Enzalutamide and DNA-PK / TOR Kinase Inhibitor CC-115 in Treating Patients with Metastatic Castration-Resistant Prostate Cancer

Status: Active

Description

This phase Ib trial studies the side effects and best dose of deoxyribonucleic acid-dependent protein kinase (DNA-PK) / target of rapamycin (TOR) kinase inhibitor CC-115 when given together with enzalutamide in treating patients with castration-resistant prostate cancer that has spread to other places in the body. DNA-PK / TOR kinase inhibitor CC-115 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Enzalutamide is an androgen receptor inhibitor that may slow down the growth of prostate cancer by blocking the action of the male hormone testosterone and other male hormones called androgens. Giving DNA-PK / TOR kinase inhibitor CC-115 and enzalutamide may work better in treating patients with castration-resistant prostate cancer.

Eligibility Criteria

Inclusion Criteria

  • Willing and able to provide written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization for the release of personal health information; NOTE: HIPAA authorization may be either included in the informed consent or obtained separately
  • Life expectancy of at least 6 months
  • Histological or cytological proof of prostate cancer
  • Willing to provide a tumor sample via biopsy from a metastatic site of disease to be collected at screening if safe and feasible per treating investigator discretion; adequate archival metastatic tissue can be used if available in lieu of baseline biopsy if done when patient had CRPC
  • Documented progressive metastatic CRPC based on at least one of the following criteria: * Rise in PSA: a minimum of 3 rising levels, with an interval of at least 1 week between each determination; the last determination must have a value >= 1 ng/mL, obtained within 4 weeks of starting study drug * Measurable disease: new or progressive soft tissue disease on computerized tomography (CT) or magnetic resonance imaging (MRI) scans * Radionuclide bone scan: at least 2 new bone lesions, as defined by the Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria
  • Serum testosterone < 50 ng/dL; patients must continue primary androgen deprivation with a luteinizing-releasing hormone (LHRH) analogue (agonist or antagonist) if they have not undergone orchiectomy
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
  • Finasteride, bicalutamide and nilutamide discontinued at least 4 weeks prior to registration
  • Physiologic doses of corticosteroids are permitted (i.e., no more than 10 mg of prednisone daily)
  • At least 4 weeks must have elapsed from the use of palliative radiation, strontium-89, radium-223, or approved immunotherapy prior to registration
  • Less than or equal to 5 half lives or 4 weeks, whichever is shorter, from the use of any investigational therapy prior to registration
  • Absolute neutrophil count (ANC) >= 1500/uL (within 14 days of registration)
  • Hemoglobin >= 9 g/dL (within 14 days of registration)
  • Platelet count >= 100,000/uL (within 14 days of registration)
  • Creatinine =< 1.5 x the institutional upper limit of normal (ULN), or 24-hr clearance >= 50 mL/min (within 14 days of registration)
  • Potassium >= 3.5 mmol/L (within institutional normal range, or correctable with supplements) (within 14 days of registration)
  • Bilirubin =< 1.5 x ULN (unless documented Gilbert's disease) (within 14 days of registration)
  • Serum glutamic-oxaloacetic transaminase (SGOT) aspartate aminotransferase (AST) =< 2.5 x ULN (within 14 days of registration)
  • Serum glutamate pyruvate aminotransferase (SGPT) alanine transferase (ALT) =< 2.5 x ULN (within 14 days of registration)
  • Glycated hemoglobin (HbA1c) < 6.4% (within 14 days of registration)
  • Able to take oral medication without crushing, dissolving or chewing tablets
  • Able to adhere to the study visit schedule and other protocol requirements

Exclusion Criteria

  • Prior exposure to enzalutamide, ARN-509, or other investigational androgen receptor (AR)-directed therapy
  • Prior exposure to abiraterone acetate, ketoconazole or other specific cytochrome (CYP)-17 inhibitors
  • Prior exposure to agents specifically targeting both mammalian target of rapamycin (mTOR) complexes (dual target of rapamycin complex 1 [TORC1] + target of rapamycin complex 2 [TORC2] inhibitors) and/or phosphoinositide 3-kinase (PI3K)/ protein kinase B (AKT) pathways
  • Prior chemotherapy for castration resistant disease; chemotherapy given in the castration-sensitive setting is permissible; at least 6 months from registration must have elapsed since chemotherapy was last received
  • Symptomatic central nervous system metastases
  • Known history of acute or chronic pancreatitis
  • Persistent diarrhea or malabsorption National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade 2, despite medical management
  • Clinically significant cardiac diseases, including any of the following: * Unstable angina pectoris * Myocardial infarction =< 3 months prior to registration * Other clinically significant heart disease such as congestive heart failure requiring treatment or uncontrolled hypertension
  • Uncontrolled diabetes mellitus
  • Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g., active or uncontrolled infection) that could cause unacceptable safety risks or compromise compliance with the protocol
  • Major surgery =< 2 weeks prior to registration or who have not recovered from side effects of such therapy; subjects must have recovered from any effects of recent radiotherapy that might confound the safety evaluation of study drug
  • Hematopoietic stem cell transplant =< 3 months prior to registration
  • Adults of reproductive potential not employing two forms of birth control: * Males having partners who are female with child-bearing potential must agree that they and/or their partners will use at least two effective contraceptive methods (including one barrier method) when engaging in reproductive sexual activity throughout the study from the time of informed consent, and will avoid conceiving for 28 days after the last dose of CC-115
  • Known human immunodeficiency virus (HIV) infection
  • Known chronic hepatitis B or C virus (HBV/HCV) infection
  • Concurrent active second malignancy for which the subject is receiving therapy, other than non-melanomatous skin cancer or superficial transitional cell carcinoma
  • History of seizure or any condition that may predispose to seizure including, but not limited to, underlying brain injury, stroke in the past 6 months, primary brain tumors, brain metastases
  • Active treatment with medications that lower the seizure threshold which cannot be held: * Aminophylline/theophylline * Atypical antipsychotics (e.g., clozapine, olanzapine, risperidone, ziprasidone) * Bupropion * Lithium * Pethidine * Phenothiazine antipsychotics (e.g., chlorpromazine, mesoridazine, thioridazine) * Tricyclic and tetracyclic antidepressants (e.g., amitriptyline, desipramine, doxepin, imipramine, maprotiline, mirtazapine)
  • Any other condition which, in the opinion of the investigator, would preclude participation in this trial

Locations & Contacts

California

San Francisco
UCSF Medical Center-Mount Zion
Status: Active
Contact: Felix Yi-Chung Feng
Email: felix.feng@ucsf.edu

Maryland

Baltimore
Johns Hopkins University / Sidney Kimmel Cancer Center
Status: Active
Contact: Emmanuel S. Antonarakis
Phone: 410-464-6641

New York

New York
Memorial Sloan Kettering Cancer Center
Status: Active
Contact: Dana Rathkopf
Phone: 646-422-4379
Email: rathkopd@mskcc.org

Washington

Seattle
University of Washington Medical Center
Status: Active
Contact: Heather H. Cheng
Phone: 206-606-7486

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To determine the safety, pharmacokinetics (PK), and the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of DNA-PK/TOR kinase inhibitor CC-115 (CC-115) plus enzalutamide.

SECONDARY OBJECTIVES:

I. To evaluate prostate-specific antigen (PSA) response (>= 50% and >= 90% decline at 12 weeks) of the combination of enzalutamide plus CC-115 in a metastatic castration-resistant prostate cancer (mCRPC) expansion cohort.

II. To further evaluate the safety of CC-115 plus enzalutamide at the MTD/RP2D in a mCRPC expansion cohort.

III. To evaluate preliminary anti-tumor activity as measured by radiographic progression-free survival (rPFS) of the combination of CC-115 plus enzalutamide in a mCRPC expansion cohort.

EXPLORATORY OBJECTIVES:

I. To evaluate possible mechanisms of sensitivity and resistance with correlative studies of pre- and post-treatment tumor biopsies, and molecular profiling of circulating tumor cells (CTC) and circulating tumor DNA (ctDNA).

OUTLINE: This is a dose escalation study of DNA-PK/TOR kinase inhibitor CC-115.

Patients receive DNA-PK/TOR kinase inhibitor CC-115 orally (PO) twice daily (BID) and enzalutamide PO once daily (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 periodically.

Trial Phase & Type

Trial Phase

Phase I

Trial Type

Treatment

Lead Organization

Lead Organization
Memorial Sloan Kettering Cancer Center

Principal Investigator
Dana Rathkopf

Trial IDs

Primary ID 16-074
Secondary IDs NCI-2016-01114, c15-160
Clinicaltrials.gov ID NCT02833883