Clinical Trials /

Enzalutamide and Decitabine in Treating Patients With Metastatic Castration Resistant Prostate Cancer

NCT03709550

Description:

This phase I/II trial studies the side effects and best dose of decitabine and how well it works when given together with enzalutamide in treating patients with castration resistant prostate cancer that has spread to other places in the body. Androgen can cause the growth of prostate cancer cells. Drugs, such as enzalutamide, may lessen the amount of androgen made by the body. Decitabine may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving decitabine and enzalutamide may work better in treating participants with castration resistant prostate cancer.

Related Conditions:
  • Prostate Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Enzalutamide and Decitabine in Treating Patients With Metastatic Castration Resistant Prostate Cancer
  • Official Title: Phase Ib/II Study of Enzalutamide With Decitabine, a DNA Hypomethylating Agent, in Patients With Metastatic Castrate Resistant Prostate Cancer (mCRPC)

Clinical Trial IDs

  • ORG STUDY ID: I 51317
  • SECONDARY ID: NCI-2018-01755
  • SECONDARY ID: I 51317
  • SECONDARY ID: P30CA016056
  • NCT ID: NCT03709550

Conditions

  • Castration Levels of Testosterone
  • Castration-Resistant Prostate Carcinoma
  • Metastatic Prostate Carcinoma in the Soft Tissue
  • Prostate Carcinoma Metastatic in the Bone
  • PSA Level Greater Than or Equal to Two
  • PSA Progression
  • Stage IV Prostate Cancer AJCC v8
  • Stage IVA Prostate Cancer AJCC v8
  • Stage IVB Prostate Cancer AJCC v8

Interventions

DrugSynonymsArms
Decitabine5-Aza-2'-deoxycytidine, Aza-TdC, Dacogen, Decitabine for Injection, Deoxyazacytidine, DezocitidineTreatment (decitabine, enzalutamide)
EnzalutamideASP9785, MDV3100, XtandiTreatment (decitabine, enzalutamide)

Purpose

This phase I/II trial studies the side effects and best dose of decitabine and how well it works when given together with enzalutamide in treating patients with castration resistant prostate cancer that has spread to other places in the body. Androgen can cause the growth of prostate cancer cells. Drugs, such as enzalutamide, may lessen the amount of androgen made by the body. Decitabine may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving decitabine and enzalutamide may work better in treating participants with castration resistant prostate cancer.

Detailed Description

      PRIMARY OBJECTIVES I. To determine the maximum tolerated dose (MTD) and recommended phase II
      dose (RP2D) of decitabine in combination with enzalutamide in patients with refractory
      metastatic castrate resistant prostate cancer (mCRPC). (Phase 1b) II. To determine the
      12-month progression free survival rate of patients with enzalutamide-naive metastatic
      castrate resistant prostate cancer (mCRPC) treated with decitabine plus enzalutamide. (Phase
      2)

      SECONDARY OBJECTIVES:

      I. To determine the safety and tolerability of decitabine in combination with enzalutamide in
      patients with refractory metastatic castrate resistant prostate cancer (mCRPC). (Phase 1b)
      II. To determine the overall response rate, overall survival and prostate specific antigen
      (PSA) changes in enzalutamide-naive mCRPC patients treated with decitabine plus enzalutamide.
      (Phase 2) III. To determine the safety and tolerability of decitabine in combination with
      enzalutamide in the study population. (Phase 2)

      EXPLORATORY OBJECTIVES:

      I. To determine the relationship between decitabine dose and plasma biomarkers (e.g., levels
      of HbF, LINE-1 methylation, number of circulating tumor cell's [CTC?s] and, NY-ESO expression
      in CTC?s). (Phase 1b) II. To explore plasma and tumor immune biomarkers associated with
      efficacy to the study combination. (Phase 2) III. To determine if treatment emergent
      neuroendocrine transformation is present as a result of the treatment combination of
      enzalutamide plus decitabine. (Phase 2) IV. Evaluate changes in stem cell reprogramming
      factors and deoxyribonucleic acid (DNA)/ribonucleic acid (RNA) markers resulting from the
      treatment combination. (Phase 2)

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

      Participants receive decitabine intravenously (IV) over 1 hour on days 1-5 and enzalutamide
      orally (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, participants are followed up every 3 months for 24
      months.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (decitabine, enzalutamide)ExperimentalParticipants receive decitabine IV over 1 hour on days 1-5 and enzalutamide PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Decitabine
  • Enzalutamide

Eligibility Criteria

        Inclusion Criteria:

          -  Histological or cytological documentation of diagnosis of prostate cancer, all
             histological sub-types included.

          -  Documented progressive metastatic castrate resistant prostate cancer (mCRPC) based on
             at least one of the following criteria:

               -  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 1week 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 (if adequate formalin-fixed, paraffin-embedded (FFPE) archival
             mCRPC samples are not available (or biopsy was taken longer than 6 months from start
             of study treatment), a fresh pre-treatment mCRPC biopsy needs to be obtained)

          -  Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1

          -  Have testosterone < 50 ng/dL. Note: Patients must continue primary androgen
             deprivation with an 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)

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

          -  Serum creatinine (CREAT) =< 1.5 mg/dL or creatinine clearance > 50 mL/min (obtained
             within 14 days prior to treatment start)

          -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN. If
             the patient has liver metastases, ALT and AST must still be =< 2.5 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; 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 na?ve 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 sign 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 hypomethylating agents like azacytidine or decitabine

          -  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

          -  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
             ornon-melanomatous skin cancer

          -  Participant has a known history of human immunodeficiency virus (HIV) infection
             (testing not mandatory)

          -  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, coronary artery bypass grafting, coronary angioplasty, or stenting) or
                  symptomatic pericarditis within 12 months prior to treatment start

               -  History of documented congestive heart failure (New York Heart Association
                  functional classification III-IV)

               -  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

          -  Patient is currently receiving any of the following medications and cannot be
             discontinued 7 days prior to treatment start:

               -  Known strong inducers or inhibitors of CYP3A4/5, including grapefruit, grapefruit
                  hybrids and pummelos, star-fruit and, Seville oranges

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

               -  Herbal preparations/medications, dietary supplements

          -  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 4.03 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:Dose limiting toxicity determined by estimation of maximum tolerated dose assessed by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 (Phase Ib)
Time Frame:Up to 28 days
Safety Issue:
Description:The dose level at which at least 2 out of 6 patients within the same cohort experience dose-limiting toxicity (DLT).

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Roswell Park Cancer Institute

Last Updated

October 24, 2019