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.
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.
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 ≥ 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;
- Hemoglobin ≥ 9 gm/dL prior to biopsy;
- Absolute neutrophil count (ANC) ≥ 1000 cells/mm3 prior to biopsy;
- Serum creatinine ≤ 1.5 x the upper limit of normal (ULN) prior to biopsy;
- Liver Function: Total bilirubin ≤ 1.5 x ULN prior to biopsy (Exception: Patient
has known Gilbert's Syndrome or patient has suspected Gilbert's Syndrome, for
which additional lab testing of direct and/or indirect bilirubin supports this
diagnosis. In these instances, a total bilirubin of ≤ 3.0 x ULN is acceptable.);
AST (aspartate aminotransferase)/ALT (alanine aminotransferase) ≤ 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 severe allergy to Gadolinium-DTPA. Patients with mild allergies
(e.g., rash only) will be pretreated with acetaminophen and diphenhydramine prior to
injection of the contrast agent;
- 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);
- Patients who have not completed standard of care treatment prior to participation in
this trial, i.e. surgical procedure and radiation therapy (at least 59 Gy). Note: If
tumor is unmethylated, patients are not mandated to have received chemotherapy prior
to participation in this trial. However, if tumor is methylated, patients must have
received at least one chemotherapy regimen prior to participation in this trial.
- 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.
