On December 5, 2016 Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) reported preliminary safety and efficacy data from a phase 1 study of DS-3032, an investigational oral selective MDM2 inhibitor, suggesting that DS-3032 may be a promising treatment for hematological malignancies including relapsed/refractory acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS) (Press release, Daiichi Sankyo, DEC 5, 2016, View Source [SID1234516945]). Preliminary results from the dose esclation part of the phase 1 study of DS-3032 were presented in an oral presentation at the 58th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper).

A total of 38 patients with relapsed/refractory AML or high-risk MDS were enrolled into the study. Five dose levels of DS-3032 (60 mg, 90 mg, 120 mg, 160 mg and 210 mg) were given. The maximum tolerated dose of DS-3032 was determined to be 160 mg once daily for 21 days in a 28 day cycle based on results from 37 patients who received at least one dose of DS-3032.

Clinical activity of DS-3032 was observed by a reduction of bone marrow blasts at the end of the first cycle of treatment in 15 out of 26 patients who had at least one post-dose bone marrow evaluation. Complete remission was seen in two patients with relapsed/refractory AML receiving 120 mg and 160 mg of DS-3032 with a duration of approximately four months and 13 months, respectively. One patient with high-risk MDS receiving the 120 mg dose of DS-3032 achieved marrow complete remission with platelet improvement for four months. Each of the three patients experiencing a complete response showed a TP53 gene mutation while receiving treatment, which was not identified at the start of the study.

"MDM2 inhibitors such as DS-3032 represent a promising approach in cancer therapy as they have the potential to restore the tumor suppressor protein function of p53 via release from the inhibitory effects of MDM2. Wild-type p53 plays an important role in preventing the uncontrolled growth of cancer cells," said Courtney DiNardo, MD, MSCE, Assistant Professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX. "While these findings are encouraging in that single-agent clinical activity in refractory hematologic malignancies was demonstrated with DS-3032, further study with optimized dosing regimens including combination strategies is needed."

Five patients experienced dose limiting toxicities including two patients in the 160 mg cohort (grade 3 hypokalemia and diarrhea) and three patients in the 210 mg cohort (grade 3 nausea/vomiting, grade 3 anorexia/fatigue and grade 2 creatinine elevation/renal insufficiency leading to early discontinuation of treatment). The most common treatment-emergent adverse events (TEAEs) of any grade (greater than 20 percent) included nausea (73 percent), diarrhea (57 percent), vomiting (33 percent), fatigue (37 percent), anemia (33 percent), thrombocytopenia (33 percent), neutropenia (20 percent), hypotension (30 percent), hypokalemia (23 percent), and hypomagnesemia (20 percent).

"Additional research is currently underway to further explore the appropriate dose and treatment schedule of DS-3032 as well as determine how it can be combined with other therapies," said Antoine Yver, MD, MSc, Executive Vice President and Global Head, Oncology Research and Development, Daiichi Sankyo. "We are committed to investigating novel approaches to treat AML and MDS in hopes of changing the standard of care for these patients."

About the Study
The primary objectives of the dose escalation part of the phase l study are to assess the safety, tolerability, and maximum tolerated dose or the tentative recommended phase 2 dose of DS-3032 in several hematological malignancies including refractory or relapsed acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myleoid leukemia (CML) in blast phase, and myelodysplastic syndrome (MDS). Secondary objectives include evaluating the pharmacokinetics and pharmacodynamic effects of DS-3032. Exploratory objectives include evaluating the efficacy of DS-3032. Further evaluation of alternative dosing schedules of DS-3032 is currently underway. For more information about the study visit ClinicalTrials.gov.

About DS-3032
DS-3032 is an investigational oral selective inhibitor of the murine double minute 2 (MDM2) protein currently being investigated in three phase 1 clinical trials for solid and hematological malignancies including acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML) in blast phase, lymphoma and myelodysplastic syndrome (MDS). DS-3032 has not been approved by any regulatory authority for uses under investigation.

MDM2 is a ubiquitously expressed protein that plays an important role in tissue development and tightly regulates p53, a protein that functions as a tumor suppressor.1 Overexpression or oncogenic activation of MDM2 can disrupt the balanced MDM2 and p53 interaction, blocking the tumor suppressor activity and leading to solid tumors and hematological malignancies.1,2 Small molecules designed to block the MDM2-p53 interaction, reactivating p53 to suppress tumors, may be a promising therapeutic approach for the treatment of wild-type (non-mutant) p53 cancer.1

Unmet Need in AML and MDS
Acute myeloid leukemia (AML) is the most common type of acute leukemia, accounting for about 33 percent of all new cases of leukemia.3 The five-year survival rate of AML is approximately 26 percent, which is the lowest of all leukemias.3 In the U.S., each year there are about 13,000 new cases of myelodysplastic syndrome (MDS), a type of cancer that can occur when the blood-forming cells in the bone marrow are damaged.4 In about one in three patients, MDS progresses to AML.4 Currently, there are no approved targeted treatments for AML, with little progress in approval of new drugs for AML over the past 30 years.5,6

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