A Phase I/II Study of High-dose L-methylfolate in Combination With Temozolomide and Bevacizumab in Recurrent High Grade Glioma
Dietary Supplement: Vitamin C
|Study Design:||Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Phase I/II Study of High-dose L-methylfolate in With Combination Temozolomide and Bevacizumab in Recurrent High Grade Glioma.|
- Maximum Tolerated Dose (Phase I) [ Time Frame: every 4 weeks, 28-day cycle, up to 6 months ] [ Designated as safety issue: Yes ]
- Progression-free survival (Phase II) [ Time Frame: On treatment to disease progression or death for any reason, up to 12 months ] [ Designated as safety issue: No ]Disease progression is defined as either radiological or clinical/neurological progression (whichever occurs first), PFS is the time interval between the date of starting treatment and the date of disease progression or death, whichever comes first. If neither event has been observed, then the patient is censored at the date last documented to be free of progression. Progression-free and overall survival will be summarized non-parametrically using the method of Kaplan and Meier with standard errors based on Greenwood's formula.
- Objective Response (Phase I) [ Time Frame: every 8 weeks, up to 6 months ] [ Designated as safety issue: No ]Response will be determined by neurologic examination and contrast-enhanced MRI initially after 8 weeks and then subsequently prior to every other cycle based on the Response Assessment in Neuro-Oncology criteria (RANO).
- Number of patients with each worst-grade toxicity. (Phase I) [ Time Frame: every 4 weeks (28-day cycle), up to 6 months ] [ Designated as safety issue: Yes ]To determine the safety profile of high-dose L-methylfolate (15mg, 30 mg, 60 mg or 90 mg) in combination with bevacizumab and temozolomide in patients with recurrent high-grade glioma as determined by number of patients with each worst grade toxicity using the Common Terminology Criteria for Adverse Events 4.0, 1 = mild through 5 = death.
- Overall Survival (Phase II) [ Time Frame: on study to date of death, up to 12 month ] [ Designated as safety issue: No ]median overall survival and time to survival in patients treated with L-methylfolate in combination with temozolomide and bevacizumab. The Duration of survival is the time interval between the date of starting treatment and the date of death. Patients still alive will be censored at the date of last follow-up.
|Study Start Date:||July 2013|
|Estimated Study Completion Date:||March 2017|
|Estimated Primary Completion Date:||July 2016 (Final data collection date for primary outcome measure)|
Experimental: L-methylfolate with Bevacizumab & Temozolomide
28-day cycle, dose levels L-methylfolate: Phase I 15 mg (once a day) 30 mg (15 mg twice a day) 60 mg (30 mg twice a day) 90 mg (45 mg twice a day) Phase II will use the MTD of L-methylfolate daily with bevacizumab & temozolomide.
bevacizumab at 10mg/kg IV every 14 days (Phase I & phase II)Drug: Temozolomide
150 mg/m2/day for a 5-day regimen per month (Phase I & Phase II)Dietary Supplement: Vitamin C
250 mg vitamin C once a day (oral) - Phase I & Phase II
The phase I part of the study will be completed to determine the Maximum Tolerated Dose (MTD) of high-dose L-methylfolate in combination with bevacizumab at 10mg/kg IV every 14 days, a 5-day regimen per month of temozolomide at 150 mg/m2/day and a 250 mg tablet of vitamin C. Dose escalation will involve 3 patients treated at each dose level of L-methylfolate (15mg, 30 mg, 60 mg or 90 mg), and the MTD will be confirmed by expansion of 3 additional patients. It is anticipated that 6 to 15 patients will be enrolled in the phase 1 part of the study. Patients will continue treatment until disease progression. Once the MTD of L-methylfolate has been determined, patients enrolled at a lower dose level may increase L-methylfolate dose to the MTD dose, per investigator discretion.
The phase II part of the study will consist of patients taking the MTD of L-methylfolate daily in combination with bevacizumab at 10 mg/kg IV every 14 days, a 5-day regimen per month of temozolomide at 150 mg/m2/day and a 250 mg tablet of vitamin C. There will be 32 patients treated in the Phase II study and the patients will continue treatment until progression. The 6 patients treated at the MTD cohort in Phase
Please refer to this study by its ClinicalTrials.gov identifier: NCT01891747
|United States, Tennessee|
|Vanderbilt-Ingram Cancer Center|
|Nashville, Tennessee, United States, 37232|
|Principal Investigator:||Stephen Clark, MD||Vanderbilt-Ingram Cancer Center|