TY  - JOUR
AB  - 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.
AU  - Schliemann, Christoph
AU  - Gerß, Joachim
AU  - Wiebe, Stefanie
AU  - Nolting, Stefanie
AU  - Mikesch, Jan-Henrik
AU  - Knoblauch, Nicola
AU  - Knoblauch, Nicola Tamara Mirjam
AU  - Sauer, Tim
AU  - Angenendt, Linus
AU  - Kewitz, Tobias
AU  - Urban, Marc
AU  - Butterfass-Bahloul, Trude
AU  - Edemir, Sabine
AU  - Vehring, Kerstin
AU  - Müller-Tidow, Carsten
AU  - Berdel, Wolfgang E.
AU  - Berdel, Wolfgang
AU  - Berdel, W. E.
AU  - Krug, Utz
DA  - 2016-10-07
DO  - 10.1371/journal.pone.0164499
LA  - eng
N1  - PLoS ONE 11 (2016) 10, e0164499, 1-13
PY  - 2016-10-07
SN  - 1932-6203
TI  - A Phase I Dose Escalation Study of the Triple Angiokinase Inhibitor Nintedanib Combined with Low-Dose Cytarabine in Elderly Patients with Acute Myeloid Leukemia
UR  - https://nbn-resolving.org/urn:nbn:de:hbz:6-63239606676
Y2  - 2024-11-22T04:51:25
ER  -