:

4 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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/assent.
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 or INRC
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. Females who are not of childbearing potential are defined as 1) prior to onset of menses 2) documented infertility.
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 3 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Participating Site 1014	Chicago	Illinois	United States	60611
2	Participating Site 1006	Boston	Massachusetts	United States	02114
3	Participating Site 1002	Boston	Massachusetts	United States	02215
4	Participating Site 1004	New York	New York	United States	10065
5	Participating Site 1005	Durham	North Carolina	United States	27710
6	Participating Site 1007	Providence	Rhode Island	United States	02903
7	Participating Site 1003	Nashville	Tennessee	United States	37203
8	Participating Site 1001	Houston	Texas	United States	77030
9	Participating Site 2001	Toronto	Ontario	Canada	M5G 2M9
10	Participating Site 4001	Copenhagen	DK	Denmark	2100 Ø
11	Participating Site 3003	London		United Kingdom	W1G 6AD
12	Participating Site 3001	Manchester		United Kingdom	M20 4BX
13	Participating Site 3002	Newcastle Upon Tyne		United Kingdom	NE7 7DN

Sponsors and Collaborators

Repare Therapeutics

Investigators

Principal Investigator: Timothy A Yap, MBBS PhD FRCP, M.D. Anderson Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

Responsible Party:

Repare Therapeutics

ClinicalTrials.gov Identifier:

NCT04497116

Other Study ID Numbers:

RP-3500-01
2020-000301-87

First Posted:

Aug 4, 2020

Last Update Posted:

Apr 27, 2022

Last Verified:

Apr 1, 2022

Individual Participant Data (IPD) Sharing Statement:

Plan to Share IPD:

Studies a U.S. FDA-regulated Drug Product:

Yes

Studies a U.S. FDA-regulated Device Product:

Keywords provided by Repare Therapeutics

Adult, Children

Additional relevant MeSH terms:

Neoplasms

Gemcitabine

Talazoparib

Study Results

No Results Posted as of Apr 27, 2022