Clinical trial NCT04855656: Study of RP-6306 Alone or in Combination with RP-3500 or Debio 0123 in Patients with Advanced Solid Tumors
Official title: Phase 1/1b Study of the Safety, Pharmacokinetics, Pharmacodynamics and Preliminary Clinical Activity of RP-6306 Alone or in Combination with RP-3500 or Debio 0123 in Patients with Advanced Solid Tumors
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Advanced Solid Tumor
Lead sponsor: Repare Therapeutics
Sponsor class: INDUSTRY
Collaborators: name: Debiopharm International SA
First posted: 2021-04-22
Enrollment: 364
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The primary purpose of this study is to assess the safety and tolerability of RP-6306 alone and in combination with RP-3500 or in combination with Debio 0123 in patients with eligible advanced solid tumors, determine the maximum tolerated dose (MTD) and assess preliminary anti-tumor activity.

Detailed description: Phase 1/1b, multi-center, open-label, dose-escalation study to:

* Evaluate the safety profile and MTD of RP-6306 alone and in combination with RP-3500 or in combination with Debio 0123 when administered orally to establish the recommended Phase 2 dose and schedule
* Characterize the PK and pharmacodynamics of RP-6306 alone and in combination with RP-3500 or in combination with Debio 0123
* Assess preliminary anti-tumor activity associated with RP-6306 alone and in combination with RP-3500 or in combination with Debio 0123

Eligibility criteria: Inclusion Criteria:

* Male or female and ≥12 years-of-age at the time of informed consent.
* Lansky performance status ≥50% for patients ≤16 years of age, or ECOG score of 0, 1, (or 2 for module 1) for patients \>16 years of age.
* Locally advanced or metastatic resistant or refractory solid tumors.
* Patients \<18 years of age must weigh at least 40 kg.
* Submission of available tumor tissue at screening or willingness to have a biopsy performed if safe and feasible
* Next generation sequencing (NGS) report obtained in a CLIA-certified or equivalent laboratory demonstrating eligible tumor biomarker.
* CCNE1 amplification (non-equivocal) as determined by either a tumor or plasma NGS test, or FISH
* FBXW7 deleterious mutations identified by either a tumor or plasma NGS test
* PPP2R1A deleterious mutations identified by either a tumor or plasma NGS test
* Measurable disease as per RECIST v1.1. For certain modules, patients with prostate cancer or ovarian cancer that have non-measurable disease but have elevated tumor markers (PSA or CA-125, respectively) can also be eligible
* Ability to swallow and retain oral medications.
* Acceptable hematologic and organ function at screening.
* Negative pregnancy test (serum) for women of childbearing potential (WOCBP) at Screening.
* Resolution of all toxicities of prior therapy or surgical procedures.
* Any prior radiation must have been completed at least 7 days prior to the start of study drugs, and patients must have recovered from any acute adverse effects prior to the start of study treatment.

Exclusion Criteria:

* Chemotherapy or small molecule antineoplastic agent given within 21 days or \<5 half-lives, whichever is shorter, prior to first dose of study drug.
* History or current condition, 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.
* Patients who are pregnant or breastfeeding.
* Life-threatening illness, medical condition, active uncontrolled infection, or organ system dysfunction or other reasons which, in the investigator's opinion, could compromise the participating patient's safety.
* Major surgery within 4 weeks prior to first dose of RP-6306.
* Uncontrolled, symptomatic brain metastases.
* Uncontrolled hypertension.
* Certain prior anti-cancer therapy
* Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol and/or follow-up procedures outlined in the protocol.

Primary outcomes:
measure: Safety and Tolerability of RP-6306 either in monotherapy or in combination with RP-3500 or with Debio 0123 in patients with eligible advanced solid tumors
timeFrame: Up to 90 days after last administration of study intervention
measure: To define the MTD of RP-6306 monotherapy, and determine a recommended Phase 2 dose (RP2D) and preferred schedule
timeFrame: Up to 90 days after last administration of study intervention
measure: To define the MTD of RP-6306 in combination with RP-3500 or in combination with Debio 0123, and determine a recommended Phase 2 dose (RP2D) and preferred schedule
timeFrame: Up to 90 days after last administration of study intervention
measure: The relative bioavailability of RP-6306 capsule formulation as compared to RP-6306 tablet formulation in the fasted state
timeFrame: Time 0 (time of dosing) to 72 hours post-dose for each treatment condition
measure: The effect of food on the PK of tablet formulation of RP-6306 when administered in fed conditions compared to administration under fasted conditions
timeFrame: Time 0 (time of dosing) to 72 hours post-dose for each treatment condition
measure: To assess the safety and tolerability of RP-6306 tablets in combination with RP-3500, confirm the MTD of RP-6306 tablets in combination with RP-3500, and determine a RP2D and preferred schedule
timeFrame: Up to 90 days after last administration of study intervention
Secondary outcomes:
measure: The plasma concentrations of RP-6306 monotherapy (capsule formulation) in the fasted and fed states
timeFrame: Up to 90 days after last administration of study intervention
measure: To assess the relationship between pharmacodynamic biomarkers and PK of RP-6306 at different dose levels and/or schedules
timeFrame: Up to 90 days after last administration of study intervention
measure: The plasma concentrations of RP-6306 and RP-3500 when dosed in combination
timeFrame: Up to 90 days after last administration of study intervention
measure: To assess preliminary anti-tumor activity achieved with RP-6306 monotherapy, RP-6306 in combination with RP-3500 or RP-6306 in combination with Debio 0123
timeFrame: Through Study Completion, an average of 1 year
measure: To assess the safety and anti-tumor effects of RP-6306 capsule + RP-3500
timeFrame: Through Study Completion, an average of 1 year
measure: To further characterize the PK of RP-6306 tablets and assess preliminary anti-tumor
timeFrame: Through Study Completion, an average of 1 year
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Participating Site, # 1019
state: California
city: San Francisco
country: United States
facility: Participating Site, #1025
state: California
city: New Haven
country: United States
facility: Participating Site # 1012
state: Connecticut
city: Boston
country: United States
facility: Participating site # 1002
state: Massachusetts
city: Grand Rapids
country: United States
facility: Participating Site, # 1023
state: Michigan
city: St. Louis
country: United States
facility: Participating site #1011
state: Missouri
city: New Hyde Park
country: United States
facility: Participating Site, # 1032
state: New York
city: New York
country: United States
facility: Participating Site # 1008
state: New York
city: New York
country: United States
facility: Participating Site # 1004
state: New York
city: Philadelphia
country: United States
facility: Participating Site # 1010
state: Pennsylvania
city: Providence
country: United States
facility: Participating Site # 1007
state: Rhode Island
city: Providence
country: United States
facility: Participating Site # 1030
state: Rhode Island
city: Houston
country: United States
facility: Participating Site # 1001
state: Texas
city: Salt Lake City
country: United States
facility: Participating Site #1013
state: Utah
city: Charlottesville
country: United States
facility: Participating Site, # 1027
state: Virginia
city: Toronto
country: Canada
facility: Participating site # 2002
state: Ontario
city: Toronto
country: Canada
facility: Participating site #2001
state: Ontario
city: Montréal
country: Canada
facility: Participating Site, # 2003
state: Quebec
city: Copenhagen
country: Denmark
facility: Participating Site #4001
city: London
country: United Kingdom
facility: Participating Site, #3003
Study officials:
References: