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

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.

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, dietary supplements.

- 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.