A Phase I Dose Escalation Study of the Triple Angiokinase Inhibitor Nintedanib Combined with Low-Dose Cytarabine in Elderly Patients with Acute Myeloid LeukemiaReport as inadecuate




A Phase I Dose Escalation Study of the Triple Angiokinase Inhibitor Nintedanib Combined with Low-Dose Cytarabine in Elderly Patients with Acute Myeloid Leukemia - Download this document for free, or read online. Document in PDF available to download.

Nintedanib BIBF 1120, a potent multikinase inhibitor of VEGFR-1-2-3, FGFR-1-2-3 and PDGFR-α-β, 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



Author: Christoph Schliemann, Joachim Gerss, Stefanie Wiebe, Jan-Henrik Mikesch, Nicola Knoblauch, Tim Sauer, Linus Angenendt, Tobias Kew

Source: http://plos.srce.hr/



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