Clinical Trials /

D2C7-IT With Atezolizumab for Recurrent Gliomas

NCT04160494

Description:

This is a phase 1 study of atezolizumab in combination with D2C7-IT, a dual-specific monoclonal antibody (mAB) with a high affinity for both EGFRwt- and EGFRvIII-expressing cells, in patients with recurrent World Health Organization (WHO) grade IV malignant glioma at the Preston Robert Tisch Brain Tumor Center (PRTBTC) at Duke.

Related Conditions:
  • Diffuse Midline Glioma, H3 K27M-Mutant
  • Glioblastoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: D2C7-IT With Atezolizumab for Recurrent Gliomas
  • Official Title: A Phase 1 Trial of D2C7-IT in Combination With Atezolizumab in Recurrent WHO Grade IV Malignant Glioma

Clinical Trial IDs

  • ORG STUDY ID: Pro00101898
  • SECONDARY ID: FOR0003
  • NCT ID: NCT04160494

Conditions

  • Malignant Glioma

Interventions

DrugSynonymsArms
D2C7-IT (6920 ng/mL via convection-enhanced delivery)D2C7-IT + Atezolizumab
Atezolizumab (1200 mg every three weeks)TecentriqD2C7-IT + Atezolizumab

Purpose

This is a phase 1 study of atezolizumab in combination with D2C7-IT, a dual-specific monoclonal antibody (mAB) with a high affinity for both EGFRwt- and EGFRvIII-expressing cells, in patients with recurrent World Health Organization (WHO) grade IV malignant glioma at the Preston Robert Tisch Brain Tumor Center (PRTBTC) at Duke.

Detailed Description

      Approximately eighteen patients with recurrent WHO grade IV malignant glioma will receive
      atezolizumab and D2C7-IT followed by possible surgical resection of their recurrent tumor, at
      the discretion of the treating neurosurgeon, and continued atezolizumab to determine the
      impact of the combination of D2C7-IT and atezolizumab on safety. D2C7-IT will be delivered
      intratumorally by Convection Enhanced Delivery (CED) using an intracerebral catheter placed
      within the enhancing portion of the tumor.

      Atezolizumab will be administered according to the FDA-approved dosing schedule of 1200 mg
      intravenously every 3 weeks, beginning ~2 weeks after the D2C7-IT infusion.

      Patients who choose to undergo surgical resection will have their surgery ~4 weeks after
      D2C7-IT administration. If, at the time that surgery is anticipated, the patient is
      determined by the neurosurgeon to have contraindications for surgery and does not undergo
      surgical resection, or chooses not to undergo surgical resection, the patient will continue
      with adjuvant atezolizumab and remain on-study.

      Toxicity will be carefully monitored for at least a year after D2C7-IT treatment, or at least
      30 days after the final dose of atezolizumab if the patient continues atezolizumab on-study
      for longer than a year post-D2C7-IT. Of particular interest will be the incidence of adverse
      events that occur during the first 28 days after D2C7-IT treatment and the inflammatory
      events that occur during the first year after D2C7-IT treatment. The most common risks
      associated with D2C7-IT are effects related to tumor necrosis, neurologic changes (including
      changes in function, new or increased seizures, swelling of the brain, and injury to blood
      vessels), effects related to catheter placement or removal, and effects related to fluid
      infusion into the brain. The most common risks associated with atezolizumab are fatigue,
      decreased appetite, diarrhea, and nausea. Because atezolizumab works with the immune system,
      it can cause the immune system to attack normal organs or tissue and affect how they work.
    

Trial Arms

NameTypeDescriptionInterventions
D2C7-IT + AtezolizumabExperimentalSingle D2C7-IT infusion (6920 ng/mL) plus atezolizumab intravenous (IV) infusions at a dose of 1200 mg every three weeks for up to two years
  • D2C7-IT (6920 ng/mL via convection-enhanced delivery)
  • Atezolizumab (1200 mg every three weeks)

Eligibility Criteria

        Inclusion Criteria:

          -  Histopathologically confirmed recurrent supratentorial WHO grade IV malignant glioma

          -  Patient or partner(s) meets one of the following criteria:

               1. Non-childbearing potential (i.e. not sexually active, physiologically incapable
                  of becoming pregnant, including any female who is post-menopausal or surgically
                  sterile, or any male who has had a vasectomy). Surgically sterile females are
                  defined as those with a documented hysterectomy and/or bilateral oophorectomy or
                  tubal l ligation. Postmenopausal for purposes of this study is defined as 1 year
                  without menses.; or

               2. Childbearing potential and agrees to use one of the following methods of birth
                  control: approved hormonal contraceptives (e.g. birth control pills, patches,
                  implants, or infusions), an intrauterine device, or a barrier method of
                  contraception (e.g. a condom or diaphragm) used with spermicide.

          -  Age ≥ 18 years of age at the time of entry into the study

          -  Karnofsky Performance Score (KPS) ≥ 70%

          -  Hemoglobin ≥ 9 prior to biopsy

          -  Platelet count ≥ 100,000/µl unsupported is necessary for eligibility on the study;
             however, because of risks of intracranial hemorrhage with catheter placement, platelet
             count ≥ 125,000/µl is required for the patient to undergo biopsy and catheter
             insertion, which can be attained with the help of platelet transfusion

          -  Neutrophil count ≥ 1000 prior to biopsy

          -  Creatinine ≤ 1.2 x normal range prior to biopsy

          -  Total bilirubin, serum glutamic oxaloacetic transaminase (SGOT), serum glutamic
             pyruvic transaminase (SGPT), alkaline phosphatase ≤ 2.5 x normal prior to biopsy

          -  Prothrombin and Partial Thromboplastin Times ≤ 1.2 x normal prior to biopsy

          -  At the time of biopsy, prior to administration of D2C7-IT, the presence of recurrent
             tumor must be confirmed by histopathological analysis

          -  A signed informed consent form approved by the Institutional Review Board (IRB) will
             be required for patient enrollment into the study. Patients must be able to read and
             understand the informed consent document and must sign the informed consent indicating
             that they are aware of the investigational nature of this study

          -  Able to undergo brain MRI with and without contrast

        Exclusion Criteria:

          -  Females who are pregnant or breast-feeding

          -  Patients with an impending, life-threatening cerebral herniation syndrome, based on
             the assessment of the study neurosurgeons or their designate

          -  Patients with severe, active co-morbidity, defined as follow:

               1. Patients with an active infection requiring intravenous treatment or having an
                  unexplained febrile illness (Tmax > 99.5°F/37.5°C)

               2. Patients with known immunosuppressive disease or known human immunodeficiency
                  virus infection

               3. Patients with unstable or severe intercurrent medical conditions such as severe
                  heart disease (New York Heart Association Class 3 or 4)

               4. Patients with known lung (forced expiratory volume in the first second of
                  expiration (FEV1) < 50%) disease or uncontrolled diabetes mellitus

               5. Patients with albumin allergy

               6. Patients with gadolinium allergy

          -  Patients who have not recovered from the toxic effects of prior chemo- and/or
             radiation therapy. Guidelines for this recovery period are dependent upon the specific
             therapeutic agent being used

          -  Patients may not have received chemotherapy or bevacizumab ≤ 4 weeks [except for
             nitrosourea (6 weeks) or metronomic dosed chemotherapy such as daily etoposide or
             cyclophosphamide (1 week)] prior to starting the study drug unless patients have
             recovered from side effects of such therapy

          -  Patients may not have received immunotherapy ≤ 4 weeks prior to starting the study
             drug unless patients have recovered from side effects of such therapy

          -  Patients may not be less than 12 weeks from radiation therapy, unless progressive
             disease outside of the radiation field or 2 progressive scans at least 4 weeks apart
             or histopathologic confirmation

          -  Patients who have not completed all standard of care treatments, including surgical
             procedure and radiation therapy (at least 59 Gy)

               1. If the MGMT promoter in their tumor is known to be unmethylated, patients are not
                  mandated to have received chemotherapy prior to participating in this trial

               2. If the MGMT promoter in their tumor is known to be methylated or the MGMT
                  promoter methylation status is unknown at time of screening, patients must have
                  received at least one chemotherapy regimen prior to participating in this trial

          -  Patients with neoplastic lesions in the brainstem, cerebellum, or spinal cord;
             radiological evidence of active (growing) disease (active multifocal disease);
             extensive subependymal disease (tumor touching subependymal space is allowed); tumor
             crossing the midline or leptomeningeal disease

          -  Patients on greater than 4 mg per day of dexamethasone within the 2 weeks prior to the
             D2C7-IT infusion

          -  Patients with worsening steroid myopathy (history of gradual progression of bilateral
             proximal muscle weakness, and atrophy of proximal muscle groups)

          -  Patients with prior, unrelated malignancy requiring current active treatment with the
             exception of cervical carcinoma in situ and adequately treated basal cell or squamous
             cell carcinoma of the skin

          -  Patients with a known history of hypersensitivity to atezolizumab, or any components
             of atezolizumab

          -  Patients with active autoimmune disease requiring systemic immunomodulatory treatment
             within the past 3 months
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Proportion of patients with an unacceptable adverse event
Time Frame:2 years
Safety Issue:
Description:An unacceptable adverse event includes any Grade 3 or any Grade 4 toxicity that is not reversible within 2 weeks, any life-threatening event, or any treatment-related death. Also included are any grade 2 or higher serious autoimmune toxicities, particularly those affecting vital organs (e.g. cardiac, renal, CNS) if it occurs within 2 weeks of any protocol treatment.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Darell D. Bigner, MD, PhD

Trial Keywords

  • D2C7
  • D2C7-IT
  • Atezolizumab
  • Randazzo
  • Glioblastoma
  • Glioma
  • Bigner
  • Pro00101898
  • Genentech
  • CTEP
  • Duke

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