Why are we doing this research?
- In this research study the investigators want to learn more about the safety of the study drug, PTC596 has when taken during radiation. The investigators also want to learn about the effects, if any, these drugs have on children and young adults with brain tumors.
- The investigators are asking people to be in this research study who have been diagnosed with a high grade glioma (HGG) including diffuse intrinsic pontine glioma (DIPG) to be in the research, because they have scheduled to have radiation to treat their cancer.
- The study is divided into two parts. The goal of the first part is to find the dose of PTC596 that can be given with radiation without causing serious side effects. The purpose of this surgical study is to test the amount of a study drug that may be found in the tumor and blood when given prior to and during a planned surgery for removal of the recurrent tumor.
This study consists of two parts:
- The phase I (Part A), dose-finding component of the trial, to estimate the maximum tolerated dose (MTD) or recommended phase II dose (RP2D) of PTC596 in combination with radiation therapy followed by maintenance therapy with PTC596, in children with newly-diagnosed DIPG and HGG.
- Once the RP2D has been determined, the investigators will enroll a surgical cohort (Part B) of patients with either a. newly-diagnosed DIPG who are amenable to undergo biopsy per recommendation of their treating physician OR b. Newly-diagnosed HGG for whom a second surgical resection is warranted for further debulking or to achieve a near-total or gross total resection after initial diagnosis has been made, but prior to start of therapy.
The primary objectives of the Phase I (Part A) study will be to determine the MTD or RP2D of PTC596 in combination with radiation therapy and to assess pharmacokinetic (PK) and pharmacodynamics studies. Dose-modifying toxicities for maintenance therapy will also be monitored.
- PK studies will be collected on days 1 and 4 (doses 1 and 2) of cycle 1 and day 1 of cycle 2.
- PTC596 will be given twice weekly on Monday and Thursday or Tuesday and Friday, for 6-7 weeks, during daily radiation therapy. Once radiation therapy with concomitant PTC596 is completed, all patients will continue with maintenance therapy which will begin immediately after completion of RT for up to 25 cycles.
The objectives of the Surgical Cohort Stratum are to:
- Assess the ability of PTC596 to inhibit BMI-1 activity in tumor and peripheral blood mononuclear cells (PBMNCs) of children with newly-diagnosed DIPG or HGG
- To characterize the pharmacokinetics of PTC596 in plasma, cerebrospinal fluid (CSF), and tumor tissue of children with newly-diagnosed DIPG or HGG
Once the RP2D has been established, up to 6 patients will be enrolled on the surgical study. Patients eligible for the Surgical Stratum include:
- newly-diagnosed DIPG patients who are amenable to undergo biopsy per the recommendation of their treating physician OR
- newly-diagnosed HGG patients for whom a second surgical resection is warranted for further debulking or to achieve a near-total or gross total resection after initial diagnosis has been made, but prior to start of therapy.
Patients on the surgical cohort study will commence treatment with the surgical cycle. During the surgical cycle, patients will be treated with two doses of PTC596, on days 1 and 4 of the surgical cycle prior to biopsy or re-resection; the second dose of PTC596 should ideally be administered 3-6 hours before surgery (but may be up to 12 hours prior to surgery). The concentration of PTC596 will then be measured in the tumor and accompanying blood sample by mass spectrometry. BMI-1 expression and the effects of BMI-1 inhibition in DIPG and HGG on gene regulation through gene expression profiling and epigenetic studies will be assessed in tissue and plasma. The PK and PD studies on the surgical cohort study are mandatory. The surgical cycle will end when patients begin RT.
Patients must begin RT at least two weeks after the date of surgery and may restart PTC596 on Mondays and Thursdays or Tuesdays and Fridays (twice weekly) after starting RT. Following completion of radiotherapy, patients will immediately start maintenance therapy on a Monday and Thursday or Tuesday and Friday schedule. Patients can continue to receive therapy with PTC596 for up to 25 cycles.
Study Type: Interventional
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment