Clinical Trials /

Olaparib in Men With High-Risk Biochemically-Recurrent Prostate Cancer Following Radical Prostatectomy, With Integrated Biomarker Analysis

NCT03047135

Description:

Olaparib has demonstrated preliminary efficacy in metastatic castration-resistant prostate cancer. In a trial of 49 evaluable patients treated with olaparib, 11 / 49 experienced a PSA response, and every patient with a radiographic response also had a PSA5 response. Ten of 11 responders had mutations in DNA repair genes. While PARP inhibition is showing promise in these initial studies, reserving its use for end-stage patients may not be the optimal timing for olaparib therapy in some patients. In addition, PARP enzymes function in roles beyond DNA repair, and specifically for prostate cancer are involved transcriptional regulation of the androgen receptor. PARP inhibition has not been tested in earlier disease states for prostate cancer.

Related Conditions:
  • Prostate Adenocarcinoma
  • Prostate Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Olaparib in Men With High-Risk Biochemically-Recurrent Prostate Cancer Following Radical Prostatectomy, With Integrated Biomarker Analysis
  • Official Title: Phase II Study of Olaparib in Men With High-Risk Biochemically-Recurrent Prostate Cancer Following Radical Prostatectomy, With Integrated Biomarker Analysis

Clinical Trial IDs

  • ORG STUDY ID: J16163
  • SECONDARY ID: IRB00114635
  • NCT ID: NCT03047135

Conditions

  • Prostate

Interventions

DrugSynonymsArms
OlaparibOlaparib 300 mg BID

Purpose

Olaparib has demonstrated preliminary efficacy in metastatic castration-resistant prostate cancer. In a trial of 49 evaluable patients treated with olaparib, 11 / 49 experienced a PSA response, and every patient with a radiographic response also had a PSA5 response. Ten of 11 responders had mutations in DNA repair genes. While PARP inhibition is showing promise in these initial studies, reserving its use for end-stage patients may not be the optimal timing for olaparib therapy in some patients. In addition, PARP enzymes function in roles beyond DNA repair, and specifically for prostate cancer are involved transcriptional regulation of the androgen receptor. PARP inhibition has not been tested in earlier disease states for prostate cancer.

Detailed Description

      The proposed study is an open-label single-arm phase II trial.

      Eligible patients are those with non-metastatic biochemically-recurrent prostate cancer and a
      PSADT of ≤6 months and a minimum PSA of 1.0.

      After enrollment, patients will be treated with olaparib at the established dose of 300mg
      tablets by mouth twice daily. Patients will be followed monthly with clinic visits, safety
      labs (including CBC w/diff, Comp), PSA, and toxicity assessments. Treatment [with a minimum
      drug exposure of 12 weeks] will be continued until PSA doubling from study entry (confirmed
      with another measurement at least 4 weeks later), development of radiographic metastatic
      disease, or toxicity requiring drug cessation. CT scans and NM bone scans will be performed
      every 6 months for patients remaining on olaparib treatment.

      This study will enroll up to 50 subjects. The study design will employ a stepwise adaptive
      statistical plan, derived in part from Biankin et al, Nature 2015 Oct 15;526(7573):361-70.
      The design is adapted from a multi-stage design, with interim stopping rules to determine
      futility or need for enrichment of the study population.

      The study will initiate with a two-stage design in an unselected population. The assumptions
      for the trial of the unselected population are: null hypothesis of 0.1 PSA response rate and
      alternative hypothesis of 0.3 for the unselected population. The first stage is 20 subjects.
      If ≤2 subjects responds in the first stage, then unselected population study is halted for
      futility and an assessment of DNA mutations present in the initial cohort will be undertaken.
      If less than 3 subjects with a known/suspected deleterious mutation in the following genes
      (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C,
      RAD51D, or other DNA repair genes) have been accrued in the first stage, then the trial will
      proceed with enrichment. If 3 or more subjects with known/suspected deleterious mutation in
      the genes of interest have been accrued, then the trial will proceed with enrichment, as long
      as the response rate in that subset of subjects is ≥20%. In the case that 3 or more subjects
      have been accrued, yet the response rate in that subset is <20%, then the trial is halted for
      futility.

      However, if ≥3 subjects among the first 20 respond, then additional 10 unselected subjects
      are accrued. If ≥6 subjects respond out of 30 in the unselected population after the second
      stage, then the null hypothesis is rejected in the unselected population and broad efficacy
      will be concluded.

      The trial proceeds to complete accrual of 50 subjects in order to better estimate PSA
      response rate and strengthen data for correlative studies. If <6 respond, then the null
      hypothesis is not rejected. Again, if less than 3 subjects with a known/suspected deleterious
      mutation in the following genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCL,
      PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, or other DNA repair genes) have been accrued in the
      first and second stage combined, then the trial will proceed with enrichment. If 3 or more
      subjects with those mutations have been accrued, then enrichment will again proceed as long
      as the response rate in that subject of subjects is ≥20%.
    

Trial Arms

NameTypeDescriptionInterventions
Olaparib 300 mg BIDExperimentalPatients will be administered olaparib orally twice daily at 300mg bid continually. Two 150mg of olaparib tablets should be taken twice daily, approximately 12 hours apart with one glass of water.
  • Olaparib

Eligibility Criteria

        Inclusion Criteria:

          1. Histologic diagnosis of adenocarcinoma of the prostate

          2. Prior local therapy with prostatectomy required, with available tissue from
             prostatectomy specimen to send for genomic and transcriptomic testing.

          3. Prior salvage or adjuvant radiation therapy is allowed but not mandated. Radiation
             therapy must have been completed for at least 6 months.

          4. Absolute PSA ≥1 ng/ml. Prior undetectable PSA post-prostatectomy is not required.

          5. PSADT ≤6 months, based upon ≥3 consecutive measurements collected in the past 12
             months, at least 4 weeks apart

          6. No radiographic evidence of metastatic disease by CT scan and bone scan, performed
             within the prior 4 weeks.

          7. Serum testosterone ≥ 150 ng/dl

          8. Participants 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 with no blood transfusion in the past 28 days

               -  Absolute neutrophil count (ANC) ≥ 1.5 x 109/L

               -  Platelet count ≥ 75 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. Note: Patients with elevations in
                  bilirubin, AST, or ALT should be thoroughly evaluated for the etiology of this
                  abnormality prior to entry and patients with evidence of viral infection should
                  be excluded.

               -  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

          9. Eastern Cooperative Oncology Group (ECOG) performance status 0-1

         10. Male participants and their partners, who are sexually active and of childbearing
             potential, must agree to the use of two highly effective forms of contraception in
             combination [see appendix F for acceptable methods], throughout the period of taking
             study treatment and for 3 months after last dose of study drug to prevent pregnancy in
             a partner.

         11. For enrichment stage of trial only (if necessary): Confirmation of a suspected/known
             deleterious mutation in a gene of interest (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12,
             CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, or other DNA repair
             genes) via CLIA certified testing.

        Exclusion Criteria:

          1. Prior ADT in the past 6 months. Prior ADT in context of neoadjuvant/adjuvant primary;
             prior ADT for biochemical recurrence is allowed, as long as no ADT has been
             administered in past 6 months and testosterone has recovered (>150 ng/dl). The total
             duration of prior ADT should not exceed 24 months.

          2. Prior oral anti-androgen (e.g. bicalutamide, nilutamide, enzalutamide, apalutamide),
             or androgen synthesis inhibitor (e.g. abiraterone, orteronel) in the past 6 months.
             5-alpha reductase inhibitor therapy (e.g. finasteride, dutasteride) is allowed, as
             long as subject has been stable on medication for past 6 months.

          3. Prior treatment with intravenous chemotherapy.

          4. Involvement in the planning and/or conduct of the study

          5. Participation in another clinical study with an investigational product during the
             last 1 month.

          6. Any previous treatment with PARP inhibitor, including olaparib

          7. Resting ECG with QTc > 470 msec on 2 or more time points within a 24 hour period or
             family history of long QT syndrome

          8. Concomitant use of known strong CYP3A inhibitors (eg. itraconazole, telithromycin,
             clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir,
             saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg.
             ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout
             period prior to starting olaparib is 2 weeks.

          9. Concomitant use of known strong CYP3A inducers (eg. phenobarbital, enzalutamide,
             phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's
             Wort ) or moderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). The required
             washout period prior to starting olaparib is 5 weeks for phenobarbital and 3 weeks for
             other agents.

         10. Myelodysplastic syndrome/acute myeloid leukaemia or with features suggestive of
             MDS/AML.

         11. Major surgery within 2 weeks of starting study treatment and patients must have
             recovered from any effects of any major surgery.

         12. Poor medical risk due to a serious, uncontrolled medical disorder, non- malignant
             systemic disease or active, uncontrolled infection. Examples include, but are not
             limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial
             infarction, uncontrolled major seizure disorder, extensive interstitial bilateral lung
             disease on High Resolution Computed Tomography (HRCT) scan or any psychiatric disorder
             that prohibits obtaining informed consent.

         13. Unable to swallow orally administered medication and patients with gastrointestinal
             disorders likely to interfere with absorption of the study medication.

         14. Immunocompromised patients, e.g., patients who are known to be serologically positive
             for human immunodeficiency virus (HIV).

         15. Known hypersensitivity to olaparib or any of the excipients of the product.

         16. Known active hepatitis (i.e. Hepatitis B or C) due to risk of transmitting the
             infection through blood or other body fluids

         17. Whole blood transfusions in the last 120 days prior to entry to the study (packed red
             blood cells and platelet transfusions are acceptable, for timing refer to inclusion
             criteria no.10)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure:Response rate (PSA) to olaparib for patients with high-risk biochemically-recurrent prostate cancer. Measured by decline in PSA to 50% of baseline level, confirmed with a second measurement at least 4 weeks apart.
Time Frame:4 weeks
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Time Frame:2 years
Safety Issue:
Description:
Measure:To evaluate PSA progression-free survival, defined as a time from initiation on olaparib therapy until PSA increase of 25%, confirmed with another measurement at least 4 weeks later.
Time Frame:6 months
Safety Issue:
Description:
Measure:To evaluate time to PSA doubling from baseline,
Time Frame:6 months
Safety Issue:
Description:
Measure:To evaluate duration of undetectable PSA
Time Frame:12 weeks
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Trial Keywords

  • high-risk biochemically-recurrent

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