Anticancer Agent Offers Hope for Targeting Drug-Resistant Solid Tumors

THE TOPLINE

  • In a recent Phase I study, a unique compound called MLN2480 demonstrated potential to treat a number of solid tumors
  • Fox Chase is partnering with Millennium Pharmaceuticals to conduct a multicenter Phase Ib study of the compound

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Phase Ib clinical trial of three combination therapies for a broad range of solid tumors holds promise for overcoming resistance to currently available cancer drugs and expanding personalized treatment options. At the center of the trial is a compound called MLN2480, whose clinical development was made possible by a partnership between Fox Chase Cancer Center and Millennium Pharmaceuticals. The investigational drug, which targets a family of proteins strongly implicated in cancer, has shown promise in a recent Phase I study.

“The growth signals governing cancer development and proliferation are complex and often rely on multiple pathway perturbations,” says Anthony J. Olszanski, MD, RPh, director of the Early Clinical Drug Development Phase I Program and co-director of the Melanoma Program at Fox Chase. “By blocking more than one pathway, we expect to discover improved efficacy in a multitude of tumor types.”
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RAF protein kinases such as BRAF are mutated in a wide range of human cancers, including nearly 50% of malignant melanomas. Although several selective BRAF inhibitors have recently been approved by the FDA for advanced melanoma, drug resistance develops early in the course of treatment, highlighting the need for alternative therapeutic approaches. Because resistance to BRAF inhibitors is thought to occur in part through other RAF kinases, the researchers reasoned that one potential solution would be to block all three RAF kinases at once.

Olszanski helped to design the first-in-human Phase I trial of a pan-RAF inhibitor called MLN2480, which proved to be safe and tolerable in patients with solid tumors. Fox Chase and Millennium are now conducting a multi-center Phase Ib study of MLN2480 in combination with three other anticancer agents: MLN0128, MLN8237, or paclitaxel. “This trial is important because it is combining drugs that act through different mechanisms in an effort to cripple cancer’s ability to become resistant to a single agent, thereby enhancing the effectiveness compared to either agent when given alone,” Olszanski says.

As reported by the researchers at the ASCO 2015 Annual Meeting, the goals of the trial are to determine the safety, tolerability, and antitumor activity associated with the combination treatments in patients with solid tumors. They are currently enrolling patients, and expect to determine the optimal combination doses in about one year, with plans to test the most promising combinations in specific tumor types in a Phase II study. As a nationally recognized early clinical drug development site, Fox Chase has led the recruitment of patients for both MLN2480 trials conducted to date.

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Images courtesy of Takeda Pharmaceuticals.

Tony-Olszanski

Anthony J. Olszanski, MD

“This trial, as well as other trials within the Phase I Program, offers our patients exciting treatment opportunities and further hope in the fight against cancer,” Olszanski says.

Olszanski’s co-investigators are Mark R. Middleton, MD, PhD, Oxford University Hospitals NHS Trust, England; Rastislav Bahleda, MD, University Paris Sud, Gustave Roussy; Rebecca S. Heist, MD, Massachusetts General Hospital; Lakshmi Rangachari, PhD, Xiaofei Zhou, PhD, Viviana Bozón, MD, and Michelle Kneissl, PhD, Millennium Pharmaceuticals in Cambridge, MA; and Teresa Macarulla, MD, Vall d’Hebron University Hospital, Barcelona.