A Phase I Study of the HDAC Inhibitor LBH589 in Combination with Imatinib for Patients with CML in Cytogenetic Remission with Residual Disease Detectable by Q-PCR.

Abstract 2194

Poster Board II-171

Imatinib mesylate (IM) is effective in inducing remission and improving survival in CML patients. However IM-treated patients continue to harbor residual leukemia stem cells (Blood 101:4701, 2003). Most patients relapse if treatment is discontinued, and it is generally recommended that treatment with IM be continued indefinitely. The inability of IM to cure CML, the potential for side effects and the financial burden of life-long treatment provide an impetus to develop approaches to eliminate residual leukemia stem cells. We have shown in preclinical studies that treatment with the HDAC inhibitor LBH589 (LBH) combined with IM effectively eliminates CML stem cells resistant to IM alone. The safety and MTD of LBH589 in combination with Imatinib has not been previously evaluated. We have initiated a phase I, open label clinical trial to determine the safety and tolerability of LBH589 given in combination with IM in CML patients, and to determine the MTD and dose-limiting toxicity (DLT). CML patients in chronic phase (CP) treated with IM 400mg/d for >1 year with major or complete cytogenetic response and residual disease on Q-PCR are eligible. LBH589 is administered in combination with IM 400mg PO daily in 28 day cycles, with successive cohorts of patients receiving escalating doses of LBH 3 times a week (level 1: 10mg; level 2: 15mg; level 3: 20mg). Treatment is scheduled for 6 cycles of 28 days each. Five patients have been enrolled thus far (Table). No dose limiting toxicity (DLT), defined as Grade 3 hematological or non-hematological toxicity in the first 28 days, was observed in 3 patients enrolled at dose level 1. DLT (Grade 3 thrombocytopenia) was observed in 1 of the 2 patients enrolled at dose level 2. Other toxicities included thrombocytopenia (Grade 3 [n=2]; Grade 1-2 [n=4]), hypophosphatemia (Grade 3 [n=1]; Grade 2 [n=2]), fatigue (Grade 1 [n=3]), hypocalcemia (Grade 1 [n=2] and Grade 1-2 GI symptoms (diarrhea [n=2]; nausea [n=3]; anorexia [n=2]; vomiting [n=3]; constipation [n=1]). Of note, significant QTc prolongation was not observed on intensive EKG monitoring. IM did not require to be held for any of these toxicities. Two patients have completed 6 cycles of treatment, with one opting to receive an additional 3 cycles, 2 are currently receiving treatment, and one withdrew after 1.5 cycles because of fatigue and GI symptoms. Bone marrow aspirates for assessment of BCR-ABL status were performed at the end of cycles 3 and 6 of treatment. Q-PCR analyses showed reduction in BCR-ABL levels in patient #2 (LBH 10mg) after 3 months, which was not sustained at 6 months. Patient #4 (LBH 15mg), followed for 5 months so far, had undetectable BCR-ABL after 3 months of treatment. These results suggest that LBH589 can be safely administered in combination with IM. Reduction in BCR-ABL levels was seen in two patients but the durability is unclear as yet. We are continuing accrual of patients to define the MTD and safety of this combination.