NCT03696355

Study of GDC-0084 in Pediatric Patients With Newly Diagnosed Diffuse Intrinsic Pontine Glioma or Diffuse Midline Gliomas

Phase I Study of GDC-0084, a Brain-Penetrant PI3 Kinase/mTOR Inhibitor, in Pediatric Patients With Newly Diagnosed Diffuse Intrinsic Pontine Glioma or Diffuse Midline Gliomas After Radiation Therapy

• Status: Completed
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 27 (actual)
• Sponsor: St. Jude Children's Research Hospital · Academic / Other
• Sex: All
• Age: 2 Years – 21 Years
• Healthy volunteers: Not accepted

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.

Conditions

• Brain and Central Nervous System Tumors

Interventions

Type	Name	Description
DRUG	GDC-0084	Given PO
RADIATION	radiation therapy	Both photon and proton therapy modalities will be allowed.

Timeline

• Start date: 2018-11-19
• Primary completion: 2021-04-02
• Completion: 2022-09-04
• First posted: 2018-10-04
• Last updated: 2023-01-18

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study