D2C7 for Adult Patients With Recurrent Malignant Glioma

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 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 ≥ 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.