Advanced solid tumors with CCNE1 amplification or deleterious mutations in FBXW7 or other proprietary gene MedDRA version: 21.1 Level: LLT Classification code 10065252 Term: Solid tumor System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Product Name: RP-6306
Product Code: RP-6306
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Not assigned yet
CAS Number: Not assigned
Current Sponsor code: RP-6306
Other descriptive name: D199
Sponsors
Repare Therapeutics
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Written informed consent and assent, according to local guidelines, signed and dated by the participating patient or legal guardian prior to the performance of any study-specific procedures, sampling, or analyses. 2. Male or female and =12 years-of-age at the time of signature of the informed consent form (ICF). 3. Lansky performance status =50 for patients =16 years of age, or ECOG score of 0, 1, or 2 (Module 2 ECOG 0 or 1) for patients >16 years of age. 4. All patients must have locally advanced or metastatic resistant or refractory solid tumors. Patients <18 years-of-age will be eligible only if standard or available curative therapy does not exist. Patients =18 years-of-age are eligible if, in the opinion of the investigator, the patient is not a candidate for, or would be unlikely to tolerate or derive significant clinical benefit from, appropriate standard-of-care therapy, or if the patient declines standard-of-care therapy. 5. Patients <18 years of age must weigh at least 40 kg. 6. Archived tumor tissue sample available or lesion that can be safely biopsied if the archival sample is not available. 7. All patient’s tumors, except for types of endometrial cancer listed in criteria #8, must have evidence of at least one of the following as reported by a local CLIA-certified or equivalent (ex-United States [US]) laboratory and centrally confirmed by PODS: a. CCNE1 amplification (non-equivocal) as determined by either a tumor or plasma NGS test, or FISH b. FBXW7 deleterious mutations identified by either a tumor or plasma NGS test c. Proprietary gene deleterious mutations identified by either a tumor or plasma NGS test d. For backfill cohorts, tumors with other genes with mechanistic rationale agreed upon between the Sponsor and Investigator will be accepted. 8. The following types of endometrial cancer are eligible (for Module 1 only): a. Serous endometrial cancer (p53 IHC must be confirmed to be aberrant or local NGS report confirming TP53 loss of function mutation must be provided) b. Carcinosarcoma of the endometrium c. Grade 3 endometrioid and undifferentiated carcinoma (p53 IHC must be confirmed to be aberrant or local NGS report confirming TP53 loss of function mutation must be provided; MMR IHC must be retained and/or tumor must be MSS; polymerase epsilon (POLE) hypermutated type must be excluded) 9. Measurable disease as per RECIST v1.1. 10. Ability to comply with the protocol and study procedures detailed in the Schedule of Assessments. 11. Ability to swallow and retain oral medications. 12. Acceptable organ function at Screening, as evidenced by the following laboratory data: a. Serum creatinine =1.5 × ULN or calculated creatinine clearance =60 mL/min using the Cockcroft-Gault equation or by 24-hour urine collection b. Total bilirubin =1.5 × ULN or <3.0 × ULN if known Gilbert’s disease c. Serum albumin =2.5 g/dL d. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =3.0 × ULN 13. Acceptable hematologic function at Screening: a. No red blood cell (RBC) or platelet transfusions or growth factors within 7 days of the first dose of RP-6306 b. Hemoglobin =9.0 g/dL (or =10.0 g/dL for Module 2 only) c. ANC =1500 cells/mm3 d. Platelet count =100,000 cells/mm3 14. Negative pregnancy test (serum) for women of childbearing potential at Screening. 15. Male patients with female partners of childbearing potential must follow a contraception method (oral contraceptives allowed) during their participation in the study
Exclusion criteria
Exclusion criteria: 1. Chemotherapy or small molecule antineoplastic agent given within 21 days or <5 half-lives, whichever is shorter, prior to first dose of study drug. For drugs for which 5 half-lives is =21 days, a minimum of 10 days between termination of the prior treatment and administration of RP-6306 treatment is required. For patients with breast or prostate cancer, continuation of long-term luteinizing hormone-releasing hormone (LHRH), gonadotrophin releasing hormone (GnRH), or previously prescribed Receptor Activator of Nuclear Factor kB Ligand (RANKL) inhibitor are allowed if these medications were prescribed for at least 3 months before trial entry. Bisphosphonates are allowed if prescribed at least 28 days prior to enrollment. 2. 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. 3. Patients who are pregnant or breastfeeding. 4. Known sensitivity to any of the ingredients of RP-6306 (and RP-3500 for Module 2). 5. Patient who are unable to swallow oral medications. 6. Life-threatening illness, medical condition, active uncontrolled infection, or organ system dysfunction (such as ascites requiring drainage within 4 weeks prior to enrollment, coagulopathy, or encephalopathy), or other reasons which, in the investigator’s opinion, could compromise the participating patient’s safety, or interfere with or compromise the integrity of the study outcomes. 7. Major surgery (excluding placement of vascular access) within 4 weeks prior to first dose of RP-6306. 8. Uncontrolled, symptomatic brain metastases. Patients with previously treated brain metastases may participate provided the metastases are stable (without evidence of progression by imaging for at least 4 weeks prior to the first dose of study drug and any neurologic symptoms are controlled and stable), have no evidence of new or enlarged brain metastases, and are clinically stable and off steroids for at least 7 days prior to study drug. 9. Uncontrolled hypertension (systolic blood pressure [BP] =160 mmHg; diastolic BP =100 mmHg) despite adequate treatment prior to first dose of RP-6306 (and RP-3500 for Module 2). 10. 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. In equivocal cases, patients whose viral load is negative, may be eligible. HIV seropositive patients who are healthy and low risk for AIDSrelated outcomes could be considered eligible. Eligibility criteria for HIV positive patients should be evaluated and discussed with the sponsor’s medical monitor and will be based on current and past CD4 and T-cell counts, history (if any) of AIDS defining conditions (e.g., opportunistic infections), and status of HIV treatment 11. Moderate or severe hepatic impairment (i.e., Child-Pugh class B or C). 12. Any of the following cardiac diseases currently or within the last 6 months as defined by New York Heart Association (NYHA) =Class 2: a. Unstable angina pectoris b. Congestive heart failure c. Acute myocardial infarction d. Conduction abnormality not controlled with pacemaker or medication e. Significant ventricular or supraventricular arrhythmias (patients with chronic rate-controlled atrial fibrillation in the absence
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Module 1: • Assess the safety and tolerability of RP-6306 in patients with eligible advanced solid tumors • Define the maximum tolerated dose (MTD) of RP- 6306 monotherapy, and determine a recommended Phase 2 dose (RP2D) and preferred schedule Module 2: • Assess the safety and tolerability of RP-6306 in combination with RP-3500 in patients with molecularly selected, advanced solid tumors • Define the maximum tolerated dose (MTD) of RP-6306 in combination with RP-3500, and determine a recommended Phase 2 dose (RP2D) and preferred schedule ;Secondary Objective: Module 1: • Assess pharmacokinetic (PK) parameters of RP- 6306 monotherapy in fasted and fed states • Assess the relationship between pharmacodynamic biomarkers and PK of RP-6306 at different dose levels and/or schedules • Assess preliminary anti-tumor activity achieved with RP-6306 monotherapy in patients with each of the molecular subsets of advanced solid tumors: harboring either CCNE1 amplification or deleterious mutations in F-box and WD repeat domain containing 7 (FBXW7) or other proprietary gene Module 2: • Assess pharmacokinetic (PK) parameters of RP-6306 and RP-3500 when dosed in combination • Assess preliminary anti-tumor activity achieved with RP-6306 in combination with RP-3500 in patients with advanced solid tumors harboring CCNE1 amplification, FBXW7 or proprietary gene deleterious mutations, or other genomic alterations with mechanistic rationale as agreed upon by the Sponsor and Investigator;Primary end point(s): • Treatment-emergent adverse events (TEAEs), physical examinations (PEs), safety laboratory assessments, electrocardiograms (ECGs), and vital sign measurements • Dose-limiting toxicities (DLTs) ;Timepoint(s) of evaluation of this end point: Throughout the trial | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Module 1: • Plasma concentrations of RP-6306) with calculation of maximum observed plasma concentration (Cmax), time to maximum observed plasma concentration (Tmax), minimum observed plasma concentration (Cmin), area under the plasma concentration-time curve (AUC), elimination t1/2, and other parameters as appropriate. • Assessment of biomarkers (e.g., g-H2AX, p-CDK1 Thr14) in pre- and on-treatment biopsies, and circulating tumor DNA (ctDNA) dynamics during treatment. • Best percent change in tumor size from baseline, objective response rate (ORR), tumor marker response, duration of response (DOR), clinical benefit rate (CBR), available progression-free survival (PFS), and overall survival (OS) data Module 2: • Plasma concentrations of RP-6306 and RP-3500 with calculation of maximum observed plasma concentration (Cmax), time to maximum observed plasma concentration (Tmax), minimum observed plasma concentration (Cmin), area under the plasma concentration-time curve (AUC), elimination t1/2, and other parameters as appropriate. • Best percent change in tumor size from baseline, ORR, DOR, CBR, tumor marker response; PFS, and OS data ;Timepoint(s) of evaluation of this end point: Throughout the trial | — |
Countries
Canada, Denmark, United States
Contacts
Public ContactClinical Operations
Repare Therapeutics
Outcome results
None listed