HiTeCH: Bipolar Androgen Therapy + Carboplatin in mCRPC

Sponsor

St Vincent's Hospital, Sydney (Other)

Overall Status

Recruiting

CT.gov ID

NCT03522064

Collaborator

(none)

Enrollment

Location

Arm

Anticipated Duration (Months)

0.6

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to determine the efficacy of BAT and carboplatin in men with metastatic castrate-resistant prostate cancer (mCRPC).

Condition or Disease	Intervention/Treatment	Phase
Castration-resistant Prostate Cancer Homologous Recombination Deficiency	Drug: Testosterone Enanthate 100 MG/ML Injectable Solution Drug: Testosterone Enanthate 100 MG/ML Injectable Solution / Carboplatin AUC 5	Phase 2

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 based on the pre-clinical studies, the combination with carboplatin

Study Design

Study Type:

Interventional

Anticipated Enrollment :

30 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

High Dose Testosterone + Carboplatin in Men With Advanced Prostate Cancer

Actual Study Start Date :

Jul 30, 2018

Anticipated Primary Completion Date :

Dec 30, 2022

Anticipated Study Completion Date :

Dec 30, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: High dose testosterone + Carbolplatin 500mg IM enanthate every 4 weeks in combination with ongoing LHRH agent (unless post-orchidectomy) plus Carboplatin AUC 5	Drug: Testosterone Enanthate 100 MG/ML Injectable Solution Testosterone Enanthate is the oil-soluble ester of the androgenic hormone testosterone. Testosterone Enanthate is a clear to pale yellow solution for intramuscular injection. Each pre-filled syringe contains 250mg testosterone enanthate/1mL. Other Names: Primoteston Depot Drug: Testosterone Enanthate 100 MG/ML Injectable Solution / Carboplatin AUC 5 Testosterone Enanthate is the oil-soluble ester of the androgenic hormone testosterone. Testosterone Enanthate is a clear to pale yellow solution for intramuscular injection. Each pre-filled syringe contains 250mg testosterone enanthate/1mL. Carboplatin as per standard procedures

Arm

Intervention/Treatment

Experimental: High dose testosterone + Carbolplatin

500mg IM enanthate every 4 weeks in combination with ongoing LHRH agent (unless post-orchidectomy) plus Carboplatin AUC 5

Drug: Testosterone Enanthate 100 MG/ML Injectable Solution

Testosterone Enanthate is the oil-soluble ester of the androgenic hormone testosterone. Testosterone Enanthate is a clear to pale yellow solution for intramuscular injection. Each pre-filled syringe contains 250mg testosterone enanthate/1mL.

Other Names:

Primoteston Depot

Drug: Testosterone Enanthate 100 MG/ML Injectable Solution / Carboplatin AUC 5

Outcome Measures

Primary Outcome Measures

PSA Response Rate [1 year]
>/= 50% fall from baseline PSA

Secondary Outcome Measures

Time to PSA progression [1 year]
Time to increase in PSA >/=25% from baseline or nadir confirmed on subsequent test >1 week later
Radiological Response Rate [1 year]
RECIST or PCWG3 Criteria
Safety and Tolerability (Frequency of adverse events as assessed by NCI CTCAE v4.0) [1 year]
Frequency of adverse events as assessed by NCI CTCAE v4.0

Other Outcome Measures

Changes in ctDNA expression from baseline [1 year]
Exploratory
Change in serum testosterone and oestradiol levels [1 year]
Change in serum levels from baseline to Days 14 and 28 of cycle 1

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Male

Accepts Healthy Volunteers:

Inclusion Criteria:

Males with histologically confirmed adenocarcinoma of the prostate
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.
Age ≥ 18 years
ECOG performance status ≤ 1
Rising PSA confirmed on two sequential tests ≥1 week apart and a minimum value of 2 ug/L despite castrate levels of testosterone
Serum testosterone < 1.7 nmol/L and on an LHRH agent or post orchidectomy ≥ 1 year.
Washout of ≥ 4 weeks from prior line of treatment, radiotherapy or surgery (aside from LHRH agent)
Adequate bone marrow function (platelets > 100 x 109/L, ANC > 1.5 x 109/L, Hb >100)
Adequate liver function (ALT/AST < 1.5 x ULN, bilirubin < 2 x ULN)
Adequate renal function (creatinine clearance > 50 ml/min)
Adequate cardiac function and reserve after cardiology assessment
Archived tissue sample available or willingness to undergo fresh biopsy
Willing and able to comply with all study requirements, including treatment, timing and/or nature of required assessments
Signed, written informed consent

Exclusion Criteria:

Contraindications to investigational product
Pain due to metastatic prostate cancer requiring opioid analgesics
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).
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.
Life expectancy of less than 3 months.
Brain metastases or leptomeningeal disease
History of thromboembolic event and not currently on anticoagulation
Prior myocardial infarction or unstable angina within 2 years of study entry
Haematocrit ≥ 50%, untreated severe obstructive sleep apnoea or poorly controlled heart failure (NYHA >1)
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.
Concurrent illness, including severe infection that may jeopardize the ability of the patient to undergo the procedures outlined in this protocol with reasonable safety.
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.