Clinical Trials /

Study of Olaparib Maintenance Following Cabazitaxel-Carbo in Men With AVPC

NCT03263650

Description:

The goal of this clinical research study is to learn if olaparib, when given after treatment with cabazitaxel, carboplatin, and prednisone, can help to control aggressive variant prostate cancer (AVPC). The safety of these drugs will also be studied. This is an investigational study. Cabazitaxel and carboplatin are FDA approved and commercially available for the treatment of certain types of prostate cancer. Prednisone is FDA-approved and commercially available as a corticosteroid. Olaparib is FDA approved and commercially available for the treatment of certain types of ovarian cancer. The combination of cabazitaxel and carboplatin followed by olaparib in this study is investigational. The study doctor can describe how the study drugs are designed to work. Up to 96 participants will be enrolled on this study. All will take part at MD Anderson.

Related Conditions:
  • Prostate Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study of Olaparib Maintenance Following Cabazitaxel-Carbo in Men With AVPC
  • Official Title: Randomized Phase II Study of Olaparib Maintenance Following Cabazitaxel-Carboplatin Induction Chemotherapy in Men With Aggressive Variant Prostate Cancer (AVPC)

Clinical Trial IDs

  • ORG STUDY ID: 2017-0133
  • NCT ID: NCT03263650

Conditions

  • Prostate Cancer Aggressiveness
  • Prostate Carcinoma

Interventions

DrugSynonymsArms
CabazitaxelJevtanaCabazitaxel + Carboplatin
CarboplatinParaplatinCabazitaxel + Carboplatin
Prednisone 5MgCabazitaxel + Carboplatin
OlaparibOlaparib PillOlaparib Maintenance

Purpose

The goal of this clinical research study is to learn if olaparib, when given after treatment with cabazitaxel, carboplatin, and prednisone, can help to control aggressive variant prostate cancer (AVPC). The safety of these drugs will also be studied. This is an investigational study. Cabazitaxel and carboplatin are FDA approved and commercially available for the treatment of certain types of prostate cancer. Prednisone is FDA-approved and commercially available as a corticosteroid. Olaparib is FDA approved and commercially available for the treatment of certain types of ovarian cancer. The combination of cabazitaxel and carboplatin followed by olaparib in this study is investigational. The study doctor can describe how the study drugs are designed to work. Up to 96 participants will be enrolled on this study. All will take part at MD Anderson.

Detailed Description

      Study Groups:

      If you are found to be eligible to take part in this study, you will be randomly assigned (as
      in a roll of dice) to 1 of 2 study groups. This is done because no one knows if one study
      group is better, the same, or worse than the other group. You will have a 2 in 3 chance of
      being assigned to Group 1 and a 1 in 3 chance of being assigned to Group 2:

        -  If you are in Group 1, you will receive olaparib.

        -  If you are in Group 2, you will not receive olaparib.

      All participants will receive cabazitaxel and carboplatin.

      You and the study staff will know to which group you have been assigned.

      Study Drug Administration:

      Each study cycle is 21 days.

      You will receive cabazitaxel by vein over 60 minutes on Day 1 of Cycles 1-6. You will then
      receive carboplatin by vein over 60 minutes on Day 1 of Cycles 1-6.

      You will take 1 tablet of prednisone by mouth 2 times each day of Cycles 1-6.

      You will be given standard drugs to help decrease the risk of side effects (for example,
      filgrastim) before and/or after each dose of cabazitaxel and continuing through several days.
      Your doctor will describe these drugs to you in more detail, including how they are given and
      any side effects you may expect.

      If you are in Group 1, you will take tablets of olaparib 2 times by mouth each day starting
      on Day 1 of Cycle 7. Swallow the whole tablet or tablets. Do not chew, crush, divide, or
      dissolve the tablets. If you vomit shortly after taking your olaparib tablet you can retake a
      new dose as long as you can see that the tablet came out whole. You should take the doses at
      the same time each day (or within 2 hours of the scheduled times). Do not take the dose if
      you forget and it is more than 2 hours since your scheduled time. Take olaparib at least 1
      hour after and 2 hours before eating.

      If you are in Group 2, you will receive standard of care treatment and follow-up after Cycle
      6. The study doctor will tell you more about what this may mean for you.

      Length of Treatment:

      You will receive carboplatin and cabazitaxel for up to 6 cycles. If you are in Group 1, you
      may continue receiving olaparib for as long as the doctor thinks it is in your best interest.
      You may no longer be able to take the study drugs if the disease gets worse, if intolerable
      side effects occur, or if you are unable to follow study directions.

      Your participation on the study will be over after the follow-up visits.

      Study Visits:

      On Day 1 of Cycles 1-6:

        -  You will have a physical exam.

        -  Blood (up to 5 tablespoons) will be drawn for routine tests, biomarker testing, tumor
           marker testing, and to measure your PSA level. At some of these visits, this sample will
           also be used for CTC testing. You must fast for up to 12 hours before the Cycle 4 visit.

        -  Urine will be collected for tumor marker testing.

        -  At Cycle 4 only, you will have a bone scan and either MRIs or CT scans to check the
           status of the disease.

      After Cycle 6, you will have a second tumor biopsy for biomarker testing to compare to the
      one taken at screening. The type of biopsy you have will depend on where the disease has
      spread and/or what the doctor thinks is in your best interest. The doctor will discuss with
      you the type of biopsy you will have.

      On Day 1 of Cycle 7:

        -  Blood (up to 5 tablespoons) will be drawn to check your testosterone levels, biomarker
           testing, and for tumor marker testing.

        -  You will have an EKG.

        -  You will have a bone scan and either MRIs or CT scans.

      On Day 1 of Cycles 8-10:

        -  You will have a physical exam.

        -  Blood (up to 5 tablespoons) will be drawn for routine tests, tumor marker testing,
           biomarker testing, and to measure your PSA level. At some of these visits, this sample
           will also be used for CTC testing.

        -  Urine will be collected for tumor marker testing.

      After Cycle 10, you will only have study visits every 3 cycles. Beginning on Day 1 of Cycle
      13, every 3 cycles (Cycles 13, 16, 19, and so on):

        -  You will have a physical exam.

        -  Blood (up to 5 tablespoons) will be drawn for routine tests, tumor marker testing,
           biomarker testing, and to measure your PSA level. At some of these visits, this sample
           will also be used for CTC testing. You must fast for up to 12 hours before the visits at
           Cycle 10 and every 3 cycles after that.

        -  Urine will be collected for tumor marker testing.

        -  You will have a bone scan and either MRIs or CT scans to check the status of the
           disease.

        -  You will have an EKG.

      If you have severe side effects, you may return to the clinic more often so the study doctor
      can check on your health.

      End of Study Visit:

      When you leave the study, the following tests and procedures will be performed:

        -  You will have a physical exam.

        -  You will have a bone scan and either MRIs or CT scans to check the status of the
           disease.

        -  You will have an EKG.

        -  Blood (about 3 tablespoons) will be drawn for routine tests, tumor marker testing, and
           to measure your PSA level. You must fast for up to 12 hours before this visit.

        -  Urine will be collected for tumor marker testing.

      Follow-Up:

      About every 6 months after the end-of-study visit, the study staff will check your health.
      This will be done either by a chart review or a phone call. If you are called, this call will
      last about 5 minutes. These calls will stop if you withdraw from the study.
    

Trial Arms

NameTypeDescriptionInterventions
Cabazitaxel + CarboplatinExperimentalCabazitaxel, Cabazitaxel and Carboplatin intravenously on day 1 of cycles 1-6. Prednisone by mouth twice daily on days 1-21 of cycles 1-6.
  • Cabazitaxel
  • Carboplatin
  • Prednisone 5Mg
Olaparib MaintenanceExperimentalParticipants randomized to receive Olaparib by mouth twice daily on Day 1 of cycle 7.
  • Olaparib
Observation OnlyNo InterventionParticipants randomized to observation only beginning cycle 7.

    Eligibility Criteria

            Inclusion Criteria:
    
              1. Provision of informed consent prior to any study specific procedures.
    
              2. Provision of informed consent for genetic research. If a patient declines to
                 participate in the genetic research, there will be no penalty or loss of benefit to
                 the patient. The patient will not be excluded from other aspects of the study
                 described in this Clinical Study Protocol, so long as they consent to that part.
    
              3. Patients must agree to tissue collection for correlative studies at the specified
                 timepoints.
    
              4. Male aged 18 years and above.
    
              5. Histologically or cytologically confirmed prostate carcinoma.
    
              6. Presence of metastatic disease documented on imaging studies (bone scan, computed
                 tomography (CT) and/or magnetic resonance imaging (MRI) scans).
    
              7. Patients must meet at least one of the following AVPC criteria: i. Histologically
                 proven small cell (neuroendocrine) prostate carcinoma ii. Exclusive visceral
                 metastases. iii. Predominantly lytic bone metastases identified by plain x-ray or CT
                 scan. iv. Bulky (>/= 5cm in longest dimension) lymphadenopathy or high-grade tumor
                 mass in prostate/pelvis. v. Low PSA (</= 10ng/mL) at initial presentation (prior to
                 androgen ablation or at symptomatic progression in the castrate-setting) plus high
                 volume (>/= 20) bone metastases. vi. Elevated serum lactate dehydrogenase (>/=2 x
                 upper limit of normal) or elevated serumcarcinoembryonic antigen (>/= 2 x upper limit
                 of normal ) in the absence of other etiologies. vii. Short interval (</= 180 days) to
                 castrate-resistant progression following initiation of hormonal therapy. viii. Known
                 loss or mutation (by CLIIA certified molecular testing, IHC and/or DNA sequencing) in
                 at least 2 of the following: Tp53, RB1 and PTEN.
    
              8. Patients must have documented evidence of progressive disease as defined by any of the
                 following: a) PSA progression: minimum of 2 rising values (3 measurements) obtained a
                 minimum of 7 days apart with the last result being at least >/= 1.0 ng/mL; b) New or
                 increasing non-bone disease (RECIST); c) Positive bone scan with 2 or more new lesions
                 (PCWG2).
    
              9. Surgically or ongoing medically castrated, with baseline testosterone levels of </= 50
                 ng/dL </= 2.0 nM).
    
             10. Eastern Cooperative Oncology Group (ECOG) Performance Status of </=2.
    
             11. Patients must have normal organ and bone marrow function measured within 7 days prior
                 to administration of study treatment as defined below: i. Hemoglobin >/= 10.0 g/dL dL
                 (unless due to bone marrow infiltration by tumor, in which case hemoglobin >/=8gdL is
                 allowed) and no blood transfusions in the 7 days prior to entry. ii. Absolute
                 neutrophil count (ANC) >/= 1.5 x 10^9/L (unless due to bone marrow infiltration by
                 tumor, in which case ANC >1,000/mm3 is allowed) iii. White blood cells (WBC) >3x10^9/L
                 iv. No features suggestive of myelodysplastic syndrome/acute myeloid leukemia on
                 peripheral blood smear v. Platelet count >/= 100 x 10^9/L (unless due to bone marrow
                 infiltration by tumor, in which case platelet >/=50,000/ mm3 is allowed) vi. Total
                 bilirubin </=1.5 x institutional upper limit of normal (ULN) (except for patients with
                 known Gilbert's disease).
    
             12. (continued from Inclusion Criteria #11 vii. aspartate aminotransferase (serum
                 glutamine oxaloacetic transminase) and alanine aminotransferase (serum glutamic
                 pyruvic transaminase) </= 2.5 x institutional upper limit of normal unless liver
                 metastases are present in which case it must be </= 5x ULN viii. Calculated creatinine
                 clearance (Cockcroft-Gault Equation) >/= 40 mL/min.
    
             13. Able to swallow study drugs whole as a tablet/capsule.
    
             14. Patients who have partners of childbearing potential (e.g. female that has not been
                 surgically sterilized or who are not amenorrheic for >/= 12 months) must be willing to
                 use a method of birth control in addition to adequate barrier protection as determined
                 to be acceptable by the investigator during the study and for 13 weeks after last
                 study drug administration. Please note that the efficacy of hormonal contraception may
                 be decreased if administered with olaparib.
    
             15. Patient is willing and able to comply with the protocol for the duration of the study
                 including undergoing treatment and scheduled visits and examinations including follow
                 up.
    
            Exclusion Criteria:
    
              1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca
                 staff and/or staff at MD Anderson)
    
              2. Previous enrollment or randomization in the present study
    
              3. Any prior treatment for castration-resistant prostate cancer (CRPC) with carboplatin,
                 cisplatin, cabazitaxel or olaparib.
    
              4. Patients whose disease is refractory (defined as evidence of disease progression while
                 on drug or within 3 months of its discontinuation) to more than 2 lines of
                 chemotherapy given for CRPC. Any number of chemotherapies to which the patient's
                 disease is not refractory are allowed, as long as time on treatment did not exceed 6
                 months (counted from day 1 of cycle 1 to day 1 of the last cycle of treatment).
    
              5. Patients undergoing any systemic therapy (except for luteinizing hormone-releasing
                 (LHRH) hormone agonist or antagonist treatment for prostate cancer, and
                 bisphosphonates or receptor activator of Nf kappa (RANK) ligand inhibitors for bone
                 strengthening), major surgery or radiotherapy for the treatment of prostate cancer
                 within 2 weeks of study entry.
    
              6. Persistent toxicities (>/= common terminology criteria for adverse events grade 2)
                 with the exception of alopecia, caused by previous cancer therapy.
    
              7. Chronic use of known strong CYP3A4 inhibitors (e.g. ketoconazole, itraconazole,
                 ritonavir, indinavir, saquinavir, telithromycin, clarithromycin, voriconazole,
                 nefazodone, posaconazole, ritonavir, lopinavir/ritonavir, indinavir, saquinavir,
                 boceprevir, telaprevir and nelfinavir), moderate CYP3A4 inhibitors (e.g. amprenavir,
                 aprepitant, atazanavir, ciprofloxacin, crizotinib, darunavir/ritonavir, diltiazem,
                 erythromycin, fluconazole, fosamprenavir, imatinib, verapamil), strong CYP3A4 inducers
                 (e.g. phenytoin, rifampicin, carbamazepine, St.John's Wort, phenobarbital) and
                 moderate CYP3A4 inducers (e.g. bosentan, efavirenz, etravirine, modafinil and
                 nafcillin). Concomitant use of these drugs with olaparib is not allowed. Patients may
                 undergo limited courses of them prior to starting olaparib but will be required to
                 have >/= 5 week washout period from phenobarbital, and >/=3 week washout period from
                 the rest, before initiating treatment with olaparib.
    
              8. Resting ECG with QTc > 470msec on 2 or more time points within a 24 hour period or
                 family history of long QT syndrome.
    
              9. Active infection (requiring oral or intravenous antibiotics or antiviral therapy).
    
             10. Active or symptomatic viral hepatitis or chronic liver disease.
    
             11. A diagnosis or suspicion of myelodysplastic syndrome/acute myeloid leukemia.
    
             12. A history of pneumonitis or extensive bilateral lung disease of non-malignant
                 etiology.
    
             13. A malignancy [other than the one treated in this study] which required radiotherapy or
                 systemic treatment within the past 5 years, or has a >/= 30% probability of recurrence
                 within 24 months (except for adequately treated non-melanoma skin cancer, curatively
                 treated in-situ cancer of the Ta urothelial carcinomas).
    
             14. Any underlying medical or psychiatric condition, which in the opinion of the
                 Investigator, will make the administration of study drug hazardous or obscure the
                 interpretation of adverse events. Examples include, but are not limited to,
                 uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction,
                 superior vena cava syndrome, extensive bilateral lung disease on high-resolution
                 computed tomography scan, uncontrolled seizures or any psychiatric disorder that
                 prohibits obtaining informed consent.
    
             15. Patients unable to swallow orally administered medication and patients with
                 gastrointestinal disorders likely to interfere with absorption of the study
                 medication.
    
             16. Patients with symptomatic uncontrolled brain metastases or spinal cord compressions. A
                 scan to confirm the absence of brain metastases is not required. The patient can
                 receive a stable dose of corticosteroids before and during the study as long as these
                 were started at least 28 days prior to treatment.
    
             17. Patients with a known hypersensitivity to the olaparib, carboplatin or cabazitaxel.
    
             18. Prisoners or subjects who are involuntarily incarcerated.
    
             19. Subjects who are compulsorily detained for treatment of either a psychiatric or
                 physical (e.g. infectious disease) illness.
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:Male
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Progression-free survival (PFS) of men with AVPC treated with 6 cycles of cabazitaxel + carboplatin followed by olaparib maintenance versus observation
    Time Frame:Up to one year from time of randomization
    Safety Issue:
    Description:Progression Free Survival (PFS) calculated as the time from randomization until any one of the following events occurs, whichever comes first: Documented disease progression Start of a new therapy in the absence of progression Death in the absence of progression

    Secondary Outcome Measures

    Measure:Genomic alterations in DNA damage repair (DDR) pathway genes induced and/or selected by carboplatin and cabazitaxel chemotherapy [biopsy #2 vs biopsy #1]: Association with clinical outcome (PFS>6 months)
    Time Frame:Up to one year
    Safety Issue:
    Description:
    Measure:Rate of adverse events possibly, probably or definitely attributable to olaparib following cabazitaxel plus carboplatin in men with AVPC
    Time Frame:Up to one year
    Safety Issue:
    Description:
    Measure:Overall survival (OS) of men with AVPC treated with 6 cycles of cabazitaxel + carboplatin followed by olaparib maintenance vs observation
    Time Frame:Up to one year
    Safety Issue:
    Description:
    Measure:Response evaluation criteria in solid tumors (RECIST) and prostate specific antigen (PSA) response rate (RR) to cabazitaxel + carboplatin induction, and to olaparib maintenance in men with AVPC
    Time Frame:Up to one year
    Safety Issue:
    Description:
    Measure:Association between DDR pathway gene expression changes following carboplatin + cabazitaxel chemotherapy and clinical outcome (PFS>6 months)
    Time Frame:Up to one year
    Safety Issue:
    Description:
    Measure:Collection and archiving of serum, plasma, and urine samples in study patients for later hypothesis generating associations
    Time Frame:Up to one year
    Safety Issue:
    Description:

    Details

    Phase:Phase 2
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:M.D. Anderson Cancer Center

    Trial Keywords

    • prostate cancer
    • genomic alterations
    • DNA damage repair
    • DDR pathway gene expression
    • aggressive-variant prostate carcinomas
    • small cell prostate carcinoma
    • neuroendocrine prostate carcinoma

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