Randomized, phase 2 trial of low-dose cytarabine with or without volasertib in AML patients not suitable for induction therapy

Abstract

Key Points• Volasertib plus low-dose cytarabine increased the response rate and improved survival in AML patients ineligible for intensive treatment.• Volasertib plus low-dose cytarabine resulted in responses across all AML genetic subgroups and had a clinically manageable safety profile.Treatment outcomes for older patients with acute myeloid leukemia (AML) have remained dismal. This randomized, phase 2 trial in AML patients not considered suitable for intensive induction therapy compared low-dose cytarabine (LDAC) with or without volasertib, a highly potent and selective inhibitor of polo-like kinases. Eighty-seven patients (median age 75 years) received LDAC 20 mg twice daily subcutaneously days 1-10 or LDAC 1 volasertib 350 mg IV days 1 1 15 every 4 weeks. Response rate (complete remission and complete remission with incomplete blood count recovery) was higher for LDAC 1 volasertib vs LDAC (31.0% vs 13.3%; odds ratio, 2.91; P 5 .052). Responses in the LDAC 1 volasertib arm were observed across all genetic groups, including 5 of 14 patients with adverse cytogenetics. Median event-free survival was significantly prolonged by LDAC 1 volasertib compared with LDAC (5.6 vs 2.3 months; hazard ratio, 0.57; 95% confidence interval, 0.35-0.92; P 5 .021); median overall survival was 8.0 vs 5.2 months, respectively (hazard ratio, 0.63; 95% confidence interval, 0.40-1.00; P 5 .047). LDAC 1 volasertib led to an increased frequency of adverse events that was most pronounced for neutropenic fever/infections and gastrointestinal events; there was no increase in the death rate at days 60 1 90. This study was

Efficacy and Mechanism of Action of Volasertib, a Potent and Selective Inhibitor of Polo-Like Kinases, in Preclinical Models of Acute Myeloid Leukemia

“…Early clinical studies in patients with solid tumors had indicated that the compound has therapeutic potential and is well tolerated (Gjertsen and Schoffski, 2015), with mainly hematologic toxicities and the notable absence of neuropathies, and thus may be particularly beneficial for patients unable to tolerate aggressive chemotherapy. Importantly, recent clinical data in AML patients showed that volasertib combined with low-dose cytarabine (LDAC) was associated with higher response rates and improved event-free survival than LDAC alone (Dohner et al, 2014). On this basis, volasertib in combination with LDAC is currently being evaluated in a phase III clinical study in patients with previously untreated AML who are ineligible for intensive therapy (NCT01721876; POLO-AML-2).…”

Intermediate-risk acute myeloid leukemia therapy: current and future

“…96 In a recent randomized trial comparing low-dose cytarabine with or without volasertib in older patients ineligible for intensive therapy, the combination therapy doubled the response rate and even showed a signal for a survival benefit. 97 A pivotal placebo-controlled phase 3 trial in this patient population is ongoing (www.ClinicalTrials.gov identifier NCT01721876) and a randomized phase 2 trial evaluating volasertib in combination with intensive therapy, including younger adult patients (18 years and older) with newly diagnosed AML, is in the planning phase (www.ClinicalTrials.gov identifier NCT02198482).…”

Emerging therapeutic drugs for AML

“…27 The dose of volasertib was 350 mg on days 1 and 15 of a 28-day cycle. CRc was 31% in the combination arm compared with 13.3% with LDAC monotherapy with a strong trend toward statistical significance (P 5 .052).…”