Clinical trial NCT05011383: High Dose Testosterone for ATM, CDK12 or CHEK2 Altered Prostate Cancers
Official title: High-dose Testosterone in Men With Metastatic Castration-resistant Prostate Cancer and ATM or CDK12 Deficiency
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Metastatic Prostate Cancer
Keywords: Prostatic Neoplasms
Lead sponsor: VA Office of Research and Development
Sponsor class: FED
First posted: 2021-08-18
Enrollment: 51
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Intervention model description: 3 cohort phase II study
Primary purpose: TREATMENT

Brief summary: 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

Detailed description: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: PSA response
timeFrame: 12 weeks
Secondary outcomes:
Other outcomes:
Locations:
city: Aurora
country: United States
facility: Rocky Mountain Regional VA Medical Center, Aurora, CO
state: Colorado
city: West Haven
country: United States
facility: VA Connecticut Healthcare System West Haven Campus, West Haven, CT
state: Connecticut
city: Gainesville
country: United States
facility: North Florida/South Georgia Veterans Health System, Gainesville, FL
state: Florida
city: Orlando
country: United States
facility: Orlando VA Medical Center, Orlando, FL
state: Florida
city: Decatur
country: United States
facility: Atlanta VA Medical and Rehab Center, Decatur, GA
state: Georgia
city: Louisville
country: United States
facility: Robley Rex VA Medical Center, Louisville, KY
state: Kentucky
city: Kansas City
country: United States
facility: Kansas City VA Medical Center, Kansas City, MO
state: Missouri
city: Saint Louis
country: United States
facility: St. Louis VA Medical Center John Cochran Division, St. Louis, MO
state: Missouri
city: Durham
country: United States
facility: Durham VA Medical Center, Durham, NC
state: North Carolina
city: Salisbury
country: United States
facility: Salisbury W.G. (Bill) Hefner VA Medical Center, Salisbury, NC
state: North Carolina
city: Portland
country: United States
facility: VA Portland Health Care System, Portland, OR
state: Oregon
city: Charleston
country: United States
facility: Ralph H. Johnson VA Medical Center, Charleston, SC
state: South Carolina
city: Memphis
country: United States
facility: Memphis VA Medical Center, Memphis, TN
state: Tennessee
city: Nashville
country: United States
facility: Tennessee Valley Healthcare System Nashville Campus, Nashville, TN
state: Tennessee
city: Houston
country: United States
facility: Michael E. DeBakey VA Medical Center, Houston, TX
state: Texas
city: Seattle
country: United States
facility: VA Puget Sound Health Care System Seattle Division, Seattle, WA
state: Washington
city: Madison
country: United States
facility: William S. Middleton Memorial Veterans Hospital, Madison, WI
state: Wisconsin
Study officials:
affiliation: VA Puget Sound Health Care System Seattle Division, Seattle, WA
name: Robert B. Montgomery, MD
role: PRINCIPAL_INVESTIGATOR
References: