Erweiterte Suche

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-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.

Titel: A Phase I Dose Escalation Study of the Triple Angiokinase Inhibitor Nintedanib Combined with Low-Dose Cytarabine in Elderly Patients with Acute Myeloid Leukemia
Verfasser: Schliemann, Christoph GND
Gerß, Joachim GND
Wiebe, Stefanie
Mikesch, Jan-Henrik GND
Knoblauch, Nicola GND
Sauer, Tim GND
Angenendt, Linus
Kewitz, Tobias GND
Urban, Marc
Butterfass-Bahloul, Trude
Edemir, Sabine
Vehring, Kerstin
Müller-Tidow, Carsten GND
Berdel, Wolfgang E. GND
Krug, Utz GND
Organisation: FB 05: Medizinische Fakultät
Dokumenttyp: Artikel
Medientyp: Text
Erscheinungsdatum: 07.10.2016
Publikation in MIAMI: 30.01.2017
Datum der letzten Änderung: 19.07.2017
Quelle: PLoS ONE 11 (2016) 10, e0164499, 1-13
Fachgebiete: Medizin und Gesundheit
Lizenz: CC BY 4.0
Sprache: Englisch
Format: PDF-Dokument
URN: urn:nbn:de:hbz:6-63239606676
Permalink: http://nbn-resolving.de/urn:nbn:de:hbz:6-63239606676
DOI: 10.1371/journal.pone.0164499
ISSN: 1932-6203
Onlinezugriff: