Updated interim results from a Phase I clinical trial of ABT-414 (AbbVie) in patients with glioblastoma multiforme (GBM), an aggressive form of brain cancer, were presented at the 19th Annual Scientific Meeting and Education Day of the Society for Neuro-Oncology (SNO), held at the Loew’s Hotel, in Miami, Florida, November 13-16, 2014.

ABT-414 has demonstrated high antitumor activity in preclinical glioblastoma multiforme. In this Phase I trial, 4 out of 12 patients (33%) with measurable disease and epidermal growth factor receptor (EGFR) amplification, four of 12 patients (33%) achieved an objective response, including two patients whom achieved complete responses or complete remission (disappearance of all signs of cancer in response to this treatment). [1] The results from the three-arm clinical trial, which evaluated ABT-414 as a monotherapy, in combination with chemotherapy, or in combination with radiation and chemotherapy, were also presented at the Miami meeting.

Glioblastoma multiforme is the most common and usually highly aggressive type of malignant primary brain tumor. Because tumors come from normal brain cells, they can easily invade and live within normal brain tissue. However, glioblastoma rarely spreads elsewhere in the body.

Prior to diagnosis, most patients experience a serious symptom of glioblastoma multiforme, such as a seizure. [2] Typically patients succumb to the disease approximately 15 months after diagnosis. [2][3] With a median survival between 1 and 2 years and no long-term curative treatments, treatment for glioblastoma multiforme remains challenging. Standard treatment is surgical resection, radiotherapy and concomitant adjunctive chemotherapy. [3]

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ABT-414 is a novel, investigational, monoclonal antibody drug conjugate (ADC) being evaluated for the treatment of patients with various cancer and tumor types. As an antibody-drug conjugate, the trial drug, with a cytotoxic payload of Monomethyl Auristatin F or MMAF, targeted to active EGFR (epidermal growth factor receptor) or mutant EGFRvIII, is designed to be stable in the bloodstream and only release the potent cytotoxic agent once inside targeted cancer cells. Developed by AbbVie, a global research-based biopharmaceutical company formed in 2013 following separation from Abbott Laboratories, researchers with components in-licensed from Life Science Pharmaceuticals, Inc. and Seattle Genetics, ABT-414. In addition to be  investigated for the treatment of glioblastoma multiforme, the drug is also in clinical trials for the treatment of patients with squamous cell tumors, including non-small cell lung cancer. [4]

Study design
The Phase I, open-label, multicenter, international trial evaluated the safety, pharmacokinetics and maximum tolerated dose of ABT-414. Results were presented from all three arms of the study, which evaluated ABT-414 with concurrent radiotherapy and temozolomide in patients with newly diagnosed glioblastoma (Arm A), with temozolomide in patients with recurrent/unresectable glioblastoma (Arm B) or as monotherapy in patients with recurrent glioblastoma (Arm C). Pharmacokinetic and safety data from arms A, B and C support recommended Phase II doses of 2.0, 1.25 and 1.25 mg/kg, respectively. Other important assessments included adverse events, pharmacokinetic parameters, objective response and tumor tissue epidermal growth factor receptor biomarkers.

Study results
Of the two patients who achieved a complete response, one was enrolled in the monotherapy arm and the other in the arm evaluating ABT-414 as an addition to chemotherapy. These patients each had disease that recurred after radiation and chemotherapy – a patient population where effective therapies are very limited.

“The objective responses, including two complete responses, in this Phase I trial suggest further evaluation of ABT-414’s potential as both a monotherapy and as an adjuvant to chemotherapy and radiation in glioblastoma multiforme is warranted,” said Hui Gan, medical oncologist at Austin Health and senior research fellow at the Ludwig Institute for Cancer Research, Heidelberg, Australia. “These early results are encouraging in an aggressive brain cancer with some of the worst outcomes.”

“As one of the most aggressive types of primary brain tumors with few treatment options, patients with glioblastoma multiforme are in need of new targeted treatment options,” noted Gary Gordon, MD, vice president, oncology clinical development at AbbVie. “The data presented at SNO highlights the commitment of AbbVie’s research and development program in oncology. We are pleased to share these data with the neuro-oncology community, as primary care givers of these patients.”

The researchers noted common adverse events in Arms A, B and C included fatigue, blurred vision, nausea, photophobia, constipation, increased aspartate aminotransferase, increased alanine aminotransferase, keratitis, thrombocytopenia, dry eye, eye pain and foreign body sensation in the eye. Grade 3/4 AEs included keratitis, lymphopenia and thrombocytopenia. Dose-limiting toxicities occurred at multiple doses and affected the eye (keratitis) and liver.

Earlier this year results from a Phase I Study Evaluating ABT-414 with concurrent radiotherapy and temozolomide in newly diagnosed glioblastoma were presented at the meeting of the European Society of Medical Oncology (ESMO) in Madrid, Spain [5] These results were a follow-up on results presented earlier this year at ASCO, the meeting of the American Society of Clinical Oncology.

Based on these results of the various clinical trial results, AbbVie will advance ABT-414 – which was granted orphan drug designation by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) earlier this year – to a randomized Phase II clinical trial in patients with glioblastoma multiforme.

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