Clinical Trials /

D2C7 for Adult Patients With Recurrent Malignant Glioma

NCT02303678

Description:

This is a Phase I study to determine the maximum tolerated dose (MTD) and/or recommended phase II dose of D2C7-IT (D2C7 Immunotoxin) when delivered intratumorally by convection-enhanced delivery (CED) to recurrent World Health Organization (WHO) grade III and IV malignant glioma patients, and/or to determine what dose will be considered in a Phase II trial. Patients with recurrent WHO grade III and IV malignant glioma who meet eligibility criteria will be enrolled into the study. Immediately following the stereotactically-guided tumor biopsy conducted as standard of care, up to three additional core biopsies will be obtained for molecular genetic testing. After these biopsies are obtained, subjects will have up to 2 catheters inserted. If the biopsy indicates a proven diagnosis of recurrent malignant glioma (diagnosis results are typically received within 24-48 hours following biopsy), the investigators will proceed with the D2C7-IT infusion. If no tumor is identified, the catheters will be removed. A continuous intratumoral infusion of D2C7-IT will be administered over 72 hours while in the hospital.

Related Conditions:
  • Malignant Glioma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: D2C7 for Adult Patients With Recurrent Malignant Glioma
  • Official Title: Phase I Single-Center, Dose Escalation Study of D2C7-IT Administered Intratumorally Via Convection-Enhanced Delivery for Adult Patients With Recurrent Malignant Glioma

Clinical Trial IDs

  • ORG STUDY ID: Pro00053325
  • NCT ID: NCT02303678

Conditions

  • Malignant Glioma
  • Brain Tumor, Recurrent

Interventions

DrugSynonymsArms
D2C7-ITD2C7-IT

Purpose

This is a Phase I study to determine the maximum tolerated dose (MTD) and/or recommended phase II dose of D2C7-IT (D2C7 Immunotoxin) when delivered intratumorally by convection-enhanced delivery (CED) to recurrent World Health Organization (WHO) grade III and IV malignant glioma patients, and/or to determine what dose will be considered in a Phase II trial. Patients with recurrent WHO grade III and IV malignant glioma who meet eligibility criteria will be enrolled into the study. Immediately following the stereotactically-guided tumor biopsy conducted as standard of care, up to three additional core biopsies will be obtained for molecular genetic testing. After these biopsies are obtained, subjects will have up to 2 catheters inserted. If the biopsy indicates a proven diagnosis of recurrent malignant glioma (diagnosis results are typically received within 24-48 hours following biopsy), the investigators will proceed with the D2C7-IT infusion. If no tumor is identified, the catheters will be removed. A continuous intratumoral infusion of D2C7-IT will be administered over 72 hours while in the hospital.

Detailed Description

      This is a Phase I study to determine the maximum tolerated dose (MTD) of D2C7-IT, when
      delivered intratumorally by convection-enhanced delivery (CED) following confirmatory
      diagnostic biopsy in recurrent World Health Organization (WHO) grade III and IV malignant
      glioma patients, and/or to determine what dose will be considered in a phase II trial. The
      patient will remain in the hospital during the entire infusion. At the completion of the
      infusion, the catheters will be removed within 6 hours and a CT scan will be obtained after
      the catheters are pulled. The patient will be observed in hospital for a minimum of another 6
      hours.

      A two-stage continual reassessment method (CRM) design will be used to determine the MTD of
      D2C7-IT where the first stage involves dose escalation in successive patients until an
      initial dose-limiting toxicity (DLT) is observed. Cohorts of 2 patients will be accrued to
      this study within both stages of the trial. The first patient of each cohort will be observed
      through the completion of the D2C7-IT infusion, before additional patients in that cohort are
      treated. Once the optimal dose level of D2C7-IT is determined (dose escalation completed), a
      total of 27 recurrent patients with WHO grade IV malignant glioma patients will be treated at
      that dose level as a dose expansion cohort.

      Following D2C7-IT infusion, subjects will be evaluated in clinic at 2 weeks for adverse
      events and followed at 4 and 8 weeks and every 8 weeks thereafter until 48 weeks.
    

Trial Arms

NameTypeDescriptionInterventions
D2C7-ITExperimentalRecurrent malignant glioma patients will receive D2C7-IT, delivered intratumorally by CED following confirmatory diagnostic biopsy.
  • D2C7-IT

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have a recurrent supratentorial WHO grade III or IV malignant glioma
             based on imaging studies;

          -  Prior histopathology consistent with a supratentorial WHO grade III or IV malignant
             glioma;

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

          -  Age ≥ 18 years of age;

          -  Karnofsky Performance Status (KPS) ≥ 70%;

          -  Laboratory Values:

               -  Platelet Count ≥ 125,000 cells/mm3 prior to biopsy. Platelets ≥ 100,000 cells/mm3
                  prior to infusion;

               -  Hemoglobin ≥ 10 gm/dL prior to biopsy;

               -  Absolute neutrophil count (ANC) ≥ 1500 cells/mm3 prior to biopsy;

               -  Serum creatinine ≤ 1.2 x the upper limit of normal (ULN) prior to biopsy;

               -  Liver Function: Total bilirubin ≤ 1.6 mg/dL prior to biopsy; AST/ALT ≤ 2.5 x the
                  ULN prior to biopsy;

               -  Prothrombin (PT) and activated Partial Thromboplastin Time (aPTT) ≤ 1.2 x upper
                  limit of normal (ULN) prior to biopsy. Patients with prior history of
                  thrombosis/embolism are allowed to be on anticoagulation, understanding that
                  anti-coagulation will be held in the peri-operative period per the neurosurgical
                  team's recommendations. Low molecular weight heparin (LMWH) is preferred. If a
                  patient is on warfarin, the international normalized ratio (INR) is to be
                  obtained and value should be below 2.0 prior to biopsy;

          -  Ability to comply with study and follow-up procedures;

               -  If the patient is a sexually active female of child bearing potential, whose
                  partner is male, or if the patient is a sexually active male, whose partner is a
                  female of child bearing potential, the patient must agree to use appropriate
                  contraceptive measures for the duration of the treatment of the tumor and for 6
                  months afterwards as stated in the informed consent. Female patients of child
                  bearing potential must have a negative serum pregnancy test at the time of
                  screening and within 48 hours of starting the D2C7-IT infusion

          -  Patients will sign an IRB-approved informed consent form prior to any study-related
             procedures.

          -  Able to undergo brain MRI with and without contrast.

        Exclusion Criteria:

          -  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;

          -  Pregnant or breastfeeding;

          -  Patients with contrast-enhancing tumor component crossing the midline, actively
             growing multi-focal tumor, infratentorial tumor or extensive tumor dissemination
             (subependymal or leptomeningeal);

          -  Patients with clinically significant increased intracranial pressure (e.g., impending
             herniation), uncontrolled seizures, or requirement for immediate palliative treatment;

          -  Patients with a known allergy to Gadolinium-DTPA;

          -  Unstable systemic disease in the opinion of the treating physician, for example active
             infection requiring IV antibiotics;

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

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

          -  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;

          -  Treated with immunotherapeutic agents within 4 weeks before enrollment, unless the
             patient has recovered from the expected toxic effects of such therapy;

          -  Treated with antiangiogenic agents (like bevacizumab) within 4 weeks before biopsy;

          -  Treated with alkylating agents within 4 weeks before enrollment (6 weeks for
             nitrosoureas) or treated within 1 week before enrollment with daily or metronomic
             chemotherapy, unless the patient has recovered from the expected toxic effects of such
             therapy;

          -  Prior chemotherapy (non-alkylating agents) within 2 weeks before enrollment, unless
             the patient has recovered from the expected toxic effects of such therapy.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD) and/or recommended phase II dose of D2C7-IT
Time Frame:2 weeks after D2C7 administration
Safety Issue:
Description:The MTD is the dose that results in an estimated DLT rate based upon the CRM model that is nearest to the target DLT rate of 0.25. DLTs include any ≥ Gr.3 non-hematologic toxicities, any ≥ Gr.3 neurological toxicities, and any ≥ Gr.3 hematologic toxicities that do not resolve to pre-treatment baseline or ≤ Gr.1 within 2 weeks or any toxicity that resolves within the 2 week period, but then recurs during that same 2 week period. Adverse events will be collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

Secondary Outcome Measures

Measure:Overall survival (OS)
Time Frame:3 years
Safety Issue:
Description:OS is defined at the time between administration of D2C7-IT and death. For patients alive, OS will be censored at the time of last follow-up. Kaplan-Meier methods will be used to estimate median OS and PFS.
Measure:Association between EGFRvIII and EGFRwt expression and PFS and OS.
Time Frame:3 years
Safety Issue:
Description:Cox proportional hazards models will explore the relationship between EGFRvIII and EGFRwt expression as measured by immunohistochemistry (IHC), polymerase chain reactions (PCR), and fluorescence in situ hybridization (FISH) and PFS and OS.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Darell D. Bigner, MD, PhD

Trial Keywords

  • D2C7
  • Randazzo
  • Bigner
  • Pro00053325
  • recurrent malignant glioma

Last Updated

May 23, 2019