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Unique randomized trial tests VEGF inhibitor in patients with recurrent glioblastoma

Glioblastoma, the most common and lethal type of malignant brain tumor, has a poor prognosis and very few chemotherapeutic options. Despite surgery, radiotherapy, and temozolomide—the first-line drug treatment for glioblastoma—these highly angiogenic tumors inevitably return. Patients with recurrent disease typically receive conventional chemotherapy drugs like lomustine, which rarely prolongs life more than six months. Recently, however, a phase II study of cediranib, a potent inhibitor of vascular endothelial growth factor (VEGF) receptor, demonstrated biological activity in recurrent glioblastoma. Now Tracy Batchelor, MD, MPH, (MGH) is leading an international, randomized clinical trial to determine whether cediranib alone or in combination with lomustine can improve progression-free survival in patients with recurrent disease.

Objectives and importance of this trial

This phase Ib/III study is designed to definitively establish the safety and efficacy of cediranib in patients whose disease has progressed while on temozolomide. The study is unique in many ways: it is the first to combine cediranib with lomustine, and it’s one of the few randomized trials—the gold standard of medical research—in patients with recurrent glioblastoma. Moreover, the two-tiered study exploits a molecularly targeted strategy that is unique for glioblastoma trials, says principal investigator Batchelor.
“Lomustine has been around for decades, and historically, it’s shown some activity against glioblastoma. So it’s become a standard of care in recurrent disease,” he explains. “The real point of this trial is to see whether we can achieve better outcomes by combining lomustine with cediranib,” which targets the VEGF receptor and inhibits its pro-angiogenic activity.  
Phase Ib, which involved 12 patients at MGH and DFCI in Boston and the Royal Marsden Hospital in London, demonstrated the safety and tolerability of combining cediranib and lomustine and confirmed the optimal dose of the two agents, which turns out to be 110 mg/m2 of lomustine and 20 mg of cediranib.
The phase III part of the study, expected to begin in the next few months, will enroll up to 300 patients in 80 sites around the world, including all adult DF/HCC hospitals in the US, as well as hospitals in Canada, Europe, Australia, and New Zealand. Phase III will have three arms: lomustine as the current standard of care (the control), the combination of cediranib and lomustine, and cediranib alone, says Batchelor. “We’ll compare both cediranib arms against the control to see which patients have better progression-free survival and overall survival.”
The study will also track steroid usage as one of the secondary endpoints in the cediranib arms. Patients with glioblastoma frequently experience vasogenic edema, an accumulation of fluid in the brain (due to the tumor’s disruption of the blood-brain barrier) that contributes significantly to morbidity. This swelling is generally treated with steroids, which bring their own side effects.     
Batchelor hopes that this study will extend survival and improve quality of life for patients. “That’s always the hope when we embark on these studies—that we’ve hit on something that’s going to make a difference in patient care. We’ve designed the phase III trial to definitively answer that question, and I think we will.”

Protocol title
A Phase I, Open Label, Multi-Centre Study to Assess the Safety and Tolerability of Cediranib (RECENTIN™, AZD2171) in Combination With Lomustine Chemotherapy for Patients With Primary Recurrent Malignant Brain Tumours for Whom Lomustine Would be a Standard Therapy

Principal investigator

Tracey Batchelor, MD, MPH

More information
For eligibility criteria, contact information, and sites, go to NCT00503204 on ClinicalTrials.gov.

—Lonnie Christiansen