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.Trial Registration: ClinicalTrials.gov NCT01488344

The role of the extracellular matrix in primary myelofibrosis

“…Although bevacizumab (anti-VEGF antibody) was ineffective in treating PMF, inhibition of multiple cytokine receptors involved in the pathogenesis may be efficacious by interrupting cytokine-mediated disruptions of the BM niches and ECM. 141 , 142 TNF inhibitors have shown promise in treating the constitutional symptoms of PMF, although larger trials are necessary to assess safety and efficacy. 143 …”

Kinase Inhibition in Relapsed/Refractory Leukemia and Lymphoma Settings: Recent Prospects into Clinical Investigations

“…Patients suffering from myeloproliferative disorders under treatment regimens that included KIs with molecular targets other than FLT3 inhibition did not report significant clinical responses and parameters of survival and disease progression were generally poor. However, the occurrence of adverse events (AE) was not drastically different from what is reported of most KI therapies, indicating a tolerable profile that may permit further studies in the investigation of their association with synergetic compounds [ 92 , 95 , 98 , 99 , 105 , 107 , 108 ].…”

“…The other half of the analyzed studies focused primarily on lymphoid malignancies, especially of B-cell origin, and had phosphatidylinositol 3-kinase (PI3K) and Bruton’s tyrosine kinase (BTK) being the most targeted kinases ( Figure 3 ). A large spectrum of different KIs and treatment protocols were covered, and kinase inhibition was mainly evaluated as a single-agent strategy in the treatment of R/R hematologic disorders, with only 10 out of 32 clinical trials associating KI usage with another cytotoxic agent [ 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 ].…”

A randomized phase 2 trial of nintedanib and low-dose cytarabine in elderly patients with acute myeloid leukemia ineligible for intensive chemotherapy

“…In order to translate these preclinical findings, we investigated the safety and efficacy of nintedanib added to LDAC in a phase 1/2 study in patients 60 years or older with untreated or relapsed/refractory (r/r) AML ineligible for intensive chemotherapy. The results of the dose-finding phase 1 part have been previously published and suggested a continuation of the trial with a phase 2 recommended dose (P2RD) of 200 mg nintedanib twice daily in combination with LDAC [ 19 ]. Here, we report the findings of the randomized, double-blind, placebo-controlled phase 2 part of the study.…”