D2C7 for Adult Patients With Recurrent Malignant Glioma

NCT02303678 | Completed Phase 1

• 1 other identifier: Pro00053325
• Study Type: interventional
• Target: 81
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Malignant Glioma; Brain Tumor, Recurrent

Keywords

D2C7; Randazzo; Bigner; Pro00053325; recurrent malignant glioma; Landi; Desjardins

Outcome Measures

Primary Outcomes (1)

• Maximum tolerated dose (MTD) and/or recommended phase II dose of D2C7-IT

  The MTD is the dose that results in an estimated DLT rate based upon the CRM model that is nearest to the target DLT rate of 0.25. DLTs include any ≥ Gr.3 non-hematologic toxicities, any ≥ Gr.3 neurological toxicities, and any ≥ Gr.3 hematologic toxicities that do not resolve to pre-treatment baseline or ≤ Gr.1 within 2 weeks or any toxicity that resolves within the 2 week period, but then recurs during that same 2 week period. Adverse events will be collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

  2 weeks after D2C7 administration

Secondary Outcomes (2)

• Overall survival (OS)

  3 years

• Association between EGFRvIII and EGFRwt expression and PFS and OS.

  3 years

Study Arms (1)

D2C7-IT

EXPERIMENTAL

Recurrent malignant glioma patients will receive D2C7-IT, delivered intratumorally by CED following confirmatory diagnostic biopsy.

Drug: D2C7-IT

Interventions

D2C7-IT DRUG

D2C7-IT is a single-chain fragment variable (scFv) monoclonal antibody (Mab) fragment immunotoxin with high binding affinity for both EGFRwt- and EGFRvIII-expressing glioblastoma multiforme (GBM) cells.

D2C7-IT

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Darell Bigner: lead

Study Sites (1)

Preston Robert Tisch Brain Tumor Center at Duke

Durham, North Carolina, 27710, United States

Location

Related Publications (2)

• Bao X, Pastan I, Bigner DD, Chandramohan V. EGFR/EGFRvIII-targeted immunotoxin therapy for the treatment of glioblastomas via convection-enhanced delivery. Receptors Clin Investig. 2016;3(4):e1430. doi: 10.14800/rci.1430.

  PMID: 28286803 DERIVED

• Chandramohan V, Pegram CN, Piao H, Szafranski SE, Kuan CT, Pastan IH, Bigner DD. Production and quality control assessment of a GLP-grade immunotoxin, D2C7-(scdsFv)-PE38KDEL, for a phase I/II clinical trial. Appl Microbiol Biotechnol. 2017 Apr;101(7):2747-2766. doi: 10.1007/s00253-016-8063-x. Epub 2016 Dec 24.

  PMID: 28013405 DERIVED

Related Links

• The Preston Robert Tisch Brain Tumor Center
• Duke Cancer Institute

MeSH Terms

Conditions

Glioma; Brain Neoplasms

Interventions

D2C7-(scdsFv)-PE38KDEL

Condition Hierarchy (Ancestors)

Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Study Officials

• Annick Desjardins, MD, FRCPC

  Preston Robert Tisch Brain Tumor Center at Duke University Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Edwin L. Jones, Jr. and Lucille Finch Jones Cancer Research Professor

Study Record Dates

• First Submitted: November 19, 2014
• First Posted: December 1, 2014
• Study Start: May 5, 2015
• Primary Completion: May 9, 2019
• Study Completion: March 25, 2024
• Last Updated: March 6, 2026

Record last verified: 2024-03

Locations

US (1)