Clinical Trials /

Enzalutamide and Cabazitaxel in Treating Patients With Metastatic, Castration-Resistant Prostate Cancer

NCT02522715

Description:

This phase I/II trial studies the side effects and best dose of cabazitaxel when given together with enzalutamide in treating patients with prostate cancer that has spread to other places in the body (metastatic) and has not responded to treatment with hormones or no longer responds to treatment with hormones (hormone-resistant). Drugs used in chemotherapy, such as cabazitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Androgen can cause the growth of prostate cancer cells. Hormone therapy using enzalutamide may fight prostate cancer by blocking the use of androgen by the tumor cells. Giving cabazitaxel together with enzalutamide may work better in treating metastatic, hormone-resistant prostate cancer.

Related Conditions:
  • Prostate Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Enzalutamide and Cabazitaxel in Treating Patients With Metastatic, Hormone-Resistant Prostate Cancer
  • Official Title: A Phase I/II Trial of Concurrent Chemohormonal Therapy Using Enzalutamide (MDV-3100) and Cabazitaxel in Patients With Metastatic Castration Resistant Prostate Cancer

Clinical Trial IDs

  • ORG STUDY ID: IRB00011227
  • SECONDARY ID: NCI-2015-01103
  • SECONDARY ID: 11227
  • SECONDARY ID: CRS00001390
  • SECONDARY ID: IRB00011227
  • SECONDARY ID: P30CA069533
  • NCT ID: NCT02522715

Conditions

  • Hormone-Resistant Prostate Cancer
  • Metastatic Prostate Carcinoma
  • Recurrent Prostate Carcinoma
  • Stage IV Prostate Cancer

Interventions

DrugSynonymsArms
CabazitaxelJevtana, RPR-116258A, Taxoid XRP6258, XRP-6258Treatment (cabazitaxel, enzalutamide)
EnzalutamideMDV3100, XtandiTreatment (cabazitaxel, enzalutamide)
Prednisone.delta.1-Cortisone, 1, 2-Dehydrocortisone, Adasone, Cortancyl, Dacortin, DeCortin, Decortisyl, Decorton, Delta 1-Cortisone, Delta-Dome, Deltacortene, Deltacortisone, Deltadehydrocortisone, Deltasone, Deltison, Deltra, Econosone, Lisacort, Meprosona-F, Metacortandracin, Meticorten, Ofisolona, Orasone, Panafcort, Panasol-S, Paracort, PRED, Predicor, Predicorten, Prednicen-M, Prednicort, Prednidib, Prednilonga, Predniment, Prednisonum, Prednitone, Promifen, Servisone, SK-PrednisoneTreatment (cabazitaxel, enzalutamide)

Purpose

This phase I/II trial studies the side effects and best dose of cabazitaxel when given together with enzalutamide in treating patients with prostate cancer that has spread to other places in the body (metastatic) and has not responded to treatment with hormones (hormone-resistant). Drugs used in chemotherapy, such as cabazitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Androgen can cause the growth of prostate cancer cells. Hormone therapy using enzalutamide may fight prostate cancer by blocking the use of androgen by the tumor cells. Giving cabazitaxel together with enzalutamide may work better in treating metastatic, hormone-resistant prostate cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the safety and tolerability of combination treatment with enzalutamide and
      cabazitaxel (as determined by percent dose limiting toxicities (DLT), where DLT < 17% is
      consistent with it being a tolerable combination).

      II. To determine the efficacy of treatment with the hormonal agent enzalutamide and the
      chemotherapy cabazitaxel in combination in men with metastatic castration-resistant prostate
      cancer (CRPC) (as determined by percent of patients achieving >= 90% prostate specific
      antigen (PSA) declines following initiation of treatment).

      SECONDARY OBJECTIVES:

      I. To further define the anticancer effect and safety profile of the combination of
      enzalutamide and cabazitaxel.

      II. Collect toxicity data (description of adverse events). III. Determine PSA response
      (percent of patients who achieve >= 50% PSA decline and >= 30% PSA decline).

      IV. Examine pharmacokinetic (PK) data of cabazitaxel to characterize enzalutamide and
      cabazitaxel pharmacokinetic blood levels.

      V. Determine tumor response by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 for
      measurable disease and Prostate Cancer Working Group 2 criteria for non-measurable (bone)
      disease.

      VI. Determine overall survival.

      TERTIARY OBJECTIVES:

      I. To determine baseline (and at progression) biological tumor characteristics to evaluate
      for possible biomarkers indicative or predictive of response: apoptosis by cleaved caspase
      3; androgen signaling axis (including but not limited to: androgen receptor expression,
      androgen receptor splice variants, and intratumoral androgen levels), and glucocorticoid
      receptor.

      II. To collect circulating tumor cells (CTCs) and determine the degree to which tumor
      characteristics (delineated above) are shared by the CTCs.

      III. To collect plasma and serum pre-treatment and at progression for assessment of
      circulating micro-ribonucleic acid (RNA)s and other circulating markers.

      IV. To collect buffy coat to evaluate for steroid transporters.

      OUTLINE: This is a dose de-escalation study of cabazitaxel.

      Patients receive cabazitaxel intravenously (IV) over 1 hour on day 1 and enzalutamide orally
      (PO) once daily (QD) on days 1-21 (days 2-21 of course 1). Patients also receive prednisone
      PO twice daily (BID) as standard of care with cabazitaxel. Courses repeat every 21 days for
      6-10 courses in the absence of disease progression or unacceptable toxicity. Patients may
      continue enzalutamide PO QD on days 1-28 in the absence of disease progression or
      unacceptable toxicity.

      After completion of study treatment, patients are followed up at 28 days and then every 6
      months for up to 5 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (cabazitaxel, enzalutamide)ExperimentalPatients receive cabazitaxel IV over 1 hour on day 1 and enzalutamide PO QD on days 1-21 (days 2-21 of course 1). Patients also receive prednisone PO BID as standard of care with cabazitaxel. Courses repeat every 21 days for 6-10 courses in the absence of disease progression or unacceptable toxicity. Patients may continue enzalutamide PO QD on days 1-28 in the absence of disease progression or unacceptable toxicity.
  • Cabazitaxel
  • Enzalutamide
  • Prednisone

Eligibility Criteria

        Inclusion Criteria:

          -  Metastatic CRPC with at least one biopsy-accessible metastasis

          -  Evidence of prostate cancer progression by any of the following criteria:
             radiographic or PSA criteria, or symptomatic progression related to prostate cancer

          -  Castrate testosterone levels (< 50 ng/dL) achieved by orchiectomy or maintenance on a
             luteinizing hormone-releasing hormone (LHRH) agonist or antagonist

          -  Histologic confirmation of original prostate cancer diagnosis per institutional
             standard; life expectancy of greater than 6 months

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

          -  Leukocytes >= 3,000/mm^3

          -  Absolute neutrophil count >= 1,500/mm^3

          -  Platelets >= 100,000/mm^3

          -  Total bilirubin within normal institutional limits (or < 2 X the upper limit of
             normal in those with Gilbert's disease)

          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
             (SGOT))/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase (SGPT))
             =< 1.5 X institutional upper limit of normal

          -  Creatinine within normal institutional limits OR creatinine clearance >= 45
             mL/min/1.73 m^2 for patients with creatinine levels above institutional normal

          -  Subject agrees to use a double barrier method of birth control during the course of
             study treatment period with enzalutamide and/or cabazitaxel treatment and for at
             least 3 months after study is discontinued

               -  A double-barrier method of contraception involves the use of a condom in
                  combination with 1 of the following: contraceptive sponge, diaphragm, or
                  cervical ring with spermicidal gel or foam

               -  Subject who has had a vasectomy at least 6 months prior to starting study
                  treatment period and those whose female sexual partner(s) are more than 55 years
                  of age and postmenopausal for at least 2 years or surgically sterile (tubal
                  ligation, hysterectomy, or bilateral oophorectomy) agree to use at least a
                  condom

          -  Ability to understand, and the willingness to sign, a written informed consent
             document, as well as comply with study requirements

          -  Must have appropriate wash out (> 6 half-lives) of androgen receptor antagonists, 5
             alpha reductase inhibitors or ketoconazole prior to the start of cycle 1; if the
             agent is not in the table below, the washout should be 2 weeks

               -  Bicalutamide; approximate half-life: 6 days; washout period: 36 days

               -  Flutamide; approximate half-life: 6 hours; washout period: 36 hours

               -  Nilutamide approximate half-life: 4 days; washout period: 24 days

               -  Finasteride; approximate half-life: 8 hours; washout period: 48 hours

               -  Aminoglutethimide; approximate half-life: 15 hours; washout period: 4 days

               -  Ketoconazole; approximate half-life: 8 hours; washout period: 48 hours

        Exclusion Criteria:

          -  Prior chemotherapy for prostate cancer, unless given neoadjuvantly or adjuvantly and
             > 6 months have elapsed)

          -  Patients may not have received any other investigational agents within the last 14
             days at the time of treatment start

          -  Patients may not have received enzalutamide or ARN-509 (another androgen receptor
             antagonist) in the past

          -  Patients may not have received cabazitaxel in the past

          -  Subject has clinical signs suggestive of high or imminent risks for pathological
             fracture, spinal cord compression and/or cauda equina syndrome

          -  History of severe hypersensitivity reaction (>= grade 3) to docetaxel, polysorbate 80
             containing drugs, or any of the capsule components of enzalutamide, including
             Labrasol, butylated hydroxyanisole, and butylated hydroxytoluene

          -  Concurrent or planned treatment with strong inhibitors or strong inducers of
             cytochrome P450 family 3, subfamily A, polypeptide 4/5 (3A4/5); (a one-week wash-out
             period is necessary for patients who are already on these treatments)

          -  Uncontrolled, intercurrent illness including, but not limited to, ongoing or active
             infection, uncontrolled diabetes, symptomatic congestive heart failure, unstable
             angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that
             would limit compliance with study requirements

          -  Subject has a 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, prior seizures

          -  Subject is on medications that lower the seizure threshold and cannot be discontinued
             during the study

               -  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)

               -  Tramadol

          -  Subject has a history of unexplained loss of consciousness or transient ischemic
             attack within 12 months of treatment start

          -  Subject is unwilling to stop using herbal supplements that can affect the PSA, such
             as saw palmetto or prostate cancer (PC)-SPES

          -  Subject has another active malignancy other than non-melanomatous skin cancer (unless
             it is metastatic) or superficial bladder cancer

          -  Must not have a gastrointestinal condition that would interfere with absorption

          -  Subjects may not be on other therapies that effect hormone levels, such as estrogens,
             testosterones, ketoconazole during this study; however, megestrol for hot flashes is
             permitted
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of DLT graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 (Phase I)
Time Frame:Up to 42 days
Safety Issue:
Description:Descriptive statistical analysis will be conducted. The proportion estimate will be reported with 95% confidence interval using exact method.

Secondary Outcome Measures

Measure:Incidence of adverse events graded by NCI CTCAE, version 4.0
Time Frame:Up to 28 days after the last dose of study medication
Safety Issue:
Description:Descriptive statistical analysis will be conducted. The proportion estimate will be reported with 95% confidence interval using exact method.
Measure:Overall survival
Time Frame:Up to 5 years
Safety Issue:
Description:Descriptive statistical analysis will be conducted. The median overall survival will be estimated with 95% confidence interval (if available). Kaplan-Meier plot will be used to graphically illustrate the overall survival distribution.
Measure:Pharmacokinetic profile of cabazitaxel
Time Frame:Day 1 at 0.5, 1, 1.5, 2, 4, 8, and 24 hours after the start of cabazitaxel infusion of courses 1 and 2
Safety Issue:
Description:Individual and mean plasma concentration data will be plotted over time for cabazitaxel alone (day 1, cycle 1) and for cabazitaxel co-administered with enzalutamide (day 1, cycle 2). Noncompartmental PK analysis will be performed on individual concentration-time data to calculate PK parameters, including, but not limited to maximum concentration, area under the curve (AUC) from 0 hours to last measureable concentration and to infinity, and half-life, for cabazitaxel administered alone or coadministered with enzalutamide. Descriptive statistics will be presented for plasma PK parameters.
Measure:PSA response 2, defined as >= 50% PSA decline from baseline
Time Frame:Baseline to week 28
Safety Issue:
Description:Descriptive statistical analysis will be conducted. The proportion estimate will be reported with 95% confidence interval using exact method.
Measure:PSA response 3, defined as >= 30% PSA decline from baseline
Time Frame:Baseline to week 28
Safety Issue:
Description:Descriptive statistical analysis will be conducted. The proportion estimate will be reported with 95% confidence interval using exact method..
Measure:PSA response 2a (subgroup Prior Abiraterone), defined as >= 50% PSA decline from baseline
Time Frame:Baseline to week 28
Safety Issue:
Description:Descriptive statistical analysis will be conducted. The proportion estimate will be reported with 95% confidence interval using exact method.
Measure:PSA response 2a (subgroup No Prior Abiraterone), defined as >= 50% PSA decline from baseline
Time Frame:Baseline to week 28
Safety Issue:
Description:Descriptive statistical analysis will be conducted. The proportion estimate will be reported with 95% confidence interval using exact method.
Measure:PSA response 3a (subgroup Prior Abiraterone), defined as >= 30% PSA decline from baseline
Time Frame:Baseline to week 28
Safety Issue:
Description:Descriptive statistical analysis will be conducted. The proportion estimate will be reported with 95% confidence interval using exact method.
Measure:PSA response 3b (subgroup No Prior Abiraterone), defined as >= 30% PSA decline from baseline
Time Frame:Baseline to week 28
Safety Issue:
Description:Descriptive statistical analysis will be conducted. The proportion estimate will be reported with 95% confidence interval using exact method.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:OHSU Knight Cancer Institute

Last Updated

September 27, 2016