Study of Vinblastine and Sirolimus in Pediatric Patients With Recurrent or Refractory Solid Tumors Including Central Nervous System Tumors
This study is a Phase I study using vinblastine and sirolimus in patients with relapsed solid tumors including selected brain tumors and lymphoma. The investigators hypothesis is that the combination administration of weekly vinblastine and sirolimus is safe.
Central Nervous System Tumors
Drug: Vinblastine and Sirolimus
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Phase I Study of Vinblastine and Sirolimus in Pediatric Patients With Recurrent or Refractory Solid Tumors Including CNS Tumors|
- Maximum tolerated dose of vinblastine in combination with sirolimus [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]Dose will be escalated every 3 to 6 patients using the 3+3 standard design regimen. Enrollment of the next cohort will occur after the previous cohort has completed a full cycle without any dose limiting toxicity (DLT). If a DLT is observed in 1 out of 3 patients during the first cycle, 3 additional patients will be enrolled to receive the same dose. If a DLT is observed in another patient, 3 additional patients will be enrolled to receive a dose level below this dose. The MTD will be defined as the dose level below which DLTs are seen in ≥ 2 of at least 6 patients dosed.
- Safety data [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]Safety data will be described for all patients receiving at least one dose of vinblastine and sirolimus. Safety data will include values for hematology, serum chemistry, vital signs, and adverse events. The proportion of patients experiencing adverse events, serious adverse events, dose limiting toxicities and treatment delays will be summarized for each dosing cohort.
- Response Rate [ Time Frame: 12 months ] [ Designated as safety issue: No ]The proportion of patients experiencing progressive disease, stable disease, partial responses or complete responses will be summarized in tabular format. Progression free survival and duration of any responses will also be summarized.
|Study Start Date:||April 2010|
|Study Completion Date:||April 2012|
|Primary Completion Date:||April 2012 (Final data collection date for primary outcome measure)|
Experimental: Vinblastine and Sirolimus
The standard 3+3 Phase 1 trial design will be used for the conduct of this study. Three to six patients can be concurrently enrolled onto a dose level. Accrual is suspended when a cohort of three has been enrolled until toxicity data for that cohort have been reported, or when the study endpoints have been met.
Drug: Vinblastine and Sirolimus
Patients will be enrolled to receive vinblastine and sirolimus in 28 day cycles. Using the 3+3 standard Phase1 design, vinblastine will be administered via IV push on Days 1, 8, 15, 22. The starting dose of 4 mg/m2 (Dose Level 1) is 67% of the established MTD (6 mg/m2) for this schedule in pediatrics. Dose escalation will take place in a standard 3+3 design, in which doses will increase by approximately 20 to 25% in successive 3-patient cohorts.
Sirolimus (rapamycin) will be given by mouth (tablet or suspension) once daily throughout the cycle. Ideally patients will remain on the same dose form (tablet or suspension) for the duration of the study. All patients will be assigned a target sirolimus serum trough
Published data demonstrating a survival advantage of the vinblastine-sirolimus regimen vs single agent in an orthopotic neuroblastoma mouse model and our unpublished data support a VBL in vitro pro-apoptotic plasma concentration of 1-2 nM range and an anti angiogenic concentration of 2pM. These plasma concentrations are achievable with a 6 mg/m2 (apoptosis) and 1 mg/m2 VBL regimen (anti-angiogenesis) weekly regimen. We expect that vinblastine delivered at any given dose, as described in the protocol, will carry both anti-apoptotic and antiangiogenic activity. Safety and preliminary efficacy of both drugs in pediatric tumors support the development of a clinical trial.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01135563
|United States, California|
|Rady Children's Hospital-San Diego|
|San Diego, California, United States, 92123|
|United States, Missouri|
|SSM Cardinal Glennon Children's Medical Center|
|St. Louis, Missouri, United States, 63104|
|United States, Vermont|
|Fletcher Allen Health Care|
|Burlington, Vermont, United States, 05401|
|The Hospital for Sick Children|
|Toronto, Ontario, Canada, M5G 1X8|
|Montreal, Quebec, Canada, H3T 1C5|
|Principal Investigator:||Sylvain Baruchel, MD||The Hospital for Sick Children, Toronto Canada|