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
Study type: Interventional
Phase: Phase 2

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.
    

Detailed description: 
      Background:

      The dual antiangiogenic therapy with bevacizumab and thalidomide in combination with
      docetaxel and prednisone (ATTP) is highly active in patients with metastatic castration
      resistant prostate cancer (mCRPC), associated with unprecedented results (90% patients had
      PSA declines of greater than or equal to 50% and 64% ORR in measurable disease).

      Most patients in the ATTP trial required dose reduction due to thalidomide toxicities.

      Lenalidomide, an analogue of thalidomide, possesses both antiangiogenesis and inhibition of
      TNF-alpha, but has a favorable toxicity profile. Lenalidomide is well tolerated in patients
      with solid tumors when used alone or in combination with docetaxel.

      To preserve the efficacy of ATTP and to potentially reduce toxicity, lenalidomide may be a
      good substitute for thalidomide.

      Objectives

      Primary:

      To assess if lenalidomide at its approved dosing schedule can be safely combined with
      docetaxel, bevacizumab, and prednisone in patients with mCRPC (less than 25% Grade 4
      toxicity)

      To evaluate the efficacy of the combination

      Eligibility:

      Patients with progressive mCRPC who have not received any chemotherapy or antiangiogenic
      therapy for mCRPC

      Design:

      A single-stage Phase 2 study, with an early stopping rule for excessive toxicity: the goal is
      to enroll 45 patients at the 25-mg dose level of lenalidomide. However, if 7 in the first 18
      or fewer patients receiving lenalidomide at 25 mg develop grade 4 non-hematologic toxicity at
      anytime during study, no further patients will be enrolled. With respect to the stopping
      rule, a grade 4 hematologic toxicity will be considered if the episode has lasted for greater
      than or equal to 5 days. Grade 4 lymphopenia of any duration will not be counted. If less
      than 7 of the first 18 patients experience the above level of toxicity, accrual will continue
      until 45 patients have been enrolled at the 25 mg dose level of lenalidomide.

      A run-in phase with lenalidomide at 15 mg will be conducted in the first three patients and
      at 20mg for the next three patients for assessing its tolerability within the combination
      prior to dosing at 25 mg thereafter.

      An expansion cohort of a lower dose of lenalidomide (15 mg) in combination with docetaxel and
      and Avastin will be conducted to asses if this lower dose of lenalidomide could have similar
      efficacy with less toxicity.

      Treatment Schema of ART-P

      Dex -Dexamethasone 8 mg. po 12 hours pre, 3 hours pre, and 1 hour pre infusion of docetaxel
      (patients who were on prior regimen which included a lower dose of decadron and did not have
      a reaction do not have to increase their decadron to the 8 mg dose)

      Len - Lenalidomide 25 mg po, days 1-14. Lenalidomide 15 mg and 20mg for the proposed run-in
      phase. Lenalidomide 15 mg for the expansion cohort.

      Doc - Docetaxel 75 mg/m2 IV

      Bev - Bevacizumab 15 mg/kg IV

      Pre - Prednisone 10 mg PO daily throughout cycle

      E - Enoxaparin given SQ daily based on weight (see dosing chart in section 4.2)

      Peg - Pegfilgrastim 6mg SQ given at least 24 hours after docetaxel administration

      Baseline screening evaluations are to be conducted within 15 days prior to protocol
      enrollment. Baseline scans and x-rays must be performed 4 weeks prior to protocol enrollment.
      Patients must be evaluated at the NCI clinic each cycle for treatment continuation. Staging
      scans will be performed after the first 2 cycles of treatment and then every three cycles.
      All follow-up evaluations can be done on the last week of the prior cycle.
    

Intervention name(s): Bevacizumab; Lenalidomide; Docetaxel; Prednisone
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): 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
Other intervention name(s): Avastin; Revlimid; Taxotere; Deltasone
Intervention MeSH terms: Prednisone; Bevacizumab; Lenalidomide; Docetaxel
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
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