Clinical Trials /

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

NCT03516812

Description:

This phase II trial studies how well testosterone (enanthate or cypionate) and olaparib work in treating patients 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.

Related Conditions:
  • Prostate Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Testosterone and Olaparib in Treating Participants With Castration-Resistant Prostate Cancer
  • Official Title: Bipolar Androgen Therapy Plus Olaparib in Patient With Castration-Resistant Prostate Cancer

Clinical Trial IDs

  • ORG STUDY ID: 9984
  • SECONDARY ID: NCI-2018-00542
  • SECONDARY ID: 9984
  • SECONDARY ID: P30CA015704
  • SECONDARY ID: RG1718004
  • NCT ID: NCT03516812

Conditions

  • Castration Levels of Testosterone
  • Castration-Resistant Prostate Carcinoma
  • Prostate Adenocarcinoma
  • PSA Level Greater Than or Equal to One
  • PSA Progression

Interventions

DrugSynonymsArms
OlaparibAZD2281, KU-0059436, Lynparza, PARP Inhibitor AZD2281Treatment (olaparib, testosterone enanthate or cypionate)
Testosterone EnanthateAndro LA, Androtardyl, Delatestryl, Everone, Primosteston, Testate, Testinon, Testo-EnantTreatment (olaparib, testosterone enanthate or cypionate)
Testosterone CypionateDepo-Testosterone, TC, TCPP, Testosterone cyclopentylpropionate, Testosterone cyclopentanepropionate, Testosterone 17β-cyclopentylpropionateTreatment (olaparib, testosterone enanthate or cypionate)

Purpose

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (olaparib, testosterone enanthate or cypionate)ExperimentalParticipants 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.
  • Olaparib
  • Testosterone Enanthate
  • Testosterone Cypionate

Eligibility 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Radiographic response rate
Time Frame:Up to 2 years
Safety Issue:
Description:Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 guidelines. Will be presented in a waterfall plot.
Measure:PSA progression free survival (PFS)
Time Frame:From the start of treatment until PSA progression, assessed up to 2 years
Safety Issue:
Description: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.
Measure:Overall survival (OS)
Time Frame:Up to 2 years
Safety Issue:
Description: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.
Measure:Radiographic PFS
Time Frame:Up to 2 years
Safety Issue:
Description:Will be presented in a waterfall plot.
Measure:PSA50 response rate (i.e. decline in PSA ≥ 50% from baseline)
Time Frame:Up to 2 years
Safety Issue:
Description:Will be presented in a waterfall plot.
Measure: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
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of Washington

Last Updated

July 15, 2019