Study of GDC-0084 in Pediatric Patients With Newly Diagnosed Diffuse Intrinsic Pontine Glioma or Diffuse Midline Gliomas
Condition: Brain and Central Nervous System Tumors
MeSH terms: Glioma; Nervous System Neoplasms; Central Nervous System Neoplasms; Diffuse Intrinsic Pontine Glioma
Study type: Interventional
Phase: Phase 1

Summary: 
      Pediatric high-grade gliomas are highly aggressive and treatment options are limited. The
      purpose of this first-in-pediatrics study is to examine the safety, tolerability, and
      pharmacokinetics of GDC-0084 and to estimate its maximum tolerated dose (MTD) when
      administered to pediatric patients with diffuse intrinsic pontine glioma (DIPG) or other
      diffuse midline H3 K27M-mutant gliomas after they have received radiation therapy (RT).
      GDC-0084 is a brain-penetrant inhibitor of a growth-promoting cell signaling pathway that is
      dysregulated in the majority of diffuse midline glioma tumor cells. This study is also
      designed to enable a preliminary assessment of the antitumor activity of single-agent
      GDC-0084, in the hope of enabling rational combination therapy with systemic therapy and/or
      radiation therapy (RT) in this patient population, which is in desperate need of therapeutic
      advances.

      Primary Objectives

        1. To estimate the maximum tolerated dose (MTD) and/or the recommended phase 2 dosage
           (RP2D) of GDC-0084 in pediatric patients with newly diagnosed diffuse midline glioma,
           including diffuse intrinsic pontine glioma (DIPG)

        2. To define and describe the toxicities associated with administering GDC-0084 after
           radiation therapy (RT) in a pediatric population

        3. To characterize the pharmacokinetics of GDC-0084 in a pediatric population

      Secondary Objectives

        1. To estimate the rate and duration of radiographic response in patients with newly
           diagnosed DIPG or other diffuse midline glioma treated with RT followed by GDC-0084

        2. To estimate the progression-free survival (PFS) and overall survival (OS) distributions
           for patients with newly diagnosed DIPG or other diffuse midline glioma treated with RT
           followed by GDC-0084
    

Detailed description: 
      There are two research strata: Stratum A1 and Stratum A2. All subjects will receive standard
      RT no later than 14 days after study enrollment and no later than 42 days after the date of
      radiographic diagnosis or surgery, whichever date is the later. Four to 12 weeks after the
      completion of standard RT, subjects without radiographic evidence of progression will receive
      single-agent oral GDC-0084 once daily in cycles of 28 days. Treatment may be continued for up
      to 2 years in the absence of disease progression or unacceptable toxicity.

      Subjects enrolled on Stratum A1 will be enrolled on the dose-escalation phase of the study.
      Up to 4 different dose levels will be evaluated: Dose level 0, 21 mg/m2; Dose level 1, 27
      mg/m2; Dose level 2, 35 mg/m2; and Dose level 3, 45 mg/m2. The Rolling 6 design will be used
      to determine the maximum tolerated dose (MTD)/recommended phase 2 dosage (RP2D) of GDC-0084.

      Subjects enrolled on Stratum A1 must be able to swallow capsules during the first cycle of
      therapy (the dose-limiting toxicity (DLT) evaluation period). Subjects who complete the DLT
      evaluation period and are no longer able to swallow the whole capsule may take GDC-0084
      opened, sprinkled in purée. Additionally, subjects who gain the ability to swallow whole
      capsules after initially receiving the opened formulation and have completed the DLT
      evaluation period may transition to the whole capsule formulation. Subjects who change
      administration methods after course 1 will have mandatory intrapatient pharmacokinetic
      studies performed. Subjects enrolled on Stratum A1 who are no longer able to swallow whole
      capsules of GDC-0084 during the DLT evaluation period (cycle 1) will be taken off treatment.

      Once the MTD has been established in Stratum A1, the Stratum A1 expansion cohort and Stratum
      A2 will open simultaneously. Subjects enrolled on the Stratum A1 expansion cohort will be
      required to swallow capsules. Subjects enrolled on Stratum A2 will be restricted to subjects
      who are unable to swallow capsules until the Stratum A1 expansion cohort is filled. Once the
      Stratum A1 expansion cohort has been filled, both subjects who are able to swallow capsules
      and those unable to swallow capsules may be enrolled on Stratum A2. Subjects enrolled on
      Stratum A2 who are unable to swallow capsules will take GDC-0084 as an open capsule sprinkled
      in purée and will undergo mandatory interpatient pharmacokinetic studies.
    

Intervention name(s): GDC-0084; radiation therapy
Intervention type(s): Drug; Radiation
Intervention description(s): Given PO; Both photon and proton therapy modalities will be allowed.
Other intervention name(s): irradiation; radiotherapy; radiation; external beam radiation therapy (EBRT)
Intervention MeSH terms: GDC-0084
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Anaplastic Astrocytoma; Atypical Brainstem Glioma; Brain Cancer; Brain Stem Glioma; Brain Tumors in Children; Diffuse Intrinsic Pontine Glioma; Diffuse Midline Glioma; Glioblastoma; H3 K27M mutant; Newly Diagnosed; Non-brainstem Midline Glioma; Pediatric Brain Tumor; Radiation Therapy; St. Jude Brain Tumor Studies; St. Jude Studies; St. Jude Treatment