INCB7839 in Treating Children With Recurrent/Progressive High-Grade Gliomas

NCT04295759 | Completed Phase 1 Results DMC FDA Drug

• 3 other identifiers: PBTC-056UM1CA081457NCI-2019-08964
• Study Type: interventional
• Target: 13
• Locations: 1 country
• Sites: 11

Brief Summary

This is a multicenter phase 1 trial of INCB7839 for children with recurrent or progressive high-grade gliomas, including, but not limited to, diffuse intrinsic pontine glioma (DIPG) and other diffuse midline gliomas (DMGs), after upfront therapy.

Conditions

Glioblastoma Multiforme; Anaplastic Astrocytoma; Anaplastic Oligodendroglioma; DIPG; High-grade Astrocytoma NOS; CNS Primary Tumor, NOS (Malignant Glioma)

Outcome Measures

Primary Outcomes (6)

• Number of Patients Who Experienced Dose-limiting Toxicities (DLTs)

  All subjects evaluable for dose-finding were classified as having DLT or not having DLT, and the number of subjects having DLT was reported. Any INCB7839-related adverse events during the first course of treatment that led to dose reduction, permanent cessation of therapy, or a delay in treatment of \>7 days were considered DLTs. Hematologic DLTs included any grade 4 hematologic toxicity except lymphopenia; grade 3 neutropenia with fever; or requiring a platelet transfusion on 2 separate days during a single course. Non-hematologic DLTs included any grade 4 non-hematologic toxicity; any grade 3 non-hematologic toxicities with some exceptions such as grade 3 fever or infection of fewer than 5 days in duration; any grade 2 non-hematologic toxicity persisting for \>7 days and considered medically significant; and any deep venous thrombotic event (superficial phlebitis was excluded unless grade 3 or 4 or unless it met another criteria for DLT).

  Approximately 28 days

• Maximum Tolerated Dose (MTD) and/or Recommend Phase II Dose (RP2D) of INCB7839

  A design similar to the Rolling-6 design was used and 6 slots were initially opened on the starting dose level (dose level 1, INCB7839 120 mg/m\^2/dose BID). If no more than one dose-limiting toxicity (DLT) was observed in these 6 subjects, we would expand this cohort to at least 12 patients for additional safety and pharmacokinetic information. If more than 3 DLTs were observed in 12 subjects at dose level 1, then the initially identified maximum tolerated dose based on 6 subjects would be considered unsafe and de-escalation to a lower dose level (INCB7839 80 mg/m\^2/dose BID) would be considered.

  Approximately 28 days

• Area Under the Curve (AUC) of INCB7839

  Pharmacokinetic (PK) studies were performed after an oral INCB7839 dose on days 1, 2, and 3 of Course 1. Beginning day 1 of Course 1, INCB7839 serial blood PK samples were drawn pre-dose and at approximately 1, 4, 8, 24, and 48 hours after the first dose. Time points at which data were collected to create the curve were 0, 1, 4, 8, 24 and 48 hours post-dose. The area under the curve (AUC) was estimated using a noncompartmental method.

  Up to 3 days after the start of treatment

• Maximum Concentration [Cmax] of INCB7839

  Pharmacokinetic (PK) studies were performed after an oral INCB7839 dose on days 1, 2, and 3 of Course 1. Beginning day 1 of Course 1, INCB7839 serial blood PK samples were drawn pre-dose and at approximately 1, 4, 8, 24, and 48 hours after the first dose. Time points at which data were collected were 0, 1, 4, 8, 24 and 48 hours post-dose. The maximum concentration (Cmax) was estimated using a noncompartmental method.

  Up to 3 days after the start of treatment

• Apparent Oral Clearance [CL/F] of INCB7839

  Pharmacokinetic (PK) studies were performed after an oral INCB7839 dose on days 1, 2, and 3 of Course 1. Beginning day 1 of Course 1, INCB7839 serial blood PK samples were drawn pre-dose and at approximately 1, 4, 8, 24, and 48 hours after the first dose. Time points at which data were collected were 0, 1, 4, 8, 24 and 48 hours post-dose. Clearance (CL/F) was estimated using a noncompartmental method.

  Up to 3 days after the start of treatment

• Time to Reach Maximum Concentration [Tmax] of INCB7839

  Pharmacokinetic (PK) studies were performed after an oral INCB7839 dose on days 1, 2, and 3 of Course 1. Beginning day 1 of Course 1, INCB7839 serial blood PK samples were drawn pre-dose and at approximately 1, 4, 8, 24, and 48 hours after the first dose. Time points at which data were collected were 0, 1, 4, 8, 24 and 48 hours post-dose. The time to reach maximum concentration (Tmax) was estimated using a noncompartmental method.

  Up to 3 days after the start of treatment

Secondary Outcomes (3)

• Percent Probability of Progression-free Survival

  3 months from first dose of INCB7839

• Percent Probability of Overall Survival

  3 months from first dose of INCB7839

• Duration of Response

  Up to 2 years following last dose of INCB7839

Other Outcomes (3)

• ADAM10 Inhibition of HER2

  Baseline and Day 14 of Course 1

• ADAM10 Inhibition of Neuroligin-3 (NLGN3)

  Up to 30 days post treatment.

• Maximum Concentration [CMAX] of INCB7839 in Cerebrospinal Fluid

  Up to 30 days post treatment

Study Arms (1)

Dose-finding

EXPERIMENTAL

INCB7839 dosing will begin at 120 mg/m2/dose BID which is equivalent to the adult RP2D (200 mg PO BID) based on a typical adult size of 1.67m2. The INCB7839 dose may be decreased to 80 mg/m2/dose BID if the staring dose is not tolerable. 28 consecutive days (4 weeks) will constitute one course. Patients may continue to receive INCB7839 for 26 courses (approximately 2 years).

Drug: INCB7839

Interventions

INCB7839 DRUG

INCB7839 dosing will begin at 120 mg/m2/dose BID which is equivalent to the adult RP2D (200 mg PO BID) based on a typical adult size of 1.67m2. The INCB7839 dose may be decreased to 80 mg/m2/dose BID if the staring dose is not tolerable. 28 consecutive days (4 weeks) will constitute one course. Patients may continue to receive INCB7839 for 26 courses (approximately 2 years).

Dose-finding

Eligibility Criteria

• Age: 3 Years - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Histologic diagnosis:
• Patients with recurrent/progressive high-grade gliomas, as defined by progressive neurologic abnormalities or worsening neurologic status not explained by causes unrelated to tumor progression (e.g., anticonvulsant or corticosteroid wean, electrolyte disturbances, sepsis, hyperglycemia, etc.), OR a ≥ 25% increase in the bi-dimensional measurement, taking as a reference the smallest disease measurement recorded since diagnosis utilizing the MRI sequence best demonstrating tumor, OR the appearance of a new/metastatic tumor lesion(s) since diagnosis.
• Eligible diagnoses include but are not limited to the following: diffuse intrinsic pontine glioma (DIPG), H3K27M-altered diffuse midline glioma (DMG), glioblastoma multiforme, anaplastic astrocytoma and anaplastic oligodendroglioma. Spinal cord tumors are eligible with pathologic confirmation of the above.
• Please note: Patients with a radiographically typical DIPG at diagnosis, defined as a tumor with a pontine epicenter and diffuse involvement of more than 2/3 of the pons, are eligible without histologic confirmation.
• Patients with pontine lesions that do not meet these radiographic criteria will be eligible if there is histologic confirmation of pontine glioma WHO II-IV.
• Patients with diffuse or multi-focal disease are eligible; patients with leptomeningeal spread are eligible.
• Age
• Patients must be ≥ 3 but ≤ 21 years of age at the time of enrollment.
• BSA
• Patients must have a BSA ≥ 0.70-2.50 m2 for dose 120 mg/m2/dose BID.
• Patients must have a BSA ≥ 0.55-2.80 m2 for dose 80 mg/m2/dose BID (Patients who have BSA 0.55-1.00 m2 will only receive 100 mg AM dose).
• Ability to Swallow
• Patients must be able to swallow tablets whole.
• Measurable disease
• Patients must have measurable disease in two dimensions on MRI to be eligible.

You may not qualify if:

• Pregnancy or Breast-feeding
• Pregnant women or nursing mothers are excluded from this study. Female patients of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• Pregnant or breast-feeding women are excluded from this study due to risks of fetal and teratogenic adverse events as seen in animal studies.
• Concurrent Illness
• Patients with any clinically significant unrelated systemic illness (e.g., serious infections or significant cardiac, pulmonary, hepatic or other organ dysfunction), that in the opinion of the investigator would compromise the patient's ability to tolerate protocol therapy, put them at additional risk for toxicity or would interfere with the study procedures or results.
• Patients with any other current malignancy.
• Patients with uncontrolled hypertension (i.e., a blood pressure (BP) \> 95th percentile for age, height, and gender; patients with values above these levels must have their blood pressure controlled with medication prior to starting study drug).
• The normal blood pressure by height, age, and gender tables can be accessed in the Generic Forms section of the PBTC member's webpage.
• Patients who are ≥ 18 years of age must have blood pressure that is \< 140/90 mm of Hg at the time of registration.
• Concomitant Medications
• Patients who are receiving any other anti-cancer, investigational or alternative (e.g., cannabinoids) drug therapy are ineligible.
• Prisoners
• Prisoners will be excluded from this study.
• Inability to participate
• Patients who in the opinion of the investigator are unwilling or unable to return for required follow-up visits or obtain follow-up studies required to assess toxicity to therapy or to adhere to drug administration plan, other study procedures and study restrictions.

Sponsors & Collaborators

• Pediatric Brain Tumor Consortium: lead
• National Cancer Institute (NCI): collaborator
• American Lebanese Syrian Associated Charities: collaborator

Study Sites (11)

Children's Hospital Los Angeles

Los Angeles, California, 90026, United States

Location

Stanford University and Lucile Packard Children's Hospital

Palo Alto, California, 94304, United States

Location

Children's Hospital Colorado

Aurora, Colorado, 80045, United States

Location

Children's National Medical Center

Washington D.C., District of Columbia, 20010, United States

Location

Ann & Robert H. Lurie Children's Hospital of Chicago

Chicago, Illinois, 60614, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02245, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

Cincinnati Children Hospital Medical Center

Cincinnati, Ohio, 45229, United States

Location

Children Hospital of Pittsburgh

Pittsburgh, Pennsylvania, 15224, United States

Location

St. Jude Children's Research Hospital

Memphis, Tennessee, 38105, United States

Location

Texas Children's Hospital

Houston, Texas, 77030, United States

Location

MeSH Terms

Conditions

Glioblastoma; Astrocytoma; Oligodendroglioma; Pyloric Stenosis, Hypertrophic; Glioma

Condition Hierarchy (Ancestors)

Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Pyloric Stenosis; Gastric Outlet Obstruction; Stomach Diseases; Gastrointestinal Diseases; Digestive System Diseases

Results Point of Contact

• Title: Catherine Billups
• Organization: PediatricBTC

catherine.billups@stjude.org

901-595-3370

Study Officials

• Michelle Monje, MD, PhD

  Stanford University and Lucile Packard Children's Hospital

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Model Details: This is a phase I study and we will use a design similar to the Rolling-6 design and open 6 slots initially on Dose level 1. If we observe no-more than 1 DLT in these 6 subjects then we would expand this cohort to at least 12 patients for PK and additional safety information. If more than 1 DLT is observed on dose level 1 in 2-6 subjects, then further enrollment to dose level 1 will stop, the dose will be de-escalated to dose level 0 and the same approach will be repeated. Based on the above-outlined de-escalation rules, if dose level 0 is found to be too toxic, then the trial will be closed to accrual and the merits of amending or closing the trial permanently will be reconsidered.

Study Record Dates

• First Submitted: February 27, 2020
• First Posted: March 4, 2020
• Study Start: July 27, 2020
• Primary Completion: December 31, 2023
• Study Completion: December 1, 2024
• Last Updated: January 5, 2026
• Results First Posted: February 19, 2025

Record last verified: 2025-12

Locations

US (11)