Advanced Solid Tumor
Conditions
Brief summary
The primary objective of this study is to identify a safe and tolerated dose and schedule of the orally administered PLK4 inhibitor RP-1664. In addition, this study will examine the pharmacokinetics (PK), pharmacodynamics (PD) and preliminary anti-tumor activity of RP-1664 in advanced solid tumors.
Detailed description
This is a first-in-human, Phase 1, multi-center, open-label, dose-escalation and expansion study to: Evaluate the safety profile and MTD of RP-1664 and establish a recommended dose and schedule for further clinical investigation, In addition, the study aims to characterize the PK, PD, and preliminary anti-tumor activity of orally administered RP-1664. Exploratory objectives include examination of biomarker responses in relationship to RP-1664 exposure. After the recommended dose and schedule is determined, expansion cohorts with molecularly selected advanced solid tumors will be enrolled to preliminarily assess the anti-tumor effect, and further examine the safety and PK of RP-1664 at the RP2D.
Interventions
DRUGRP-1664
RP-1664 will be supplied as immediate-release solid dosage form for oral self-administration.
Sponsors
Repare Therapeutics
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
* Written informed consent or assent, 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 ≥ 12 years-of-age at the time of signature of the consent or assent, and are at least 6th grade reading level to consent; participants \< 18 years of age must weigh at least 40 kg. * Life expectancy ≥ 4 months. * Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1. * Locally advanced or metastatic solid tumor that has progressed or was nonresponsive or intolerant to available therapies and for which no standard or available curative therapy exists. * Measurable disease as per RECIST v1.1 or INRC. * Existing biomarker profile (tumor tissue or plasma) reported from a local test obtained in a CLIA-certified or equivalent laboratory demonstrating eligible tumor biomarkers. * Available tumor tissue. * Molecularly eligible tumor profile from a CLIA-certified pathology report. * 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 while on study drug. * Resolution of all toxicities of prior treatment or surgery. * Use of highly effective forms of contraception.
Exclusion criteria
* 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. * 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. * Presence of other known second malignancy with the exception of any cancer that has been in complete remission for ≥ 2 years or completely resected squamous and basal cell carcinomas of the skin. * 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. * Clinically significant vascular (both arterial and venous) and non-vascular cardiac conditions, active or within 6 months prior to enrollment. * Moderate or severe hepatic impairment (ie, Child-Pugh class B or C). * Uncontrolled high blood pressure. * Chemotherapy, small molecule or biologic antineoplastic agent given within 21 days. * Previously prescribed receptor activator of nuclear factor kappa B ligand (RANKL) inhibitor initiated less than 4 months prior to trial entry. Bisphosphonates are allowed if initiated/administered at least 28 days prior to enrollment. * I-131 Meta-Iodo-Benzyl-Guanidine (MIGB) therapy within 6 weeks prior to initiation of trial treatment. * Prior treatment with a PLK4 inhibitor. * Current treatment with medications that are known to prolong the QT interval.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Treatment Related Treatment-Emergent Adverse Events (TRAE) With ≥3 CTCAE Grade | Start of treatment through up to 6 months post last dose (up to 18 months) | Number of participants with TRAE |
| Dose Limiting Toxicities (DLT) to Determine a Maximum Tolerated Dose and Schedule of RP-1664 Based on Safety and Tolerability | During the first cycle (either 21 or 28 days) following the initiation of the study treatment | The number of participants with DLTs during the DLT observation period |
Countries
Denmark, United States
Participant flow
Recruitment details
Dose Escalation phase only; Dose expansion was not conducted
Participants by arm
| Arm | Count |
|---|---|
| 10 mg QD RP-1664, 2w on/1w Off 10 mg QD oral (PO) RP-1664 daily, on a 2 weeks on and 1 week of schedule (21-day treatment cycle) | 1 |
| 30 mg QD RP-1664, 2w on/1w Off 30 mg QD oral (PO) RP-1664 daily, on a 2 weeks on and 1 week of schedule (21-day treatment cycle) | 1 |
| 40 mg QD RP-1664, 2w on/1w Off 40 mg QD oral (PO) RP-1664 daily, on a 2 weeks on and 1 week of schedule (21-day treatment cycle) | 4 |
| 60 mg QD RP-1664, 2w on/1w Off 60 mg QD oral (PO) RP-1664 daily, on a 2 weeks on and 1 week of schedule (21-day treatment cycle) | 3 |
| 60 mg QD RP-1664, 1w on/1w Off 60 mg QD oral (PO) RP-1664 daily, on a 1 week on and 1 week of schedule (28-day treatment cycle) | 16 |
| 90 mg QD RP-1664, 1w on/1w Off 90 mg QD oral (PO) RP-1664 daily, on a 1 week on and 1 week of schedule (28-day treatment cycle) | 4 |
| Total | 29 |
Baseline characteristics
| Characteristic | 10 mg QD RP-1664, 2w on/1w Off | 30 mg QD RP-1664, 2w on/1w Off | 40 mg QD RP-1664, 2w on/1w Off | 60 mg QD RP-1664, 2w on/1w Off | 60 mg QD RP-1664, 1w on/1w Off | 90 mg QD RP-1664, 1w on/1w Off | Total |
|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 2 Participants | 0 Participants | 4 Participants |
| Age, Categorical >=65 years | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 5 Participants | 1 Participants | 9 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 1 Participants | 1 Participants | 2 Participants | 9 Participants | 3 Participants | 16 Participants |
| Age, Continuous | 84 years STANDARD_DEVIATION 0 | 53 years STANDARD_DEVIATION 0 | 33.3 years STANDARD_DEVIATION 28.34 | 61.7 years STANDARD_DEVIATION 14.01 | 45.4 years STANDARD_DEVIATION 20.71 | 54.5 years STANDARD_DEVIATION 14.2 | 48.3 years STANDARD_DEVIATION 21.43 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants | 1 Participants | 4 Participants | 3 Participants | 16 Participants | 4 Participants | 29 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 1 Participants | 3 Participants | 12 Participants | 3 Participants | 19 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 3 Participants | 0 Participants | 4 Participants | 1 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 |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 1 | 0 / 1 | 0 / 4 | 1 / 3 | 2 / 16 | 1 / 4 | 4 / 29 |
| other Total, other adverse events | 1 / 1 | 1 / 1 | 4 / 4 | 3 / 3 | 15 / 16 | 4 / 4 | 28 / 29 |
| serious Total, serious adverse events | 0 / 1 | 0 / 1 | 1 / 4 | 3 / 3 | 5 / 16 | 3 / 4 | 12 / 29 |
Outcome results
Primary
Dose Limiting Toxicities (DLT) to Determine a Maximum Tolerated Dose and Schedule of RP-1664 Based on Safety and Tolerability
The number of participants with DLTs during the DLT observation period
Time frame: During the first cycle (either 21 or 28 days) following the initiation of the study treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 10 mg QD RP-1664, 2w on/1w Off | Dose Limiting Toxicities (DLT) to Determine a Maximum Tolerated Dose and Schedule of RP-1664 Based on Safety and Tolerability | 0 Participants |
| 30 mg QD RP-1664, 2w on/1w Off | Dose Limiting Toxicities (DLT) to Determine a Maximum Tolerated Dose and Schedule of RP-1664 Based on Safety and Tolerability | 0 Participants |
| 40 mg QD RP-1664, 2w on/1w Off | Dose Limiting Toxicities (DLT) to Determine a Maximum Tolerated Dose and Schedule of RP-1664 Based on Safety and Tolerability | 0 Participants |
| 60 mg QD RP-1664, 2w on/1w Off | Dose Limiting Toxicities (DLT) to Determine a Maximum Tolerated Dose and Schedule of RP-1664 Based on Safety and Tolerability | 2 Participants |
| 60 mg QD RP-1664, 1w on/1w Off | Dose Limiting Toxicities (DLT) to Determine a Maximum Tolerated Dose and Schedule of RP-1664 Based on Safety and Tolerability | 0 Participants |
| 90 mg QD RP-1664, 1w on/1w Off | Dose Limiting Toxicities (DLT) to Determine a Maximum Tolerated Dose and Schedule of RP-1664 Based on Safety and Tolerability | 1 Participants |
Primary
Treatment Related Treatment-Emergent Adverse Events (TRAE) With ≥3 CTCAE Grade
Number of participants with TRAE
Time frame: Start of treatment through up to 6 months post last dose (up to 18 months)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 10 mg QD RP-1664, 2w on/1w Off | Treatment Related Treatment-Emergent Adverse Events (TRAE) With ≥3 CTCAE Grade | 1 Participants |
| 30 mg QD RP-1664, 2w on/1w Off | Treatment Related Treatment-Emergent Adverse Events (TRAE) With ≥3 CTCAE Grade | 0 Participants |
| 40 mg QD RP-1664, 2w on/1w Off | Treatment Related Treatment-Emergent Adverse Events (TRAE) With ≥3 CTCAE Grade | 3 Participants |
| 60 mg QD RP-1664, 2w on/1w Off | Treatment Related Treatment-Emergent Adverse Events (TRAE) With ≥3 CTCAE Grade | 3 Participants |
| 60 mg QD RP-1664, 1w on/1w Off | Treatment Related Treatment-Emergent Adverse Events (TRAE) With ≥3 CTCAE Grade | 9 Participants |
| 90 mg QD RP-1664, 1w on/1w Off | Treatment Related Treatment-Emergent Adverse Events (TRAE) With ≥3 CTCAE Grade | 3 Participants |