Overview

This is a single arm Phase Ib/II, open label, safety, pharmacokinetic and efficacy clinical study in adult patients with metastatic castration-resistant prostate cancer (mCRPC). Patients will be treated with the combination of copanlisib and rucaparib for as long as the patient does not have clinically significant progressive disease and/or unacceptable toxicity and/or as long as the investigator deems that the patient is benefiting from treatment. Treatment may also be stopped if the patient withdraws consent, or study termination occurs.

Eligibility

Inclusion Criteria:

1. Age 18 years
2. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
3. Life expectancy of at least 3 months
4. Histologically confirmed prostate cancer. Small cell/neuroendocrine differentiation allowed but not required for study participation. Pure small cell carcinoma of the prostate will not be allowed.
5. Progressive metastatic prostate cancer despite castrate levels of testosterone (< 50 ng/dL).
6. Patients may have either non-measurable disease OR measurable disease (by RECIST criteria)
7. Progressive disease during treatment (or within 4 weeks of completion) with abiraterone, enzalutamide, and/or apalutamide based on any one of the following:
   • For patients with measurable disease, progression by the RECIST 1.1 criteria
   • PSA evidence for progressive prostate cancer consists of a PSA level of at least 2 ng/ml which has risen on at least 2 successive occasions, at least one week apart. If the confirmatory PSA value is less than the screening PSA value, then an additional test for rising PSA will be required to document progression for the purposes of eligibility
   • Radionuclide bone scan: At least two new foci consistent with metastatic lesions
8. Testosterone < 50 ng/dL. Patients must continue primary androgen deprivation with an LHRH analogue if they have not undergone bilateral orchiectomy.
9. Progression or refractoriness to androgen pathway inhibitors (e.g., abiraterone, enzalutamide). Prior therapy with taxane in the castrate-sensitive or castration-resistant settings will be allowed. Prior treatment with radium-223 or sipuleucel-T is permitted, but not required.
10. No other systemic therapies for prostate cancer within 28 days prior to cycle 1 day 1 of study therapy
11. Left ventricular ejection fraction (LVEF) 50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO) obtained during screening
12. Patients must have adequate organ and bone marrow function within 14 days of inclusion in the study as defined below:
    • Absolute Neutrophil Count 1,500/mcL
    • Hemoglobin 9 g/dL
    • Platelets 100,000 /mm3
    • PT/INR 1.5 x ULN
    • Bilirubin 1.5 x institutional upper limit of normal (ULN) except for unconjugated hyperbilirubinemia or Gilbert's Syndrome, who can have total bilirubin <3.0 mg/dL
    • AST/ALT 3 x ULN ( 5 x ULN if liver metastases present)
    • Lipase 1.5 x ULN
    • HbA1c < 8.5 %
    • Serum Creatinine 1.5 X ULN (upper limit of normal) or creatinine clearance 45 mL/minute (using Cockcroft/Gault formula)
    • Proteinuria Grade 3 as assessed by a 24h protein quantification or estimated by a urine protein : creatinine ratio < 3.5 on a random urine sample
13. Sexually active males must use a condom with spermicide during intercourse while taking the drug and for 6 months after stopping treatment, even if patient is vasectomized to prevent delivery of the drug via seminal fluid.
14. Patients must agree to provide tumor tissue, either fresh or archival specimen of primary tumor and/or metastatic lesion, if available. Availability of tissue will not be required for enrollment.
15. Subjects must have the ability to understand and the willingness to sign a written informed consent prior to registration on study. Subjects should be willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations at the institution.
16. Only during phase 2, patients will be required to have mutations in DNA repair genes based on molecular tests performed on germline DNA, prostate cancer tissue or ctDNA. Qualifying mutations (i.e. deleterious/pathogenic alterations) in at least one of the following genes involved with homologous recombination repair will be required: BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK1, FANCL, FANCA, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L. Variants of unknown significance in one of the above genes are not eligible.

Exclusion Criteria:

1. History of myelodysplastic syndrome or acute myeloid leukemia.
2. During phase 2, patients must not have received previous treatment with a DNA-damaging cytotoxic chemotherapy (e.g. prior platinum-based chemotherapy and mitoxantrone are not permitted) or PARP inhibitor. Prior treatment with PARP inhibitor is allowed during phase I dose escalation.
3. Untreated leptomeningeal or metastatic CNS disease; patients with treated disease may be eligible if stable for 4 weeks after radiation or surgery. Steroid treatment should be stable for 4 weeks at a prednisone equivalent dose of 10 mg or less. Patients with spinal cord compression unless considered to have received definitive treatment for this and evidence of stable disease for 28 days.
4. Clinically significant, uncontrolled heart disease and/or recent events including any of the following:
   • History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty or stenting) or symptomatic pericarditis within 6 months prior to screening
   • History of documented congestive heart failure (New York Heart Association functional classification III-IV)
   • History of any cardiac arrhythmias, e.g., ventricular, supraventricular, nodal arrhythmias, or conduction abnormality within 12 months of screening. Patients with rate-controlled atrial fibrillation or flutter are permitted.
   • QTcF > 470 msec on screening 12-lead ECG
   • Documented cardiomyopathy
5. Clinically significant uncontrolled hypertension (systolic blood pressure > 150 mmHg or diastolic pressure > 90 mmHg despite optimal medical management). For the purpose of this protocol definition of uncontrolled hypertension is based on persistent (72 hours) and symptomatic.
6. Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 6 months before the start of study medication. However, patients with a venous thrombosis, including a pulmonary embolus, how have had stable anticoagulation (more than 1 month without bleeding on a stable dose) is permitted. Patients with evidence or history of uncontrolled bleeding diathesis. Any hemorrhage or bleeding event CTCAE Grade 3 within 4 weeks prior to the start of study medication
7. History or concurrent condition of clinically significant interstitial lung disease and/or severely impaired lung function. History of renal failure requiring peritoneal dialysis or hemodialysis. History of cirrhosis Child-Pugh B or C. Intestinal malabsorption.
8. Active, clinically serious infections of CTCAE (v 5.0) Grade 2 or per investigator discretion.
9. History of uncontrolled human immunodeficiency virus (HIV) infection defined as CD4 < 200 cells/mm3 or detectable viral load is not allowed.
10. Hepatitis B (HBV) or hepatitis C (HCV). All patients must be screened for HBV and HCV up to 28 days prior to study drug start using the routine hepatitis virus laboratorial panel. Patients positive for HBsAg or HBcAb will be eligible if they are negative for HBV-DNA. These patients should receive prophylactic antiviral therapy. Patients positive for anti-HCV antibody will be eligible if they are negative for HCV-RNA. CMV PCR positive or active tuberculosis are exclusion criteria.
11. Previous or concurrent history of malignancies within 5 years prior to study treatment except for curatively treated cervical carcinoma in situ, non-melanoma skin cancer, superficial bladder cancer (Ta [non-invasive tumor], Tis [carcinoma in situ] and T1 [tumor invades lamina propria]) or other T1 tumor that has been surgically removed with a low chance of recurrence in the next 3 years.
12. Known hypersensitivity to any of the test drugs, test drug classes, or excipients in the formulation
13. Ongoing substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results.
14. Prior radiation within 7 days of start drug. Prior major surgery, open biopsy or significant trauma within 28 days of start drug.
15. Patients with severe psychiatric illness/social situations that would limit compliance with study requirements in the judgment of study investigator
16. Patient has a history of non-compliance to medical regimen or inability to grant consent