Randomized phase II trial of cytosine arabinoside with and without the CHK1 inhibitor MK-8776 in relapsed and refractory acute myeloid leukemia.

PURPOSE: 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. METHODS: 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). RESULTS: 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). CONCLUSION: 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.

Phase II trial of tipifarnib as maintenance therapy in first complete remission in adults with acute myelogenous leukemia and poor-risk features.

PURPOSE: Acute myelogenous leukemia (AML) does not have a high cure rate, particularly in patients with poor-risk features. Such patients might benefit from additional therapy in complete remission (CR). Tipifarnib is an oral farnesyltransferase inhibitor with activity in AML. We conducted a phase II trial of maintenance tipifarnib monotherapy for 48 adults with poor-risk AML in first CR. EXPERIMENTAL DESIGN: Tipifarnib 400 mg twice daily for 14 of 21 days was initiated after recovery from consolidation chemotherapy, for a maximum of 16 cycles (48 weeks). RESULTS: Twenty (42%) patients completed 16 cycles, 24 (50%) were removed from study for relapse, and 4 (8%) discontinued drug prematurely for intolerance. Nonhematologic toxicities were rare, but tipifarnib dose was reduced in 58% for myelosuppression. Median disease-free survival (DFS) was 13.5 months (range, 3.5-59+ months), with 30% having DFS >2 years. Comparison of CR durations for 25 patients who received two-cycle timed sequential therapy followed by tipifarnib maintenance with 23 historically similar patients who did not receive tipifarnib showed that tipifarnib was associated with DFS prolongation for patients with secondary AML and adverse cytogenetics. CONCLUSIONS: This study suggests that some patients with poor-risk AML, including patients with secondary AML and adverse cytogenetics, may benefit from tipifarnib maintenance therapy. Future studies are warranted to examine alternative tipifarnib dosing and continuation beyond 16 cycles.