Phase I/II Study of BI 6727 (volasertib), An Intravenous Polo-Like Kinase-1 (Plk1) Inhibitor, In Patients with Acute Myeloid Leukemia (AML): Results of the Dose Finding for BI 6727 In Combination with Low-Dose Cytarabine

Patients with refractory or relapsed AML have a poor prognosis and new treatments are needed for this patient population. While younger AML patients might benefit from intensive salvage treatments, a substantial number of elderly patients are considered ineligible for intensive treatment approaches. For these patients, repeated cycles of low-dose cytarabine (LD-Ara-C) are an accepted therapeutic option for palliative treatment.

The serine/threonine kinase Polo-like kinase 1 (Plk1) controls several key steps in mitosis. BI 6727 is a first in class, highly selective and potent cell cycle kinase inhibitor targeting Plk1, and has demonstrated antiproliferative activity in multiple cell lines and animal models. Targeting Plk1 with BI 6727 results in cell cycle arrest in prometaphase (referred to as polo arrest) leading to eventual apoptosis. In a phase I dose escalation trial in patients with advanced solid tumors a favorable safety profile and encouraging antitumor activity was reported. BI 6727 has demonstrated a long terminal half life of 111 hours and a high volume of distribution suggesting excellent tissue distribution in patients.

Here, we present preliminary results from the Phase I part of an ongoing Phase I/II study of BI 6727 in combination with LD-Ara-C in patients with relapsed or refractory AML considered ineligible for intensive treatment.

This study follows a two stage design: the maximum tolerated dose (MTD) of BI 6727 in combination with fixed dose LD-Ara-C was evaluated in the Phase I dose escalation part of the trial following a 3+3 design with de-escalation. In a second ongoing treatment schedule the MTD of single agent BI 6727 is investigated, the MTD of single agent BI 6727 has not been reached yet. In the planned randomized Phase II part of the study, efficacy of BI 6727 plus LD-Ara-C will be compared to LD-Ara-C alone.

BI 6727 was administered as a one hour intravenous infusion on days 1+15 every 28 days in combination with fixed dose LD-Ara-C (20 mg bid s.c). The BI 6727 starting dose was based on the MTD previously determined in solid tumor patients. Patients with no progression after the first cycle were allowed to continue treatment.

Patient characteristics were as follows: median age was 71 years (range 40 – 81); ECOG performance score 0: 9 pts; 1: 17 pts; 2: 5 pts.

Increasing BI 6727 doses in combination with LD-Ara-C were evaluated in 31 patients (21 males, 10 females).

Safety: Drug related adverse events (AEs) were reported in 17 of the 31 patients. The most frequent AEs reported (>5%) were: anemia and febrile neutropenia (each 9.7%), infections (pneumonia), decreased appetite and headache (each 6.5%). Dose-limiting toxicities (DLTs) were reported in 4 patients treated with BI 6727 + LD-Ara-C. DLTs as rated per protocol were: pneumonia, mucositis, hypersensitivity/allergic reaction and myocardial infarction. Based on the preliminary reports on DLTs the MTD for BI 6727 in combination with LD-Ara-C was determined.

Preliminary response data of 28 patients with relapsed/refractory AML treated at different BI 6727 doses in combination with LD-Ara-C are available: 5 patients achieved a CRi or CR, 2 patients achieved a PR. Six patients had temporarily stable blood values (“no change” as best response). 10 patients suffered from progression during or at the end of the 1^st treatment cycle, and 5 patients were ineligible for response assessment.

An update of the phase I part of this trial with further details on patient/disease characteristics, safety and efficacy of BI 6727 in combination with LD-Ara-C will be reported at the meeting.

Preliminary results indicate that BI 6727 in combination with LD-Ara-C is well tolerated in patients with relapsed/refractory AML ineligible for intensive treatment. The MTD of BI 6727 in combination with LD-Ara-C was determined. BI 6727 in combination with LD-Ara-C showed first signs of clinical activity in AML patients. Safety and efficacy of BI 6727 + LD-Ara-C will be further explored in the phase II part of the trial.

Off Label Use: LD-Ara-C in combination with BI 6727 for treatment of patients with relapsed refractory AML ineligible for intensive treatment. Fleischer:Boehringer Ingelheim Pharma GmbH & Co KG: Employment. Taube:Boehringer Ingelheim Pharma GmbH & Co KG: Employment.