Clinical Trials /

A Study of Copanlisib Combined With Rucaparib in Patients With Metastatic Castration-resistant Prostate Cancer

NCT04253262

Description:

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.

Related Conditions:
  • Prostate Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Phase Ib/II Study of Copanlisib Combined With Rucaparib in Patients With Metastatic Castration-resistant Prostate Cancer
  • Official Title: A Phase Ib/II Study of Copanlisib Combined With Rucaparib in Patients With Metastatic Castration-resistant Prostate Cancer

Clinical Trial IDs

  • ORG STUDY ID: BrUOG 360
  • NCT ID: NCT04253262

Conditions

  • Metastatic Castration-resistant Prostate Cancer

Interventions

DrugSynonymsArms
RucaparibRubracaDose Level -1
CopanlisibAliqopaDose Level -1

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Dose Level -2Experimental300 mg Rucaparib, 45 mg (day 1 & 15) Copanlisib
  • Rucaparib
  • Copanlisib
Dose Level -1Experimental400 mg Rucaparib, 45 mg (day 1 & 15) Copanlisib
  • Rucaparib
  • Copanlisib
Dose Level 1Experimental400 mg Rucaparib, 45 mg Copanlisib
  • Rucaparib
  • Copanlisib
Dose Level 2Experimental500 mg Rucaparib, 45 mg Copanlisib
  • Rucaparib
  • Copanlisib
Dose Level 3Experimental600 mg Rucaparib, 45 mg Copanlisib
  • Rucaparib
  • Copanlisib
Dose Level 4Experimental600 mg Rucaparib, 60 mg Copanlisib
  • Rucaparib
  • Copanlisib

Eligibility Criteria

        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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose
Time Frame:Cycle 1 (each cycle is 28 days) through pre-dosing cycle 2, approximately 1 month.
Safety Issue:
Description:To evaluate the maximum tolerated dose of copanlisib with rucaparib in patients with metastatic castration-resistant prostate cancer.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Brown University

Last Updated

January 31, 2020