Cabozantinib Plus Docetaxel and Prednisone for Advanced Prostate Cancer
- Conditions
- Prostatic Neoplasms
- Interventions
- Registration Number
- NCT01683994
- Lead Sponsor
- National Cancer Institute (NCI)
- Brief 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- Male
- Target Recruitment
- 49
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description combination of cabozantinib, docetaxel and prednisone Cabozantinib combination of cabozantinib, docetaxel and prednisone PII/Arm 2 -docetaxel+ prednisone + cabozantinib Cabozantinib docetaxel+ prednisone + cabozantinib combination of cabozantinib, docetaxel and prednisone Docetaxel combination of cabozantinib, docetaxel and prednisone PII/ Arm 1-docetaxel + prednisone only Prednisone docetaxel + prednisone only combination of cabozantinib, docetaxel and prednisone Prednisone combination of cabozantinib, docetaxel and prednisone PII/ Arm 1-docetaxel + prednisone only Docetaxel docetaxel + prednisone only PII/Arm 2 -docetaxel+ prednisone + cabozantinib Docetaxel docetaxel+ prednisone + cabozantinib PII/Arm 2 -docetaxel+ prednisone + cabozantinib Prednisone docetaxel+ prednisone + cabozantinib
- Primary Outcome Measures
Name Time Method Maximum Tolerated Dose (MTD) First two cycles of treatment (each cycle is 21 days), approximately 42 days. MTD is defined as the dose level at which no more than 1 of 6 patients experiences a dose limiting toxicity (DLT) at the level below that which had two instances of DLT. A DLT are defined as adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0) occurring during the first two cycles of therapy and related to the study medications (attributions: possible, probable, and definite) while fulfilling one of the following criteria: Any Grade 3 or greater non-hematologic toxicity except asymptomatic grade 3 hypertension, hypomagnesemia, hyponatremia, hypophosphatemia, hypocalcemia, and asymptomatic grade 4 uric acid. A treatment delay of \> 2 weeks due to an adverse event (delays due to dental procedures are not included). Grade 4 neutropenia (absolute neutrophil count \<500/µL lasting \> 5 days. Febrile neutropenia. Grade 3 thrombocytopenia lasting for 7 days or more or thrombocytopenia \< 50K/µL requiring platelet transfusion for bleeding.
Progression Free Survival (PFS) of Cabozantinib + Docetaxel + Prednisone Compared to Docetaxel + Prednisone Alone From start date of treatment until the date of first documented progression, date of death from any cause and up to 40 months, whichever occurred first. PFS is the time interval from start of treatment to documented evidence of disease progression or death. Disease progression was assessed by the Response Criteria in Solid Tumors (RECIST) and is defined as at least a 20% increase in the sum of the diameters of target lesions as referenced by the smallest sum on study. Appearance of one or more new lesions on bone scan and/or two consecutive rising prostatic-specific antigen values above the baseline at a minimum of one week intervals. A normal PSA value is 4.0 ng/ml and lower.
- Secondary Outcome Measures
Name Time Method Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0) Adverse events were assessed from the date treatment consent signed to date off study, approximately 45 months and 14 days for Arm A; 43 months and 14 days for Arm B; 9 months and 11 days for DL1; 27 months and 1 day for DL2; & 11 months & 25 days for DL3 Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center, 9000 Rockville Pike
🇺🇸Bethesda, Maryland, United States