Adult Solid Tumor
Conditions
Brief summary
The primary purpose of this study is to assess the safety and tolerability of RP-6306 in combination gemcitabine, in patients with eligible advanced solid tumors, determine the maximum tolerated dose (MTD) of RP-6306 in combination with gemcitabine, identify a recommended phase 2 dose (RP2D) and preferred schedule, examine preliminary pharmacokinetics (PK) and assess anti-tumor activity.
Detailed description
Phase 1, multi-center, open-label, dose-escalation study to: * Evaluate the safety profile and MTD of RP-6306 with gemcitabine to establish the RP2D and schedule * Characterize the PK and pharmacodynamics of RP-6306 with gemcitabine * Assess preliminary anti-tumor activity associated with RP-6306 with gemcitabine The Sponsor of the study has changed from 'Repare Therapeutics' to 'Debiopharm International SA' in the United States.
Interventions
RP-6306 in combination with gemcitabine
Sponsors
Repare Therapeutics
Debiopharm International SA
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Dose Escalation and Expansion
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 informed consent. * ECOG Performance status 0 or 1. * Locally advanced or metastatic resistant or refractory solid tumors. * Submission of available tumor tissue at screening or willingness to have a biopsy performed if safe and feasible. * Measurable disease as per RECIST v1.1. * 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. * Life expectancy ≥12 weeks after the start of the 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. * Known sensitivity to any of the ingredients of RP-6306 or gemcitabine. * 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 and gemcitabine. * Uncontrolled, symptomatic brain metastases. * Uncontrolled hypertension. * Moderate or severe hepatic impairment * Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol and/or follow-up procedures outlined in the protocol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With of Treatment-related Adverse Event Data Per CTCAE v5.0 Criteria to Determine Safety and Tolerability of RP-6306 in Combination With Gemcitabine. | Start of treatment to 30 days post last dose. up to 1.5 years | Incidence of grade 3 and above Treatment Related Emergent Adverse Events (TRAEs) |
| Number of Dose Limiting Toxicities, as Defined Per Protocol, That Occur During the First Cycle (21 Days) of Treatment at Each Dose Level | During 21 days from the initiation of the study treatment (C1D1) | Evaluation of dose-limiting toxicities (DLTs) at or below a frequency of 25% |
Countries
Canada, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Module 1a: 40 mg QD Lunresertib Continue + 800 mg/m2 Gemcitabine 40 mg QD oral (PO) lunresertib continuously daily in combination with 800 mg/m2 intravenous (IV) gemcitabine given over 30 minutes on Day 1 and 8 of each 21-day treatment cycle | 1 |
| Module 1a: 80 mg QD Lunresertib Continue + 800 mg/m2 Gemcitabine 80 mg QD oral (PO) lunresertib continuously daily in combination with 800 mg/m2 intravenous (IV) gemcitabine given over 30 minutes on Day 1 and 8 of each 21-day treatment cycle | 7 |
| Module 1a: 80 mg QD Lunresertib Continue + 600 mg/m2 Gemcitabine 40 mg QD oral (PO) lunresertib continuously daily in combination with 600 mg/m2 intravenous (IV) gemcitabine given over 30 minutes on Day 1 and 8 of each 21-day treatment cycle | 4 |
| Module 1a: 40 mg BID Lunresertib Continue + 800 mg/m2 Gemcitabine 40 mg BID oral (PO) lunresertib continuously daily in combination with 800 mg/m2 intravenous (IV) gemcitabine given over 30 minutes on Day 1 and 8 of each 21-day treatment cycle | 4 |
| Module 1a: 40 mg BID Lunresertib Continue + 600 mg/m2 Gemcitabine 40 mg BID oral (PO) lunresertib continuously daily in combination with 600 mg/m2 intravenous (IV) gemcitabine given over 30 minutes on Day 1 and 8 of each 21-day treatment cycle | 10 |
| Module 1a: 40 mg BID Lunresertib Continue + 400 mg/m2 Gemcitabine 40 mg BID oral (PO) lunresertib continuously daily in combination with 400 mg/m2 intravenous (IV) gemcitabine given over 30 minutes on Day 1 and 8 of each 21-day treatment cycle | 8 |
| Module 1b: 120 mg QD Lunresertib 3 Days on/4 Days Off + 800 mg/m2 Gemcitabine 120 mg QD oral (PO) lunresertib for the first 3 day per week ( 3 days on/4 days off) in combination with 800 mg/m2 intravenous (IV) gemcitabine given over 30 minutes on Day 1 and 8 of each 21-day treatment cycle | 5 |
| Module 1b: 120 mg QD Lunresertib 3 Days on/4 Days Off + 600 mg/m2 Gemcitabine 120 mg QD oral (PO) lunresertib for the first 3 day per week ( 3 days on/4 days off) in combination with 600 mg/m2 intravenous (IV) gemcitabine given over 30 minutes on Day 1 and 8 of each 21-day treatment cycle | 5 |
| Module 1b: 40 mg BID Lunresertib 3 Days on/4 Days Off + 800 mg/m2 Gemcitabine 40 mg BID oral (PO) lunresertib for the first 3 day per week ( 3 days on/4 days off) in combination with 800 mg/m2 intravenous (IV) gemcitabine given over 30 minutes on Day 1 and 8 of each 21-day treatment cycle | 4 |
| Module 1b: 60 mg BID Lunresertib 3 Days on/4 Days Off + 600 mg/m2 Gemcitabine 60 mg BID oral (PO) lunresertib for the first 3 day per week ( 3 days on/4 days off) in combination with 600 mg/m2 intravenous (IV) gemcitabine given over 30 minutes on Day 1 and 8 of each 21-day treatment cycle | 4 |
| Module 1b: 60 mg BID Lunresertib 3 Days on/4 Days Off + 400 mg/m2 Gemcitabine Day 60 mg BID oral (PO) lunresertib for the first 3 day per week ( 3 days on/4 days off) in combination with 400 mg/m2 intravenous (IV) gemcitabine given over 30 minutes on Day 1 and 8 of each 21-day treatment cycle | 6 |
| Module 1b: 80 mg BID Lunresertib 3 Days on/4 Days Off + 800 mg/m2 Gemcitabine Day 1 and 8 80 mg BID oral (PO) lunresertib for the first 3 day per week ( 3 days on/4 days off) in combination with 800 mg/m2 intravenous (IV) gemcitabine given over 30 minutes on Day 1 and 8 of each 21-day treatment cycle | 4 |
| Module 1b: 80 mg BID Lunresertib 3 Days on/4 Days Off + 600 mg/m2 Gemcitabine Day 1 and 8 80 mg BID oral (PO) lunresertib for the first 3 day per week ( 3 days on/4 days off) in combination with 600 mg/m2 intravenous (IV) gemcitabine given over 30 minutes on Day 1 and 8 of each 21-day treatment cycle | 3 |
| Module 1b: 120 mg BID Lunresertib 3 Days on/4 Days Off + 800 mg/m2 Gemcitabine Day 1 and 8 120 mg BID oral (PO) lunresertib for the first 3 day per week ( 3 days on/4 days off) in combination with 800 mg/m2 intravenous (IV) gemcitabine given over 30 minutes on Day 1 and 8 of each 21-day treatment cycle | 2 |
| Total | 67 |
Baseline characteristics
| Characteristic | Module 1a: 40 mg QD Lunresertib Continue + 800 mg/m2 Gemcitabine | Module 1a: 80 mg QD Lunresertib Continue + 800 mg/m2 Gemcitabine | Module 1a: 80 mg QD Lunresertib Continue + 600 mg/m2 Gemcitabine | Module 1a: 40 mg BID Lunresertib Continue + 800 mg/m2 Gemcitabine | Module 1a: 40 mg BID Lunresertib Continue + 600 mg/m2 Gemcitabine | Module 1a: 40 mg BID Lunresertib Continue + 400 mg/m2 Gemcitabine | Module 1b: 120 mg QD Lunresertib 3 Days on/4 Days Off + 800 mg/m2 Gemcitabine | Module 1b: 120 mg QD Lunresertib 3 Days on/4 Days Off + 600 mg/m2 Gemcitabine | Module 1b: 40 mg BID Lunresertib 3 Days on/4 Days Off + 800 mg/m2 Gemcitabine | Module 1b: 60 mg BID Lunresertib 3 Days on/4 Days Off + 600 mg/m2 Gemcitabine | Module 1b: 60 mg BID Lunresertib 3 Days on/4 Days Off + 400 mg/m2 Gemcitabine Day | Module 1b: 80 mg BID Lunresertib 3 Days on/4 Days Off + 800 mg/m2 Gemcitabine Day 1 and 8 | Module 1b: 80 mg BID Lunresertib 3 Days on/4 Days Off + 600 mg/m2 Gemcitabine Day 1 and 8 | Module 1b: 120 mg BID Lunresertib 3 Days on/4 Days Off + 800 mg/m2 Gemcitabine Day 1 and 8 | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Customized Age (years) | 66 years STANDARD_DEVIATION 0 | 59.1 years STANDARD_DEVIATION 8.53 | 71.0 years STANDARD_DEVIATION 4.69 | 61 years STANDARD_DEVIATION 10.85 | 61.4 years STANDARD_DEVIATION 12.58 | 62.1 years STANDARD_DEVIATION 10.69 | 62.4 years STANDARD_DEVIATION 10.64 | 58.6 years STANDARD_DEVIATION 6.73 | 66.0 years STANDARD_DEVIATION 10.86 | 65.3 years STANDARD_DEVIATION 5.19 | 62.5 years STANDARD_DEVIATION 10.72 | 54.8 years STANDARD_DEVIATION 4.58 | 75.0 years STANDARD_DEVIATION 0.71 | 67.5 years STANDARD_DEVIATION 9.59 | 62.6 years STANDARD_DEVIATION 10.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants | 6 Participants | 4 Participants | 4 Participants | 10 Participants | 7 Participants | 5 Participants | 3 Participants | 2 Participants | 3 Participants | 5 Participants | 4 Participants | 3 Participants | 2 Participants | 59 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 6 Participants |
| Sex: Female, Male Female | 1 Participants | 7 Participants | 3 Participants | 3 Participants | 8 Participants | 8 Participants | 5 Participants | 5 Participants | 3 Participants | 4 Participants | 3 Participants | 2 Participants | 3 Participants | 2 Participants | 57 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 3 Participants | 2 Participants | 0 Participants | 0 Participants | 10 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 | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 1 | 5 / 7 | 3 / 4 | 4 / 4 | 2 / 10 | 3 / 8 | 4 / 5 | 1 / 5 | 3 / 4 | 1 / 4 | 2 / 6 | 2 / 4 | 1 / 3 | 1 / 2 |
| other Total, other adverse events | 1 / 1 | 7 / 7 | 4 / 4 | 4 / 4 | 10 / 10 | 8 / 8 | 5 / 5 | 5 / 5 | 4 / 4 | 4 / 4 | 6 / 6 | 4 / 4 | 3 / 3 | 2 / 2 |
| serious Total, serious adverse events | 1 / 1 | 3 / 7 | 2 / 4 | 1 / 4 | 5 / 10 | 3 / 8 | 1 / 5 | 1 / 5 | 2 / 4 | 2 / 4 | 2 / 6 | 2 / 4 | 1 / 3 | 1 / 2 |
Outcome results
Primary
Number of Dose Limiting Toxicities, as Defined Per Protocol, That Occur During the First Cycle (21 Days) of Treatment at Each Dose Level
Evaluation of dose-limiting toxicities (DLTs) at or below a frequency of 25%
Time frame: During 21 days from the initiation of the study treatment (C1D1)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Module 1a: 40 mg QD Lunresertib Continue + 800 mg/m2 Gemcitabine | Number of Dose Limiting Toxicities, as Defined Per Protocol, That Occur During the First Cycle (21 Days) of Treatment at Each Dose Level | 0 Participants |
| Module 1a: 80 mg QD Lunresertib Continue + 800 mg/m2 Gemcitabine | Number of Dose Limiting Toxicities, as Defined Per Protocol, That Occur During the First Cycle (21 Days) of Treatment at Each Dose Level | 2 Participants |
| Module 1a: 80 mg QD Lunresertib Continue + 600 mg/m2 Gemcitabine | Number of Dose Limiting Toxicities, as Defined Per Protocol, That Occur During the First Cycle (21 Days) of Treatment at Each Dose Level | 2 Participants |
| Module 1a: 40 mg BID Lunresertib Continue + 800 mg/m2 Gemcitabine | Number of Dose Limiting Toxicities, as Defined Per Protocol, That Occur During the First Cycle (21 Days) of Treatment at Each Dose Level | 2 Participants |
| Module 1a: 40 mg BID Lunresertib Continue + 600 mg/m2 Gemcitabine | Number of Dose Limiting Toxicities, as Defined Per Protocol, That Occur During the First Cycle (21 Days) of Treatment at Each Dose Level | 4 Participants |
| Module 1a: 40 mg BID Lunresertib Continue + 400 mg/m2 Gemcitabine | Number of Dose Limiting Toxicities, as Defined Per Protocol, That Occur During the First Cycle (21 Days) of Treatment at Each Dose Level | 4 Participants |
| Module 1b: 120 mg QD Lunresertib 3 Days on/4 Days Off + 800 mg/m2 Gemcitabine | Number of Dose Limiting Toxicities, as Defined Per Protocol, That Occur During the First Cycle (21 Days) of Treatment at Each Dose Level | 2 Participants |
| Module 1b: 120 mg QD Lunresertib 3 Days on/4 Days Off + 600 mg/m2 Gemcitabine | Number of Dose Limiting Toxicities, as Defined Per Protocol, That Occur During the First Cycle (21 Days) of Treatment at Each Dose Level | 3 Participants |
| Module 1b: 40 mg BID Lunresertib 3 Days on/4 Days Off + 800 mg/m2 Gemcitabine | Number of Dose Limiting Toxicities, as Defined Per Protocol, That Occur During the First Cycle (21 Days) of Treatment at Each Dose Level | 0 Participants |
| Module 1b: 60 mg BID Lunresertib 3 Days on/4 Days Off + 600 mg/m2 Gemcitabine | Number of Dose Limiting Toxicities, as Defined Per Protocol, That Occur During the First Cycle (21 Days) of Treatment at Each Dose Level | 1 Participants |
| Module 1b: 60 mg BID Lunresertib 3 Days on/4 Days Off + 400 mg/m2 Gemcitabine Day | Number of Dose Limiting Toxicities, as Defined Per Protocol, That Occur During the First Cycle (21 Days) of Treatment at Each Dose Level | 2 Participants |
| Module 1b: 80 mg BID Lunresertib 3 Days on/4 Days Off + 800 mg/m2 Gemcitabine Day 1 and 8 | Number of Dose Limiting Toxicities, as Defined Per Protocol, That Occur During the First Cycle (21 Days) of Treatment at Each Dose Level | 1 Participants |
| Module 1b: 80 mg BID Lunresertib 3 Days on/4 Days Off + 600 mg/m2 Gemcitabine Day 1 and 8 | Number of Dose Limiting Toxicities, as Defined Per Protocol, That Occur During the First Cycle (21 Days) of Treatment at Each Dose Level | 3 Participants |
| Module 1b: 120 mg BID Lunresertib 3 Days on/4 Days Off + 800 mg/m2 Gemcitabine Day 1 and 8 | Number of Dose Limiting Toxicities, as Defined Per Protocol, That Occur During the First Cycle (21 Days) of Treatment at Each Dose Level | 2 Participants |
Primary
Number of Patients With of Treatment-related Adverse Event Data Per CTCAE v5.0 Criteria to Determine Safety and Tolerability of RP-6306 in Combination With Gemcitabine.
Incidence of grade 3 and above Treatment Related Emergent Adverse Events (TRAEs)
Time frame: Start of treatment to 30 days post last dose. up to 1.5 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Module 1a: 40 mg QD Lunresertib Continue + 800 mg/m2 Gemcitabine | Number of Patients With of Treatment-related Adverse Event Data Per CTCAE v5.0 Criteria to Determine Safety and Tolerability of RP-6306 in Combination With Gemcitabine. | 0 Participants |
| Module 1a: 80 mg QD Lunresertib Continue + 800 mg/m2 Gemcitabine | Number of Patients With of Treatment-related Adverse Event Data Per CTCAE v5.0 Criteria to Determine Safety and Tolerability of RP-6306 in Combination With Gemcitabine. | 3 Participants |
| Module 1a: 80 mg QD Lunresertib Continue + 600 mg/m2 Gemcitabine | Number of Patients With of Treatment-related Adverse Event Data Per CTCAE v5.0 Criteria to Determine Safety and Tolerability of RP-6306 in Combination With Gemcitabine. | 3 Participants |
| Module 1a: 40 mg BID Lunresertib Continue + 800 mg/m2 Gemcitabine | Number of Patients With of Treatment-related Adverse Event Data Per CTCAE v5.0 Criteria to Determine Safety and Tolerability of RP-6306 in Combination With Gemcitabine. | 4 Participants |
| Module 1a: 40 mg BID Lunresertib Continue + 600 mg/m2 Gemcitabine | Number of Patients With of Treatment-related Adverse Event Data Per CTCAE v5.0 Criteria to Determine Safety and Tolerability of RP-6306 in Combination With Gemcitabine. | 8 Participants |
| Module 1a: 40 mg BID Lunresertib Continue + 400 mg/m2 Gemcitabine | Number of Patients With of Treatment-related Adverse Event Data Per CTCAE v5.0 Criteria to Determine Safety and Tolerability of RP-6306 in Combination With Gemcitabine. | 7 Participants |
| Module 1b: 120 mg QD Lunresertib 3 Days on/4 Days Off + 800 mg/m2 Gemcitabine | Number of Patients With of Treatment-related Adverse Event Data Per CTCAE v5.0 Criteria to Determine Safety and Tolerability of RP-6306 in Combination With Gemcitabine. | 5 Participants |
| Module 1b: 120 mg QD Lunresertib 3 Days on/4 Days Off + 600 mg/m2 Gemcitabine | Number of Patients With of Treatment-related Adverse Event Data Per CTCAE v5.0 Criteria to Determine Safety and Tolerability of RP-6306 in Combination With Gemcitabine. | 5 Participants |
| Module 1b: 40 mg BID Lunresertib 3 Days on/4 Days Off + 800 mg/m2 Gemcitabine | Number of Patients With of Treatment-related Adverse Event Data Per CTCAE v5.0 Criteria to Determine Safety and Tolerability of RP-6306 in Combination With Gemcitabine. | 1 Participants |
| Module 1b: 60 mg BID Lunresertib 3 Days on/4 Days Off + 600 mg/m2 Gemcitabine | Number of Patients With of Treatment-related Adverse Event Data Per CTCAE v5.0 Criteria to Determine Safety and Tolerability of RP-6306 in Combination With Gemcitabine. | 3 Participants |
| Module 1b: 60 mg BID Lunresertib 3 Days on/4 Days Off + 400 mg/m2 Gemcitabine Day | Number of Patients With of Treatment-related Adverse Event Data Per CTCAE v5.0 Criteria to Determine Safety and Tolerability of RP-6306 in Combination With Gemcitabine. | 4 Participants |
| Module 1b: 80 mg BID Lunresertib 3 Days on/4 Days Off + 800 mg/m2 Gemcitabine Day 1 and 8 | Number of Patients With of Treatment-related Adverse Event Data Per CTCAE v5.0 Criteria to Determine Safety and Tolerability of RP-6306 in Combination With Gemcitabine. | 1 Participants |
| Module 1b: 80 mg BID Lunresertib 3 Days on/4 Days Off + 600 mg/m2 Gemcitabine Day 1 and 8 | Number of Patients With of Treatment-related Adverse Event Data Per CTCAE v5.0 Criteria to Determine Safety and Tolerability of RP-6306 in Combination With Gemcitabine. | 3 Participants |
| Module 1b: 120 mg BID Lunresertib 3 Days on/4 Days Off + 800 mg/m2 Gemcitabine Day 1 and 8 | Number of Patients With of Treatment-related Adverse Event Data Per CTCAE v5.0 Criteria to Determine Safety and Tolerability of RP-6306 in Combination With Gemcitabine. | 2 Participants |