Patient case: 82-year-old male with glioma; genetic feature: BRAF

Clinical trial: D2C7 for Adult Patients With Recurrent Malignant Glioma

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 (dose escalation only) and IV (dose escalation and dose expansion) malignant glioma patients, and to determine what dose will be considered in a single-arm Phase II trial. Patients with recurrent WHO grade III (dose escalation only) and IV (dose escalation and dose expansion) 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 recurrent 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.

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.
  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.
  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. Molecular genetic tests, such as, but not limited to, DNA sequencing, gene amplification, and gene expression, will be performed on the tissue obtained at biopsy. The goal of these molecular genetic tests is to identify genetic predictors of response or failure of response to treatment with D2C7-IT.
  A continuous intratumoral infusion of D2C7-IT will be administered in the Neurosciences Step down unit at Duke. 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.
  Patients who are taking (and are stable on) less than or equal to 4 mg per day of dexamethasone (i.e. low-dose corticosteroid) within the 2 weeks prior to admission for D2C7-IT infusion (i.e. patients who meet the relevant eligibility criterion) may continue on this dose. Patients taking corticosteroids for other medical indications (e.g., asthma or skin condition) will be advised to continue use of these medications. 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. Seizure prophylaxis may be administered to patients prior to, during, and after the infusion at the discretion of the treating neuro-surgeon. Prophylactic antiepileptic medication may also be continued 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 an Adverse Event. This study limits the administration of high-dose corticosteroids due to concerns that high-dose corticosteroids might negatively impact the efficacy of D2C7-IT. Specifically, high-dose corticosteroids may be administered on a limited basis to patients prior to, during, or after D2C7-IT infusion only when determined to be medically necessary.
  Gd-DTPA (gadolinium-diethylene triamine pentaacetic acid) will be co-infused along with the D2C7-IT to monitor infusate distribution. MR mages will be obtained within 24-30 hours 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.
  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. 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 and imaging, if available.

Eligibility: Inclusion Criteria:
  -  Dose escalation only: Patients must have a recurrent supratentorial WHO grade III or IV malignant glioma based on imaging studies;
  -  Dose expansion only: Patients must have a recurrent supratentorial WHO grade IV malignant glioma based on imaging studies
  -  Prior histopathology consistent with a supratentorial WHO grade III (dose escalation only) or IV (dose escalation and dose expansion) 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;
  o 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 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 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 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.

Relevance to patient case: not relevant