Acute myeloid leukemia (AML) is a cancer of the blood and bone marrow. AML is the most common type of acute leukemia in adults. Each year in the United States, about 19,900 people (usually older than 45 years of age) are diagnosed, and about 10,400 people die from all forms of the disease, according to the American Cancer Society. Unlike other cancers that start in an organ and spread to the bone marrow, AML is known for rapid growth of abnormal white blood cells that gather in the bone marrow, getting in the way of normal blood cell production. The lack of normal blood cells can cause some AML symptoms, including anemia, neutropenia (shortage of white blood cells that may lead to increased infections), and thrombocytopenia (shortage of platelets in the blood that may lead to excessive bleeding). Current treatment options for AML consist of reducing and eliminating cancer cells mainly through chemotherapy, radiation therapy, and stem cell transplantation.
GMI-1271 is designed to block E-selectin (an adhesion molecule on cells in the bone marrow) from binding with AML cells as a targeted approach to disrupting well-established mechanisms of leukemic cell resistance within the bone marrow microenvironment. Preclinical research points to the drug’s potential role in moving cancerous cells out of the protective environment of the bone marrow where they hide and escape the effects of chemotherapy. In preclinical studies using animal models of AML, the results of which were presented at meetings of the American Society of Hematology (ASH), GMI-1271 improved survival in combination with chemotherapy, compared to chemotherapy alone. In preclinical studies, GMI-1271 was also associated with a reduction of chemotherapy-induced neutropenia and chemotherapy-induced mucositis.
GMI-1271 has received Fast Track designation from the U.S. Food and Drug Administration (FDA), which may lead to speedier delivery to people living with AML if the treatment is found to be effective. The FDA has also granted a Breakthrough Therapy designation for GMI-1271 for adults with relapsed/refractory AML. The European Union granted Orphan Drug Designation for GMI-1271 in AML, a designation the FDA granted the drug candidate in 2015. GMI-1271 has not been approved for use by any worldwide health authority.
About the Phase 1/2 Clinical Trial in AML
GMI-1271 has been tested in healthy volunteers and in a Phase 1/2 clinical trial in the U.S. and worldwide. The trial evaluated GMI-1271’s safety, absorption by the body and effect on AML when given with standard chemotherapy. The drug was given to trial participants throughout their chemotherapy treatment period. Some additional bone marrow and blood samples were obtained during routine bone marrow assessments, to learn more about drug activity.
Results from the Phase 1 portion were reported at the annual meeting of the European Hematology Association (EHA) in June 2016. Additional findings showing high rates of remission and favorable tolerability among study participants were reported during a poster session at the American Society of Hematology Annual Meeting in December 2016. Further results were also presented at the meetings of the American Society of Clinical Oncology and EHA in June 2017.
During the 59th American Society of Hematology (ASH) Annual Meeting and Expo in December 2017, GlycoMimetics announced updated data from the Phase 1/2 trial as follows:
For patients with relapsed/refractory AML treated at the Phase 2 dose (n = 54) and for whom median follow up was 6.6 months:
Clinical remission (CR+CRi) was 43%.
Median overall survival was 9.4 months (95% CI: 5.7 – 15.1 months; calculated by Kaplan Meier method). This compares favorably to a median overall survival of up to 5.4 months reported for historical, matched controls treated with mitoxantrone, etoposide and cytarabine (MEC) alone. 1,2
Median duration of remission was 11.1 months (95% CI: 5.8-NA; calculated by Kaplan Meier method).
For older patients with newly diagnosed disease (n=25) and for whom median follow up was 10.5 months:
Clinical remission rate was 68%.
Median overall survival was 15.8 months (95% CI: 10.3 – NA; calculated by Kaplan Meier method). This compares favorably to a historical median overall survival of approximately 12 months in matched controls treated with 7+3 chemotherapy alone. 3,4
Median duration of remission was 14.8 months (95% CI: 8.3 – NA; calculated by Kaplan Meier method).
Median event free survival was 11.3 months.
Feldman EJ, Brandwein J, Stone R, et al. Phase III randomized multicenter study of a humanized anti-CD33 monoclonal antibody, lintuzumab, in combination with chemotherapy, versus chemotherapy alone in patients with refractory or first-relapsed acute myeloid leukemia. Journal of clinical oncology. 2005;23(18):4110-4116. 47.
Greenberg PL, Lee SJ, Advani R, et al. Mitoxantrone, etoposide, and cytarabine with or without valspodar in patients with relapsed or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome: a phase III trial (E2995). Journal of clinical oncology. 2004;22(6):1078-1086
Foran JM, Sun Z, Claxton DF, et al. North American Leukemia, Intergroup phase III randomized trial of single agent clofarabine as induction and post-remission therapy, and decitabine as maintenance therapy in newly-diagnosed acute myeloid leukemia in older adults (age? 60 years): A trial of the ECOG-ACRIN Cancer Research Group (E2906). Blood. 2015;126(23):217-217. 45.
Lancet JE, Cortes JE, Hogge DE, et al. Phase 2 trial of CPX-351, a fixed 5:1 molar ratio of cytarabine/daunorubicin, vs cytarabine/daunorubicin in older adults with untreated AML. Blood. 2014;123(21):3239-3246.