📋 Eligibility rules (as published)
Inclusion Criteria:
Main study cohort:
1. Histologically or cytologically confirmed malignancy of the pancreas, prostate, breast, or ovary.
2. Documented evidence of pathogenic or likely pathogenic somatic or germline mutation in BRCA1/2 and/or PALB2, and/or any genetic alterations listed below as indicated in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory report. The report must be submitted to and approved by study sponsor prior to registration. Other HRD-associated mutations could be eligible if prior approval by the sponsor is granted.
ATM, ATR, BARD1, BRCA1, BRCA2, BRIP1, CCNE1, CHEK1, CHEK2, CDK12, CREBBP, FANCA, FANCI, FANCL, FANC2, FANCB, FANCC, FANCD2, FANC family\*, MRE11A, MYC, NBN, NCL, PALB2, RAD50, RAD51B, RAD51C, RAD51D, RAD54L, SLFN11, PTIP, MLL3, MLL4, EZH2, CtIP(RBBP8), MUS81, CDH4, DYNLL11, TOPBP1, NBS1, CDC25A, CDC25C, RAD17, WEE1
\* In addition to the genes already specified, the "FANC family" genes may also include the following: FANCE, FANCF, FANCG, FANCM, FANCP, FANCQ/ERCC4/XPF, FANCR/RAD51, FANCT/UBE2T, FANCU/XRCC2, FANCV/REV7/MAD2L2, and FANCW/RFWD3.
Exploratory cohort:
1. Histologically confirmed ovarian, fallopian tube or primary peritoneal cancer, with a high grade serous or high grade endometrioid histology subtype.
2. Documented evidence of pathogenic or likely pathogenic germline mutation or a clinically actionable somatic mutation in BRCA1 and/or other HRD-associated mutation, as indicated in a CLIA-certified laboratory report. The report must be submitted to and approved by study sponsor prior to registration.
3. Meet one of the following criteria:
1. Platinum Sensitive with no evidence of disease progression within 6 months of the last dose of platinum-based chemotherapy (n=10 patients); OR
2. Platinum Resistant with disease progression within 6 months of the last dose of a platinum-based chemotherapy.
All participants:
1. Age ≥ 18 years.
2. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 within 14 days of registration.
3. Radiographically documented disease progression within 28 days of registration and evaluable as per RECIST v1.1.
4. Patient must have measurable disease as per RECIST v1.1.
5. Patients must have adequate bone marrow, renal and hepatic function per local laboratory reference ranges as follows within 14 days of registration:
1. Absolute Neutrophil Count ≥ 1.5 x 10\^9/L
2. Platelets ≥ 100 x 10\^9/L
3. Hemoglobin ≥ 9 g/dL (blood transfusion ≤ 7 days of screening not permitted).
4. Calculated creatinine clearance \> 51mL/min (Cockcroft-Gault formula)
5. AST/ALT ≤ 2.5× the upper limit of normal (ULN). Subjects with liver metastasis may have AST, ALP, and ALT ≤ 5.0 X ULN.
6. Bilirubin ≤ 1.5×ULN. This will not apply to patients with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of haemolysis or hepatic pathology), who will be allowed only at the discretion of the Study Investigator.
7. INR/PT and aPTT ≤1.5 X ULN unless patient is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants.
8. Albumin ≥3.0 g/dL
6. Patients are willing to undergo tumour biopsy pre-treatment and at time of progression on treatment. If a biopsy at the time of progression on prior therapy is available and can be submitted to the Central Lab for this study, this procedure does not need to be repeated. Patients who consent but have tumour that is not amenable to safe biopsy will be allowed to enter the trial and continue therapy as per protocol if this has been addressed and permission is granted from the sponsor prior to registration.
7. Life expectancy of greater than 3 months from the date of registration.
8. Able to provide written informed consent.
9. Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
10. Female patients of childbearing potential must have a negative serum pregnancy test within 14 days prior to registration. (Note: a negative urine/serum pregnancy test is required on Cycle 1, Day 1 prior to treatment unless the screening pregnancy test was done within 48hrs of registration).
11. Female patients of childbearing potential and male patients who are sexually active must agree to practice true abstinence or at least two effective methods of contraception (ie: condoms with spermicide, hormonal methods such as oral contraceptive pills, vaginal ring, injectables, implants and intrauterine devices (IUDs), non-hormonal IUDs, such as ParaGard, bilateral tubal ligation, vasectomy, complete abstinence) within 14 days prior to registration, and agree to continue using such precautions while on treatment with CX-5461 (including dose interruptions) and for 6 months following the last dose of CX-5461.
12. There is no minimum or maximum number of lines of prior therapy and prior PARP inhibitor therapy is allowed.
13. Patient is clinically stable at the time of entering the study.
Exclusion Criteria:
1. For pancreatic cancer; non-adenocarcinoma histology is excluded from this study.
2. Patients with malignant bowel obstruction.
3. Untreated, unstable brain or meningeal metastases or tumor. Patients with radiological evidence of stable brain metastases are eligible provided that they are asymptomatic and either do not require corticosteroids or have been treated with corticosteroids, with clinical and radiological evidence of stabilization at least 10 days after discontinuation of steroids.
4. Unresolved toxicity \> CTCAE grade 1 from previous anti-cancer therapy (including radiotherapy) except hematological toxicity, Grade 1 or 2 neuropathy, and alopecia.
5. Any evidence of severe or uncontrolled diseases such as but not limited to active infection, unstable or uncompensated respiratory, cardiac, neurological, hepatic, renal di
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