With a median survival between 1 and 2 years and no long-term curative treatments, the management of patients with Glioblastoma Multiforme (GBM), the most common and most aggressive type of malignant primary brain tumor, remains challenging. Prior to initial diagnosis, most patients experience a serious symptom, such as a seizure. Standard treatment is surgical resection, radiotherapy and concomitant adjunctive chemotherapy. Abnormal EGFR (epidermal growth factor receptor) -expression and signaling are common features in GBM.
ABT-414, an novel anti-EGFR monoclonal antibody drug conjugate or ADC being developed by Abbvie, is currently being evaluated in a Phase I trial with concurrent radiotherapy and temozolomide (Temodar®; Merck, Sharp & Dome/MSD) in newly diagnosed glioblastoma (GBM) patients.
As an antibody-drug conjugate, ABT-414 is designed to be stable in the bloodstream and only release the potent cytotoxic agent once inside targeted cancer cells. The trial drug, with a cytotoxic payload of Monomethyl Auristatin F or MMAF, targeted to active EGFR or mutant EGFRvIII, has demonstrated high antitumor activity in preclinical GBM tumor models. 
Phase I Study objectives
The objective of the phase I study was to evaluate the safety, pharmacokinetics, and the maximum tolerated dose (MTD) of ABT-414 when administered every 14 days with concurrent radiotherapy and temozolomide in newly diagnosed GBM patients. As part of the trial, adverse events, pharmacokinetics parameters, objective response (RANO), and tumor tissue EGFR biomarkers were also assessed. Dose escalation was determined by the exposure-adjusted continual reassessment method (EACRM).
Initial phase I results were presented at the 2014 European Society of Medical Oncology (ESMO) Annual Congress, September 26-30, in Madrid, Spain. These results were a follo-up on results presented earlier this year at ASCO, the meeting of the American Society of Clinical Oncology.
Results from an initial analysis of data from 22 treated patients (13 male/9 female median age 58 years, range 34-79) showed that pharmacokinetics and safety data support a dose of 2.4 mg/kg as the predicted maximum tolerated dose. Preliminary safety data further demonstrate increased liver and eye toxicities in addition to common toxicities of radiotherapy and temozolomide. Based on these initial results, the researchers conclude that further follow-up may demonstrate whether ABT-414 improves outcome.
ABT-414 is, addition to Glioblastoma Multiforme, also in clinical trials for the treatment of patients with squamous cell tumors, including non-small cell lung cancer.
“[These initial results presented at ESMO] highlight AbbVie’s continued commitment to developing potential new medicines for patients with prevalent cancers who have few treatment options,” noted Gary Gordon, MD, vice president, oncology clinical development, AbbVie. “At AbbVie, we have implemented innovative approaches to developing compounds … which could potentially provide additional options for treating patients across many types of cancer.”