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Testosterone and Olaparib in Treating Participants With Castration-Resistant Prostate Cancer

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ClinicalTrials.gov Identifier: NCT03516812
Recruitment Status : Recruiting
First Posted : May 4, 2018
Last Update Posted : July 18, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
University of Washington

Brief Summary:
This phase II trial studies how well testosterone (enanthate or cypionate) and olaparib work in treating participants with prostate cancer that has progressed despite hormonal therapy. Hormonal therapy, such as leuprolide, may lessen the amount of male sex hormones made by the body. In patients that have developed progressive cancer in spite of standard hormonal treatment (i.e. castration-resistant prostate cancer), administering testosterone may result in regression of tumors by causing DNA damage in cancer cells that have adapted to low testosterone conditions. Olaparib may stop the growth of tumor cells by blocking some of the enzymes involved in repairing DNA damage. Therefore, giving testosterone and olaparib together may work better in treating castration-resistant prostate cancer by generating DNA damage that the cancer cell is unable to repair.

Condition or disease Intervention/treatment Phase
Castration Levels of Testosterone Castration-Resistant Prostate Carcinoma Prostate Adenocarcinoma PSA Level Greater Than or Equal to One PSA Progression Other: Laboratory Biomarker Analysis Drug: Olaparib Other: Quality-of-Life Assessment Other: Survey Administration Drug: Testosterone Enanthate Drug: Testosterone Cypionate Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. Determine the prostate-specific antigen (PSA)50 response rate (i.e., percent of patients with a PSA decline of at least 50% below baseline) following 12-weeks of treatment with bipolar androgen therapy (BAT) (i.e., intermittent high dose testosterone) plus olaparib in men with asymptomatic metastatic castration-resistant prostate cancer (mCRPC) who have progressed on abiraterone and/or enzalutamide.

SECONDARY OBJECTIVES:

I. Determine the percent of mCRPC patients achieving a radiographic response per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria following treatment with BAT plus olaparib.

II. Determine the radiographic progression free survival (PFS) in mCRPC patients treated with BAT plus olaparib using RECIST 1.1 criteria for soft tissue metastases and Prostate Cancer Working Group 3 (PCWG3) criteria for bone metastases.

III. Determine the PSA PFS rate according to PCWG3 criteria in mCRPC patients treated with BAT plus olaparib.

IV. Determine the PFS (i.e. whichever occurs first: clinical, radiographic or PSA progression) in mCRPC patients treated with BAT plus olaparib.

V. Determine the overall survival in mCRPC patients treated with BAT plus olaparib.

VI. Track changes in quality of life (QoL) as determined using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) and International Index of Erectile Function (IIEF) surveys.

VII. Assess the incidence and severity of adverse events according to the National Cancer Institute - Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

OUTLINE:

Participants receive olaparib orally (PO) twice daily (BID) on days 1-28 and testosterone enanthate or cypionate intramuscularly (IM) on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of the study treatment, participants are followed up at 30 days and every 6 months for up to 2 years.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Bipolar Androgen Therapy Plus Olaparib in Patient With Castration-Resistant Prostate Cancer
Actual Study Start Date : August 29, 2018
Estimated Primary Completion Date : March 1, 2021
Estimated Study Completion Date : March 1, 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Prostate Cancer

Arm Intervention/treatment
Experimental: Treatment (olaparib, testosterone enanthate or cypionate)
Participants receive olaparib PO BID on days 1-28 and testosterone enanthate or cypionate IM on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Olaparib
Given PO
Other Names:
  • AZD2281
  • KU-0059436
  • Lynparza
  • PARP Inhibitor AZD2281

Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment

Other: Survey Administration
Correlative studies

Drug: Testosterone Enanthate
Given IM
Other Names:
  • Andro LA
  • Androtardyl
  • Delatestryl
  • Everone
  • Primosteston
  • Testate
  • Testinon
  • Testo-Enant

Drug: Testosterone Cypionate
Given IM
Other Names:
  • Depo-Testosterone
  • TC
  • TCPP
  • Testosterone cyclopentylpropionate
  • Testosterone cyclopentanepropionate
  • Testosterone 17β-cyclopentylpropionate




Primary Outcome Measures :
  1. Percent of patients with a prostate-specific antigen (PSA) decline of at least 50% below baseline PSA50 response rate [ Time Frame: Up to 12 weeks after initiating therapy ]
    PSA response will be defined as a decline in PSA ≥ 50% compared to baseline. Will be calculated as the percentage with 95% confidence interval (CI) of the total number of subjects that achieved a PSA response.

  2. Incidence of adverse events (AEs) according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 [ Time Frame: Up to 30 days after last dose ]
    Safety will be summarized as the severity and frequency of a given AE.


Secondary Outcome Measures :
  1. Radiographic response rate [ Time Frame: Up to 2 years ]
    Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 guidelines. Will be presented in a waterfall plot.

  2. PSA progression free survival (PFS) [ Time Frame: From the start of treatment until PSA progression, assessed up to 2 years ]
    This will be defined by PCWG3 criteria). Survival endpoints will be presented with Kaplan-Meier curves, and the median survival with 95% CI will be calculated. Rates will be reported as percentages with 95% CI. Best on study PSA for each patient will be presented in a waterfall plot.

  3. Overall survival (OS) [ Time Frame: Up to 2 years ]
    Survival endpoints will be presented with Kaplan-Meier curves, and the median survival with 95% CI will be calculated. Rates will be reported as percentages with 95% CI.

  4. Radiographic PFS [ Time Frame: Up to 2 years ]
    Will be presented in a waterfall plot.

  5. PSA50 response rate (i.e. decline in PSA ≥ 50% from baseline) [ Time Frame: Up to 2 years ]
    Will be presented in a waterfall plot.

  6. Average change in quality of life (QOL) assessed by the Functional Assessment of Cancer Therapy-Prostate (FACT-P) survey [ Time Frame: Up to 12 weeks after initiating therapy ]
    Average change in QOL scores (total and for each domain) for each survey will be calculated at each timepoint. A paired t-test will be used to assess for statistically significant changes in QOL from baseline to the 12-week timepoint, and linear mixed effects models will be used to evaluate trends over all timepoints.

  7. Average change in quality of life (QOL) assessed by the International Index of Erectile Function (IIEF) survey [ Time Frame: Up to 12 weeks after initiating therapy ]
    Average change in QOL scores (total and for each domain) for each survey will be calculated at each timepoint. A paired t-test will be used to assess for statistically significant changes in QOL from baseline to the 12-week timepoint, and linear mixed effects models will be used to evaluate trends over all timepoints.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Must be willing to provide informed consent prior to any study specific procedures
  • Documented histologically confirmed adenocarcinoma of the prostate
  • Patient must have evidence of castration resistant prostate cancer as evidenced by PSA progression (per Prostate Cancer Working Group 3 [PCWG3] criteria) and a castrate serum testosterone level (i.e., ≤ 50 mg/dL)
  • PSA must be at least 1 ng/ml and rising on two successive measurements at least two weeks apart
  • Patients must have progressed on abiraterone and/or enzalutamide; there must be at least a 3-week washout period after stopping the most recent approved therapy for mCRPC (i.e., abiraterone, enzalutamide, Ra-223, sipuleucel-t); if applicable, patients should be weaned off steroids at least 1 week prior to starting treatment
  • No prior chemotherapy for the treatment of mCRPC; patients may have received docetaxel for the treatment of hormone-sensitive prostate cancer
  • Prior treatment with non-chemotherapy investigational agents is permitted; there must be at least a 3-week washout period after stopping any investigational cancer agent
  • Hemoglobin ≥ 10.0 g/dL with no blood transfusion in the past 28 days (within 28 days prior to administration of study treatment)
  • Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L (within 28 days prior to administration of study treatment)
  • Platelet count ≥ 100 x 10^9/L (within 28 days prior to administration of study treatment)
  • Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) (within 28 days prior to administration of study treatment)
  • 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 ≤ 5 x ULN (within 28 days prior to administration of study treatment)
  • Patients must have creatinine clearance estimated using the Cockcroft-Gault equation of ≥ 51 mL/min (within 28 days prior to administration of study treatment)
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-1
  • Patients must have a life expectancy ≥ 16 weeks
  • Male patients 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 throughout the period of taking study treatment and for 3 months after last dose of study drug(s) to prevent pregnancy in a partner
  • Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations
  • At least one lesion (measurable and/or non-measurable) that can be accurately assessed at baseline by computed tomography (CT), positron-emission tomography (PET), magnetic resonance imaging (MRI) and/or bone scan and is suitable for repeated assessment
  • Must have archival tissue available, be willing to undergo metastatic biopsy or have a sufficient plasma circulating tumor DNA (ctDNA) concentration in order to perform next-generation DNA sequencing
  • The study will require that 50% of enrolled subjects have homozygous deletions, deleterious mutations, or both in one or more of the DNA damage response (DDR) genes; the other 50% of patients must have an intact DDR pathway

Exclusion Criteria:

  • Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
  • Previous enrollment in this study
  • Participation in another clinical study with an investigational product during the last 3 weeks
  • Any previous treatment with poly-adenosine diphosphate ribose polymerase (PARP) inhibitor, including olaparib
  • Other malignancy within the last 5 years except: adequately treated non-melanoma skin cancer or other solid tumors including lymphomas (without bone marrow involvement) curatively treated with no evidence of disease for ≥ 5 years
  • Resting electrocardiogram (ECG) with corrected QT interval (QTc) > 470 msec on 2 or more time points within a 24 hour period or family history of long QT syndrome
  • Patients receiving any systemic chemotherapy or radiotherapy (except for palliative reasons) within 3 weeks prior to study treatment
  • 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
  • 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 3 weeks for enzalutamide, 5 weeks for phenobarbital and 3 weeks for other agents
  • Persistent toxicities (> Common Terminology Criteria for Adverse Event [CTCAE] grade 2) caused by previous cancer therapy, excluding alopecia
  • Patients with myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML)
  • Patients with symptomatic uncontrolled brain metastases; 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 4 weeks prior to treatment; patients with spinal cord compression unless considered to have received definitive treatment for this and evidence of clinically stable disease for 28 days
  • Major surgery within 2 weeks of starting study treatment and patients must have recovered from any effects of any major surgery
  • Patients considered a 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, history of prior myocardial infarction, uncontrolled major seizure disorder, uncontrolled hypertension (blood pressure [BP] ≥ 160/100), history of prior stroke, uncontrolled diabetes (hemoglobin [hgb] A1C > 7), unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on high resolution computed tomography (HRCT) scan or any psychiatric disorder that prohibits obtaining informed consent
  • Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication
  • Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV)
  • Patients with a known hypersensitivity to olaparib or any of the excipients of the product
  • Patients with a known hypersensitivity to the testosterone cypionate or any of the excipients of the product
  • Patients with known active hepatitis (i.e., hepatitis B or C) due to risk of transmitting the infection through blood or other body fluids
  • Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT)
  • Whole blood transfusions in the last 120 days prior to entry to the study (packed red blood cells and platelet transfusions are acceptable)
  • Evidence of serious and/or unstable pre-existing medical, psychiatric or other condition (including laboratory abnormalities) that could interfere with patient safety or provision of informed consent to participate in this study
  • Any psychological, familial, sociological, or geographical condition that could potentially interfere with compliance with the study protocol and follow-up schedule
  • Evidence of disease that, in the opinion of the investigator, would put the patient at risk from testosterone therapy (e.g. femoral metastases with concern over fracture risk, spinal metastases with concern over spinal cord compression, lymph node disease with concern for ureteral obstruction)
  • Patients with pain attributable to their prostate cancer
  • Tumor causing urinary outlet obstruction that requires catheterization for voiding; patients that require catheterization to void secondary to benign strictures or other non-cancer causes will be permitted to enroll
  • Prior history of deep venous thrombosis or pulmonary embolism within 5 years prior to enrollment in the study and not currently on systemic anticoagulation
  • Patients with NYHA (New York Heart Association) class III or IV heart failure or history of a prior myocardial infarction (MI) within the last five years prior to enrollment in the study

Information from the National Library of Medicine

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): NCT03516812


Contacts
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Contact: Michael T. Schweizer (206) 288-6252 schweize@uw.edu

Locations
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United States, Washington
Fred Hutch/University of Washington Cancer Consortium Recruiting
Seattle, Washington, United States, 98109
Contact: Michael Schweizer         
Principal Investigator: Michael Schweizer         
Sponsors and Collaborators
University of Washington
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Michael T. Schweizer Fred Hutch/University of Washington Cancer Consortium

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Responsible Party: University of Washington
ClinicalTrials.gov Identifier: NCT03516812     History of Changes
Other Study ID Numbers: 9984
NCI-2018-00542 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
9984 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium )
P30CA015704 ( U.S. NIH Grant/Contract )
RG1718004 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium )
First Posted: May 4, 2018    Key Record Dates
Last Update Posted: July 18, 2019
Last Verified: July 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Prostatic Neoplasms
Adenocarcinoma
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Genital Diseases, Male
Prostatic Diseases
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Testosterone
Testosterone undecanoate
Testosterone enanthate
Testosterone 17 beta-cypionate
Methyltestosterone
Olaparib
Androgens
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Anabolic Agents
Poly(ADP-ribose) Polymerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action