A Phase 2 Trial of Bevacizumab, Lenalidomide, Docetaxel, and Prednisone (ART-P) for Treatment of Metastatic Castrate-Resistant Prostate Cancer
Condition: Metastatic Prostate Cancer
MeSH terms: Prostatic Neoplasms
Intervention: Bevacizumab; Lenalidomide; Docetaxel; Prednisone
Intervention description: 15 mg/kg cycle 1 day 1, repeated every 21 days; Once daily days 1-14 of every 21; 75 mg/m^2 intravenous (IV) over 60 minutes on cycle 1 day 1, repeated every 21 days (a 3-week cycle); 10 mg orally every day
Intervention MeSH terms: Prednisone; Bevacizumab; Lenalidomide; Docetaxel
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 63.0
Sex: Male
Minimum age: 18 Years
Maximum age: 100 Years
Healthy volunteers: No
Keywords: Dual Antiangiogenic Combination Therapy for mCRPC; Efficacy and Toxicity Profile; Single Stage Phase 2 With Early Stopping, Run In Phase For Toxicity; Correlative Measurements; Overall Survival Assessment; Metastatic Prostate Cancer; Prostate Cancer

Summary:

      Background:

        -  Prednisone and docetaxel have been used successfully in treating patients with prostate
           cancer, either when used alone or in combination with other agents. Researchers believe
           that these anticancer effects can be increased by giving them in this specific
           combination.

        -  A previous study at the National Cancer Institute combined docetaxel and prednisone with
           bevacizumab and thalidomide. The results of this study were promising; however, most
           patients in the study required a dose reduction of thalidomide because of its side
           effects.

        -  Lenalidomide, a drug similar to thalidomide, may have less severe side effects. Based on
           previous studies, lenalidomide is well tolerated in patients with solid tumors when used
           alone or in combination with docetaxel, and it may be a good substitute for thalidomide.

      Objectives:

        -  To determine if lenalidomide is an appropriate and effective substitute for thalidomide
           in treating prostate cancer.

        -  To evaluate the safety and effectiveness of bevacizumab, lenalidomide, docetaxel, and
           prednisone as a prostate cancer treatment, and to study any side effects.

      Eligibility:

      - Men 18 years of age and older who have been diagnosed with metastatic prostate cancer that
      has not responded to standard treatment, including surgical removal of the testicles or
      treatment with androgen (sex-hormone) suppressing drugs.

      Design:

        -  Participants will have a complete medical history and physical examination before
           beginning the study.

        -  Patients will be treated with 21-day cycles with a combination of four drugs:

        -  (1) Docetaxel, which will be given into a vein for 60 minutes on the first day of each
           21-day cycle. Patients will take dexamethasone (a steroid agent) before and after taking
           docetaxel.

        -  (2) Prednisone, which will be taken by mouth daily.

        -  (3) Bevacizumab, which will be given through a vein over 30 to 90 minutes on the first
           day of each 21-day cycle following the infusion of docetaxel.

        -  (4) Lenalidomide, which will be taken by mouth during the first 2 weeks of each 21-day
           cycle. The dose of lenalidomide may be adjusted if side effects develop.

        -  Patients will also receive enoxaparin, a subcutaneous injection administered daily, to
           prevent blood clots and/or pegfilgrastim, a subcutaneous injection on day 2 of each
           cycle, to improve white blood cell counts, as directed by researchers.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

        Castrate-resistant metastatic adenocarcinoma of the prostate defined as progressive
        metastatic disease (see below) while on GnRH agonists or post surgical castration. All
        patients enrolled will be required to have evaluable disease on imaging studies.

        Histopathological documentation of prostate cancer confirmed in the NCI Laboratory of
        Pathology at the National Institutes of Health, the Pathology Department at Walter Reed
        Medical Center, or the Pathology Department at National Naval Medical Center, prior to
        starting this study. In addition, patients whose slides are lost or unavailable will be
        eligible for the study if they provide documentation of prostate cancer and if they meet
        criteria of clinically progressive prostate cancer as outlined (see below).

        Clinically progressive prostate cancer documented prior to entry. Progression must be
        evidenced and documented by any of the following parameters:

        i) Two consecutively rising prostatic specific-antigen (PSA) levels apart of 2 weeks

        ii) At least one new lesion on bone scans.

        iii) Progressive measurable disease.

        Patients must have undergone bilateral surgical castration or must continue on GnRH
        agonist.

        Those patients receiving an anti-androgen agent for at least 6 months and are entering the
        trial due to a rise in PSA must demonstrate a continued rise in PSA 4 weeks after stopping
        flutamide and 6 weeks after stopping bicalutamide or nilutamide.

        May not have received any chemotherapy or antiangiogenic therapy (including thalidomide,
        lenalidomide, bevacizumab and its targets receptor inhibitors) for metastatic prostate
        cancer. (Prior immunotherapy/vaccine, experimental hormonal therapy, radiation and
        (neo)adjuvant chemotherapy is permitted)

        Age greater than or equal to 18 years

        Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2

        Must have adequate organ and marrow function as defined below:

        Laboratory Test and Required Value:

          -  Leukocytes greater than or equal to 3,000/microL

          -  Absolute neutrophil count greater than or equal to 1,500/ microL

          -  Platelets greater than or equal to 100,000/ microL

          -  Total bilirubin less than or equal to 1.5 times the institutional upper limits of
             normal, or less than or equal to 3 mg/dl in a subject with Gilbert Syndrome

          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase (SGOT) and
             alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase (SGPT) less than
             or equal to 2.5 times the institutional upper limit of normal

          -  Creatinine less than or equal to 1.5 times the institutional upper limits of normal

        OR

        -Creatinine clearance greater than or equal to 50 mL/min/1.73 m(2) for patients with
        creatinine levels above institutional normal.

        Recovered from any acute toxicity from surgery or radiotherapy, with minimum 4 weeks from
        major surgical procedures and 2 weeks from radiotherapy

        Must be willing to travel from their home to the National Institutes of Health (NIH) for
        follow-up visits

        Able and willing to follow instructions and conform to protocol.

        Patients may have had no other active malignancy within the past 2 years with the exception
        of non-melanoma skin cancer and superficial bladder carcinoma.

        No history of myocardial infarction within the past 6 months, uncontrolled congestive heart
        failure (CHF) or uncontrolled angina pectoris

        Patients must agree to use adequate contraception (abstinence; hormonal or barrier method
        of birth control) prior to the study, during the study, and at least six months after
        completion. Males must agree to use a latex condom during sexual contact with females of
        childbearing potential while participating in the study and for at least six months
        following, even if a man has undergone a successful vasectomy. All patients must be
        counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal
        exposure as indicated in the consent.

        Subjects must agree not to share study drug and not donate blood, sperm, or semen. A female
        of childbearing potential is a sexually mature woman who: 1) has not undergone a
        hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at
        least 24 consecutive months (i.e., has had menses at any time in the preceding 24
        consecutive months).

        Ability to understand and the willingness to sign a written informed consent document.

        EXCLUSION CRITERIA:

        Present clinical signs or symptoms of current active brain and/or leptomeningeal metastases
        confirmed by computed tomography (CT) or magnetic resonance imaging (MRI) brain scan.
        Patients with previously treated brain metastases are allowed to participate in the study.

        --Treated brain metastases are defined as having no ongoing requirement for steroids and no
        evidence of progression or hemorrhage after treatment for at least 3 months, as ascertained
        by clinical examination and brain imaging (MRI or CT). (Stable dose of anticonvulsants are
        allowed). Treatment for brain metastases may include whole brain radiotherapy (WBRT),
        radiosurgery (RS; Gamma Knife, term linear accelerator (LINAC), or equivalent) or a
        combination as deemed appropriate by the treating physician. Patients with central nervous
        system (CNS) metastases treated by neurosurgical resection or brain biopsy performed within
        3 months prior to Day 1 will be excluded.

        Uncontrolled, intercurrent illness including, but not limited to, symptomatic congestive
        heart failure (American Heart Association (AHA) Class II or worse), unstable angina
        pectoris

        Psychiatric illness/social situations that would limit compliance with study requirements.

        Prior history of hypertensive crisis or hypertensive encephalopathy

        Proteinuria, as demonstrated by a 24 hour protein of greater than or equal to 2000 mg.
        Urine protein should be screened by urine analysis. If urine dipstick is greater than 1.0+,
        then a 24 hour urine collection for total protein will need to be obtained and the level
        should be less than 2000 mg for patient enrollment.

        Serious, non-healing wound, active ulcer, or untreated bone fracture, including
        tumor-related pathological fracture

        Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic
        anticoagulation)

        Human immunodeficiency virus (HIV)-positive patients receiving combination anti-retroviral
        therapy are excluded from the study because of possible pharmacokinetic interactions with
        docetaxel, bevacizumab, and/or the combination.

        Greater than Grade 2 peripheral neuropathy at baseline

        History of allergic reaction to docetaxel, prednisone, lenalidomide and/or bevacizumab or
        related products.

        Patients who are unable to ingest oral medication.

        Patients on treatment for venous thromboembolism (VTE).

        History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess
        within 6 months prior to day 1

        Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior
        to Day 1 therapy

        Anticipation of need for major surgical procedures during the course of the study

        Core biopsy or other minor surgical procedure, excluding placement of a vascular access
        device, within 7 days prior to Day 1

        Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair, aortic
        dissection or recent peripheral arterial thrombosis) within 6 months prior to Day 1

        Patients with clinically significant cardiovascular disease are excluded

          -  Inadequately controlled hypertension (HTN) (systolic blood pressure (SBP) greater than
             160 mmHg and/or diastolic blood pressure (DBP) greater than 90 mmHg despite
             antihypertensive medication)

          -  History of cerebrovascular accident (CVA) within 6 months (see additional requirement
             for adjuvant protocols), myocardial infarction or unstable angina within 6 months (see
             additional requirement for adjuvant protocols)

          -  New York heart association grade II or greater congestive heart failure

          -  Serious and inadequately controlled cardiac arrhythmia

          -  Clinically significant vascular disease as stated above

        Patients with known hypersensitivity of Chinese hamster ovary cell products or other
        recombinant human antibodies