Clinical Hold

Current therapies for diffuse, intrinsic pontine glioma (DIPG) provide very limited benefit to the patient. The rationale for the use of Antineoplaston therapy in this protocol study derives from experience with subjects from prior Phase 2 studies and Compassionate Exemption patients treated with Antineoplaston therapy at the Burzynski Clinic.

This study is designed to analyze the efficacy and safety of Antineoplaston therapy in five separate DIPG patient cohorts, which are defined by age and prior therapy. This is a two stage study with 20 patients in each cohort being enrolled in the first stage and an additional 20 patients being enrolled in the second stage, if pre-determined efficacy endpoints in the first stage are realized.

This study is designed to analyze the response of diffuse, intrinsic brainstem glioma (DIPG) to Antineoplaston therapy in 5 separate patient cohorts, which are defined by age and prior therapy. The primary endpoint is objective response (OR), but the determination of OR in DIPG is problematic. Determination of OR using the Macdonald, RANO, and RECIST criteria relies on postgadolinium TI-weighted MRI images of enhancing disease. However, DIPG shows variable enhancement and has a non-enhancing component as seen on T2/FLAIR-weighted MRI images. Recent reviews have proposed OR assessment in diffuse low grade gliomas using modified RANO criteria and in recurrent glioblastoma using RECIST + F (T2/FLAIR-weighted images).Neither of these methodologies have been validated.

This single-arm Phase 2 study of the efficacy of Antineoplaston therapy in DIPG will utilize both bidimensional assessment of enhancing DIPG (RANO), a validated primary endpoint, and unidimensional assessment of enhancing + non-enhancing DIPG (RECIST + F), an exploratory endpoint.

This Phase 2 protocol has a strategy for early assessment of response rates with procedures for termination of enrollment for lack of efficacy. A minimax two-stage design is utilized.

Ten patients with enhancing disease will be enrolled in stage 1 for each cohort. If none of the 10 patients in a particular cohort achieves an OR based on bidimensional measurements, no additional patients with enhancing disease will be enrolled into that particular cohort. However, if 1 of the 10 patients with enhancing disease in a particular cohort achieves an OR, then an additional 10 patients with enhancing disease will be enrolled in stage 2 of the minimax design for that cohort, yielding a maximum of 20 patients with enhancing disease for that cohort. As exploratory endpoints, complete response (CR), partial response (PR), and progressive disease (PD) rates, as well as 6-, 12-, and 24-month overall survival (OS) will be analyzed.

Patients with no enhancing disease will also be enrolled into each cohort but will not count against the numbers designated in the two-stage minimax design. An exploratory endpoint for these patients will be 6-, 12-, and 24-month OS.

Other exploratory endpoints will be determination of OR, CR, PR, and PD based on unidimensional measurement of the enhancing + non-enhancing components of DIPG (RECIST + F).

At completion of this study, the efficacy of Antineoplaston therapy in each cohort and the desirability of its further development in any particular cohort will be determined in discussion with the FDA.

Inclusion Criteria:

Five cohorts of patients with diffuse, intrinsic pontine glioma will be studied:

1. Patients age 3 months to < 3 years;
2. Patients age 3-21 years with progressive disease (PD) following radiation therapy (RT) ± chemotherapy and/or other therapies;
3. Patients age 3-21 years with newly diagnosed DIPG who (or whose parents / guardians) have refused RT;
4. Patients age > 21 years with PD following RT ± chemotherapy and/or other therapies; and
5. Patients age > 21 years with newly diagnosed DIPG who have refused RT.

Exclusion Criteria include:

1. Disseminated disease, multicentric tumors, or leptomeningeal disease;
2. Uncontrolled intercurrent illness;
3. A history of New York Heart Association Class II congestive heart failure or above;
4. Pregnancy.