RP-6306 in Patients With Advanced Cancer

Inclusion Criteria:

• Patients must have histologically confirmed cancer, that isadvanced/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 primaryor metastatic tumour) available and must have provided informed consent for therelease of the block

• Presence of clinically and/or radiologically documented disease. All radiologystudies 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 asymptomaticpatients).

• 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 xUNL; Creatinine clearance ≥ 50 mL/min

• Patients must be able to swallow oral medications and have no known gastrointestinaldisorders that may interfere with absorption (such as malabsorption)

• Patients must have had recovered (to at least grade 0 or 1) from all reversibletoxicity related to prior chemotherapy or systemic therapy and have adequate washoutlongest 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. Exceptionsmay be made for low-dose, non-myelosuppressive radiotherapy after consultation withCCTG. Concurrent radiotherapy is not permitted

• Previous surgery is permitted provided that a minimum of 21 days (3 weeks) haveelapsed between any major surgery and date of enrollment, and that wound healing hasoccurred

• Patient consent must be appropriately obtained in accordance with applicable localand regulatory requirements. Each patient must sign a consent form prior toscreening (if applicable)/enrollment in the trial to document their willingness toparticipate

• Protocol treatment is to begin within 2 working days of patient enrollment

• Patients must be accessible for treatment and follow-up. Patients enrolled on thistrial must be treated and followed at the participating centre

• Women/men of childbearing potential must have agreed to use a highly effectivecontraceptive method.

Cohort-Specific Eligibility Criteria

Cohort A: Endometrial Cancer

• Patients must have histologically confirmed diagnosis of high-grade serousendometrial cancer, that is advanced/metastatic/recurrent or unresectable, for whichno 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 anysetting but may not have received prior gemcitabine therapy.

Cohort B1: HGSOC

• Patients must have a histologically confirmed diagnosis of high-grade serous ovariancancer/fallopian tube/primary peritoneal carcinoma (HGSOC) which isplatinum-refractory per standard definitions.

• Patients must have abnormal TP53 on IHC/genomic testing*.

• Platinum refractory disease refers to patients with progressive disease onfirst-line platinum-based chemotherapy or progressive disease within 12 weeks of thelast dose of first-line platinum-based therapy [Gynecologic Cancer IntergroupConsensus Recommendations 2022].

Cohort B2: Uterine Carcinosarcoma

• Patients must have had at least 1 prior line of platinum-based chemotherapy but maynot 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 maynot 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 orhave 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 combinationchemotherapy, standard salvage chemotherapy, immunotherapy, and targeted therapiesas applicable.

• Patients may not have received prior gemcitabine.

Cohort C1: Colorectal Cancer

• Patients must have histologically confirmed diagnosis of colorectal cancer, that isadvanced/metastatic/recurrent or unresectable, for which no curative therapy exists.

• Patients must have both a RAS mutation (KRAS) and a TP53 mutation based on localtesting*.

• Patients must be eligible to receive FOLFIRI; patients homozygous for UGT1A1*28allele 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.

• 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 therapyexists.

• 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 ovariancancer/fallopian tube/primary peritoneal carcinoma (HGSOC) which is platinumrefractory per standard definitions.

• Patients must have one of the following for enrolment - Known CCNE1 amplification ordeleterious mutations in either FBXW7 or PPP2R1A on local testing

• Tumour designated as CCNE1 biomarker positive based on central testing (seeSection 12.2)

• Platinum refractory disease refers to patients with progressive disease on firstline platinum-based chemotherapy, or progressive disease within 12 weeks of the lastdose of first line platinum-based therapy [Gynecologic Cancer Intergroup ConsensusRecommendations 2022].

Exclusion Criteria:

• Patients with a history of other malignancies, except: adequately treatednon-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or othersolid tumours curatively treated with no evidence of disease for > 2 years and whichdo not require ongoing treatment

• Patients with active or uncontrolled infections or with serious illnesses or medicalconditions which would not permit the patient to be managed according to theprotocol

• 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 pulmonarydisease, or active CNS disease or infection. Patients should have a LVEF ≥ 50%.

• Patients may not receive concurrent treatment with other anti-cancer therapy (otherthan bone-targeted therapy, if already taking and stable) or investigational agentswhile on protocol therapy

• Patients who have received growth factors within 28 days prior to initiation ofdosing of RP-6306 or who will require treatment with growth factors throughout theduration of the trial

• Pregnant or breastfeeding women

• Patients with history of central nervous system metastases or spinal cordcompression unless they have received definitive treatment, are clinically stableand do not require corticosteroids

• Patients with any medical condition that would impair the administration of oralagents including significant bowel resection, inflammatory bowel disease oruncontrolled nausea or vomiting

• Patients who cannot discontinue the use of proton pump inhibitors, strong CYP3Ainhibitors or inducers.