Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

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Prostatic Neoplasms

Genital Neoplasms, Male

Urogenital Neoplasms

Genital Diseases

Genital Diseases, Male

Urogenital Diseases

Prostatic Diseases

Male Urogenital Diseases

All Drugs and Chemicals

Androgens

Testosterone

Hormones

Hormone Antagonists

Patients with castration resistant prostate cancer which contains ATM alterations are treated with high dose testosterone

Patients with castration resistant prostate cancer which contains CDK12 alterations are treated with high dose testosterone

Patients with castration resistant prostate cancer which contains CHEK2 alterations are treated with high dose testosterone

High dose testosterone is administered subcutaneously once monthly until progression or toxicity

High dose testosterone

Robert B Montgomery, MD

Elahe Mostaghel, MD

Daniel Bowles, MD

Herta Chao, MD

Jess D Delaune, MD

Priya K Gopalan, MD

Maria Ribeiro, MD

Fred Hendler, MD

Linda Verkruyse, MD

Eric Knoche, MD

Rhonda Bitting, MD

Michael Goodman, MD

Julie Graff, MD

Steven Savage, MD

Alva Weir, MD

Sally York, MD

Anita Sabichi, MD

Robert B. Montgomery, MD

This study will determine whether the presence of DNA repair deficiency in the form of alterations in the genes ATM, CDK12 or CHEK2 predicts for a high likelihood of responding to the use of intermittent high dose testosterone. This therapy may result in responses in tumors which are genetically unstable because of DNA repair deficiency and this is a prospective study to test that hypothesis

This is an unblinded, three cohort phase II study evaluating the efficacy of high dose testosterone (BAT) for patients with mCRPC and inactivating mutations in ATM, CDK12 or CHEK2. Patients will receive BAT until disease progression or intolerance, whichever occurs first. Throughout the study, safety and tolerability will be assessed by frequent recording of adverse events, vital signs and safety laboratory assessments. Progression will be evaluated with bone scan, CT of the abdomen/pelvis and PSA as per PCWG3 criteria.

High Dose Testosterone for ATM, CDK12 or CHEK2 Altered Prostate Cancers

High-dose Testosterone in Men With Metastatic Castration-resistant Prostate Cancer and ATM or CDK12 Deficiency

PSA response as measured by a 50% decline from baseline maintained for 12 weeks

VA Office of Research and Development

Antineoplastic Agents

Reproductive Control Agents

Anti-Infective Agents

Amino Acids

Methyltestosterone

Leuprolide

Relugolix

Testosterone undecanoate

Testosterone enanthate

Testosterone 17 beta-cypionate

Goserelin

Prolactin Release-Inhibiting Factors

Triptorelin Pamoate

Eflornithine

Antineoplastic Agents, Hormonal

Anabolic Androgenic Steroids

Anabolic Agents

Androgen Antagonists

Antiprotozoal Agents

Antiparasitic Agents

Enzyme Inhibitors

Ornithine

Eligible patients will receive 7 days of DFMO (1000 mg PO bid) (days 1-7 of cycle), followed by 56 days of combined testosterone (testosterone cypionate 400 mg IM on day 8 and day 36) and DFMO (1000 mg PO bid) (days 8-63 of cycle), followed by 56 days of enzalutamide (160 mg PO daily) (days 64-119).

Each 119 day cycle, Days 1-7 patient will take 1000 mg by mouth (PO) twice a day (bid), and then on Day 8 - 63 patient will take 1000 mg PO bid while receiving high dose testosterone IM on Day 8 and Day 36 of cycle.

DFMO

On Day 8 and Day 36 of each 119 day cycle, patient will receive high dose testosterone at 400 mg through intramuscular (IM) injection.

testosterone cypionate

Patients who have progressive disease after treatment with Abiraterone (Abi) will continue with androgen depravation therapy (ADT) with LHRH analogue (LHRH agonist drug (i.e. Zoladex, Trelstar, Eligard or Lupron) or LHRH antagonist drug (Degarelix or Relugolix)). Dosing instructions will vary between the different LHRH analogues. Patients should follow the dosing instructions as directed by their physician.

Luteinizing hormone-releasing hormone (LHRH) analogue

Each 119 day cycle, Days 64-119 patient will take 160 mg by mouth (PO) once a day (qd).

Enzalutamide

Laura Sena, MD, PhD

Kathy Schultz, RN

Laura Sena, MD,PhD

Asymptomatic patients with metastatic castrate resistant prostate cancer (mCRPC) without pain due to prostate cancer will be treated on an open label study to evaluate effectiveness of sequential treatment with the combination of difluoromethylornithine (DFMO) and high dose testosterone in sequence with enzalutamide to improve primary and secondary outcomes.

Eligible patients are those with mCRPC who have progressive disease after treatment with Abiraterone (Abi) used as treatment for castration-sensitive or castration-resistant disease. Patients will continue on androgen deprivation therapy (ADT) with luteinizing hormone-releasing hormone (LHRH) agonist (i.e. Zoladex, Trelstar, Eligard, or Lupron) or LHRH antagonist (Degarelix or Relugolix) if not surgically castrated throughout the duration of the study to inhibit endogenous testosterone production. One cycle of treatment will be 119 days and will involve:

1. 7 days of DFMO at a dose of 1000 mg PO BID (D1-D7), followed by
2. 56 days of combined testosterone and DFMO (testosterone cypionate 400 mg IM on D8 and D36 with continued DFMO 1000 mg PO BID) (D8-D63), followed by
3. 56 days of enzalutamide (enzalutamide 160 mg PO daily) (D64-D119)

Patients will receive repeat cycles of treatment until clinical or radiographic progression or toxicity requiring drug cessation.

Difluoromethylornithine and High Dose Testosterone With Enzalutamide in Metastatic Castration-Resistant Prostate Cancer

Repeat Difluoromethylornithine and High Dose Testosterone With Enzalutamide in Asymptomatic Patients With Metastatic Castration-Resistant Prostate Cancer: The APEX (Androgen and Polyamine Elimination Alternating With Xtandi) Trial

Number of participants with \>50% PSA decline from baseline by Cycle 1 Day 64.

Time to radiographic or clinical progression or death.

Number of participants with \>50% PSA decline from baseline at any point on trial.

Number of participants who experience adverse events grade 3 or high and serious adverse events, as defined by Common Terminology Criteria for Adverse Events (CTCAE) v5.0.

Time from the date of first dose to the time of PSA progression.

Number of participants with measurable disease with complete response or partial response per RECIST 1.1.

The modified Patient-Reported Outcomes Measurement Information System (PROMIS) short form (SF) (v1.0 short forms 3a and 6b) pain scale is a validated self-reported instrument assessing average pain intensity and interference over the past 7-day period. Possible scores for each pain intensity questions range from 1 (no pain) to 5 (very severe) with higher scores reflecting higher pain intensity. Possible scores for each pain interference range from 1 (not at all) to 5 (very much) with higher scores reflecting higher pain interference.

Number of participants with changes in pain scores between baseline and post-treatment. Positive change scores are indicative of improvement in pain.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
High Dose Testosterone for ATM, CDK12 or CHEK2 Altered Prostate Cancers	NCT05011383	Metastatic Pros...	High dose testo...	18 Years -	VA Office of Research and Development
Difluoromethylornithine and High Dose Testosterone With Enzalutamide in Metastatic Castration-Resistant Prostate Cancer	NCT06059118	Prostate Cancer	DFMO testosterone cy... Luteinizing hor... Enzalutamide	18 Years -	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

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