Murine double minute 2 inhibition alone or with cytarabine in acute myeloid leukemia: Results from an idasanutlin phase 1/1b study⋆
| Autor: | S. Muehlbauer, Karen Seiter, Margaret Kasner, Gwen Nichols, Annabelle Monnet, Jianguo Zhi, Marion Gabriele Ott, Kevin R. Kelly, Silke Simon, William E. Pierceall, Sarit Assouline, Michael Dickinson, Sung-Soo Yoon, Lin-Chi Chen, Mark Drummond, Cristina Papayannidis, Norbert Vey, Karen W.L. Yee, Je-Hwan Lee, Giovanni Martinelli, Lori Jukofsky, Steven Blotner, Brian Higgins |
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| Rok vydání: | 2020 |
| Předmět: |
Adult
Male Cancer Research medicine.medical_specialty Myeloid Pyrrolidines Childhood leukemia Combination therapy Maximum Tolerated Dose Gastroenterology 03 medical and health sciences Young Adult 0302 clinical medicine Internal medicine Antineoplastic Combined Chemotherapy Protocols medicine para-Aminobenzoates Secondary Acute Myeloid Leukemia Humans Tissue Distribution Aged Aged 80 and over business.industry Remission Induction Cytarabine Myeloid leukemia Proto-Oncogene Proteins c-mdm2 Hematology Middle Aged medicine.disease Prognosis Pediatric cancer Leukemia Leukemia Myeloid Acute medicine.anatomical_structure Oncology 030220 oncology & carcinogenesis Female business 030215 immunology medicine.drug Follow-Up Studies |
| Zdroj: | Leukemia research. 100 |
| ISSN: | 1873-5835 |
| Popis: | The prognosis remains poor for patients with relapsed or refractory (r/r) acute myeloid leukemia; thus, novel therapies are needed. We evaluated idasanutlin-a new, potent murine double minute 2 antagonist-alone or with cytarabine in patients with r/r acute myeloid leukemia, de novo untreated acute myeloid leukemia unsuitable for standard treatment or with adverse features, or secondary acute myeloid leukemia in a multicenter, open-label, phase 1/1b trial. Primary objectives were to determine the maximum tolerated dose (MTD) and recommended dose for expansion (RDE) and characterize the safety profile of idasanutlin monotherapy and combination therapy. Clinical activity and pharmacokinetics were secondary objectives. Two idasanutlin formulations were investigated: a microprecipitate bulk powder (MBP) and optimized spray-dried powder (SDP). Following dose escalation, patients (N = 122) received idasanutlin at the RDE in the extension cohorts. No formal MTD was identified. Idasanutlin was tolerable alone and in combination with cytarabine. The RDE was determined as 600 mg twice a day for the MBP formulation and 300 mg twice a day for the SDP formulation. Adverse events were mostly grade 1/2 (76.2 %). The most common any-grade adverse events were gastrointestinal (including diarrhea [90.2 %]). The early death rate across all patients was 14.8 %. Plasma idasanutlin exposure was dose related. In TP53 wild-type patients, composite complete remission rates were 18.9 % with monotherapy and 35.6 % with combination therapy. Based on these results, idasanutlin development continued with further investigation in the treatment of acute myeloid leukemia. ClinicalTrials.gov: NCT01773408. |
| Databáze: | OpenAIRE |
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