Summary

This phase I trial studies the side effects and best dose of aderbasib (INCB007839) in treating patients with high-grade glioma that has come back (recurrent) or that is growing, spreading, or getting worse (progressive). Aderbasib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Objectives

PRIMARY OBJECTIVES:
I. To evaluate the safety and tolerability of INCB007839 in children with recurrent/progressive high-grade gliomas, including diffuse intrinsic pontine glioma (DIPG), diffuse midline glioma (DMG), glioblastoma (GBM) and anaplastic astrocytoma.
II. To estimate the maximum tolerated dose (MTD) and/or recommend phase II dose (RP2D) of INCB007839 administered orally in children with recurrent/progressive high-grade glioma.
III. To characterize the plasma pharmacokinetics of INCB007839 administered on this schedule in children with recurrent/progressive high-grade glioma.

SECONDARY OBJECTIVE:
I. To make a preliminary assessment of efficacy via objective response and overall survival in children with recurrent/progressive high-grade glioma.

EXPLORATORY OBJECTIVES:
I. To assess and monitor ADAM10 inhibition of HER2 (human epidermal growth factor receptor 2) extracellular domain in serum, and explore potential correlation with patient outcome.
II. To assess and monitor ADAM10 inhibition of neuroligin-3 (NLGN3) in cerebral spinal fluid.
III. To characterize the pharmacokinetics of INCB007839 in cerebrospinal fluid.

OUTLINE:
Patients receive aderbasib orally (PO) twice daily (BID) on day 1-28. Patients also undergo magnetic resonance imaging (MRI) and X-ray imaging on study. Treatment repeats every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed every 3 months for 2 years.

Eligibility

1. 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 magnetic resonance imaging (MRI) sequence best demonstrating tumor, OR the appearance of a new/metastatic tumor lesion since diagnosis. * Eligible diagnoses include but are not limited to the following: diffuse intrinsic pontine glioma (DIPG), H3K27M-mutant 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 World Health Organization (WHO) II-IV. * Patients with diffuse or multi-focal disease are eligible; patients with leptomeningeal spread are eligible
2. Patients must be >= 3 but =< 21 years of age at the time of enrollment
3. Patients must have a body surface area (BSA) >= 0.70-2.50 m^2 for dose 120 mg/m^2/dose BID
4. Patients must have a BSA >= 0.55-2.80 m^2 for dose 80 mg/m^2/dose BID (Patients who have BSA 0.55-1.00 m^2 will only receive 100 mg AM dose)
5. Patient must be able to swallow tablets whole
6. Patient must have measurable disease in two dimensions on MRI to be eligible
7. Patients must have failed at least 1 standard, tumor-directed treatment besides surgery and recovered from the acute treatment-related toxicities (defined as < grade 1) of all prior chemotherapy, immunotherapy, or radiotherapy prior to enrollment on this study
8. Patients must be >= 28 days from any prior surgery at the time of study enrollment (with the exception of minor dental and dermatological procedures)
9. Patients must have received their last dose of known myelosuppressive anticancer therapy at least 21 days prior to enrollment or at least 42 days if nitrosourea
10. Biologic or investigational agent (anti-neoplastic): Patient must have recovered from any acute toxicity potentially related to the agent and received their last dose of the investigational or biologic agent >= 7 days prior to study enrollment. * For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur
11. Monoclonal antibody treatment and agents with known prolonged half-lives: * Patient must have recovered from any acute toxicity potentially related to the agent and received their last dose of the agent >= 28 days prior to study enrollment
12. Patients who have received checkpoint inhibitors or other immunotherapies with a known potential for pseudoprogression and who have assumed tumor progression must be at least 12 weeks from prior immunotherapy AND have at least two MRI scans at least 4 weeks apart demonstrating further progression OR have a biopsy to confirm tumor progression OR have new site(s) of disease
13. Patients must have had their last fraction of: * Craniospinal irradiation, whole brain radiation, total body irradiation or radiation to >= 50% of pelvis or spine >= 42 days prior to enrollment. * Focal irradiation >= 14 days prior to enrollment. * Local palliative irradiation to site other than primary tumor progression site >= 14 days prior to enrollment
14. Patient must be: * >= 6 months since allogeneic stem cell transplant prior to enrollment with no evidence of active graft versus (vs.) host disease * >= 3 months since autologous stem cell transplant prior to enrollment
15. Patients with neurological deficits should have deficits that are stable for a minimum of 7 days prior to enrollment
16. Patients with seizure disorders may be enrolled if seizures are well controlled
17. Karnofsky performance scale (KPS for > 16 years of age) or Lansky performance score (LPS for =< 16 years of age) assessed within two weeks of enrollment must be >= 60, including ability to ambulate with or without assistance
18. Absolute neutrophil count >= 1.0 x 10^9 cells/L
19. Platelets > 100 x 10^9 cells/L (unsupported, defined as no platelet transfusion within 7 days)
20. Hemoglobin >= 8 g/dl (may receive transfusions)
21. Total bilirubin =< 1.5 times institutional upper limit of normal (ULN)
22. Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) and aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) < 3 x institutional upper limit of normal (ULN)
23. Albumin >= 2 g/dL
24. Serum creatinine based on age/gender. Patients that do not meet the criteria but have a 24-hour creatinine clearance or glomerular filtration rate (GFR) (radioisotope or iothalamate) >= 70 mL/min/1.73 m^2 are eligible * Age 3 to < 6 years, maximum serum creatinine (mg/dL) male 0.8, female 0.8 * Age 6 to < 10 years, maximum serum creatinine (mg/dL) male 1, female 1 * Age 10 to < 13 years, maximum serum creatinine (mg/dL) male 1.2, female 1.2 * Age 13 to < 16 years, maximum serum creatinine (mg/dL) male 1.5, female 1.4 Age >= 16 years, maximum serum creatinine (mg/dL) male 1.7, female 1.4
25. Patients who are receiving dexamethasone must be on a stable or decreasing dose for at least 7 days prior to enrollment
26. Patients must be off all colony-forming growth factor(s) for at least 7 days prior to enrollment (e.g. filgrastim, sargramostim or erythropoietin). 14 days must have elapsed if patient received a long-acting formulation
27. Patients of childbearing or child fathering potential must be willing to use a medically acceptable form of birth control, which includes abstinence, while being treated on this study
28. The patient or parent/guardian is able to understand the consent and is willing to sign a written informed consent document according to institutional guidelines
29. Human immunodeficiency virus (HIV)-positive patients are eligible if the following criteria are met: * Stable on their antiretroviral agents * Have CD4 counts above 400/mm^3 * Undetectable viral loads, and * No need for prophylactic medications for an opportunistic infection

Treatment Sites in Georgia