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2722 Safety and Tolerability of Lurbinectedin (PM01183) in Patients with Acute Myeloid Leukemia and Myelodysplastic Syndrome

Program: Oral and Poster Abstracts
Session: 616. Acute Myeloid Leukemia: Novel Therapy, excluding Transplantation: Poster II
Hematology Disease Topics & Pathways:
AML, Diseases, Adult, Therapies, Non-Biological, MDS, chemotherapy, Study Population, Clinically relevant, Myeloid Malignancies
Sunday, December 2, 2018, 6:00 PM-8:00 PM
Hall GH (San Diego Convention Center)

Kelly S. Chien, MD1, Christopher B. Benton, MD2, Ayalew Tefferi, MD3, José Rodríguez, MD PhD4*, Farhad Ravandi, MBBS2, Naval G. Daver, MD2, Elias J. Jabbour, MD 2, Nitin Jain, MD5, Yesid Alvarado, MD2, Monica Kwari, BSN2, Sherry A. Pierce, BSN, BA2*, Abhishek Maiti, MBBS2, Marisa J Hornbaker, BS2, Margarida Almeida Santos, PhD6, Sara Martinez, MD4, Mariano Siguero4*, Darci Zblewski, APRN, C-NP3*, Aref Al-Kali, MD3, William J. Hogan, MBBCh3, Hagop M. Kantarjian, MD2, Animesh Pardanani, MBBS, PhD 3 and Guillermo Garcia-Manero, MD2

1Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
2Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
3Division of Hematology, Mayo Clinic, Rochester, MN
4PharmaMar, Colmenar Viejo, Madrid, Spain
5Department of Leukemia, MD Anderson Cancer Center, Houston, TX
6Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX

Background: Trabectedin is an FDA-approved DNA minor groove binder (MGB) that has activity against translocation-associated sarcomas. Lurbinectedin is a next-generation MGB with pre-clinical activity against myeloid leukemia cells. A dose-finding phase 1 clinical trial was performed in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) with further assessment of safety and tolerability.

Methods: Forty-two patients with relapsed/refractory AML/MDS received lurbinectedin administered as a 1-hour intravenous infusion in a 3+3 study design. Two dosing schedules were used: 3.5 mg, 5 mg, 7 mg, or 6 mg on days 1 and 8 or 2 mg, 3 mg, 1 mg, or 1.5 mg for 3 consecutive days on days 1 to 3. Patients 18 years or older with a diagnosis of advanced, relapsed/refractory AML (non-acute promyelocytic leukemia) and MDS were eligible and treated on study. Eligible patients had adequate hepatic, renal, and cardiac function and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. Patients with uncontrolled infection, human immunodeficiency virus, cardiac and neurological disorders, or those who were pregnant were ineligible. Clinical trial information: NCT01314599.

Results: Three patients experienced dose-limiting toxicities of rhabdomyolysis (grade 4), hyperbilirubinemia (grade 3), and oral herpes (grade 3) with the days 1 and 8 schedule. Otherwise, adverse events mainly consisted of gastrointestinal manifestations (n=11), febrile neutropenia/infections (n=4), pulmonary toxicity (n=2), and renal failure (n=2). The most common laboratory abnormalities observed were an increase in creatinine (93%) and anemia, neutropenia, and thrombocytopenia (100%). Overall, 33 of 42 patients (79%) had reduction in blasts in peripheral blood or bone marrow. One patient achieved a partial response and two patients a morphologic leukemia-free state. Most (n=30, 71%) were discontinued due to progressive disease. Early deaths occurred from disease-related causes that were not attributable to lurbinectedin. Four patients with a chromosome 11q21-23 abnormality had significantly greater bone marrow blast reduction than those without such abnormality, with decrease of 31±14% (n=4) vs. 8±8% (n=16), respectively (P=0.04).

Conclusions: Overall, lurbinectedin was safe and tolerated using the schedules and dose levels tested. While no sustained remissions were observed, single-agent lurbinectedin was transiently leukemia suppressive for some patients.

Disclosures: Rodríguez: PharmaMar: Employment. Ravandi: Bristol-Myers Squibb: Research Funding; Jazz: Honoraria; Abbvie: Research Funding; Seattle Genetics: Research Funding; Abbvie: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Orsenix: Honoraria; Seattle Genetics: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Sunesis: Honoraria; Orsenix: Honoraria; Macrogenix: Honoraria, Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Jazz: Honoraria; Xencor: Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Macrogenix: Honoraria, Research Funding; Xencor: Research Funding; Sunesis: Honoraria. Daver: Novartis: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Pfizer: Research Funding; Incyte: Consultancy, Research Funding; Kiromic: Research Funding; Karyopharm: Consultancy, Research Funding; Sunesis: Consultancy; BMS: Consultancy, Research Funding; Novartis: Research Funding; Pfizer: Consultancy, Research Funding; Daiichi-Sankyo: Consultancy, Research Funding; Otsuka: Consultancy; ImmunoGen: Consultancy, Research Funding; ARIAD: Research Funding; Alexion: Consultancy. Jabbour: Spectrum: Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Jazz: Consultancy; Astellas: Consultancy. Jain: BMS: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Cellectis: Research Funding; Adaptive Biotechnologioes: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Maiti: Celgene Corporation: Other: Research funding to the institution. Martinez: PharmaMar: Employment. Siguero: PharmaMar: Employment. Al-Kali: Novartis: Research Funding. Kantarjian: Pfizer: Honoraria, Research Funding; Orsenix: Honoraria; Novartis: Research Funding; Immunogen: Honoraria; BMS: Honoraria, Research Funding; Astex: Research Funding; ARIAD: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Actinium: Honoraria; AbbVie: Honoraria.

*signifies non-member of ASH