Bipolar Androgen Therapy + Carboplatin in mCRPC (HiTeCH)

High Dose Testosterone + Carboplatin in Men With Advanced Prostate Cancer

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

Study Overview

• Status: Recruiting
• Conditions: Castration-resistant Prostate Cancer; Homologous Recombination Deficiency
• Intervention / Treatment: Drug: Testosterone Enanthate 100 MG/ML Injectable Solution; Drug: Testosterone Enanthate 100 MG/ML Injectable Solution / Carboplatin AUC 5

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 Type: Interventional
• Enrollment (Anticipated): 30
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Robert Kent; Phone Number: +61293555611; Email: svhs.cancerresearch@svha.org.au

Study Locations

• Australia
  • New South Wales
    • Sydney, New South Wales, Australia, 2010
      • Recruiting
      • Kinghorn Cancer Centre, St. Vincent's Hospital
      • Contact: Robert Kent; Phone Number: 0293555611; Email: SVHS.CancerResearch@svha.org.au

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in ctDNA expression from baseline	Exploratory	1 year
Change in serum testosterone and oestradiol levels	Change in serum levels from baseline to Days 14 and 28 of cycle 1	1 year

Collaborators and Investigators

• Sponsor: St Vincent's Hospital, Sydney
• Investigators: Principal Investigator: Anthony M Joshua, MBBS, PhD, FRACP, St Vincent's Hospital

Publications and helpful links

General Publications

• Maia MC, Salgia M, Pal SK. Harnessing cell-free DNA: plasma circulating tumour DNA for liquid biopsy in genitourinary cancers. Nat Rev Urol. 2020 May;17(5):271-291. doi: 10.1038/s41585-020-0297-9. Epub 2020 Mar 17.
• Teply BA, Wang H, Luber B, Sullivan R, Rifkind I, Bruns A, Spitz A, DeCarli M, Sinibaldi V, Pratz CF, Lu C, Silberstein JL, Luo J, Schweizer MT, Drake CG, Carducci MA, Paller CJ, Antonarakis ES, Eisenberger MA, Denmeade SR. Bipolar androgen therapy in men with metastatic castration-resistant prostate cancer after progression on enzalutamide: an open-label, phase 2, multicohort study. Lancet Oncol. 2018 Jan;19(1):76-86. doi: 10.1016/S1470-2045(17)30906-3. Epub 2017 Dec 14.
• Schweizer MT, Wang H, Luber B, Nadal R, Spitz A, Rosen DM, Cao H, Antonarakis ES, Eisenberger MA, Carducci MA, Paller C, Denmeade SR. Bipolar Androgen Therapy for Men With Androgen Ablation Naive Prostate Cancer: Results From the Phase II BATMAN Study. Prostate. 2016 Sep;76(13):1218-26. doi: 10.1002/pros.23209. Epub 2016 Jun 24.

Study record dates

Study Major Dates

• Study Start (Actual): July 30, 2018
• Primary Completion (Anticipated): December 30, 2024
• Study Completion (Anticipated): December 30, 2025

Study Registration Dates

• First Submitted: April 17, 2018
• First Submitted That Met QC Criteria: May 10, 2018
• First Posted (Actual): May 11, 2018

Study Record Updates

• Last Update Posted (Actual): April 12, 2023
• Last Update Submitted That Met QC Criteria: April 10, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: homologous recombination deficiency; BRCA; Castrate-resistant prostate cancer; bipolar androgen therapy
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Prostatic Neoplasms; Physiological Effects of Drugs; Antineoplastic Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Androgens; Anabolic Agents; Carboplatin; Pharmaceutical Solutions; Testosterone; Methyltestosterone; Testosterone undecanoate; Testosterone enanthate; Testosterone 17 beta-cypionate
• Other Study ID Numbers: HiTECH

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No