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PARP Inhibitor for Metastatic Prostate Cancer With DNA Repair Defects

PARP Inhibitor for Metastatic Prostate Cancer With DNA Repair Defects

Clinicaltrials.gov identifier:
NCT03012321

Treatment

Study Contact Information:

 For more information, contact the study coordinator by phone (312)695-1301 or email.


Abiraterone/Prednisone, Olaparib, or Abiraterone/Prednisone + Olaparib in Patients With Metastatic Castration-Resistant Prostate Cancer With DNA Repair Defects

About the Study

This is a phase II study looking at different treatment combinations for men with , castration resistant cancer (mCRPC) to see which is most effective for improving progression free survival (keeping the cancer from progressing). The study will include testing for genes within the tumor to determine eligibility for the study. 

The study multiple treatment arms. Patients with tumors that have , and/or mutations or defects will be randomly assigned to one of the treatment arms of the study. Patients with tumors that have mutations in other  repair genes including FANCA, , RAD51, ERCC3, MRE11, , MLH3, CDK12, , HDAC2, ATR, , GEN1, , , , or FAM175A will be assigned to Arm IV with single agent olaparib.

Type of Study

This is a , 4-arm study. This study allows crossover. 

  • The study has four arms. This means that patients in the study are placed in one of four different groups. 
  • This is a  study for men with an , and/or mutation or defect within their tumor. Men with these defects will be to one of three separate treatment arms:
    • Active Comparator: Arm I: Abiraterone + Prednisone
    • Active Comparator: Arm II: Olaparib
    • Active Comparator: Arm III: Abiraterone + Prednisone + Olaparib
  • Men whose tumors have a mutation in another  repair genes including FANCA, , RAD51, ERCC3, MRE11, , MLH3, CDK12, , HDAC2, ATR, , GEN1, , , , or FAM175A will not be but will be assigned to Arm IV with single agent olaparib.
  • The study is . All participating patients will know which group they have been assigned to and what treatment they are receiving. There is no in this study.
  • The study allows crossover. This means that patients who progress on the abiraterone arm will be given the opportunity to crossover into the olaparib arm if they choose. Patients who progress while on the olaparib arm will be given the opportunity to crossover into the abiraterone arm if they choose. 

What the Study Entails

  • Patients with documented castration resistant cancer must:
    • undergo a biopsy, or
    • have  tumor tissue from prior disease biopsy, or
    • for patients with an inherited (germline) mutation in , , or other known DNA-repair genes, these patients are not required to undergo a biopsy to participate, however,it is preferred that these patients also undergo a disease biopsy to better define the scope of the repair defects in their tumor
  • Patients with tumors that have , and/or mutations/deletions/loss of heterozygosity will be in a 1:1:1 fashion to one of the three following arms:
    • Arm I: Abiraterone + Prednisone
      • Abiraterone 1000 mg orally once daily and prednisone 5 mg orally twice daily, days 1-28 in 28 day cycles.
    • Arm II: Olaparib
      • Olaparib 300 mg orally twice daily for days 1-28 in 28 day cycles.
    • Arm III: Abiraterone + Prednisone + Olaparib
      • Abiraterone 1000 mg orally once daily, prednisone 5 mg orally twice daily, olaparib 300 mg orally twice daily for days 1-28 in 28 day cycles.
  • Patients with mutations in other repair genes including FANCA, , RAD51, ERCC3, MRE11, , MLH3, CDK12, , HDAC2, ATR, , GEN1, , , , or FAM175A defects will be assigned to Arm IV with single agent olaparib.
    • Arm IV Olaparib
      • Olaparib 300 mg orally twice daily for days 1-28 in 28 day cycles.

Study Sites

  • Florida
    • Tampa, FL
      • Moffitt Cancer Center: Contact Jingsong Zhang, MD    813-745-4673  
  • Illinois
    • Chicago, IL
      • Northwestern Medicine: Contact Maha Hussain 312-695-6180      
    • Chicago, IL
      • Rush University Cancer Center: Contact Nicklas Pfanzelter, MD 312-942-5904 
    • Chicago, IL
      •  University of Chicago: Contact Russell Szmulewitz, MD  773-702-7609  
    • Evanston, IL
      • Kellog Cancer Center, NorthShore University: Contact Daniel Shevrin, MD  847-570-2515 
  • Indiana
    • Indianapolis, IN
      • Indiana University/ Melvin and Bren Simon Cancer Center: Contact Roberto Pili, MD    317-948-8310
  • Maryland
    • Baltimore, MD
      • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins: Contact Emmanuel Antonarakis, MD 410-502-7528 
  • Michigan
    • Ann Arbor, MI
      • University of Michigan Health System: Contact Todd Morgan, MD 734-647-8903 
    • Detroit, MI
      •  Karmanos Cancer Center: Contact Ulka Vaishampayan, MD 313-745-5111 
  • Minnesota
    • Rochester, MN
      • Mayo Clinic: Contact Manish Kohli, MD 507-538-3270  
  • Missouri
    • St. Louis, MO
      • Washington University School of Medicine: Contact Joel Picus, MD 314-747-9281 
  • New York
    • New York, NY
      • Weill Cornell Medical Center: Contact: Himisha Beltran, MD 646-962-2072  
  • North Carolina
    • Chapel Hill, NC
      • University of North Carolina, Chapel Hill: Contact Young Whang, MD 919-966-4996 
  • Utah
    • Salt Lake City, UT
      • Huntsman Cancer Center: Contact Neeraj Agarwal, MD 801-585-0100 
  • Virginia
    • Charlottesville, VA
      • University of Virginia: Contact Robert Dreicer, MD  434-924-9333 

Principal Investigator

Maha Hussain at Northwestern University: 312-695-6180 

This Study is Open To:

Men with advanced, castration resistant  cancer who:

  • Documented progressive mCRPC 
  • Agree to undergo a biopsy of at least one site to determine repair defects. However:
    • Adequate tissue from prior disease biopsy/resection can be used if available instead of a biopsy. These patients will only be eligible for protocol therapy if the biopsy has tumor that is positive for repair defects.
    • Patients with known germline (inherited) mutation (such as , or ) are eligible without a biopsy
  • Patients must discontinue antiandrogen therapy (i.e., flutamide, bicalutamide, nilutamide) for at least 4 weeks prior to participation.
  • Serum testosterone < 50 ng/dL. Patients must continue primary ADT with an LHRH analogue (agonist or antagonist) if they have not undergone orchiectomy.
  • Patients must have a life expectancy ≥ 6 months.
  • Patients may have received prior radiation therapy or surgery. However, at least 14 days must have elapsed since completion of radiation therapy or surgery and patient must have recovered from all side effects at the time of registration (e.g. back to baseline or grade 1) .

 

This Study is Not Open To:

Patients will be excluded if they have:

  • Prior exposure to CYP-17 (other than ketoconazole) or PARP inhibitors for cancer. Patients with prior exposure to ketoconazole are eligible.
  • Prior chemotherapy for castration resistant disease. Chemotherapy given in the hormone-sensitive setting is permissible if stopped at least 4 weeks prior to registration.
  • Prior exposure to enzalutamide, ARN-509 or other investigational AR-directed therapy in the setting of mCRPC.
  • Patients with a currently active second malignancy excluding non-melanomatous skin cancer or superficial transitional cell carcinoma. Note: Patients are not considered to have a "currently active" malignancy if they have completed all therapy and are now considered without evidence of disease for 1 year.
  • Patients receiving any other investigational agents. Any prior investigational agents must be stopped at least 14 days (2 week washout) prior to registration.
  • Patients with active brain metastases. A scan to confirm the absence of brain metastases is not required for asymptomatic patients.
  • Patients who are HIV-positive on combination antiretroviral therapy because of the potential for pharmacokinetic interactions with olaparib. In addition these patients are at increased risk of lethal infections when treated with marrow suppressive therapy.
  • Patients with known active Hepatitis B or Hepatitis C.