Clinical Trials /

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

NCT03751436

Description:

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.

Related Conditions:
  • Prostate Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Enzalutamide With Venetoclax in Treating Patients With Metastatic Castration Resistant Prostate Cancer
  • Official Title: Phase Ib/II Study of Enzalutamide With Venetoclax (ABT-199) in Patients With Metastatic Castrate Resistant Prostate Cancer (mCRPC)

Clinical Trial IDs

  • ORG STUDY ID: I 63418
  • SECONDARY ID: NCI-2018-02448
  • SECONDARY ID: I 63418
  • SECONDARY ID: P30CA016056
  • NCT ID: NCT03751436

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

Interventions

DrugSynonymsArms
EnzalutamideASP9785, MDV3100, XtandiTreatment (venetoclax, enzalutamide)
VenetoclaxABT-0199, ABT-199, ABT199, GDC-0199, RG7601, VenclextaTreatment (venetoclax, enzalutamide)

Purpose

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.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the dose-limiting toxicity (DLT), maximum tolerated dose (MTD), and
      recommended phase II dose (RP2D) of enzalutamide in combination with venetoclax in patients
      with metastatic castrate resistant prostate cancer (mCRPC). (Phase Ib) II. To characterize
      the safety and tolerability profile of enzalutamide in combination with venetoclax in
      patients with metastatic castrate resistant prostate cancer (mCRPC). (Phase Ib) III. To
      evaluate the efficacy of venetoclax in combination with enzalutamide in patients with
      metastatic castrate resistant prostate cancer (mCRPC) that are enzalutamide-naive, as
      measured by 12-month progression free survival rate. (Phase II)

      SECONDARY OBJECTIVES:

      I. To assess PSA50 response as well as circulating tumor cell (CTC) response in patients who
      received venetoclax + enzalutamide. (Phase II) II. To estimate the proportion of patients who
      received venetoclax + enzalutamide and remain radiographic progression free at 6 months.
      (Phase II) III. To estimate the time to first skeletal-related event (SRE) and the time to
      first symptomatic skeletal event (SSE). (Phase II) IV. To estimate the time to clinical
      progression. (Phase II) V. To estimate the time to initiation of new systemic treatment for
      prostate cancer. (Phase II) VI. Assess the effect of venetoclax + enzalutamide on overall
      survival. (Phase II)

      PHARMACOKINETIC OBJECTIVES:

      I. To characterize the pharmacokinetic (PK) profiles of enzalutamide and venetoclax when
      given in combination to patients with metastatic castrate resistant prostate cancer (mCRPC).

      II. Comprehensive analyses of venetoclax levels to assure that they are in the therapeutic
      range.

      EXPLORATORY BIOMARKER OBJECTIVES:

      I. To identify non-inherited biomarkers that are predictive of response to study treatment
      (i.e., predictive biomarkers), are associated with progression to a more severe disease state
      (i.e., prognostic biomarkers), are associated with acquired resistance to study treatment,
      are associated with susceptibility to developing adverse events, can provide evidence of
      study treatment activity, can increase the knowledge and understanding of prostate cancer
      biology or study treatment mechanism of action, or can contribute to improvement of
      diagnostic assays.

      OUTLINE: This is a phase Ib, dose-escalation study of venetoclax followed by a phase II
      study.

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

      After completion of study treatment, patients are followed up for 1 year and then every 3
      months.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (venetoclax, enzalutamide)ExperimentalPatients 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.
  • Enzalutamide
  • Venetoclax

Eligibility Criteria

        Inclusion Criteria:

          -  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)

          -  Sodium (NA) 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)

          -  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)

          -  Institutional normalized ratio (INR) =< 1.5 (obtained within 14 days prior to
             treatment start)

          -  Adequate renal function as demonstrated by a creatinine clearance >= 30 mL/min;
             calculated by the Cockcroft Gault formula

          -  Aspartate aminotransferase (aspartate transaminase [AST]) and alanine aminotransferase
             (alanine transaminase [ALT]) =< 3 X upper limit of normal (ULN). If the patient has
             liver metastases, ALT and AST must still be =< 3 x ULN. Patients with liver metastases
             and AST/ALT above this limit will not be enrolled (obtained within 14 days prior to
             treatment start)

          -  Total serum bilirubin =< 1.5 x ULN (unless bilirubin rise is due to Gilbert?s syndrome
             or of non-hepatic origin); or total bilirubin (TBILI) =< 3.0 x ULN with direct
             bilirubin within normal range in patients with well documented Gilbert?s syndrome
             (obtained within 14 days prior to treatment start)

          -  Ability to swallow and retain oral medication (without crushing, dissolving or chewing
             tablets).

          -  Phase Ib only: Prior enzalutamide treatment and/or other approved treatments for CRPC
             are acceptable

          -  Phase II only: Participants MUST be treatment naive in the CRPC setting: i.e., no
             prior exposure to abiraterone acetate other specific CYP-17 inhibitors; no prior
             exposure to enzalutamide or investigational androgen receptor (AR) targeted agents;
             and no prior exposure to chemotherapy and or RAD-223.

          -  Sexually active males must agree to use a condom during intercourse while taking the
             study drug and for at least 3 months after stopping study treatment. Sexually active
             males should not father a child during this period. A condom is required to be used by
             vasectomized men in order to prevent delivery of the drug via seminal fluid. Should a
             woman become pregnant or suspect she is pregnant while her partner is participating in
             this study, she should inform her treating physician immediately.

          -  Participant or legal representative must understand the investigational nature of this
             study and voluntarily sign and date an Independent Ethics Committee/Institutional
             Review Board approved written informed consent form prior to receiving any study
             related procedure.

        Exclusion Criteria:

          -  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

               -  Class 2 is - Defined as cardiac disease in which patients are comfortable at rest
                  but ordinary physical activity results in fatigue, palpitations, dyspnea or
                  angina pain

               -  On screening 12 lead electrocardiography (ECG), any of the following cardiac
                  parameters: bradycardia (heart rate < 50 at rest), tachycardia (heart rate > 90
                  at rest), PR interval > 220 msec, QRS interval > 109 msec or, Fridericia's
                  correction formula (QTcF) > 450 msec. Congenital long QT syndrome or family
                  history of long QT syndrome.

          -  DLCO <=65% or FEVI <= 65&

          -  Treatment with any of the following within 7 days prior to the first dose of study
             drug:

               -  Steroid therapy for anti-neoplastic intent

               -  Moderate or strong cytochrome P450 3A (CYP3A) inhibitors

               -  Moderate or strong CYP3A inducers

               -  Medications that have a known risk to prolong the QT interval or induce Torsades
                  de Pointes

               -  Herbal preparations/medications

          -  Participants receiving any medications or substances that are inhibitors or inducers
             of CYP2C8 enzymes are ineligible.

          -  Administration or consumption of any of the following within 3 days prior to the first
             dose of study drug:

               -  Grapefruit or grapefruit products

               -  Seville oranges (including marmalade containing Seville oranges)

               -  Star fruit.

          -  Patient who has received radiotherapy =< 4 weeks prior to start of treatment or
             limited field radiation for palliation =< 2 weeks prior to treatment start and, who
             has not recovered to grade 1 or better from related side effects of such therapy
             (exceptions include alopecia) and/or in whom >= 30% of the bone marrow was irradiated.

          -  Patients with central nervous system (CNS) involvement.

          -  Patients with seizure disorder.

          -  Patient has not recovered from all toxicities related to prior anticancer therapies to
             National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE)
             (version 5.0) grade < 1 (Exception to this criterion: patients with any grade of
             alopecia are allowed to enter the study).

          -  Participant has any other concurrent severe and/or uncontrolled medical condition that
             would cause, in the investigator?s judgment, an unacceptable safety risk.

          -  Unwilling or unable to follow protocol requirements.

          -  Any condition which in the investigator?s opinion deems the participant an unsuitable
             candidate to receive study drug.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD) (Phase Ib)
Time Frame:Up to 28 days
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:PSA50 (Phase II)
Time Frame:Up to 3 years
Safety Issue:
Description:Will be defined as the proportion of patients with a >= 50% reduction in PSA from baseline.
Measure: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)
Time Frame:Up to 3 years
Safety Issue:
Description:Conversion to favorable status is defined as four or fewer cells per 7. mL of blood.
Measure:Radiographic (r)PFS (Phase II)
Time Frame: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
Safety Issue:
Description:Will be defined per PCWG3.
Measure:Proportion of patients who remain radiographic progression free defined per PCWG3 (Phase II)
Time Frame:Tt 6 months
Safety Issue:
Description:
Measure:Overall response rate (ORR) (Phase II)
Time Frame:Up to 3 years
Safety Issue:
Description:For patients with measurable soft tissue disease, ORR will be defined as the proportion of patients with a complete response (CR) or partial response (PR) per PCWG3.
Measure:Duration of response (DOR) (Phase II)
Time Frame:From the time measurement criteria are met for CR or PR (whichever status is recorded first) until the first date that radiographic progression is documented per PCWG3, assessed up to 3 years
Safety Issue:
Description:
Measure:Time to first skeletal-related event (SRE) (Phase II)
Time Frame:Time from D1 of treatment to the date of first SRE, assessed up to 3 years
Safety Issue:
Description:
Measure:Time to clinical progression (Phase II)
Time Frame:Time from D1 of treatment to the date of clinical progression, assessed up to 3 years
Safety Issue:
Description:
Measure:Time to initiation of new systemic treatment for prostate cancer (Phase II)
Time Frame:Time from D1 of treatment to the date any new systemic treatment for prostate cancer is initiated, assessed up to 3 years
Safety Issue:
Description:
Measure:Overall survival (Phase II)
Time Frame:From the time of initiation of the combination therapy until death from any cause, assessed up to 3 years
Safety Issue:
Description:The Kaplan-Meier product-limit estimator will be used.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Roswell Park Cancer Institute

Last Updated

December 2, 2019