Phase 3 Study of ANP Therapy vs. TMZ for Optic Pathway Glioma
To compare progression free survival (PFS), the time from randomization to progressive disease,in children with optic pathway glioma (OPG) age ≥ 6 months to < 18 years, who receive combination antineoplaston therapy (ANP therapy) vs. temozolomide (TMZ); study subjects will have 1) received prior treatment with carboplatin or cisplatin, which was terminated secondary to toxicity or progression of OPG, or 2) developed recurrence of OPG after completion of carboplatin or cisplatin therapy. PFS data will be censored on the date of the last tumor assessment documenting absence of progression for study subjects:
- Who are alive, on study and are progression-free at the time of the analysis;
- Who discontinue, receive no subsequent therapy and are progression-free at the time of the analysis;
- Who are given/change therapy other than the study treatment prior to observing progression;
- Who discontinued (due to personal preference or toxicity) with a change in therapy, withdrew, or was lost to follow-up;
For whom documentation of disease progression or death occurs after ≥ 2 consecutive missed tumor assessments.
- To describe the toxicity profile for ANP therapy vs. TMZ.
- To compare overall survival (OS) for subjects treated with ANP therapy vs. TMZ;
- To compare disease stabilization rates for subjects treated with ANP therapy vs. TMZ;
- To compare complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) rates for subjects treated with ANP therapy vs. TMZ.
|Study Design:||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
|Official Title:||A Randomized Phase 3 Study of Antineoplastons A10 and AS2-1 vs. Temozolomide in Subjects With Recurrent and / or Progressive Optic Pathway Glioma After Carboplatin or Cisplatin Therapy|
- Progression free survival (PFS) [ Time Frame: 5 years ]PFS will be summarized using tables produced by SAS Proc Lifetest (version 9.2 or later). Standard errors will be computed using the Greenwood formula and 95% confidence intervals produced using the loglog transform. The Log Rank test will be used to compare the two treatment groups with respect to PFS. All tests will be at the two-sided 0.050 significance level.
- Safety Analysis [ Time Frame: 5 years ]Comparison of the toxicity profile for ANP therapy vs. the toxicity profile for TMZ will be accomplished using the Fisher's exact test.
|Study Start Date:||December 2011|
|Estimated Study Completion Date:||December 2018|
|Estimated Primary Completion Date:||December 2016 (Final data collection date for primary outcome measure)|
Active Comparator: Temozolomide (TMZ)
Study subjects receive TMZ for 13 cycles
Study subjects in a fasting state receive TMZ orally once a day for five consecutive days (days 1 through 5) at a starting dose of 200 mg/m2/day. Treatment cycles are repeated every 28 days following the first daily dose of TMZ from the previous cycle. In the absence of PD or unacceptable toxicity, subjects continue to receive TMZ for a maximum of 13 cycles.
Experimental: ANP Therapy
Escalating doses of ANP therapy are given daily for 52 weeks.
Drug: ANP Therapy
Escalating doses of ANP therapy are administered for 52 weeks. If the study subject has an OR or maintains SD, ANP therapy is continued.
This is a randomized, phase 3, open-label, multicenter, protocol study in children age ≥ 6 months to < 18 yr., with recurrent and/or progressive OPG who have 1) received prior treatment with carboplatin or cisplatin, which was terminated secondary to toxicity or progression of OPG or 2) developed recurrence of OPG after completion of carboplatin or cisplatin therapy. A total of 158 subjects will be enrolled and randomized equally to one of two therapy groups: ANP therapy (79 subjects) or TMZ (79 subjects). If an average of 4 subjects is enrolled each month, enrollment will be completed in 3 years and 3 months. There will be an additional three years of follow-up.
Children of either gender and from all racial/ethnic groups will be eligible for this protocol study if they meet the criteria outlined in Section 3. Upon determination of eligibility, including the obtaining of an informed consent, study subjects will be randomized to ANP therapy or TMZ. The randomization will be stratified by prior RT (Y/N), hypothalamic involvement (Y/N) and age (< 5 years / ≥ 5 years).
In a group of children treated with TMZ after developing progressive and/or recurrent disease following first-line chemotherapy, a 2-year PFS of 49% and a 4-year PFS of 31% was reported by Gururangan and associates. Based on their results, and assuming an exponential distribution, a least squares estimate of the hazard is 0.333 per year.
For those study subjects, in the BRI Phase 2 study of ANP therapy for OPG, who 1) received prior treatment with carboplatin or cisplatin, which was terminated secondary to toxicity or progression of OPG or 2) developed recurrence of OPG after completion of carboplatin (or cisplatin) therapy, a least squares estimate of the hazard is 0.075 per year. Since the sample size in the Phase 2 study is small and may overstate the effect of ANP therapy in general use, a hazard of 0.167 per year was utilized in determining the sample size for the proposed Phase 3 protocol study, giving a hazard ratio (TMZ:ANP) of 2.0.
The primary efficacy hypothesis of the proposed protocol study is that ANP therapy provides for a significantly better PFS than does TMZ. This protocol study is event-driven (PD or death from any cause), and will be completed after 90 events have occurred. The required sample size in each treatment group is 79.
A log rank test of equality of survival curves, with a 0.05 two-sided significance level, has 90% power to detect the difference in PFS between children treated with ANP therapy vs. children treated with TMZ. Assuming an accrual rate of 4 subjects per month, the accrual period is 3 years and 3 months. There is an additional 3 years of follow-up. A common exponential dropout rate of 0.05 per year is assumed.
This study utilizes an intention-to-treat (ITT) analysis. It is event-driven (PD or death from any cause), and will be completed after 90 events have occurred. All subjects are evaluable for PFS from the time of randomization to the time of PD or death, regardless of therapy group, eligibility, or adequacy of follow-up. All study subjects who receive at least one dose of ANP therapy or TMZ are evaluable for safety.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01260103
|Study Chair:||Stanislaw R Burzynski, MD, PhD||Burzynski Research Institute|