Olaparib in Men With High-Risk Biochemically-Recurrent Prostate Cancer Following Radical Prostatectomy, With Integrated Biomarker Analysis
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|ClinicalTrials.gov Identifier: NCT03047135|
Recruitment Status : Recruiting
First Posted : February 8, 2017
Last Update Posted : June 26, 2018
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.
|Condition or disease||Intervention/treatment||Phase|
|Prostate||Drug: Olaparib||Phase 2|
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%.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||50 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Phase II Study of Olaparib in Men With High-Risk Biochemically-Recurrent Prostate Cancer Following Radical Prostatectomy, With Integrated Biomarker Analysis|
|Actual Study Start Date :||March 1, 2017|
|Estimated Primary Completion Date :||March 1, 2021|
|Estimated Study Completion Date :||March 1, 2022|
Experimental: Olaparib 300 mg BID
Patients 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 will be dispensed to patients on Day 1 and every 28 days thereafter until the patient completes the study, withdraws from the study or closure of the study.
- 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 ]
- Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: 2 years ]
- 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 ]
- To evaluate time to PSA doubling from baseline, [ Time Frame: 6 months ]
- To evaluate duration of undetectable PSA [ Time Frame: 12 weeks ]
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03047135
|Contact: Emmanuel Antonarakis, MDfirstname.lastname@example.org|
|United States, Maryland|
|Johns Hopkins Hospital||Recruiting|
|Baltimore, Maryland, United States, 21231|
|Contact: Emmanuel Antonarakis, MD 443-287-0553 email@example.com|
|Contact: Rana Sullivan, RN 410-614-6337 firstname.lastname@example.org|
|United States, Pennsylvania|
|Thomas Jefferson University||Recruiting|
|Philadelphia, Pennsylvania, United States, 19107|
|Contact: William Kelly, MD 215-503-4490 email@example.com|
|Contact: Megan Irving, BS 215-955-9548 firstname.lastname@example.org|
|Principal Investigator: William Kelly, MD|
|Allegheny Cancer Center||Recruiting|
|Pittsburgh, Pennsylvania, United States, 15212|
|Contact: Shifeng S Mao, MD 412-359-8373 email@example.com|
|Contact: Christy Milburn, MS 412-359-8379 firstname.lastname@example.org|
|Principal Investigator: Shifeng S Mao, MD|
|Principal Investigator:||Emmanuel Antonarakis, MD||Johns Hopkins University|