title: A Phase I Dose Escalation Study of the Triple Angiokinase Inhibitor Nintedanib Combined with Low-Dose Cytarabine in Elderly Patients with Acute Myeloid Leukemia.
abstract: 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.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01488344.
authors.affiliation: Department of Medicine A, University Hospital Muenster, Muenster, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Schliemann
authors.affiliation: Institute of Biostatistics and Clinical Research, University Hospital Muenster, Muenster, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Gerss
authors.affiliation: Department of Medicine A, University Hospital Muenster, Muenster, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Wiebe
authors.affiliation: Department of Medicine A, University Hospital Muenster, Muenster, Germany.
authors.forename: Jan-Henrik
authors.initials: JH
authors.lastname: Mikesch
authors.affiliation: Department of Medicine A, University Hospital Muenster, Muenster, Germany.
authors.forename: Nicola
authors.initials: N
authors.lastname: Knoblauch
authors.affiliation: Department of Medicine A, University Hospital Muenster, Muenster, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Sauer
authors.affiliation: Department of Medicine A, University Hospital Muenster, Muenster, Germany.
authors.forename: Linus
authors.initials: L
authors.lastname: Angenendt
authors.affiliation: Centre for Clinical Trials, University Hospital Muenster, Muenster, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Kewitz
authors.affiliation: Centre for Clinical Trials, University Hospital Muenster, Muenster, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Urban
authors.affiliation: Centre for Clinical Trials, University Hospital Muenster, Muenster, Germany.
authors.forename: Trude
authors.initials: T
authors.lastname: Butterfass-Bahloul
authors.affiliation: Department of Medicine A, University Hospital Muenster, Muenster, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Edemir
authors.affiliation: Department of Medicine A, University Hospital Muenster, Muenster, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Vehring
authors.affiliation: Department of Medicine A, University Hospital Muenster, Muenster, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Müller-Tidow
authors.affiliation: Department of Medicine A, University Hospital Muenster, Muenster, Germany.
authors.forename: Wolfgang E
authors.initials: WE
authors.lastname: Berdel
authors.affiliation: Department of Medicine A, University Hospital Muenster, Muenster, Germany.
authors.forename: Utz
authors.initials: U
authors.lastname: Krug
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D003561:Cytarabine / Q000008:administration & dosage / Q000009:adverse effects; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000009:adverse effects
chemical_list: D000964:Antimetabolites, Antineoplastic; D004791:Enzyme Inhibitors; D007211:Indoles; D047428:Protein Kinase Inhibitors; D003561:Cytarabine; C530716:nintedanib