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

NCT03696355 | Completed Phase 1 FDA Drug

• 2 other identifiers: SJPI3KNCI-2018-02268
• Study Type: interventional
• Target: 27
• Locations: 1 country
• Sites: 1

Brief 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. 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. 2.To define and describe the toxicities associated with administering GDC-0084 after radiation therapy (RT) in a pediatric population
3. 3.To characterize the pharmacokinetics of GDC-0084 in a pediatric population
4. 4.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
5. 5.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

Conditions

Brain and Central Nervous System Tumors

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

Outcome Measures

Primary Outcomes (3)

• Estimate the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of GDC-0084 after standard-of-care radiation therapy (RT)

  The MTD is empirically defined as the highest dose level at which six patients have been treated with at most one patient experiencing a dose-limiting toxicity (DLT) and the next higher dose level has been determined to be too toxic. The MTD estimate will not be available if the lowest dose level studied is too toxic or the highest dose level studied is considered safe. In the latter case, the highest studied safe dose may be considered as the recommended phase 2 dose (RP2D). The MTD estimation will be limited to evaluable patients and toxicity assessments from course 1 (28 days).

  1 month after start of GDC-0084 treatment

• Incidence of adverse events at least possibly associated with GDC-0084 after RT by stratum

  Adverse event data will be summarized in tables by dose level.

  Up to 2 years after start of GDC-0084 treatment

• Pharmacokinetics of GDC-0084 by stratum

  GDC-0084 area under the curve (AUC0-∞) is estimated based on course 1 day 1 (C1D1) PK samples, and AUC0-24 based on course 1 day 28 (C1D28) PK samples.

  GDC-0084 treatment course 1 days 1 and 28

Secondary Outcomes (4)

• Rate of best overall response by stratum

  Up to 1 year after completion of GDC-0084 treatment

• Duration of best overall response by stratum

  Up to 1 year after completion of GDC-0084 treatment

• Progression-free survival for patients treated with GDC-0084 after RT

  Up to 3 years from diagnosis

• Overall survival for patients treated with GDC-0084 after RT

  Up to 3 years from diagnosis

Study Arms (2)

Stratum A1

EXPERIMENTAL

Dose Escalation Phase: Four to 12 weeks after the completion of standard RT, subjects who are able to swallow capsules will receive single-agent oral GDC-0084 at one of the 4 dose levels once daily in cycles of 28 days. During cycle 1 only, a single dose of GDC-0084 will be withheld on day 2, for a total of 27 doses. Treatment may be continued for up to 24 months (26 cycles) in the absence of disease progression or unacceptable toxicity. Dose Expansion Phase Four to 12 weeks after the completion of standard RT, subjects who are able to swallow capsules will receive the MTD dose established in the Stratum A dose escalation phase. Subjects who completed the first course of therapy may take GDC-0084 as an open capsule sprinkled in purée such as applesauce. Treatment may be continued for up to 24 months (26 cycles) in the absence of disease progression or unacceptable toxicity.

Drug: GDC-0084; Radiation: radiation therapy

Stratum A2

EXPERIMENTAL

Four to 12 weeks after the completion of standard RT, subjects will received the MTD dose established in the Stratum A1 dose escalation phase. Subjects who are unable to swallow capsules will initially be enrolled 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. Subjects who are unable to swallow capsules will take GDC-0084 as an open capsule sprinkled in purée such as applesauce. Subjects who have completed the first course of therapy and are able to swallow capsules may take GDC-0084 as capsules. Treatment may be continued for up to 24 months (26 cycles) in the absence of disease progression or unacceptable toxicity.

Drug: GDC-0084; Radiation: radiation therapy

Interventions

GDC-0084 DRUG

Given PO

Stratum A1; Stratum A2

radiation therapy RADIATION

Both photon and proton therapy modalities will be allowed.

Also known as: irradiation, radiotherapy, radiation, external beam radiation therapy (EBRT)

Stratum A1; Stratum A2

Eligibility Criteria

• Age: 2 Years - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Age greater than or equal to 2 years and less than 22 years at the time of enrollment
• Subjects must have one of the following newly diagnosed tumors:
• Non-biopsied typical DIPG, defined as a tumor with a pontine epicenter and diffuse intrinsic involvement of the pons. These subjects are eligible without histologic confirmation.
• Biopsied typical DIPG: WHO grade II diffuse astrocytoma (IDH WT or IDH NOS), WHO grade III anaplastic astrocytoma (IDH WT or IDH NOS), WHO grade IV glioblastoma (IDH WT or IDH NOS), or diffuse midline glioma, H3 K27M mutant. Subjects with a typical DIPG who undergo a biopsy may be eligible for the study if the tumor does not harbor the H3 K27M mutation, yet eligibility is restricted to diffuse astrocytoma, anaplastic astrocytoma or glioblastoma, IDH WT or IDH NOS, tumors.
• Atypical brainstem glioma: diffuse midline glioma, H3 K27M mutant.
• Non-brainstem midline glioma, defined as tumors with an epicenter within midline structures, including the thalamus, spinal cord, and cerebellum: diffuse midline glioma, H3 K27M mutant.
• Subjects must have localized, non-metastatic disease; MRI of spine must be performed if disseminated disease is suspected by the treating physician.
• Subjects must be able to start radiation therapy no later than 42 days after radiographic diagnosis or surgery, whichever date is later.
• Performance score ≥ 50 (Lansky for research subjects aged 16 years or younger and Karnofsky for subjects older than 16 years). Subjects who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
• Subjects must not have received any prior therapy, including prior treatment with a PI3 kinase, mTOR, or PI3K/mTOR inhibitor, other than surgery and/or steroids.
• Subjects must have adequate organ function documented at the time of study enrollment as follows:
• Bone marrow: Hemoglobin ≥ 8g/dL \[may have received packed red blood cell transfusion\], absolute neutrophil count (ANC) ≥ 1000/mm\^3, platelets ≥ 50,000/mm\^3 \[transfusion independent\].
• Renal: Normal serum creatinine based on age (Age 2 to ≤5: 0.8; Age \>5 to \<10: 1.0; Age \>10 to \<15: 1.2; Age ≥15: 1.5) or GFR ≥ 70 mL/min/1.73m\^2
• Hepatic: ALT and AST \< 3 × the institutional upper limit of normal (ULN), total bilirubin concentration \< 1.5 x the institutional ULN, albumin ≥ 2g/dL.
• Shortening fraction of ≥ 27% by ECHO or ejection fraction of ≥ 50% by gated radionuclide study.

You may not qualify if:

• Subjects with evidence of tumor infiltration of three or more cerebral lobes on diagnostic MRI.
• Subjects with any clinically significant, unrelated systemic illness (serious infections or significant cardiac, pulmonary, hepatic, or other organ dysfunction) that would compromise the subject's ability to tolerate protocol therapy or would probably interfere with the study procedures or results.
• Diabetic subjects who require insulin therapy.
• Subject with a history of clinically significant, uncontrolled heart disease and/or repolarization abnormalities as documented by a standard 12-lead ECG.
• Subjects receiving any other anticancer (glucocorticoids are acceptable) or investigational drug therapy.
• Subjects unable to return for follow-up visits or obtain follow-up studies required to assess toxicity of therapy.
• Subjects with disseminated disease.
• Pregnant subjects or subjects breast-feeding a child.

Sponsors & Collaborators

• St. Jude Children's Research Hospital: lead
• Kazia Therapeutics Limited: collaborator

Study Sites (1)

St. Jude Children's Research Hospital

Memphis, Tennessee, 38105, United States

Location

Related Links

• St. Jude Children's Research Hospital
• Clinical Trials Open at St. Jude
• St. Jude Brain Tumor Studies

MeSH Terms

Conditions

Central Nervous System Neoplasms; Astrocytoma; Brain Neoplasms; Diffuse Intrinsic Pontine Glioma; Glioblastoma

Interventions

GDC-0084; Radiotherapy; Radiation

Condition Hierarchy (Ancestors)

Nervous System Neoplasms; Neoplasms by Site; Neoplasms; Nervous System Diseases; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Brain Diseases; Central Nervous System Diseases; Brain Stem Neoplasms; Infratentorial Neoplasms

Intervention Hierarchy (Ancestors)

Therapeutics; Physical Phenomena

Study Officials

• Christopher Tinkle, MD, PhD

  St. Jude Children's Research Hospital

  PRINCIPAL INVESTIGATOR

• Amar Gajjar, MD

  St. Jude Children's Research Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 3, 2018
• First Posted: October 4, 2018
• Study Start: November 19, 2018
• Primary Completion: April 2, 2021
• Study Completion: September 4, 2022
• Last Updated: January 18, 2023

Record last verified: 2023-01

Locations

US (1)