Cabozantinib Plus Docetaxel and Prednisone for Advanced Prostate Cancer
Condition: Prostatic Neoplasms
MeSH terms: Prostatic Neoplasms
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      Background:

      - Cabozantinib is a drug that slows the growth of blood vessels that feed tumors. It is
      approved for medullary thyroid cancer. However, studies have shown that prostate tumors
      respond to it. Docetaxel and prednisone are standard treatments for advanced prostate cancer.
      Researchers want to see if adding cabozantinib to these two drugs can be a safe and effective
      treatment for this type of cancer.

      Objectives:

      - To test the safety and effectiveness of cabozantinib with standard treatments for advanced
      prostate cancer.

      Eligibility:

      - Individuals at least 18 years of age who have advanced prostate cancer that has not
      responded to standard treatments.

      Design:

        -  Participants will be screened with a physical exam and medical history. Blood and urine
           samples will be collected. Imaging studies will also be performed.

        -  Participants will receive the cancer drugs over 21-day cycles of treatment. They will
           take docetaxel and cabozantinib on day 1 of each cycle. Each docetaxel infusion will
           take about 1 hour. They will also take prednisone by mouth twice each day.

        -  Treatment will be monitored with frequent blood tests and imaging studies.

        -  Participants will continue to take the study drugs for as long as their cancer does not
           worsen and side effects are not too severe.
    

Detailed description: 
      Background:

        -  Docetaxel is established as first-line chemotherapy in patients with metastatic castrate
           resistant prostate cancer (CRPC). However; it is increasingly recognized that combining
           docetaxel with other agents of clinical activities without overlapping toxicities could
           simultaneously target different cellular signaling pathways vital for tumor survival,
           producing either additive or synergistic activities.

        -  Inhibition of angiogenesis, either as a stand-alone approach or in combination with
           chemotherapy, has demonstrable antitumor efficacy against CRPC and there are several
           antiangiogenic agents that are now in clinical trials in this population of patients.

        -  Cabozantinib (XL184) was developed as an inhibitor of both angiogenesis and of its
           resistance mechanism. It is an inhibitor of multiple receptor tyrosine kinases including
           tyrosine-protein kinase Met (c-Met), vascular endothelial growth factor receptor 2
           (VEGFR2) and rearranged during transfection (RET).

        -  In single agent clinical studies, cabozantinib demonstrated, broad anti-tumor activities
           across many solid tumor types.

      Objectives:

        -  To determine the safety profile of cabozantinib in combination with docetaxel and
           prednisone, and to determine the maximal tolerated dose (MTD) as recommended phase II
           dose in combination with docetaxel

        -  To determine the relative efficacy (in terms of progression free survival (PFS)) of
           docetaxel and cabozantinib compared to docetaxel alone

      Eligibility:

        -  Patients must have progressive metastatic CRPC. There must be radiographic evidence of
           disease after primary treatment with surgery or radiotherapy. If patients had been on
           flutamide, they must have disease progression at least 4 weeks after withdrawal.
           Patients on bicalutamide or nilutamide must have progression at least 6 weeks after
           withdrawal. Withdrawal criteria apply only to patients on the above anti-androgens for
           at least the prior 6 months.

        -  Patients must be at least 18 years of age and able to give informed consent.

        -  Patients in the Phase II portion of the study must have progressed on abiraterone or
           enzalutamide

      Design:

        -  The initial phase I portion of this study will test fixed dose docetaxel and prednisone
           in combination with cabozantinib at three escalating doses. Using a standard 3 + 3
           design, three patients will initially be treated at each dose level until MTD has been
           defined.

        -  An expansion cohort will then be enrolled at the MTD to further characterize safety,
           toxicity and pharmacokinetic data and to obtain preliminary information on the efficacy
           of the combination treatment.

        -  In Phase II, patients will be enrolled to a randomized two-arm cohort comparing
           docetaxel in combination with cabozantinib to docetaxel alone with a primary endpoint of
           PFS.

        -  The accrual ceiling for the study, including the Phase I dose escalation and the
           expansion phases as well as the Phase II randomized phase, is set at 81.
    

Intervention name(s): Cabozantinib; Docetaxel; Prednisone
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Assigned dose given daily during each 21 day cycle. Treatment may continue until disease progression or intolerable toxicity.; 75mg/m^2 intravenous (IV) over approximately 60 minutes on cycle 1 day 1 and repeated every 21 days until disease progression or intolerable toxicity.; 5 mg by mouth (PO) twice a day during each 21 day cycle until disease progression or intolerable toxicity.
Other intervention name(s): Cometriq; Taxotere; Deltasone
Intervention MeSH terms: Prednisone; Docetaxel
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Angiogenesis Inhibitors; Small Molecules; Tyrosine Kinase Inhibitor