Randomized Phase II Trial of Cytosine Arabinoside with and without the CHK1 inhibitor MK-8776 in Relapsed and Refractory Acute Myeloid Leukemia
| Autor: | Larry M. Karnitz, Mrinal M. Patnaik, Scott H. Kaufmann, Ivana Gojo, Jonathan Webster, Lawrence E. Morris, Amanda L. Blackford, Judith E. Karp, L. Austin Doyle, B. Douglas Smith, Lihua Wang, Raoul Tibes, Gary L. Rosner, Robert J. Kinders, Mark R. Litzow, Catherine J. Huntoon |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Adult Male Cancer Research Antineoplastic Agents Article 03 medical and health sciences chemistry.chemical_compound Refractory medicine Humans CHEK1 Cytotoxicity Aged Genetics business.industry Cytarabine Myeloid leukemia Hematology Middle Aged medicine.disease CHK1 Inhibitor MK-8776 carbohydrates (lipids) Leukemia Leukemia Myeloid Acute 030104 developmental biology Pyrimidines Oncology chemistry Drug Resistance Neoplasm Checkpoint Kinase 1 Cancer research Pyrazoles Female biological phenomena cell phenomena and immunity Neoplasm Recurrence Local business Cytosine medicine.drug |
| Popis: | Cytosine arabinoside (AraC) remains the backbone of most treatment regimens for acute myeloid leukemia (AML). Incorporation of AraC into DNA activates checkpoint kinase 1 (Chk1), leading to cell-cycle arrest and diminished AraC cytotoxicity, which can be reversed by the selective Chk1 inhibitor MK-8776. Building on a Phase I trial, we conducted a phase II trial comparing timed sequential AraC with or without MK-8776.Patients with relapsed or primary refractory AML were randomized 1:1 to receive either AraC with MK-8776 (Arm A); or AraC alone (Arm B).32 patients were treated: 14 assigned to Arm A and 18 to Arm B. There were 5 (36%) complete responses (CR/CRi) and 1 (7%) partial response (PR) in Arm A, and 8 (44%) CR/CRis and 1 (6%) PR in Arm B. Median survival did not differ significantly between the two groups (5.9months in Arm A vs. 4.5 months in Arm B). MK-8776 led to a robust increase in DNA damage in circulating leukemic blasts as measured by increased γ-H2AX (16.9%±6.1% prior and 36.4%±6.8% at one hour after MK-8776 infusion, p=0.016).Response rates and survival were similar between the two groups in spite of evidence that MK-8776 augmented DNA damage in circulating leukemic blasts. Better than expected results in the control arm using timed sequential AraC and truncated patient enrollment may have limited the ability to detect clinical benefit from the combination. |
| Databáze: | OpenAIRE |
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