RP-6306 in Patients With Advanced Cancer

A Phase II Study of RP-6306 in Patients With Advanced Cancer

This study is being done to answer the following questions:

• Is the new drug, RP-6306, safe to use, and what effects does it have on cancer when given with standard treatment?
• If there are specific biomarkers, do patients have an improved response to treatment compared to those without the biomarker?

This study is being done to find out if this approach is better or worse than the usual approach for this type of cancer. The usual approach is defined as care most people get for this type of cancer.

Study Overview

• Status: Recruiting
• Conditions: Advanced Cancer
• Intervention / Treatment: Drug: RP-6306; Drug: Gemcitabine; Drug: FOLFIRI Protocol; Drug: Trastuzumab

Detailed Description

RP-6306 is a PKMYT1 inhibitor. PKMYT1 protein kinase negatively regulates CDK1 via phosphorylation of threonine 14 (Thr14) and sequestration in the cytoplasm. RP-6306 has shown single-agent anti-tumour efficacy in several xenograft models with amplified CCNE1 in a dose-dependent manner. RP-6306 has synergistic effects in combination with gemcitabine in CCNE1-amplified/overexpressing models in vitro and in vivo

• Study Type: Interventional
• Enrollment (Estimated): 78
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Lesley Seymour; Phone Number: 613-533-6430; Email: lseymour@ctg.queensu.ca

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 4E6
      • Recruiting
      • BCCA - Vancouver Cancer Centre
      • Contact: Yvette Drew; Phone Number: 4831 604 877-6000
  • Ontario
    • Kingston, Ontario, Canada, K7L 2V7
      • Recruiting
      • Kingston Health Sciences Centre
      • Contact: Andrew Robinson; Phone Number: 8104 613 549-6666
    • London, Ontario, Canada, N6A 5W9
      • Recruiting
      • London Regional Cancer Program
      • Contact: Stephen Welch; Phone Number: 519 685-8640
    • Ottawa, Ontario, Canada, K1H 8L6
      • Recruiting
      • Ottawa Hospital Research Institute
      • Contact: Moira Rushton
    • Toronto, Ontario, Canada, M5G 2M9
      • Recruiting
      • University Health Network
      • Contact: Stephanie Lheureux; Phone Number: 2415 416 946-4501

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients must have histologically confirmed cancer, that is advanced/metastatic/recurrent or unresectable, for which no curative therapy exists, and be eligible for one or more of the open cohorts
• All patients must have a formalin fixed paraffin embedded tissue block (from primary or metastatic tumour) available and must have provided informed consent for the release of the block
• Presence of clinically and/or radiologically documented disease. All radiology studies must be performed within 21 days prior to enrollment
• Patients must be ≥ 18 years of age
• Patients must have an ECOG performance status of 0 or 1
• Patients must have a life expectancy of 3 months or longer
• Abs neutrophils ≥ 1.5 x 10^9/L; Platelets ≥ 100 x 10^9/L
• Bilirubin ≤ 1.5 x UNL; AST ≤2.5 x UNL; ALT ≤ 5.0 x UNL; Serum creatinine ≤ 1.5 x UNL; Creatinine clearance ≥ 50 mL/min
• Patients must be able to swallow oral medications and have no known gastrointestinal disorders that may interfere with absorption (such as malabsorption)
• Patients must have had recovered (to at least grade 0 or 1) from all reversible toxicity related to prior chemotherapy or systemic therapy and have adequate washout longest of one of the following: two weeks; 5 half-lives for investigational agents; standard cycle length of standard therapies.
• Prior external beam radiation is permitted provided a minimum of 28 days (4 weeks) have elapsed between the last dose of radiation and date of enrollment. Exceptions may be made for low-dose, non-myelosuppressive radiotherapy after consultation with CCTG. Concurrent radiotherapy is not permitted
• Previous surgery is permitted provided that a minimum of 21 days (3 weeks) have elapsed between any major surgery and date of enrollment, and that wound healing has occurred
• Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each patient must sign a consent form prior to screening (if applicable)/enrollment in the trial to document their willingness to participate
• Protocol treatment is to begin within 2 working days of patient enrollment
• Patients must be accessible for treatment and follow-up. Patients enrolled on this trial must be treated and followed at the participating centre
• Women/men of childbearing potential must have agreed to use a highly effective contraceptive method.

Cohort-Specific Eligibility Criteria

Cohort A: Endometrial Cancer

• Patients must have histologically confirmed diagnosis of high-grade serous endometrial cancer, that is advanced/metastatic/recurrent or unresectable, for which no curative therapy exists.
• Patients must have abnormal TP53 on IHC/genomic testing*.
• Patients must have had at least 1 prior line of platinum-based chemotherapy in any setting but may not have received prior gemcitabine therapy.

Cohort B1: HGSOC

• Patients must have a histologically confirmed diagnosis of high-grade serous ovarian cancer/fallopian tube/primary peritoneal carcinoma (HGSOC) which is platinum-refractory per standard definitions.
• Patients must have abnormal TP53 on IHC/genomic testing*.
• Platinum refractory disease refers to patients with progressive disease on first-line platinum-based chemotherapy or progressive disease within 12 weeks of the last dose of first-line platinum-based therapy [Gynecologic Cancer Intergroup Consensus Recommendations 2022].

Cohort B2: Uterine Carcinosarcoma

• Patients must have had at least 1 prior line of platinum-based chemotherapy but may not have received prior gemcitabine therapy.
• Patients must have abnormal TP53 on IHC/genomic testing*.

Cohort B3: Ovarian Carcinosarcoma

• Patients must have had at least 1 prior line of platinum-based chemotherapy but may not have received prior gemcitabine therapy.
• Patients must have abnormal TP53 on IHC/genomic testing*.

Cohort B4: TNBC

• Patients must have had at least 2 prior lines of therapy in the advanced setting.
• Patients may not have received prior gemcitabine.

Cohort B5: PDAC

• Patients must have prior FOLFIRINOX either in the palliative/advanced setting or have relapsed within 6 months of completing adjuvant or neoadjuvant FOLFIRINOX.
• Patients may not have received prior gemcitabine.
• Patients must have abnormal TP53 on IHC/genomic testing*.

Cohort B6: NSCLC

• Patients must have received standard therapies including platinum combination chemotherapy, standard salvage chemotherapy, immunotherapy, and targeted therapies as applicable.
• Patients may not have received prior gemcitabine.

Cohort C1: Colorectal Cancer

• Patients must have histologically confirmed diagnosis of colorectal cancer, that is advanced/metastatic/recurrent or unresectable, for which no curative therapy exists.
• Patients must have both a RAS mutation (KRAS) and a TP53 mutation based on local testing*.
• Patients must be eligible to receive FOLFIRI; patients homozygous for UGT1A1*28 allele are not eligible

• Patients must have had at least 1 prior line of cytotoxic chemotherapy with FOLFOX, either as:

  • 1st line therapy for metastatic disease, or
  • recurrence within 6 months of completion of adjuvant FOLFOX.

Cohort D1: HER-2+ Gastroesophageal Cancer

• Patients must have histologically confirmed diagnosis of gastroesophageal cancer, that is advanced/metastatic/recurrent or unresectable, for which no curative therapy exists.
• Tumour must be HER-2+ (IHC 3+, or FISH+) and have CCNE1 amplification

Exclusion Criteria:

• Patients with a history of other malignancies, except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumours curatively treated with no evidence of disease for > 2 years and which do not require ongoing treatment
• Patients with active or uncontrolled infections or with serious illnesses or medical conditions which would not permit the patient to be managed according to the protocol
• Patients are not eligible if they have a known hypersensitivity to the study drug(s) or their components
• Prior use of WEE1 inhibitor or PKMYT1 inhibitor
• Patients with significant cardiac (including uncontrolled hypertension) or pulmonary disease, or active CNS disease or infection. Patients should have a LVEF ≥ 50%.
• Patients may not receive concurrent treatment with other anti-cancer therapy (other than bone-targeted therapy, if already taking and stable) or investigational agents while on protocol therapy
• Patients who have received growth factors within 28 days prior to initiation of dosing of RP-6306 or who will require treatment with growth factors throughout the duration of the trial
• Pregnant or breastfeeding women
• Patients with history of central nervous system metastases or spinal cord compression unless they have received definitive treatment, are clinically stable and do not require corticosteroids
• Patients with any medical condition that would impair the administration of oral agents including significant bowel resection, inflammatory bowel disease or uncontrolled nausea or vomiting
• Patients who cannot discontinue the use of proton pump inhibitors, strong CYP3A inhibitors or inducers.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: RP-6306 + Gemcitabine	Drug: RP-6306; Dose and schedule will be assigned at enrolment; Drug: Gemcitabine; Dose and schedule will be assigned at enrolment
Active Comparator: RP-6306 + FOLFIRI	Drug: RP-6306; Dose and schedule will be assigned at enrolment; Drug: FOLFIRI Protocol; Irinotecan Leucovorin FU
Active Comparator: RP-6306 + Trastuzumab	Drug: RP-6306; Dose and schedule will be assigned at enrolment; Drug: Trastuzumab; standard doses q3weekly

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Response rate of RP-6306 in patients with selected cancers receiving standard agent	2 years

Secondary Outcome Measures

Outcome Measure	Time Frame
Number and severity of adverse events	2 years
Explore the recommended dose of RP-6306	2 years

Collaborators and Investigators

• Sponsor: Canadian Cancer Trials Group
• Collaborators: Repare Therapeutics
• Investigators: Study Chair: Stephanie Lheureux, University Health Network, Princess Margaret Hospital, Toronto ON Canada; Study Chair: Yvette Drew, BCCA-Vancouver Cancer Centre, Vancouver BC Canada; Study Chair: Eric Chen, University Health Network, Princess Margaret Hospital, Toronto ON Canada

Study record dates

Study Major Dates

• Study Start (Actual): May 24, 2023
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): June 1, 2025

Study Registration Dates

• First Submitted: October 31, 2022
• First Submitted That Met QC Criteria: October 31, 2022
• First Posted (Actual): November 4, 2022

Study Record Updates

• Last Update Posted (Estimated): February 15, 2024
• Last Update Submitted That Met QC Criteria: February 14, 2024
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Antineoplastic Agents, Immunological; Trastuzumab; Gemcitabine
• Other Study ID Numbers: I243

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No