| Eligibility |
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.
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