Clinical Trials /

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

NCT04295759

Description:

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.

Related Conditions:
  • Malignant Glioma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: INCB7839 in Treating Children With Recurrent/Progressive High-Grade Gliomas
  • Official Title: A Phase I Study of the Adam-10 Inhibitor, INCB7839 in Children With Recurrent/Progressive High-Grade Gliomas to Target Microenvironmental Neuroligin-3

Clinical Trial IDs

  • ORG STUDY ID: PBTC-056
  • NCT ID: NCT04295759

Conditions

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

Interventions

DrugSynonymsArms
INCB7839Dose-finding

Purpose

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.

Detailed 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.
    

Trial Arms

NameTypeDescriptionInterventions
Dose-findingExperimentalINCB7839 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).
  • INCB7839

Eligibility Criteria

        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.

        o 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:

          -  ≥ 6 months since allogeneic stem cell transplant prior to enrollment with no evidence
             of active graft vs. host disease

          -  ≥ 3 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.
      
Maximum Eligible Age:21 Years
Minimum Eligible Age:3 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:To evaluate the incidence of INCB7839 treatment-emergent adverse events in children with recurrent/progressive High-Grade Gliomas.
Time Frame:Up to 30 days post treatment.
Safety Issue:
Description:Number of participants with treatment-emergent adverse events as assessed by CTCAE v5.0.

Secondary Outcome Measures

Measure:To make a preliminary assessment of progression-free survival in children with recurrent/progressive high-grade glioma.
Time Frame:Up to 2 years following last dose of INCB7839.
Safety Issue:
Description:The progression-free survival will be reported.
Measure:To make a preliminary assessment of overall survival in children with recurrent/progressive high-grade glioma.
Time Frame:Up to 2 years following last dose of INCB7839.
Safety Issue:
Description:The overall survival will be reported.
Measure:To make a preliminary assessment of duration of response in children with recurrent/progressive high-grade glioma.
Time Frame:Up to 2 years following last dose of INCB7839.
Safety Issue:
Description:The duration of response will be reported.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Pediatric Brain Tumor Consortium

Last Updated

March 2, 2020