RP-6306 in Patients With Advanced Cancer

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

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
• Hemoglobin ≥ 90 g/L (exceptions may be granted for well compensated and asymptomatic patients).
• 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

Cohort F1: Primary platinum refractory 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 one of the following for enrolment - Known CCNE1 amplification or deleterious mutations in either FBXW7 or PPP2R1A on local testing

• Tumour designated as CCNE1 biomarker positive based on central testing (see Section 12.2)
• 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].

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.