CTIM-09 - Phase 1/1b trial of Fc-engineered Anti-CD40 Agonist Monoclonal Antibody (2141-V11) infused with D2C7-IT in enhancing disease by Convection-Enhanced Delivery (CED) for Recurrent Malignant Glioma (rMG)

Friday, November 17, 2023

7:35 AM – 7:45 AM PT

Location: Room 109-110

Oral Abstract Presenter(s)

Annick Desjardins

Duke University
Durham, North Carolina, United States

Author(s)

Vidya Chandramohan

Duke University
Durham, North Carolina, United States
Daniel B. Landi

Duke University
Durham, North Carolina, United States
Katherine B. Peters

Duke University Medical Center
Durham, North Carolina, United States
Margaret O. O. Johnson

Duke University School of Medicine, The Preston Robert Tisch Brain Tumor Center, Department of Neurosurgery
Durham, North Carolina, United States
Justin T. Low

Duke University School of Medicine
Durham, North Carolina, United States
Mustafa Khasraw

Duke Cancer Institute
Durham, North Carolina, United States
ST

Stevie Threatt

Duke University Medical Center
Durham, North Carolina, United States
CB

Chevelle Bullock

Duke University Medical Center
Durham, North Carolina, United States
JH

James E. Herndon, II

Duke Cancer Institute, Department of Biostatistics
Durham, North Carolina, United States
EL

Eric S. Lipp

The Preston Robert Tisch Brain Tumor Center, Department of Neurosurgery
Durham, North Carolina, United States
AF

Allan H. Friedman

Department of Neurosurgery, Duke University
Durham, North Carolina, United States
HF

Henry S. Friedman

The Preston Robert Tisch Brain Tumor Center, Department of Neurosurgery
Durham, North Carolina, United States
David M. Ashley

The Preston Robert Tisch Brain Tumor Center
Durham, North Carolina, United States
JO

Juan Osorio

The Rockefeller University
New York City, New York, United States
JR

Jeffrey Ravetch

The Rockefeller University
New York City, New York, United States
DB

Darell D. Bigner

Duke University
Durham, North Carolina, United States

Background: D2C7-IT is a dual-specific immunotoxin. Recombinant antibody fragments bind the wild-type epidermal growth factor receptor (EGFRwt) and its mutant EGFR variant III (EGFRvIII), triggering internalization and intracellular delivery of the Pseudomonas exotoxin, D2C7-IT cell-killing component. Single intratumoral delivery of D2C7-IT in animals generates an antitumor response by directly killing tumor cells and indirectly activating an adaptive T-cell response. However, tumor-associated macrophages (TAMs)-mediated immunosuppression limits its efficacy. Eliminating MG immunosuppression via CD40 co-stimulation enhances D2C7-IT-induced antitumor responses by activating a TAMs proinflammatory phenotype and promoting long-term tumor-specific CD8+ T-cell immunity. We initiated a phase 1 trial of D2C7-IT+2141-V11 (Fc-engineered anti-CD40 agonist) administered via CED in rMG patients.

Methods: Eligibility includes adult patients with solitary supratentorial rMG (WHO grade 3/4); ≥ 4weeks after chemotherapy, bevacizumab, or investigational agent; adequate organ function; and KPS ≥70%. Cohorts of 3 patients were treated with increasing doses of 2141-V11 to determine the recommended phase 2 dose (RP2D) when administered sequentially following D2C7-IT (166,075ng) via CED. Five dose levels (DLs) were evaluated (2141-V11 at: DL1: 0.70mg; DL2: 2.0mg; DL2**: 3.0mg; DL2*: 4.0mg; DL3: 7.0mg).

Results: As of June 5, 2023, 27 patients had been treated (3 patients on DL1 and DL2; 2 on DL3 and DL2*; 17 on DL2**). No dose-limiting toxicities were observed; however, lower DLs were added due to higher frequency of adverse events (AEs) expected with D2C7-IT+2141-V11 within DL3 and DL2* (fever, neurologic symptoms). 13/27 patients remain alive (range 4-22months after therapy). No grade 4 or 5 AEs related to D2C7-IT+2141-V11 were observed, while grade 3 related AEs include one each of: dysphasia, encephalopathy, headache, hydrocephalus, paresthesia, and pyramidal tract disorder.

Conclusions: The RP2D for intratumoral infusion of D2C7-IT+2141-V11 via CED is identified. The protocol was amended to evaluate the addition of cervical perilymphatic injections of 2141-V11 post CED of D2C7-IT+2141-V11.