Preliminary results from an ongoing Phase I study with the investigational compound ABT-414 (Abbvie, Inc.,North Chicago, Illinois, U.S.A.), an anti-epidermal growth factor receptor (EGFR) monoclonal antibody drug conjugate or ADC, in combination with temozolomide (Temodar®; Merck & Co., Inc.) which is indicated for the treatment of adult patients with newly diagnosed glioblastoma multiforme concomitantly with radiotherapy and then as maintenance treatment, showed four objective responses, including one complete response, in patients with recurrent or unresectable glioblastoma multiform. In separate clinical trials ABT-414 is also investigated for the treatment of patients with squamous cell tumors. 

The results showed that in patients being treated for GBM, the ABT-414 in combination with temozolomide demonstrated antitumor activity. In the preliminary analysis, 15 patients with measurable disease at baseline were assessed for best response on study and four patients experienced an objective response, including one complete response (CR) and three partial responses (PR) as measured with theRevised Assessment in Neuro-Oncology (RANO) criteria.

Thirteen patients remained on therapy at the time of data analysis. The recommended phase II dose was determined to be 1.25 milligrams per kilogram (mg/kg) in combination with temozolomide.

Adverse events
Common adverse events (>4 patients) included blurred vision (9 patients), nausea (7 patients), fatigue (6 patients), headache (6 patients), foreign body sensation in the eye (5 patients), photophobia (5 patients), pyrexia (5 patients), corneal deposits (4 patients), eye pain (4 patients) and keratitis (4 patients). Grades 3/4 AEs events (>2 patients) included keratitis (2 patients). Three dose limiting toxicities were reported, including grade 3 corneal deposits (n=1) reported at 1.0 mg/kg, with symptoms improving after a dose reduction, and keratitis (n=1) and gamma-glutamyltransferase increase (n=1), both reported at 1.5 mg/kg. The only Grade 3 or 4 adverse event occurring in more than one patient was keratitis (10%).

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These trial results were presented for the first time at the 50th Annual Meeting of the American Society of Clinical Oncology (ASCO), May 30 – June 3, 2013, being held in Chicago, Ill. [1]

Incidence of GBM
“Glioblastoma multiforme is the most common and most aggressive type of malignant primary brain tumor, and patients have few treatment options and a five-year survival rate of less than 3 percent,” noted Gary Gordon, M.D. divisional vice president, oncology clinical development, AbbVie. “We look forward to continuing evaluations of this compound in additional clinical trials.”

The available data shows that each year in the U.S. and Europe, two to three out of every 100,000 people are diagnosed with glioblastoma, which has a five year survival rate of less than 3%. [3] Prior to diagnosis, most patients experience a serious symptom of glioblastoma, such as a seizure.[2] Typically patients succumb to the disease approximately 15 months after diagnosis.[2][3] Treatment for glioblastoma remains challenging and no long-term treatments are currently available. Standard treatment is surgical resection, radiotherapy and concomitant adjunctive chemotherapy.[2] More than 8,700 patients are enrolled in industry-sponsored clinical studies.[4]

Trial design
The Phase I, open-label, multicenter, international trial was designed to evaluate the toxicities, pharmacokinetics and recommended Phase II dose of ABT-414 when administered every other week in combination with temozolomide in patients with recurrent or unresectable glioblastoma. Other important assessments included adverse events, pharmacokinetic parameters, objective response and tumor tissue epidermal growth factor receptor biomarkers.

ABT-414 is an anti-EGFR (epidermal growth factor receptor) antibody conjugated to the cytotoxic agent monomethyl auristatin F (MMAF). As a monoclonal antibody drug conjugate or ADC, ABT-414 is designed to be stable in the bloodstream and only release the potent cytotoxic agent once inside targeted cancer cells. The investigational drug is being developed by AbbVie researchers with components in-licensed from Life Sciences Pharmaceuticals and Seattle Genetics,

“ABT-414 is designed to release the effects of the cytotoxic agent once inside targeted cancer cells,” said Hui Gan, medical oncologist and senior research fellow at the Austin Health and Ludwig Institute for Cancer Research, Heidelberg, Australia. “The complete response and three partial responses call for further evaluation of this compound in this extremely difficult-to-treat patient population.”

Planned Trials
The phase I study is ongoing and later stage Phase II clinical trials with ABT-414 are being planned in patients with glioblastoma multiform.

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