New drug combo shows promise for Hard-to-Treat cancers

Copied word for word from the study's registry entry, so the wording is the study team's rather than ours.

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.