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Carboplatin or Olaparib for BRcA Deficient Prostate Cancer

NCT04038502 · VA Office of Research and Development
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Official title
An Open-label, Multicenter Phase II Study to Compare the Efficacy of Carboplatin as First-line Followed by Second-line Olaparib Versus Olaparib as First-line Followed by Second-line Carboplatin in the Treatment of Patients With Castration Resistant Prostate Cancer Containing Homologous Recombination Deficiency
About this study
Study General Trial Over-view This study is designed to help better understand treatment options compared to standard therapies for patients who have targeted DNA repair mutations and metastatic castrate resistant prostate cancer (mCRPC). Cancer therapies are aimed at finding a way to kill the cancer cells while causing minimal damage to normal (non-cancer) cells. This often works because cancers cells grow faster than many normal cells, many treatments are aimed at to take advantage of that difference. One of the ways to do this is to damage the DNA of these more rapidly growing cells. However, if the cells have a way of repairing that damage then therapies may not work as well. Some research shows that when specific changes or mutations occur in the genes involved with repairing DNA damage, resulting cancers have responded well to drugs which damage DNA. Olaparib is known as a PARP inhibitor and is standard of care therapy for men with BRCA altered mCRPC. Carboplatin is a synthetic antineoplastic agent which has been used in the treatment of solid tumors and BRCA related cancers. When mutations occur in critical DNA-repair genes, research has found that treatment with carboplatin is also effective. This research is being done to determine the response of mCRPC in patients with DNA repair mutations to treatment with olaparib compared to carboplatin. This study will test whether giving one drug or the other a has a better response. Patients wishing to participate in this study are screened for safety and health eligibility before enrolling. This study is enrolling 100 male participants total, from across the VAMC nationally who have the following: * Metastatic castration-resistant prostate cancer (mCRPC) * Cancer that has gotten worse, after any number of first-line treatments * Mutations in DNA-repair genes discovered as part of a patient's routine care. Once eligibility is determined, enrolled participants are randomized into one of two groups: * Group A will start with carboplatin (IV) first, given every 21 days, then have the option to switch to the second treatment with olaparib taken daily, (orally) with cycles of every 28 days. * Group B will start with olaparib first, taken (orally), with 28 day cycles, then have the option to switch to the second treatment with carboplatin (IV) every 21 days. Both study drugs in this trial are currently FDA approved, and are prescribed at the participating VAMC clinical sites per institutional guidelines. Carboplatin given in IV is also given as prescribed at the participating VAMC, and administered per institutional guidelines. Participants are monitored for health and body function, cancer progression, toxicity and life quality at every visit during the trial and at an end of treatment visit (28 days after completion of the trial or after withdrawal). For participants who respond well to treatment during the trial, additional treatment cycles may be added and the study can be extended. Participants who experience intolerable toxicity, cancer progression, or whose doctors decide to change treatment, will either be switched to the opposite study drug or withdrawn from the study. This important trial is designed to compare response rate and duration of response using carboplatin compared to olaparib in patients who have mCRPC which contains DNA repair gene mutations.
Eligibility criteria
Inclusion Criteria: 1. Signed study informed consent form (ICF) and HIPAA authorization form 2. Male age \> 18 years 3. Diagnosis of prostate cancer (pure small-cell histology or pure high-grade neuroendocrine histology are excluded; neuroendocrine differentiation is allowed) 4. Ongoing gonadal androgen deprivation therapy with gonadotropin-releasing hormone (GnRH) analogues, antagonists or orchiectomy. Patients who have not had an orchiectomy must be maintained on effective GnRH analogue/antagonist therapy 5. mCRPC as defined by serum testosterone \< 50 ng/ml (for patients on GnRH analogues or antagonists) and at least one of the following: * PSA level of at least 2 ng/ml that has risen on at least 2 successive occasions at least 1 week apart * Evaluable disease progression by modified RECIST 1.1 (Response Evaluation Criteria in Solid Tumors) * Progression of metastatic bone disease on bone scan, CT or MRI with \> 2 new lesions 6. Prior therapy with abiraterone acetate, enzalutamide, apalutamide, or darolutamide 7. Eastern Cooperative Oncology Group (ECOG) Performance Status of \< 2 (see Appendix 3, ECOG Grading Scale) 8. Results of previous standard DNA testing, or previous research testing, which confirms RAD51B, RAD51C, RAD51D, or RAD54L mutations (see Introduction, Section 2 for study design and previous research on targeted therapy) from primary, metastatic tumor or circulating tumor DNA, or pathogenic/likely pathogenic germline variant as assessed by a CLIA certified laboratory level assay for DNA sequencing. 9. Patients must have normal organ and bone marrow function measured within 28 days prior to administration of study treatment as defined below: * Hemoglobin \> 10.0 g/dL * Absolute neutrophil count (ANC) \> 1.5 x 109/L * Platelet count \> 100 x 109/L * Total bilirubin \< 1.5 x institutional upper limit of normal (ULN) * Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase (SGOT)) / Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate Transaminase (SGPT)) \< 2.5 x institutional upper limit of normal unless liver metastases are present in which case, they must be \< 5x ULN * Patients must have creatinine clearance estimated using the Cockcroft-Gault equation of \>51 mL/min: Estimated creatinine clearance =(140-age \[years\]) x weight (kg))/ (serum creatinine (mg/dL) x 72) Exclusion Criteria: 1. Currently receiving active therapy for other neoplastic disorder(s) 2. Concurrent enrollment in another clinical investigational drug or device study 3. Histologic evidence of small cell carcinoma (morphology alone - immunohistochemical evidence of neuroendocrine differentiation without morphologic evidence is not exclusionary) 4. Prior treatment with platinum, mitoxantrone or PARP inhibitor for castration resistant prostate cancer 5. Known parenchymal brain metastasis 6. Active or symptomatic viral hepatitis or chronic liver disease AST or ALT \> 2.5 x ULN or total bilirubin \> ULN (unless Gilbert's syndrome is the etiology of hyperbilirubinemia) 7. Subjects with myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of MDS/AML 8. Concomitant use of known strong CYP3A inhibitors (e.g. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting olaparib is 2 weeks 9. Concomitant use of known strong (e.g. phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or moderate CYP3A inducers (e.g. bosentan, efavirenz, modafinil). The required washout period prior to starting olaparib is 5 weeks for phenobarbital and 3 weeks for other agents 10. Subjects unable to swallow orally administered medication and subjects with gastrointestinal disorders likely to interfere with absorption of the study medication 11. Clinically significant heart disease as evidenced by myocardial infarction, or arterial thrombotic events in the past 6 months, severe or unstable angina, or New York Heart Association (NYHA) Class II-IV heart disease or cardiac ejection fraction measurement of \< 35 % at baseline 12. Treatment with an investigational therapeutic within 30 days of Cycle-1 13. Presence of dementia, psychiatric illness, and/or social situations limiting compliance with study requirements or understanding HIPAA authorization and/or giving of informed consent 14. Any condition(s), medical or otherwise, which, in the opinion of the Investigators, would jeopardize either the patient or the integrity of the data obtained.
Study design
Enrollment target: 100 participants
Allocation: randomized
Masking: none
Age groups: adult, older_adult
Timeline
Starts: 2019-10-01
Estimated completion: 2027-08-31
Last updated: 2025-08-20
Interventions
Drug: CarboplatinDrug: Olaparib
Primary outcomes
  • Progression-free survival (PFS-1L) defined as the time interval between randomization and first documented disease progression or death due to any cause reported during, or after, first-line treatment. (Through duration of the study, up to six years)
Sponsor
VA Office of Research and Development · fed
Contacts & investigators
ContactRobert B Montgomery, MD · contact · rbmontgo@uw.edu · (206) 277-6878
ContactMakayla L DeJong, BA · contact · Makayla.Dejong@va.gov · (206) 277-4527
InvestigatorRobert B. Montgomery, MD · principal_investigator, VA Puget Sound Health Care System Seattle Division, Seattle, WA
InvestigatorRyan Burri, MD · principal_investigator, Bay Pines VA Healthcare System, Pay Pines, FL
InvestigatorPhoebe Tsao, MD MSc · principal_investigator, VA Ann Arbor Healthcare System, Ann Arbor, MI
All locations (18)
VA Greater Los Angeles Healthcare System, West Los Angeles, CARecruiting
West Los Angeles, California, United States
Rocky Mountain Regional VA Medical Center, Aurora, CORecruiting
Aurora, Colorado, United States
Washington DC VA Medical Center, Washington, DCRecruiting
Washington D.C., District of Columbia, United States
Bay Pines VA Healthcare System, Pay Pines, FLTerminated
Bay Pines, Florida, United States
Orlando VA Medical Center, Orlando, FLRecruiting
Orlando, Florida, United States
Atlanta VA Medical and Rehab Center, Decatur, GARecruiting
Decatur, Georgia, United States
Boise VA Medical Center, Boise, IDRecruiting
Boise, Idaho, United States
Jesse Brown VA Medical Center, Chicago, ILTerminated
Chicago, Illinois, United States
VA Ann Arbor Healthcare System, Ann Arbor, MIRecruiting
Ann Arbor, Michigan, United States
Minneapolis VA Health Care System, Minneapolis, MNRecruiting
Minneapolis, Minnesota, United States
Kansas City VA Medical Center, Kansas City, MORecruiting
Kansas City, Missouri, United States
Manhattan Campus of the VA NY Harbor Healthcare System, New York, NYRecruiting
New York, New York, United States
James J. Peters VA Medical Center, Bronx, NYTerminated
The Bronx, New York, United States
Durham VA Medical Center, Durham, NCRecruiting
Durham, North Carolina, United States
VA Portland Health Care System, Portland, ORRecruiting
Portland, Oregon, United States
Philadelphia MultiService Center, Philadelphia, PARecruiting
Philadelphia, Pennsylvania, United States
VA Puget Sound Health Care System Seattle Division, Seattle, WARecruiting
Seattle, Washington, United States
William S. Middleton Memorial Veterans Hospital, Madison, WIRecruiting
Madison, Wisconsin, United States
Carboplatin or Olaparib for BRcA Deficient Prostate Cancer · TrialPath