Enzalutamide With Venetoclax in Treating Patients With Metastatic Castration Resistant Prostate Cancer

NCT03751436 | Completed Phase 1 DMC FDA Drug

• 2 other identifiers: I 63418NCI-2018-02448
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief Summary

This phase Ib/II trial studies the side effects and best dose of venetoclax when given together with enzalutamide and to see how well they work in treating patients with castration resistant prostate cancer that has spread to other places in the body. Androgens can cause the growth of prostate cancer cells. Drugs, such as enzalutamide, may lessen the amount of androgens made by the body. Venetoclax may target a special group of prostate cancer cells that is known to lead to resistance to treatment. Giving enzalutamide and venetoclax may work better in treating patients with castration resistant prostate cancer.

Conditions

Castration Levels of Testosterone; Castration-Resistant Prostate Carcinoma; Metastatic Prostate Carcinoma; Metastatic Prostate Carcinoma in the Soft Tissue; Prostate Carcinoma Metastatic in the Bone; PSA Progression; Stage IV Prostate Cancer AJCC v8; Stage IVA Prostate Cancer AJCC v8; Stage IVB Prostate Cancer AJCC v8

Outcome Measures

Primary Outcomes (3)

• Maximum tolerated dose (MTD) (Phase Ib)

  The MTD will be determined based on the rate of dose-limiting toxicities (DLTs). Adverse events will be categorized and graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

  Up to 28 days

• Recommended phase 2 dose (RP2D) (Phase Ib)

  Will be selected based on the overall tolerability of the regimen, but will not exceed the MTD.

  Up to 28 days

• Progression free survival (Phase II)

  Prostate Cancer Working Group (PCWG)3 will be used to evaluate PSA response and progression as well as progression on bone scans. Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 will be used to assess response and progression for nodal and visceral metastasis. The Kaplan-Meier product-limit estimator will be used.

  Time from start of treatment combination therapy to disease progression, assessed at 12 months

Secondary Outcomes (10)

• PSA50 (Phase II)

  Up to 3 years

• Circulating tumor cell (CTC) conversion in patients who enter the trial with unfavorable CTCs (five or more cells per 7.5 mL of blood) (Phase II)

  Up to 3 years

• Radiographic (r)PFS (Phase II)

  Time from day (D) 1 of treatment to the date when the first site of disease is found to progress (using a manifestation-specific definition off progression), or death, whichever occurs first, assessed up to 3 years

• Proportion of patients who remain radiographic progression free defined per PCWG3 (Phase II)

  Tt 6 months

• Overall response rate (ORR) (Phase II)

  Up to 3 years

Other Outcomes (17)

• Observed serum concentration of enzalutamide

  Up to 3 years

• Observed serum concentration of venetoclax

  Up to 3 years

• Biomarker analysis

  Up to 3 years

Study Arms (1)

Treatment (venetoclax, enzalutamide)

EXPERIMENTAL

Patients receive venetoclax PO QD and enzalutamide PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: Enzalutamide; Drug: Venetoclax

Interventions

Enzalutamide DRUG

Given PO

Also known as: ASP9785, MDV3100, Xtandi

Treatment (venetoclax, enzalutamide)

Venetoclax DRUG

Given PO

Also known as: ABT-0199, ABT-199, ABT199, GDC-0199, RG7601, Venclexta

Treatment (venetoclax, enzalutamide)

Eligibility Criteria

• Age: 18 Years+
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histological or cytological documentation of diagnosis of prostate cancer.
• Documented progressive metastatic castrate resistant prostate cancer (mCRPC) based on at least one of the following criteria:
• Prostate specific antigen (PSA) progression defined as 25% increase over baseline value with an increase in the absolute value of at least 2 ng/mL that is confirmed by another PSA level with a minimum of a 1 week interval and a minimum PSA of 2 ng/mL.
• Soft-tissue progression defined as an increase \>= 20% in the sum of the longest diameter (LD) of all target lesions based on the smallest sum LD since treatment started or the appearance of one or more new lesions.
• Progression of bone disease (evaluable disease) or, new bone lesion(s), by bone scan.
• If on an anti-androgen, must have documented progression 6 weeks after stopping anti-androgen therapy.
• Willing to undergo a biopsy, if readily available biopsy site present (i.e., nodal or visceral metastasis).
• Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 1.
• Have testosterone level of \< 50 ng/dL. Note: Patients must continue primary androgen deprivation with a luteinizing hormone-releasing hormone (LHRH) analogue (agonist or antagonist) if they have not undergone orchiectomy.
• White blood cells \>= 1.5 x 10\^9/L (obtained within 14 days prior to treatment start)
• Platelets (UNVPLT) \>= 100 x 10\^9/L (obtained within 14 days prior to treatment start)
• Hemoglobin (HGB) \>= 9 g/dL (obtained within 14 days prior to treatment start)
• Potassium (K), total calcium (CA) (corrected for serum albumin), magnesium, sodium (NA) and phosphorus within normal limits for the institution or corrected to within normal limits with supplements before first dose of study medication (obtained within 14 days prior to treatment start)
• Total calcium (CA) (corrected for serum albumin) within normal limits for the institution or corrected to within normal limits with supplements before first dose of study medication (obtained within 14 days prior to treatment start)
• Magnesium within normal limits for the institution or corrected to within normal limits with supplements before first dose of study medication (obtained within 14 days prior to treatment start)

You may not qualify if:

• Phase II only: Prior exposure to abiraterone acetate.
• Phase II only: Prior exposure to BCL-2 inhibitors agents like venetoclax.
• Phase II only: Prior chemotherapy for castration resistant disease. Chemotherapy given in the castration-sensitive setting is permissible if stopped at least 4 weeks prior to treatment start.
• Phase II only: Prior isotope therapy with strontium-89, samarium or radium-223 within 12 weeks of treatment start.
• Subject has acute promyeloctyic leukemia
• Subject has known active CNS involvement with AML
• Participants with known symptomatic brain metastases.
• Participant has a concurrent malignancy or malignancy within 3 years of treatment start, with the exception of adequately treated, basal or squamous cell carcinoma, nonmelanomatous skin cancer or curatively resected cervical cancer.
• Participant has a known history of human immunodeficiency virus (HIV) infection (testing not mandatory);
• Chronic hepatitis B virus (HBV) or hepatitis C (HCV) requiring treatment. Note: subjects with serologic evidence of prior vaccination to HBV (i.e. hepatitis B surface (HBs) antigen negative-, anti-HBs antibody positive and anti-hepatitis B core (HBc) antibody negative) or positive anti-HBc antibody from intravenous immunoglobulins (IVIG) may participate
• Uncontrolled and/or active systemic infection (viral, bacterial or fungal).
• Participant has clinically significant, uncontrolled heart disease and/or recent events including any of the following:
• History of acute coronary syndromes (including myocardial infarction, unstable angina, uncontrolled hypertension, uncontrolled arrhythmia, stroke, coronary artery bypass grafting, coronary angioplasty, or stenting) or symptomatic pericarditis within 12 months prior to treatment start
• Cardiac history of CHF requiring treatment or Ejection fraction ≤ 50% or chronic stable angina
• A cardiovascular disability status of New York Heart Association Class \> 2

Sponsors & Collaborators

• Roswell Park Cancer Institute: lead
• AbbVie: collaborator

Study Sites (1)

Roswell Park Cancer Institute

Buffalo, New York, 14263, United States

Location

Related Publications (2)

• Perimbeti S, Jamroze A, Gopalakrishnan D, Jain R, Jiang C, Holleran JL, Parise RA, Bies R, Quinn D, Attwood K, Liu X, Green K, Kirk JS, Beumer JH, Tang DG, Chatta G. Phase Ib study of enzalutamide with venetoclax in patients with metastatic castration-resistant prostate cancer. Cancer Chemother Pharmacol. 2025 Nov 29;95(1):115. doi: 10.1007/s00280-025-04840-2.

  PMID: 41315064 DERIVED

• Rodriguez Y, Unno K, Truica MI, Chalmers ZR, Yoo YA, Vatapalli R, Sagar V, Yu J, Lysy B, Hussain M, Han H, Abdulkadir SA. A Genome-Wide CRISPR Activation Screen Identifies PRRX2 as a Regulator of Enzalutamide Resistance in Prostate Cancer. Cancer Res. 2022 Jun 6;82(11):2110-2123. doi: 10.1158/0008-5472.CAN-21-3565.

  PMID: 35405009 DERIVED

MeSH Terms

Conditions

Prostatic Neoplasms

Interventions

enzalutamide; venetoclax

Condition Hierarchy (Ancestors)

Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Genital Diseases; Urogenital Diseases; Prostatic Diseases; Male Urogenital Diseases

Study Officials

• Gurkamal Chatta

  Roswell Park Cancer Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 20, 2018
• First Posted: November 23, 2018
• Study Start: August 2, 2019
• Primary Completion: July 18, 2022
• Study Completion: August 11, 2023
• Last Updated: October 16, 2023

Record last verified: 2023-10

Locations

US (1)