Phase I/II Study of BI 2536, An Intravenous Polo-Like Kinase-1 (Plk-1) Inhibitor, in Elderly Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML): First Results of a Multi-Center Trial

Elderly patients with refractory or relapsed AML have a dismal prognosis and new treatments are needed for this patient population. BI 2536 is a potent and selective inhibitor of Plk-1, which plays a crucial role in the regulation of mitosis. BI 2536 demonstrated strong anti-proliferative effects on AML cells in vitro and in vivo xenograft models and is the first specific Plk-1 inhibitor in clinical testing. Here, we present preliminary results of a Phase I/II study of single-agent BI 2536 therapy in patients 60 years of age or older with relapsed or refractory AML. Three administration schedules were tested: BI 2536 was given as an intravenous 1h-infusion on day 1 (schedule A), on days 1, 2, and 3 (schedule B), or on days 1 and 8 (schedule C) in 3-week cycles, respectively. In the phase I part, the 3+3 dose escalation design was used to evaluate the maximum tolerated dose (MTD) in AML patients. Dose escalation started at the respective MTD as previously determined in solid tumor patients. The phase II part consisted of extension cohorts at the MTD to further investigate safety and efficacy. The following dose levels of BI 2536 were evaluated: 200, 250, 300, 350, and 400 mg in schedule A; 50 and 60 mg in schedule B; 100, 150, 200, and 225 mg in schedule C. Initially, only schedule A and B were tested. As the blast reduction was only of short duration, we decided to discontinue schedule B after the 60 mg dose level and to introduce schedule C to shorten the interval between drug administrations. Currently, 60 evaluable patients (33 males, 27 females) have been treated: median age 68.5 years (range 61 – 82); ECOG score from 59 patients: 0: 10, 1: 32, 2: 17; secondary AML in 31 (53%) of 58 patients; complex karyotype in 7 (14%) of 49 patients; median number of previous therapies = 4 (range 1 – 13); in 50 patients, data on best response to previous therapies were available: CR = 25, PR = 4, no change = 17, PD = 4. In total, 119 cycles of trial treatment were administered in 60 patients (median = 1, range 1 – 7). The most frequent drug-related AEs were thrombocytopenia (21%), alopecia, anemia, and neutropenia (each 18%), nausea (15%), constipation, cough, fatigue, infection, leukopenia, and mucosal inflammation (each 12%). Dose limiting toxicities occurred in 8 patients and included neutropenic fever (3 cases), sepsis, pneumonia/sepsis, intracranial bleeding/hyphema, somnolence/coma and anal thrombosis. The MTD was determined at 350 mg in schedule A and at 200 mg in schedule C. No MTD was determined for schedule B. A greater than 50% reduction of blasts in the peripheral blood was seen in 17 of 36 evaluable patients after treatment with BI 2536; however, the effect on blast counts was only transient in most patients. Of 58 patients evaluable for response, one patient achieved a CR, one a CRi, and one a PR. Twenty-one patients had temporarily stable blood values, 31 progressed after the first cycle. In 3 patients, the response was indeterminate. The 24 patients who achieved remission or did not progress after the first cycle received a median of 3 treatment cycles (range 1 – 7). Dose-dependent pharmacodynamic activity was demonstrated by flowcytometric and immunocytochemical analysis of the bone marrow before and after BI 2536 administration. Pharmacokinetic data will be reported at the meeting. In conclusion, BI 2536 as single agent therapy is well tolerated and can be administered at higher doses in relapsed or refractory AML than in solid tumors. BI 2536 demonstrated clinical activity in patients with relapsed and treatment refractory AML.