A Phase I Dose Escalation Study of the Triple Angiokinase Inhibitor Nintedanib Combined with Low Dose Cytarabine in Elderly Patients with Acute Myeloid Leukemia
Nintedanib (BIBF 1120) a potent multikinase inhibitor of VEGFR 1/ 2/ 3, FGFR 1/ 2/ 3 and PDGFR a/ b, exerts growth inhibitory and pro apoptotic effects in myeloid leukemic cells, especially when used in combination with cytarabine. This phase I study evaluated nintedanib in combination with low dose cytarabine (LDAC) in elderly patients with untreated or relapsed/refractory acute myeloid leukemia (AML) ineligible for intensive chemotherapy in a 3+3 design. Nintedanib (dose levels 100, 150, and 200 mg orally twice daily) and LDAC (20 mg subcutaneous injection twice daily for 10 days) were administered in 28 day cycles. Dose limiting toxicity (DLT) was defined as non hematological severe adverse reaction CTC grade 4 with possible or definite relationship to nintedanib. Between April 2012 and October 2013, 13 patients (median age 73 [range: 62 86] years) were enrolled. One patient did not receive study medication and was replaced. Nine (69% patients had relapsed or refractory disease and 6 (46% patients had unfavorable cytogenetics. The most frequently reported treatment related adverse events (AE) were gastrointestinal events. Twelve SAEs irrespective of relatedness were reported. Two SUSARs were observed, one fatal hypercalcemia and one fatal gastrointestinal infection. Two patients (17% with relapsed AML achieved a complete remission (one CR, one CRi) and bone marrow blast reductions without fulfilling PR criteria were observed in 3 patients (25% One year overall survival was 33% Nintedanib combined with LDAC shows an adequate safety profile and survival data are promising in a difficult to treat patient population. Continuation of this trial with a phase II recommended dose of 2 x 200 mg nintedanib in a randomized, placebo controlled phase II study is planned. The trial is registered to EudraCT as 2011 001086 41. Trial Registration: ClinicalTrials.gov NCT01488344
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