Clinical Trials /

Bipolar Androgen Therapy in Metastatic Castrate Resistant Prostate Cancer With Homologous Recombination Deficiency

NCT03522064

Description:

The purpose of this study is to determine the efficacy of BAT in men with metastatic castrate-resistant prostate cancer (mCRPC) and homologous recombination deficiency (HRD). Bipolar androgen therapy will be administered to men confirmed to have HRD on tumour tissue and/or circulating tumour DNA analysis on pre-screening.

Related Conditions:
  • Prostate Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Bipolar Androgen Therapy in Metastatic Castrate Resistant Prostate Cancer With Homologous Recombination Deficiency
  • Official Title: High Dose Testosterone in Men With Advanced Prostate Cancer and Homologous Recombination Deficiency

Clinical Trial IDs

  • ORG STUDY ID: HiTECH
  • NCT ID: NCT03522064

Conditions

  • Castration-resistant Prostate Cancer
  • Homologous Recombination Deficiency

Interventions

DrugSynonymsArms
Testosterone EnanthatePrimoteston DepotHigh dose testosterone

Purpose

The purpose of this study is to determine the efficacy of BAT in men with metastatic castrate-resistant prostate cancer (mCRPC) and homologous recombination deficiency (HRD). Bipolar androgen therapy will be administered to men confirmed to have HRD on tumour tissue and/or circulating tumour DNA analysis on pre-screening.

Detailed Description

      Androgen deprivation therapy (ADT) remains the mainstay of prostate cancer treatment. Though
      an effective therapy initially, the side effects of ADT are numerous and treatment resistance
      is inevitable. Castrate-refractory prostate cancer (CRPC) progresses via adaptive mechanisms
      that allow ongoing androgen receptor (AR) signalling despite castrate levels of androgens.

      The concept of cycling between supra- and sub physiological levels of testosterone has been
      tested recently in studies of "bipolar androgen therapy" (BAT) in which patients are given
      high dose testosterone in combination with androgen deprivation therapy (ADT) via an LHRH
      agonist/antagonist. Studies of BAT using IM testosterone have been promising both in terms of
      PSA responses and quality of life improvements. Additionally, these early phase studies
      suggest the potential for re-sensitisation to novel anti-androgen therapies.

      Though responses have been positive in these early studies a proportion of men fail to
      respond and data to guide patient selection is lacking. There are data to suggest that
      patients with DNA repair deficits may be particularly responsive to BAT. Whether these
      changes serve as predictors of response is unknown as the effect of BAT on the tumour, its
      microenvironment and peripheral circulating tumour DNA has not been studied in detail.
      Information on treatment effects may be key to appropriate patient selection for this
      treatment.

      The aim of this study is to assess homologous repair deficiency as a predictive biomarker of
      response to bipolar androgen therapy in men with metastatic castrate-refractory prostate
      cancer and to study the effects of this treatment on ctDNA and intra-tumoural gene
      expression.
    

Trial Arms

NameTypeDescriptionInterventions
High dose testosteroneExperimental500mg IM enanthate every 4 weeks in combination with ongoing LHRH agent (unless post-orchidectomy).
  • Testosterone Enanthate

Eligibility Criteria

        Inclusion Criteria:

          1. Males with histologically confirmed adenocarcinoma of the prostate

          2. Confirmed HRD (Homologous recombination defect) in germline and/or somatic DNA
             analysis (tumour or blood), by a validated assay (see Appendix 1). Mutations in HR
             genes not listed in appendix 1 will be considered in literature suggests
             pathogenicity. A maximum of 10 uncharacterised or heterozygous mutations will be
             included.

          3. Age ≥ 18 years

          4. ECOG performance status ≤ 1

          5. Rising PSA confirmed on two sequential tests ≥1 week apart and a minimum value of 2
             ug/L despite castrate levels of testosterone

          6. Serum testosterone < 1.7 nmol/L and on an LHRH agent or post orchidectomy ≥ 1 year.

          7. Washout of ≥ 4 weeks from prior line of treatment, radiotherapy or surgery (aside from
             LHRH agent)

          8. Adequate bone marrow function (platelets > 100 x 109/L, ANC > 1.5 x 109/L, Hb >100)

          9. Adequate liver function (ALT/AST < 1.5 x ULN, bilirubin < 2 x ULN)

         10. Adequate renal function (creatinine clearance > 50 ml/min)

         11. Adequate cardiac function and reserve after cardiology assessment

         12. Archived tissue sample available or willingness to undergo fresh biopsy

         13. Willing and able to comply with all study requirements, including treatment, timing
             and/or nature of required assessments

         14. Signed, written informed consent

        Exclusion Criteria:

          1. Contraindications to investigational product

          2. Pain due to metastatic prostate cancer requiring opioid analgesics

          3. Evidence of disease progression in sites or extent that, in the opinion of the
             investigator, would put the patient at risk from testosterone therapy and its
             potential for initial tumour flare (eg: femoral metastasis at risk of fracture,
             ureteric obstruction due to nodal disease or cord compression due to spinal
             metastases).

          4. Previous treatment with platinum chemotherapy and/or a PARP inhibitor. However up to 8
             men with prior treatment to these agents will be included as an exploratory cohort.

          5. Life expectancy of less than 3 months.

          6. Brain metastases or leptomeningeal disease

          7. History of thromboembolic event and not currently on anticoagulation

          8. Prior myocardial infarction or unstable angina within 2 years of study entry

          9. Haematocrit ≥ 50%, untreated severe obstructive sleep apnoea or poorly controlled
             heart failure (NYHA >1)

         10. History of another malignancy within 5 years prior to registration. Patients with a
             past history of adequately treated carcinoma-in-situ, basal cell carcinoma of the
             skin, squamous cell carcinoma of the skin, or superficial transitional cell carcinoma
             of the bladder are eligible. Patients with a history of other malignancies are
             eligible if they have been continuously disease free for at least 5 years after
             definitive primary treatment.

         11. Concurrent illness, including severe infection that may jeopardize the ability of the
             patient to undergo the procedures outlined in this protocol with reasonable safety.

         12. Presence of any psychological, familial, sociological or geographical condition
             potentially hampering compliance with the study protocol and follow-up schedule,
             including alcohol dependence or drug abuse.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure:PSA Response Rate
Time Frame:1 year
Safety Issue:
Description:>/= 50% fall from baseline PSA

Secondary Outcome Measures

Measure:Time to PSA progression
Time Frame:1 year
Safety Issue:
Description:Time to increase in PSA >/=25% from baseline or nadir confirmed on subsequent test >1 week later
Measure:Quality of Life
Time Frame:1 year
Safety Issue:
Description:FACT-P
Measure:Radiological Response Rate
Time Frame:1 year
Safety Issue:
Description:RECIST or PCWG3 Criteria
Measure:Safety and Tolerability (Frequency of adverse events as assessed by NCI CTCAE v4.0)
Time Frame:1 year
Safety Issue:
Description:Frequency of adverse events as assessed by NCI CTCAE v4.0

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:St Vincent's Hospital, Sydney

Trial Keywords

  • Castrate-resistant prostate cancer
  • bipolar androgen therapy
  • homologous recombination deficiency
  • BRCA

Last Updated