D2C7 for Adult Patients With Recurrent Malignant Glioma
Conditions
Glioblastoma - Glioma - Malignant Glioma - Brain Tumor, Recurrent
Conditions: official terms
Brain Neoplasms - Glioma
Study Type
Interventional
Study Phase
Phase 1
Study Design
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Intervention
Name: D2C7-IT
Type: Drug
Overall Status
Recruiting
Summary
This is a Phase I study to determine the maximum tolerated dose (MTD) 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 to determine what dose will be considered in a single-arm 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 stereotactically-guided tumor biopsy, subjects will have catheters inserted. If the frozen section of the biopsy indicates a proven diagnosis of WHO Grade III or IV malignant glioma (diagnosis results are typically received within 24-48 hours following biopsy), the investigators will proceed with the D2C7-IT infusion. If not, the catheters will be removed. A continuous intratumoral infusion of D2C7-IT will be administered and the same total flow rate for all catheters will be set at 0.5 ml/hour per catheter for 72 hours. Subjects will be evaluated in clinic 2 weeks post infusion for adverse events, and followed afterward at 4 and 8 weeks and every 8 weeks thereafter until 48 weeks or disease progression, whichever occurs first, for adverse events, radiographic response, and Health Related Quality of Life (HRQoL) and cognitive function (8-week, 16-week, 32-week, and 48-week assessments only). No other treatment intervention is allowable while on study. Subjects will be off study when progressive disease is documented. Subjects will be followed for survival.

A two-stage continual reassessment model (CRM) design will be used to determine the MTD of D2C7-IT where the first stage involves dose escalation in successive cohorts of 2 patients until an initial dose-limiting toxicity (DLT) is observed. Within the second stage, all accumulated data will be used within the context of a one-parameter logistic model to determine the appropriate dose for each subsequent cohort of 2 patients. Maximum likelihood estimation will be used. This modeling process will determine the dose with a DLT rate closest to the target DLT rate of 0.25. 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.
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 to determine what dose will be considered in a phase II trial.

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. Within the second stage, all accumulated data will be used within the context of a one-parameter logistic model to determine the appropriate dose for each subsequent patient. Maximum likelihood estimation will be used. This modeling process will determine the dose with a DLT rate closest to the target DLT rate of 0.25. 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.

Patients diagnosed with recurrent malignant glioma based on radiographic evidence may be enrolled onto the study prior to biopsy. The clinically approved BrainLab iPlan Flow (BrainLAB AG, Feldkirchen, Germany) planning station software will be used for the biopsy and catheter placement based on magnetic resonance (MR) imaging. In brief, the simulation of the spread of a drug or tracer molecule is computed by an FDA-approved computer algorithm based on the standard equations presented by Morrison et al, using data derived from MR diffusion tensor imaging (DTI) and dynamic contrasted enhanced (DCE) imaging that provides information useful in the determination of (i) advection (convection), (ii) diffusion and (iii) loss from the interstitium due to both clearance due to the vasculature and metabolism or degradation. Up to four intratumoral catheters will be placed in areas at greatest risk for infiltrating disease and in any solid-contrast-enhancing disease. Catheter placement will be based on the BrainLab software. A computed tomography (CT) scan will be used to confirm catheter placement postoperatively. Catheters found by postoperative CT scanning to be improperly placed may be replaced or removed. If frozen section of the biopsy indicates a proven diagnosis of recurrent WHO Grade III or IV malignant glioma (diagnosis results are typically received within 24-48 hours following biopsy), the investigators will proceed with D2C7-IT infusion. If not, the catheters will be removed.

A continuous intratumoral infusion of D2C7-IT will be administered in the Neurosciences Step down unit at escalating doses as outlined below. Based on our own experience, previously published reports by Laske, et al (1997)31, and Institutional Review Board (IRB)- and FDA-approved trials using similar infusion techniques, patients will be infused at a rate of 0.5 ml/hour. The same total flow rate for all catheters will be set at 0.5 ml/hour per catheter for 72 hours. Up to a total volume of 144 mL will be administered. Corticosteroids will be administered to all patients prior to, during, and after the infusion. For patients on no corticosteroids or without any neurologic deficits at study entry, a daily dose of 16 mg of dexamethasone will be used. For patients with neurological deficit receiving corticosteroids on clinical grounds at study entry, an increase in daily dose by 50-100% above pre-study requirement to at least 16 mg/day of dexamethasone will be used. Prophylactic corticosteroids will be continued for 2-4 days after completion of D2C7-IT infusions, at the discretion of the neurosurgeon or neuro-oncologist. Patients taking corticosteroids for other medical indications (e.g., asthma) will be advised to continue use at equivalent doses immediately before and during drug infusion. Any neurologic findings which prompt an increase in the corticosteroid dose will be documented as Adverse Events. Seizure prophylaxis will be administered to all patients prior to, during, after the infusion and afterward. Prophylactic antiepileptic medication will be continued, to a minimum, until the visit 1 month post infusion. Choice of antiepileptic medication and discontinuation of medication after the visit 1 month post infusion will be left at the discretion of the neurosurgeon or neuro-oncologist. Any neurologic findings which prompt an increase in the antiepileptic medication dose will be documented as Adverse Events.

124I-labeled albumin and 1 millimolar (mM) Gd-DTPA (gadolinium-diethylene triamine pentaacetic acid) will be co-infused along with the D2C7-IT to monitor infusate distribution. Labeled albumin has previously been used in this context by us32 and has been shown to be a good surrogate in this context for the intracerebral distribution of immunotoxins24,33. Gd-DTPA has previously been used safely for infusate monitoring in humans. The investigators have recently shown the safety of these infusions in patients with brain tumors. MR and positron emission tomography (PET) images will be obtained within 1 day of the start of the infusion and 0 to 6 hours after the end of the infusion, before catheter removal, to monitor volume of drug distribution. In addition, these images will be used to compare the infusate distribution outlined by Gd-DTPA to the distribution outlined by co-registered PET measurement of 124I albumin. In brief, the investigators estimate Gd-DTPA concentration at brain locations from the change in TI as computed using the variable mutation angle method 34. By obtaining whole brain 3D spoiled gradient echo (SPGR) images using two or more flip angle acquisitions, both before and after infusion of Gd-DTPA, the investigators can estimate the Gd DTPA concentrations at any brain location. The investigators use standard literature values for the relaxability, and check that during the earlier acquisition the total dose in tissue matches the dose infused. The concentration profiles for both the Gd-DTPA and 124I-albumin will be estimated and quantitatively compared to develop and validate a transformation to estimate prospectively 124I-albumin concentration distribution from the measured Gd-DTPA concentration distribution.

The radiographic imaging performed after catheter placement, during and at the completion of infusion, will also be used as a safety measure for toxicity monitoring to determine the degree of leakage into the cerebrospinal fluid (CSF). 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.

Blood will be drawn to determine if an immune response to tumor antigens is generated by the D2C7-IT infusion. Blood for this purpose will be obtained within 72 hours of beginning infusion of D2C7, before discharge after completion of the infusion, and at 2 weeks post infusion. Analysis of activated cluster of differentiation 4 (CD4)+ and cluster of differentiation 8 (CD8)+ T cells and activated regulatory T cells (T-regs) will be performed using polychromatic flow cytometry. In addition, serum samples will be analyzed for the presence of D2C7-induced Epidermal Growth Factor variant 3 (EGFRvIII)- and Epidermal Growth Factor wildtype (EGFRwt)-specific antibodies and brain tumor antigen-specific antibodies using autologous brain tumor lysate for ELISA35,36. Finally, if the investigators detect positive T-cell responses using polychromatic flow cytometry, the investigators will analyze the T cells for tumor-specific cytotoxic T lymphocyte (CTL) function, as outlined in the immune monitoring core. Serum antibody PE38 titers will be determined in ELISA against PE38 protein.

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 or disease progression, whichever occurs first, for adverse events, radiographic response, and Health Related Quality of Life (HRQoL) and cognitive function (8-week, 16-week, 32-week, and 48-week assessments only). No other treatment intervention is allowable while on study. Subjects will come off study when progressive disease is documented. If alternative anti-tumor therapy is initiated or patient undergoes a surgical procedure due to disease progression, the date and type of therapy/surgery must be documented; however, subjects will be off study when progressive disease is documented. Subjects will be followed for survival. An intent-to-treat philosophy will be used in all efficacy analyses.
Criteria for eligibility
Healthy Volunteers: No
Maximum Age: N/A
Minimum Age: 18 Years
Gender: Both
Criteria: Inclusion Criteria:

- Recurrent 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 of frozen sections;

- Age ≥ 18 years of age

- Karnofsky Performance Status (KPS) ≥ 70%

- Estimated life expectancy > 12 weeks

- Laboratory Values:

- Platelet Count ≥ 125,000 cells/mm3

- Hemoglobin ≥ 10 gm/dL

- Absolute neutrophil count (ANC) ≥ 1500 cells/mm3

- Serum creatinine ≤ 1.2 x the upper limit of normal (ULN)

- Liver Function:

Total bilirubin ≤ 1.6 mg/dL AST/ALT ≤ 2.5 x the ULN

o Prothrombin (PT) and activated Partial Thromboplastin Time (aPTT) ≤ 1.2 x upper limit of normal (ULN). Patients with prior history of thrombosis/embolism are allowed to be on anticoagulation, understanding that anticoagulation will be held in the perioperative 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 obtain and value should be between 2-3 at the time of study entry

- Ability to comply with study and follow-up procedures

- If sexually active, patients 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 must have a negative serum pregnancy test within 48 hours of starting study treatment;

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

Exclusion Criteria:

- History of any other malignancy within 5 years (except non-melanoma skin cancer or carcinoma in situ of the cervix)

- Pregnant or breastfeeding

- Patients with contrast-enhancing tumor component crossing the midline, multi-focal tumor, infratentorial tumor or 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 iodine or Gadolinium-DTPA

- Patients who have demonstrated a previous hypersensitivity to any component of the study drug

- Unstable systemic disease in the opinion of the treating physician, for example active infection requiring IV antibiotics.
Location
Preston Robert Tisch Brain Tumor Center at Duke
Durham, North Carolina, United States
Status: Recruiting
Contact: Stevie Threatt - 919-684-3657 - Stevie.Threatt@duke.edu
Start Date
February 2015
Completion Date
May 2018
Sponsors
Darell D. Bigner, MD, PhD
Source
Duke University
Record processing date
ClinicalTrials.gov processed this data on July 28, 2015
ClinicalTrials.gov page