Advanced Solid Tumor
Conditions
Brief summary
This is a multicenter, open-label Phase 1 trial to investigate the safety, PK, and pharmacodynamics of the Polθ inhibitor RP-3467 alone or in combination with the poly-ADP ribose polymerase inhibitor (PARPi) olaparib in adults with molecularly selected advanced solid tumors.
Detailed description
This is a first-in-human Phase 1, multi-center, open-label, dose-escalation study to: * Evaluate the safety profile of RP-3467 when administered orally alone and in combination with olaparib and to define the MTD or MAD for RP-3467 monotherapy and the RP2D for the combination * Characterize the PK profile of RP-3467 alone and in combination with olaparib
Interventions
DRUGRP-3467 at assigned dose and schedule
Eligible participants will be treated with escalating doses of RP-3467 monotherapy
DRUGOlaparib 200-300 mg BID, daily
Eligible participants will be treated with escalating doses of RP-3467 in combination with Olaparib
Sponsors
Repare Therapeutics
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female participants ≥18 years of age at the time of signing the informed consent * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 * Participant must have one of the following that has progressed or was non-responsive to prior systemic therapy and for which no standard or available known therapeutic option exists: 1. locally advanced or metastatic epithelial ovarian cancer (including fallopian tube or primary peritoneal), or 2. metastatic breast cancer, or 3. metastatic castration-resistant prostate cancer (mCRPC), or 4. pancreatic adenocarcinoma * Measurable disease per RECIST v1.1 (exceptions for participants with non-measurable but evaluable disease \[per RECIST and or PSA/CA-125\]) * Next generation sequencing (NGS) report demonstrating eligible tumor biomarker * Provision of archival tumor tissue, or if adequate archival tumor tissue is not available, provision of a fresh biopsy if there is a lesion that can be safely biopsied * Acceptable organ function at Screening * Acceptable hematologic function at Screening * Life expectancy ≥12 weeks after the start of the treatment according to the Investigator's judgment
Exclusion criteria
* 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. * Uncontrolled, symptomatic brain metastases. * Presence of other known active invasive cancers * History of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) diagnosis * Prior therapy with a Polθ inhibitor other than RP-3467
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Number of Participants Who Experienced Dose-limiting Toxicities (DLT) During the Study Treatment | Start of treatment to 30 days post last dose, up to 13 months | The assessment of DLTs was conducted to evaluate the safety and tolerability of RP-3467 administered as monotherapy and in combination with olaparib in participants with advanced solid tumors. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm 1: 160 mg QD RP-3467 160 mg RP-3467 taken QD (once a day) orally in 3 weeks (21 day cycle) | 1 |
| Arm 1: 320 mg QD RP-3467 320 mg RP-3467 taken QD (once a day) orally in 3 weeks (21 day cycle) | 3 |
| Arm 1: 640 mg QD RP-3467 640 mg RP-3467 taken QD (once a day) orally in 3 weeks (21 day cycle) | 4 |
| Arm 2: 80 mg QD RP-3467 + 200 mg BID Olaparib 80 mg RP-3467 taken QD orally in combination with 200 mg BID (twice daily) olaparib taken orally for 3 weeks (21 day cycle) | 3 |
| Arm 2: 80 mg QD RP-3467 + 300 mg BID Olaparib 80 mg RP-3467 taken QD orally in combination with 300 mg BID (twice daily) olaparib taken orally for 3 weeks (21 day cycle) | 2 |
| Arm 2: 40 mg QD RP-3467 + 300 mg BID Olaparib 40 mg RP-3467 taken QD orally in combination with 300 mg BID (twice daily) olaparib taken orally for 3 weeks (21 day cycle) | 13 |
| Total | 26 |
Baseline characteristics
| Characteristic | Arm 2: 80 mg QD RP-3467 + 200 mg BID Olaparib | Arm 2: 80 mg QD RP-3467 + 300 mg BID Olaparib | Arm 2: 40 mg QD RP-3467 + 300 mg BID Olaparib | Total | Arm 1: 160 mg QD RP-3467 | Arm 1: 320 mg QD RP-3467 | Arm 1: 640 mg QD RP-3467 |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 75.0 years STANDARD_DEVIATION 6.24 | 52.5 years STANDARD_DEVIATION 2.12 | 55.5 years STANDARD_DEVIATION 12.78 | 57.7 years STANDARD_DEVIATION 12.36 | 66 years STANDARD_DEVIATION 0 | 55.7 years STANDARD_DEVIATION 5.51 | 54.0 years STANDARD_DEVIATION 13.74 |
| Any Prior PARP inhibitor therapy No | 1 Participants | 0 Participants | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants |
| Any Prior PARP inhibitor therapy Yes | 2 Participants | 2 Participants | 12 Participants | 24 Participants | 1 Participants | 3 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants | 3 Participants | 0 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 2 Participants | 10 Participants | 21 Participants | 1 Participants | 3 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 2 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 12 Participants | 22 Participants | 0 Participants | 3 Participants | 4 Participants |
| Sex: Female, Male Male | 2 Participants | 0 Participants | 1 Participants | 4 Participants | 1 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 1 | 0 / 3 | 0 / 4 | 0 / 3 | 1 / 2 | 0 / 13 |
| other Total, other adverse events | 1 / 1 | 2 / 3 | 4 / 4 | 3 / 3 | 1 / 2 | 11 / 13 |
| serious Total, serious adverse events | 1 / 1 | 1 / 3 | 1 / 4 | 1 / 3 | 1 / 2 | 1 / 13 |
Outcome results
Primary
The Number of Participants Who Experienced Dose-limiting Toxicities (DLT) During the Study Treatment
The assessment of DLTs was conducted to evaluate the safety and tolerability of RP-3467 administered as monotherapy and in combination with olaparib in participants with advanced solid tumors.
Time frame: Start of treatment to 30 days post last dose, up to 13 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1: 160 mg QD RP-3467 | The Number of Participants Who Experienced Dose-limiting Toxicities (DLT) During the Study Treatment | 0 Participants |
| Arm 1: 320 mg QD RP-3467 | The Number of Participants Who Experienced Dose-limiting Toxicities (DLT) During the Study Treatment | 0 Participants |
| Arm 1: 640 mg QD RP-3467 | The Number of Participants Who Experienced Dose-limiting Toxicities (DLT) During the Study Treatment | 0 Participants |
| Arm 2: 80 mg QD RP-3467 + 200 mg BID Olaparib | The Number of Participants Who Experienced Dose-limiting Toxicities (DLT) During the Study Treatment | 0 Participants |
| Arm 2: 80 mg QD RP-3467 + 300 mg BID Olaparib | The Number of Participants Who Experienced Dose-limiting Toxicities (DLT) During the Study Treatment | 0 Participants |
| Arm 2: 40 mg QD RP-3467 + 300 mg BID Olaparib | The Number of Participants Who Experienced Dose-limiting Toxicities (DLT) During the Study Treatment | 1 Participants |