Bipolar Androgen Therapy + Carboplatin in mCRPC

Castration-resistant Prostate Cancer Clinical Trial

— HiTeCH  

Official title:

High Dose Testosterone + Carboplatin in Men With Advanced Prostate Cancer

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03522064
• Other study ID #: HiTECH
• Status: Recruiting
• Phase: Phase 2
• Start date: July 30, 2018
• Est. completion date: December 30, 2025

Study information

• Verified date: April 2023
• Source: St Vincent's Hospital, Sydney
• Contact: Robert Kent
• Phone: +61293555611
• Email: SVHS.CancerResearch[@]svha.org.au
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 30
• Est. completion date: December 30, 2025
• Est. primary completion date: December 30, 2024
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Castration-resistant Prostate Cancer
• Homologous Recombination Deficiency
• Prostatic Neoplasms

Intervention

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.
• 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

Locations

Country	Name	City	State
Australia	Kinghorn Cancer Centre, St. Vincent's Hospital	Sydney	New South Wales

Sponsors (1)

Lead Sponsor	Collaborator
St Vincent's Hospital, Sydney

Country where clinical trial is conducted

Australia, 

References & Publications (2)

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Changes in ctDNA expression from baseline	Exploratory	1 year
Other	Change in serum testosterone and oestradiol levels	Change in serum levels from baseline to Days 14 and 28 of cycle 1	1 year
Primary	PSA Response Rate	>/= 50% fall from baseline PSA	1 year
Secondary	Time to PSA progression	Time to increase in PSA >/=25% from baseline or nadir confirmed on subsequent test >1 week later	1 year
Secondary	Radiological Response Rate	RECIST or PCWG3 Criteria	1 year
Secondary	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