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
Not yet recruiting
Phase 2
| Drug | Synonyms | Arms |
|---|---|---|
| High dose testosterone | Bipolar androgen therapy | ATM |
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.
| Name | Type | Description | Interventions |
|---|---|---|---|
| ATM | Experimental | Patients with castration resistant prostate cancer which contains ATM alterations are treated with high dose testosterone |
|
| CDK12 | Experimental | Patients with castration resistant prostate cancer which contains CDK12 alterations are treated with high dose testosterone |
|
| CHEK2 | Experimental | Patients with castration resistant prostate cancer which contains CHEK2 alterations are treated with high dose testosterone |
|
Inclusion Criteria:
- Signed informed consent form (ICF) providing agreement to adhere to the dosing
schedule, report for all trial visits and authorization, use and release of health and
research trial information
- Male age > 18 years
- Histologically or cytologically confirmed adenocarcinoma of the prostate
- Ongoing gonadal androgen deprivation therapy with gonadotropin-releasing hormone
(GnRH) analogues, antagonists or orchiectomy. Patients who have not had an orchiectomy
must be maintained on effective GnRH analogue/antagonist therapy
- Castration resistant prostate cancer as defined by serum testosterone < 50 ng/ml and
one of the following:
- PSA level of at least 2 ng/ml that has risen on at least 2 successive occasions
at least 1 week apart.
- Evaluable disease progression by modified RECIST 1.1 (Response Evaluation
Criteria in Solid Tumors)
- Progression of metastatic bone disease on bone scan with > 2 new lesions
- Presence of metastatic disease on bone or CT scan
- Patients must have progressed on 1 next-generation AR-signaling inhibitor (e.g.
abiraterone, enzalutamide, apalutamide, darolutamide, etc.).
- Asymptomatic or minimal cancer related symptoms
- Eastern Cooperative Oncology Group (ECOG) Performance Status of < 2
- Presence of inactivating mutations in ATM, CDK12 or CHEK2 as determined by a CLIA
level assay for DNA sequencing.
Exclusion Criteria:
- Currently receiving active therapy for other neoplastic disorders will not be
eligible.
- Histologic evidence of small cell carcinoma (morphology alone - immunohistochemical
evidence of neuroendrocrine differentiation without morphologic evidence is not
exclusionary)
- Known parenchymal brain metastasis
- Liver metastases
- Active or symptomatic viral hepatitis or chronic liver disease AST or ALT > 2.5 x ULN
or total bilirubin > ULN (unless Gilbert's syndrome is the etiology of
hyperbilirubinemia).
- Clinically significant heart disease as evidenced by myocardial infarction, or
arterial thrombotic events in the past 6 months, severe or unstable angina, or New
York Heart Association (NYHA) Class II-IV heart disease or cardiac ejection fraction
measurement of <35 % at baseline
- Patients with pain attributable to their prostate cancer and requiring the use of
opioids.
- Tumor causing urinary outlet obstruction that requires catheterization for voiding.
Patients that require catheterization to void secondary to benign strictures or other
non-cancer causes will be permitted to enroll.
- Presence of dementia, psychiatric illness, and/or social situations limiting
compliance with study requirements or understanding and/or giving of informed consent.
- Any condition(s), medical or otherwise, which, in the opinion of the investigators,
would jeopardize either the patient or the integrity of the data obtained.
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | Male |
| Healthy Volunteers: | No |
| Measure: | PSA response |
| Time Frame: | 12 weeks |
| Safety Issue: | |
| Description: | PSA response as measured by a 50% decline from baseline maintained for 12 weeks |
| Phase: | Phase 2 |
| Primary Purpose: | Interventional |
| Overall Status: | Not yet recruiting |
| Lead Sponsor: | VA Office of Research and Development |
August 18, 2021
