REPAIR: This phase I dose-escalation study is seeking to determine the appropriate dose level of two types of targeted therapies (talazoparib and pidnarulex) in people with metastatic, castration-resistant prostate cancerPhase 1 Trial of Pidnarulex and Talazoparib in Patients With Metastatic Castration Resistant Prostate Cancer

Exclusion

1. Extensive marrow disease defined by a "Super Scan" on bone scintigraphy or diffuse marrow infiltration on prostate specific membrane antigen (PSMA) positron emission tomography (PET).
2. Previous history or presence of brain metastases or leptomeningeal metastases. A scan to confirm the absence of brain metastases is not required if there is no clinical suspicion on history.
3. Surgery or radiotherapy within < 3 weeks prior to Cycle 1 Day 1 (except for palliative reasons). Patients must have recovered from effects of any major surgery.
4. Patients with symptomatic or impending cord compression unless adequately treated and clinically stable for ≥ 4 weeks.
5. Any prior exposure to platinums, poly (ADP-ribose) polymerase (PARP) inhibitors, mitoxantrone or cyclophosphamide.
6. Uncontrolled inter-current illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial lung disease on High Resolution CT scan or psychiatric illness/social situations that are likely to impede participation and/or compliance in the study.
7. Persistent toxicities (Common Terminology Criteria for Adverse Events [CTCAE] Grade 2) caused by previous cancer therapy, excluding alopecia.
8. Other malignancies within the previous 2-years that have a high risk of recurrence other than basal cell, squamous cell carcinomas of skin, melanoma in situ or other cancers that are unlikely to recur within 24 months.
9. Previous history of interstitial lung disease or non-infectious pneumonitis.
10. Patients with a history or clinical features suggestive of myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML).
11. Patients unable to swallow orally administered medications or with gastrointestinal disorders likely to interfere with the absorption of the study medication.
12. Resting Electrocardiogram (ECG) indicating uncontrolled, potentially reversible cardiac conditions, as judged by the Investigator (e.g., unstable angina, uncontrolled or symptomatic arrhythmia, congestive heart failure, corrected QT interval by Frederica [QTcF] prolongation >500ms, electrolyte disturbances, etc.), or patients with congenital long QT syndrome.
13. Known hypersensitivity to talazoparib or pidnarulex or any of the excipients of talazoparib or pidnarulex.

14. Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV) 1/2. Serology only required if there is clinical suspicion on history. HIV-infected (HIV1/2 antibody-positive) patients may participate if they meet all the following eligibility requirements:

    • They must be on an anti-retroviral regimen with evidence of at least two undetectable viral loads within the past 6 months on the same regimen; the most recent undetectable viral load must be within the past 12 weeks They must have a CD4 count ≥250 cells/μL over the past 6 months on the same anti-retroviral regimen and must not have had a CD4 count <200 cells/μl over the past 2 years, unless it was deemed related to the cancer and/or chemotherapy-induced bone marrow suppression
    • For patients who have received chemotherapy in the past 6 months, a CD4 count <250 cells/μl during chemotherapy is permitted as long as viral loads were undetectable during this same treatment period
    • They must have an undetectable viral load and a CD4 count ≥250 cells/μL within 7 days prior to Cycle 1 Day 1
    • They must not be currently receiving prophylactic therapy for an opportunistic infection and must not have had an opportunistic infection within the past 6 months
15. Patients with active or uncontrolled infection, including hepatitis A, B or C. NOTE: Patients with controlled infection on antibiotic or antifungal therapy are eligible i.e. the patient should be afebrile for at least 72 hours and be haemodynamically stable.
16. Participation in another clinical study with an investigational product or another systemic therapy administered within 3 weeks prior to Cycle 1 Day 1.