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

  • STATUS
    Recruiting
  • End date
    Dec 31, 2023
  • participants needed
    28
  • sponsor
    Pediatric Brain Tumor Consortium
Updated on 1 October 2021
corticosteroids
total body irradiation
filgrastim
monoclonal antibodies
biologic agent
nitrosoureas
measurable disease
sargramostim
anticonvulsants
antiretroviral agents
growth factor
MRI
erythropoietin
dexamethasone
seizures
epilepsy
metastasis
neutrophil count
blood transfusion
spinal cord
glioblastoma multiforme
astrocytoma
oligodendroglioma
anaplastic astrocytoma
tumor progression
anaplastic oligodendroglioma
astrocytoma, anaplastic
platelet transfusion
oligodendroglioma, anaplastic
biologics
dipg
diffuse intrinsic pontine glioma
spinal tumors
craniospinal irradiation

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.

Description

INCB7839 is an inhibitor of the ADAM (A Disintegrin and Metalloprotease) 10 and 17 proteases. Neuronal activity regulates glioma growth through neuroligin-3 (NLGN3). ADAM 10 is the protease responsible for NLGN3 release into the tumor microenvironment and represents a promising therapeutic target.

Pre-clinical studies of INCB7839 in patient-derived pediatric high-grade gliomas (GBM and DIPG) revealed that INCB7839 inhibits pediatric high- grade glioma growth and improves overall survival. In vivo testing also demonstrated that INCB7839 penetrates brain tissue sufficient to achieve its pharmacodynamic effect of ADAM10 inhibition. Further pre-clinical studies in other animals revealed minimal toxicity, including non-adverse to mild increases in serum hepatobiliary enzymes, protein, calcium, cholesterol values, along with minimal decreases in RBC mass parameters; all parameters recovered.

INCB7839 has been evaluated in Phase I and Phase II clinical trials for previously treated solid tumors and breast cancer. Of the adverse events (AEs) noted, the majority were mild-to-moderate in severity, the most frequent being fatigue, nausea, anorexia, diarrhea, emesis, abdominal pain, anemia and constipation. The dose-limiting toxicity for monotherapy with INCB7839 in Phase I clinical trials was declared to be deep venous thrombosis (DVT). Out of 41 patients, there was a total of 9 thrombotic events including mild superficial thrombophlebitis (n=1), DVT (n=4), vena cava thrombosis with renal insufficiency in a patient with squamous cell cancer of the head and neck (n=1), atrial thrombosis in patient with breast cancer (n=1), and pulmonary embolism in patients with hormone-refractory prostate cancer (n=2). Overall, INCB7839 does exhibit a pro-coagulant effect in some adult patients, resulting in an increased incidence of DVT, whether used alone or in combination. The mechanism of this effect is unknown, and there is no clear relationship between the frequency of thrombosis and the dose administered.

Details
Condition Oligodendroglioma, Astrocytoma, Glioma, Glioblastoma Multiforme, Diffuse Intrinsic Pontine Glioma, DIPG, Gliomas, High-grade Astrocytoma NOS, CNS Primary Tumor, NOS (Malignant Glioma), High-grade Astrocytoma NOS, CNS Primary Tumor, NOS (Malignant Glioma), anaplastic astrocytoma, anaplastic oligodendroglioma, glioblastoma, astrocytoma, anaplastic, oligodendroglioma, anaplastic, High-grade Astrocytoma NOS, High-grade Astrocytoma NOS, CNS Primary Tumor, NOS (Malignant Glioma), CNS Primary Tumor, NOS (Malignant Glioma), High-grade Astrocytoma NOS, CNS Primary Tumor, NOS (Malignant Glioma)
Treatment INCB7839
Clinical Study IdentifierNCT04295759
SponsorPediatric Brain Tumor Consortium
Last Modified on1 October 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

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 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 WHO II-IV
Patients with diffuse or multi-focal disease are eligible; patients with leptomeningeal spread are eligible
Age Patient 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 Patient must be able to swallow tablets whole
Measurable disease Patient must have measurable disease in two dimensions on MRI to be eligible
Prior Therapy Patients must have recovered from the acute treatment-related toxicities (defined as < grade 1) of all prior chemotherapy, immunotherapy, or radiotherapy prior to enrollment on this study
Chemotherapy 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
Investigational/ Biologic Agent
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
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
Immunotherapies: 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 3 months 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
Radiation
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
Stem Cell Transplant
Patient must be
months since allogeneic stem cell transplant prior to enrollment with no evidence of active graft vs. host disease
months since autologous stem cell transplant prior to enrollment
\-- Neurologic Status
Patients with neurological deficits should have deficits that are stable for a minimum of 7 days prior to enrollment
Patients with seizure disorders may be enrolled if seizures are well controlled
Performance Status 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 50
Organ Function
Patients must have adequate organ and marrow function as defined below
Absolute neutrophil count 1.0 x 109 cells/ L
Platelets >100 x 109 cells/ L (unsupported, defined as no platelet transfusion within 7 days)
Hemoglobin 8g/dl (may receive transfusions)
Total bilirubin 1.5 times institutional upper limit of normal (ULN)
ALT (SGPT) and AST (SGOT) < 3 x institutional upper limit of normal (ULN)
Albumin 2 g/dL
Serum creatinine based on age/gender as noted in institutional normal range. Patients that are not within institutional normal range but have a 24-hour Creatinine Clearance or GFR (radioisotope or iothalamate) 70 mL/min/1.73 m2 are eligible
Corticosteroids Patients who are receiving dexamethasone must be on a stable or decreasing dose for at least 7 days prior to enrollment
Growth Factors 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
Pregnancy Prevention 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
Informed Consent 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
HIV Positive Patients
HIV-positive patients are eligible if the following criteria are met
Stable on their antiretroviral agents
Have CD4 counts above 400/mm3
Undetectable viral loads, and
No need for prophylactic medications for an opportunistic infections

Exclusion Criteria

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
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
Allergy Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition
Thrombosis Risk
Patients with a known coagulopathy or bleeding disorder (e.g., von Willebrands disease) are not eligible
Patients with a history of non-central line related thrombosis or disorders that promote clotting (e.g., anti-thrombin III deficiency, Lupus anticoagulant) are not eligible
Significant family history of thrombosis (i.e. deep venous thrombosis or pulmonary embolus) in a first-degree relatives (i.e., parents or siblings) are not eligible
Family history must be documented to the best extent it is known
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