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.

Fig 1. Study overview.

(A) LDAC was administered at 20 mg twice daily subcutaneously on days 1 to 10 of a 28-day cycle. Nintedanib was taken orally twice daily at three dose levels (100 mg, 150 mg, and 200 mg twice daily). Dose escalation was performed in a classical 3+3 design. (B) Patients received up to 6 cycles of combination therapy until disease progression or achievement of a CR.

Fig 2. Kaplan-Meier curve of overall survival.

Median OS of treated patients was 234 days, and one-year OS (95% CI) was 33.3% (10.3–58.8%).

Fig 3. Changes in VEGF and sVEGFR-2 serum concentrations during therapy.

While pre- and post-therapeutic levels of VEGF did not significantly differ (median 67.5 vs. 163.5 pg/mL, P = 0.173, Wilcoxon test), sVEFGR-2 serum concentrations significantly decreased after one cycle of study therapy (1500 vs. 1169.5 pg/mL, * P = 0.046).