Advanced Solid Tumor, Adult
Conditions
Brief summary
The primary purpose of this study is to assess the safety and tolerability of niraparib or olaparib in combination with RP-3500 (camonsertib), in patients with eligible advanced solid tumors, determine the maximum tolerated dose (MTD) of RP-3500 (camonsertib) in combination with niraparib or olaparib, examine pharmacokinetics (PK) and assess anti-tumor activity.
Detailed description
This is a first-in-human Phase 1b/2, multi-center, open-label, dose-escalation and expansion study to: * Evaluate the safety profile and MTD of RP-3500 (camonsertib) when administered orally in combination with niraparib or olaparib to establish the recommended Phase 2 dose and schedule. * Characterize the PK profile of RP-3500 (camonsertib) in combination with niraparib or olaparib * Assess anti-tumor activity associated with RP-3500 (camonsertib) in combination with niraparib or olaparib * Examine biomarker responses and establish a correlation with RP-3500 (camonsertib) treatment in combination with niraparib or olaparib. After the RP2D and schedule is determined, expansion cohort(s) for RP-3500 (camonsertib) in combination with niraparib or olaparib will be enrolled to study the anti-tumor effect, and further examine the safety, PK, and pharmacodynamic (PD). Sponsor decided to terminate study early therefore, the Phase 2 expansion was not conducted
Interventions
RP-3500 (camonsertib, ATR inhibitor) in combination with niraparib or olaparib (PARP inhibitors)
Sponsors
Repare Therapeutics
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Dose Escalation, expansion and Phase 2
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female and ≥18 years-of-age at the time of signature of the informed consent * Confirmed advanced solid tumors resistant or refractory to standard treatment * Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1. * Evaluable disease as per RECIST v1.1 * Next generation sequencing (NGS) report obtained in CLIA-certified or equivalent laboratory demonstrating eligible tumor biomarkers. * Submission of available tumor tissue or willingness to have a biopsy performed if safe and feasible * Acceptable hematologic and organ function at screening * Negative pregnancy test for women of childbearing potential at Screening and prior to first study drug. * Ability to swallow and retain oral medications.
Exclusion criteria
* Prior therapy with an ATR or DNA-dependent protein kinase (DNA-PK) inhibitor. * Chemotherapy, small molecule anticancer or biologic anticancer therapy given within 10 days or 5 half-lives (whichever is longer), prior to first dose of study drug. * Use of radiotherapy (except for palliative reasons) within 7 days 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. * No other anticancer therapy is to be permitted while the patient is receiving study treatment. * Major surgery ≤28 days or minor surgical procedures ≤7 days prior to first study treatment dose. * Uncontrolled, symptomatic brain metastases. * Uncontrolled high blood pressure * History of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) diagnosis * Presence of other known active invasive cancers. * Pregnant or breastfeeding women. * Psychological, familial, sociological, or geographical conditions that do not permit compliance with the study protocol and/or follow-up procedures outlined in the protocol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Determine the Safety and Tolerability of Niraparib or Olaparib in Combination With RP-3500 in Patients With Molecularly Selected Solid Tumors | Start of treatment to 30 days post last dose, up to 23.7 months | Treatment Related Treatment-Emergent Adverse Events (TRAE) with ≥3 CTCAE Grade |
| Define the Recommended Phase 2 Dose (RP2D) of RP-3500 in Combination With Niraparib or Olaparib in Patients With Molecularly Selected Solid Tumors | During 21 days (one cycle) from the initiation of the study treatment | Frequency of DLTs during the DLT observation period |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm 1: 50mg QD camonsertib + 100mg QD niraparib, 3d on/4d off, weekly 50 mg RP-3500 (camonsertib) taken QD (once a day) orally in combination with 100 mg niraparib taken QD orally, same day on a 3 days on and 4 days off schedule for 3 weeks (21 day cycle) | 9 |
| Arm 1: 80mg QD camonsertib + 100mg QD niraparib, 2d on/5d off, weekly 80 mg RP-3500 (camonsertib) taken QD orally in combination with 100 mg niraparib taken QD orally, same day on a 2 days on and 5 days off schedule for 3 weeks (21 day cycle) | 24 |
| Arm 1: 80mg QD camonsertib + 100mg QD niraparib, 3d on/4d off, weekly 80 mg RP-3500 (camonsertib) taken QD orally in combination with 100 mg niraparib taken QD orally, same day on a 3 days on and 4 days off schedule for 3 weeks (21 day cycle) | 3 |
| Arm 1: 80mg QD camonsertib + 100mg QD niraparib, 2d on/5d off, 2 weeks on/1 week off 80 mg RP-3500 (camonsertib) taken QD orally in combination with 100 mg niraparib taken QD orally, same day on a 2 days on and 5 days off schedule for 2 weeks on and 1 week off (21 day cycle) | 23 |
| Arm 1: 70mg QD camonsertib + 100mg QD niraparib, 3d on/4d off, weekly 70 mg RP-3500 (camonsertib) taken QD orally in combination with 100 mg niraparib taken QD orally, same day on a 2 days on and 5 days off schedule for 3 weeks (21 day cycle) | 8 |
| Arm 2: 50mg QD camonsertib + 150mg BID olaparib, 3d on/4d off, weekly 50 mg RP-3500 (camonsertib) taken QD orally in combination with 150 mg olaparib taken BID (twice a day) orally, same day on a 3 days on and 4 days off schedule for 3 weeks (21 day cycle) | 7 |
| Arm 2: 50mg QD camonsertib + 100mg BID olaparib, 3d on/4d off, weekly 50 mg RP-3500 (camonsertib) taken QD orally in combination with 100 mg olaparib taken BID orally, same day on a 3 days on and 4 days off schedule for 3 weeks (21 day cycle) | 19 |
| Arm 2: 50mg QD camonsertib + 200 mg QD olaparib, 3d on/4 d off, weekly 50 mg RP-3500 (camonsertib) taken QD orally in combination with 200 mg olaparib taken QD orally, same day on a 3 days on and 4 days off schedule for 3 weeks (21 day cycle) | 5 |
| Arm 2: 80mg QD camonsertib + 150mg BID olaparib, 3d on/4d off, weekly 80 mg RP-3500 (camonsertib) taken QD orally in combination with 150 mg olaparib taken BID orally, same day on a 3 days on and 4 days off schedule for 3 weeks (21 day cycle) | 3 |
| Arm 2: 50mg QD camonsertib + 100mg BID olaparib, 2d on/5d off, weekly 50 mg RP-3500 (camonsertib) taken QD orally in combination with 100 mg olaparib taken BID orally, same day on a 2 days on and 5 days off schedule for 3 weeks (21 day cycle) | 26 |
| Arm 2: 80mg QD camonsertib + 100mg BID olaparib, 2d on/5d off, 2w on/1w off 80 mg RP-3500 (camonsertib) taken QD orally in combination with 100 mg olaparib taken BID orally, same day on a 2 days on and 5 days off schedule for 2 weeks on and 1 week off (21 day cycle) | 29 |
| Total | 156 |
Baseline characteristics
| Characteristic | Total | Arm 1: 50mg QD camonsertib + 100mg QD niraparib, 3d on/4d off, weekly | Arm 1: 80mg QD camonsertib + 100mg QD niraparib, 3d on/4d off, weekly | Arm 1: 80mg QD camonsertib + 100mg QD niraparib, 2d on/5d off, 2 weeks on/1 week off | Arm 1: 70mg QD camonsertib + 100mg QD niraparib, 3d on/4d off, weekly | Arm 1: 80mg QD camonsertib + 100mg QD niraparib, 2d on/5d off, weekly | Arm 2: 50mg QD camonsertib + 150mg BID olaparib, 3d on/4d off, weekly | Arm 2: 50mg QD camonsertib + 100mg BID olaparib, 3d on/4d off, weekly | Arm 2: 50mg QD camonsertib + 200 mg QD olaparib, 3d on/4 d off, weekly | Arm 2: 80mg QD camonsertib + 150mg BID olaparib, 3d on/4d off, weekly | Arm 2: 50mg QD camonsertib + 100mg BID olaparib, 2d on/5d off, weekly | Arm 2: 80mg QD camonsertib + 100mg BID olaparib, 2d on/5d off, 2w on/1w off |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Customized Age | 58.9 years STANDARD_DEVIATION 12.25 | 60.9 years STANDARD_DEVIATION 13.51 | 61.7 years STANDARD_DEVIATION 15.18 | 56.4 years STANDARD_DEVIATION 9.01 | 63.1 years STANDARD_DEVIATION 12.14 | 61.7 years STANDARD_DEVIATION 7.7 | 53.1 years STANDARD_DEVIATION 14.24 | 56.8 years STANDARD_DEVIATION 14.6 | 59.8 years STANDARD_DEVIATION 12.4 | 59.3 years STANDARD_DEVIATION 21.08 | 58.8 years STANDARD_DEVIATION 13.38 | 59.2 years STANDARD_DEVIATION 13.73 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 11 Participants | 0 Participants | 0 Participants | 4 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 141 Participants | 9 Participants | 3 Participants | 18 Participants | 8 Participants | 22 Participants | 6 Participants | 18 Participants | 5 Participants | 3 Participants | 23 Participants | 26 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Sex: Female, Male Female | 104 Participants | 6 Participants | 2 Participants | 19 Participants | 8 Participants | 20 Participants | 3 Participants | 12 Participants | 2 Participants | 1 Participants | 15 Participants | 16 Participants |
| Sex: Female, Male Male | 52 Participants | 3 Participants | 1 Participants | 4 Participants | 0 Participants | 4 Participants | 4 Participants | 7 Participants | 3 Participants | 2 Participants | 11 Participants | 13 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 | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 9 | 10 / 24 | 0 / 3 | 8 / 23 | 1 / 8 | 4 / 7 | 10 / 19 | 1 / 5 | 1 / 3 | 6 / 26 | 5 / 29 |
| other Total, other adverse events | 9 / 9 | 24 / 24 | 3 / 3 | 23 / 23 | 8 / 8 | 7 / 7 | 19 / 19 | 5 / 5 | 3 / 3 | 26 / 26 | 27 / 29 |
| serious Total, serious adverse events | 4 / 9 | 8 / 24 | 2 / 3 | 7 / 23 | 3 / 8 | 1 / 7 | 11 / 19 | 2 / 5 | 1 / 3 | 8 / 26 | 8 / 29 |
Outcome results
Primary
Define the Recommended Phase 2 Dose (RP2D) of RP-3500 in Combination With Niraparib or Olaparib in Patients With Molecularly Selected Solid Tumors
Frequency of DLTs during the DLT observation period
Time frame: During 21 days (one cycle) from the initiation of the study treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1: 50mg QD camonsertib + 100mg QD niraparib, 3d on/4d off, weekly | Define the Recommended Phase 2 Dose (RP2D) of RP-3500 in Combination With Niraparib or Olaparib in Patients With Molecularly Selected Solid Tumors | 1 Participants |
| Arm 1: 80mg QD camonsertib + 100mg QD niraparib, 2d on/5d off, weekly | Define the Recommended Phase 2 Dose (RP2D) of RP-3500 in Combination With Niraparib or Olaparib in Patients With Molecularly Selected Solid Tumors | 1 Participants |
| Arm 1: 80mg QD camonsertib + 100mg QD niraparib, 3d on/4d off, weekly | Define the Recommended Phase 2 Dose (RP2D) of RP-3500 in Combination With Niraparib or Olaparib in Patients With Molecularly Selected Solid Tumors | 3 Participants |
| Arm 1: 80mg QD camonsertib + 100mg QD niraparib, 2d on/5d off, 2 weeks on/1 week off | Define the Recommended Phase 2 Dose (RP2D) of RP-3500 in Combination With Niraparib or Olaparib in Patients With Molecularly Selected Solid Tumors | 1 Participants |
| Arm 1: 70mg QD camonsertib + 100mg QD niraparib, 3d on/4d off, weekly | Define the Recommended Phase 2 Dose (RP2D) of RP-3500 in Combination With Niraparib or Olaparib in Patients With Molecularly Selected Solid Tumors | 1 Participants |
| Arm 2: 50mg QD camonsertib + 150mg BID olaparib, 3d on/4d off, weekly | Define the Recommended Phase 2 Dose (RP2D) of RP-3500 in Combination With Niraparib or Olaparib in Patients With Molecularly Selected Solid Tumors | 3 Participants |
| Arm 2: 50mg QD camonsertib + 100mg BID olaparib, 3d on/4d off, weekly | Define the Recommended Phase 2 Dose (RP2D) of RP-3500 in Combination With Niraparib or Olaparib in Patients With Molecularly Selected Solid Tumors | 6 Participants |
| Arm 2: 50mg QD camonsertib + 200 mg QD olaparib, 3d on/4 d off, weekly | Define the Recommended Phase 2 Dose (RP2D) of RP-3500 in Combination With Niraparib or Olaparib in Patients With Molecularly Selected Solid Tumors | 1 Participants |
| Arm 2: 80mg QD camonsertib + 150mg BID olaparib, 3d on/4d off, weekly | Define the Recommended Phase 2 Dose (RP2D) of RP-3500 in Combination With Niraparib or Olaparib in Patients With Molecularly Selected Solid Tumors | 2 Participants |
| Arm 2: 50mg QD camonsertib + 100mg BID olaparib, 2d on/5d off, weekly | Define the Recommended Phase 2 Dose (RP2D) of RP-3500 in Combination With Niraparib or Olaparib in Patients With Molecularly Selected Solid Tumors | 0 Participants |
| Arm 2: 80mg QD camonsertib + 100mg BID olaparib, 2d on/5d off, 2w on/1w off | Define the Recommended Phase 2 Dose (RP2D) of RP-3500 in Combination With Niraparib or Olaparib in Patients With Molecularly Selected Solid Tumors | 3 Participants |
Primary
Determine the Safety and Tolerability of Niraparib or Olaparib in Combination With RP-3500 in Patients With Molecularly Selected Solid Tumors
Treatment Related Treatment-Emergent Adverse Events (TRAE) with ≥3 CTCAE Grade
Time frame: Start of treatment to 30 days post last dose, up to 23.7 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1: 50mg QD camonsertib + 100mg QD niraparib, 3d on/4d off, weekly | Determine the Safety and Tolerability of Niraparib or Olaparib in Combination With RP-3500 in Patients With Molecularly Selected Solid Tumors | 8 Participants |
| Arm 1: 80mg QD camonsertib + 100mg QD niraparib, 2d on/5d off, weekly | Determine the Safety and Tolerability of Niraparib or Olaparib in Combination With RP-3500 in Patients With Molecularly Selected Solid Tumors | 20 Participants |
| Arm 1: 80mg QD camonsertib + 100mg QD niraparib, 3d on/4d off, weekly | Determine the Safety and Tolerability of Niraparib or Olaparib in Combination With RP-3500 in Patients With Molecularly Selected Solid Tumors | 3 Participants |
| Arm 1: 80mg QD camonsertib + 100mg QD niraparib, 2d on/5d off, 2 weeks on/1 week off | Determine the Safety and Tolerability of Niraparib or Olaparib in Combination With RP-3500 in Patients With Molecularly Selected Solid Tumors | 12 Participants |
| Arm 1: 70mg QD camonsertib + 100mg QD niraparib, 3d on/4d off, weekly | Determine the Safety and Tolerability of Niraparib or Olaparib in Combination With RP-3500 in Patients With Molecularly Selected Solid Tumors | 7 Participants |
| Arm 2: 50mg QD camonsertib + 150mg BID olaparib, 3d on/4d off, weekly | Determine the Safety and Tolerability of Niraparib or Olaparib in Combination With RP-3500 in Patients With Molecularly Selected Solid Tumors | 6 Participants |
| Arm 2: 50mg QD camonsertib + 100mg BID olaparib, 3d on/4d off, weekly | Determine the Safety and Tolerability of Niraparib or Olaparib in Combination With RP-3500 in Patients With Molecularly Selected Solid Tumors | 16 Participants |
| Arm 2: 50mg QD camonsertib + 200 mg QD olaparib, 3d on/4 d off, weekly | Determine the Safety and Tolerability of Niraparib or Olaparib in Combination With RP-3500 in Patients With Molecularly Selected Solid Tumors | 5 Participants |
| Arm 2: 80mg QD camonsertib + 150mg BID olaparib, 3d on/4d off, weekly | Determine the Safety and Tolerability of Niraparib or Olaparib in Combination With RP-3500 in Patients With Molecularly Selected Solid Tumors | 3 Participants |
| Arm 2: 50mg QD camonsertib + 100mg BID olaparib, 2d on/5d off, weekly | Determine the Safety and Tolerability of Niraparib or Olaparib in Combination With RP-3500 in Patients With Molecularly Selected Solid Tumors | 16 Participants |
| Arm 2: 80mg QD camonsertib + 100mg BID olaparib, 2d on/5d off, 2w on/1w off | Determine the Safety and Tolerability of Niraparib or Olaparib in Combination With RP-3500 in Patients With Molecularly Selected Solid Tumors | 23 Participants |