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Oncology Advances January 2017

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2 | Oncology Advances Hematologic oncologists in the Center for Hematologic On- cology at Dana-Farber/Brigham and Women's Cancer Center (DF/BWCC) are leading studies of venetoclax (ABT-199), a first- in-class Bcl-2 inhibitor approved for patients with relapsed chronic lymphocytic leukemia (CLL) with 17p deletion. DF/BWCC investigators played a key role in groundbreaking studies that led to venetoclax's approval by the Food and Drug Administration (FDA) in April 2016. In the phase I first-in- human study, 106 CLL patients who had received at least one prior therapy took venetoclax orally every day, beginning with 20 mg and increasing to 400 mg over a five-week period. Study results, which were published in the New England Jour- nal of Medicine (N Engl J Med. 2016 Jan 28;374(4):311-22.), showed that 79 percent responded, meaning the amount of cancer was reduced significantly. In an impressive 20 percent, the leukemia went into complete remission. In a separate phase 2 study of patients with the 17p deletion marker in 107 CLL patients, the same response rate of 79 percent was ob- served, suggesting that the drug also works well for this high- risk form of CLL. In collaboration with a group from Australia, DF/BWCC inves- tigators went on to provide insights from the laboratory into why the drug works equally well in this group of 17p deletion patients who typically do not respond well to chemotherapy (Blood. 2016 Jun 23;127(25):3215-24). Based on the initial trial results, venetoclax was granted breakthrough therapy desig- nation, priority review status, and accelerated approval by the FDA. An ongoing study of venetoclax in CLL is examining response in patients whose disease has progressed after treat- ment with other recently approved novel agents. "We are very excited about this drug's ability to achieve deep, sustained remission among patients with a traditionally poor prognosis," said Matthew S. Davids, MD, MMSc, one of the International Principal Investigators of the Phase I study of venetoclax in patients with CLL and a medical oncologist in the Center for Hematologic Oncology at DF/BWCC. "By com- bining venetoclax with other agents, we are hoping that it will have curative potential in some patients." Understanding Bcl-2 Inhibition The early-phase studies of venetoclax were derived from decades of research of Bcl-2 inhibition led by DF/BWCC med- ical oncologists Anthony Letai, MD, PhD, and Stanley Ko- rsmeyer, MD, who passed away in 2005. Dr. Korsmeyer demonstrated that Bcl-2 serves as a key survival protein for cancer cells and that lymphoma cells harness Bcl-2 proteins to intercept and block apoptotic death signals (Nature. 1991 Jan New Bcl-2 Inhibitor Studies Expand Options for Patients with Hematologic Malignancies, Build on Decades of Research 17;349(6306):254-6.). Together, he and Dr. Letai proceeded to establish the dependence of CLL on Bcl-2 and characterized Bcl-2 inhibitor compounds (J Clin Invest. 2007 Jan;117(1):112- 21.). Dr. Letai also has led research showing Bcl-2 dependence in other hematologic malignancies, including acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), and select subtypes of non-Hodgkin lymphoma (Cell. 2012 Oct 12;151(2): 344-55.). "We have found that venetoclax is a powerful agent that is well tolerated in patients," said Dr. Letai. "I expect that Bcl-2 inhibitors will eventually establish a strong role in the treatment of a broad range of solid tumors as well, likely in combination with other therapies." Current Studies Dr. Letai and Dr. Davids are currently leading studies of vene- toclax spanning numerous other hematologic malignancies, including: • Acute Myeloid Leukemia – Dr. Letai is the Site Principal In- vestigator of an ongoing phase 1b multicenter study of venetoclax plus decitabine or azacitidine in adult patients up to 65 years-of-age with untreated acute myeloid leukemia (AML) who are ineligible for standard induction therapy. Initial results of the study, which were presented at ASCO in June 2016, showed that patients achieved a 60 percent complete remission. For more information about this study, please contact Mekdes Getaneh at (617) 632-5918 or mgetaneh@partners.org. Anthony Letai, MD, PhD, and Matthew S. Davids, MD, MMSc, are leading studies of a first-in-class Bcl-2 inhibitor approved for patients with CLL with 17p deletion. dfbwcc.org

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