D2C7 for Adult Patients With Recurrent Malignant Glioma

  • STATUS
    Recruiting
  • End date
    Jan 22, 2023
  • participants needed
    115
  • sponsor
    Darell Bigner
Updated on 22 September 2021
platelet count
karnofsky performance status
MRI
prothrombin
brain mri
neutrophil count
aptt
glioblastoma multiforme
malignant glioma
recurrent malignant glioma
recurrent tumor
brain mri with and without contrast
immunotoxin

Summary

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.

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.

Details
Condition Glioma, Malignant neoplasm of brain, Brain Tumor (Pediatric), High Grade Glioma, Brain Cancer, Gliomas, Brain Tumor, malignant glioma
Treatment D2C7-IT
Clinical Study IdentifierNCT02303678
SponsorDarell Bigner
Last Modified on22 September 2021

Eligibility

Yes No Not Sure

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/l unsupported is necessary for eligibility on the study; however, because of risks of intracranial hemorrhage with catheter placement, platelet count 125,000/l 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
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