Phase I Study of the Angiogenesis Inhibitor BIBF 1120 in Patients with Advanced Solid Tumors

Abstract

Purpose: BIBF 1120 is an oral, potent angiokinase inhibitor targeting receptors of the vascular endothelial growth factors, platelet-derived growth factors, and fibroblast growth factors. This phase I, accelerated titration study assessed the maximum tolerated dose, safety, pharmacokinetics, and pharmacodynamic effects of BIBF 1120.Patients and Methods: Sixty-one patients with advanced cancers received BIBF 1120 in successive cohorts. Twenty-five received 50 to 450 mg once daily and 36 received 150 to 300 mg twice daily in 4-week treatment courses interspersed by 1 week of washout. Dynamic contrast-enhanced magnetic resonance imaging assessed antiangiogenic effect in 42 patients.Results: Most frequent BIBF 1120-related adverse events were mostly mild to moderate (Common Toxicity Criteria grade 1-2) nausea (68.9%), vomiting (45.9%), and diarrhea (44.3%). The majority of dose-limiting adverse events of Common Toxicity Criteria grade 3 or 4 were reversible liver enzyme elevations. The maximum tolerated dose was 250 mg of BIBF 1120 for once and twice daily dosing. BIBF 1120 was absorbed moderately fast (t max = 1-3 hours at steady state), with no deviation from dose linearity and no decrease of exposure over time. The gMean terminal half-life was from 13 to 19 hours. One complete and two partial responses occurred in patients with renal cell cancer (n = 2) and colorectal cancer (n = 1). Dynamic contrast-enhanced magnetic resonance imaging showed a significant reduction in tumor blood flow in 55% of evaluable patients.

Targeting Angiogenesis in Cancer Therapy: Moving Beyond Vascular Endothelial Growth Factor

“…This approval was based on the LUME-Lung 1 trial, which demonstrated a significant improvement in OS to more than 1 year in patients with lung adenocarcinoma treated with nintedanib plus docetaxel versus docetaxel alone [90]. Phase I and II clinical studies initially demonstrated beneficial clinical effects with nintedanib monotherapy in advanced HCC, RCC, and CRC, and in addition to standard chemotherapy combination regimens in various tumor types, including prostate cancer and gynecologic malignancies [114][115][116][117][118][119][120][121][122]. Encouraging PFS data in OC have been reported (Table 2), and OS data for this indication are awaited [92].…”

“…Encouraging PFS data in OC have been reported (Table 2), and OS data for this indication are awaited [92]. Nintedanib is an orally available angiokinase inhibitor of VEGFR-1 to -3, PDGFR-a and -b, and FGFR-1 to -3, in addition to FLT-3 and Src [82,114,138]. Human tumor model studies show that nintedanib can reduce vessel density, vessel integrity, and tumor growth via effects on endothelial and smooth muscle cells, pericytes, and tumor cells [82].…”

Fibroblast Growth Factor Receptor Inhibitors as a Cancer Treatment: From a Biologic Rationale to Medical Perspectives

“…The most frequently reported drug-related adverse events were gastrointestinal events (i.e., nausea, vomiting, and diarrhea). Early signs of effi cacy were observed, including one complete response in a patient with renal cell cancer and 2 PRs in a patient with renal cell cancer and a patient with colorectal cancer ( 79 ). In another open-label, phase I dose-escalation trial of BIBF1120 in Japanese patients with advanced NSCLC, SD for 2 or more treatment courses was reported in 76% of patients ( n = 16; ref.…”

Novel anti-angiogenic therapeutic strategies in colorectal cancer

“…Inhibition of tumor growth was demonstrated in vivo in several xenograft models [113] and clinically in refractory tumors, demonstrating to be active in colorectal cancer, renal cancer and hepatocarcinoma [114]. Nintedanib in combination with docetaxel is indicated in locally advanced or metastatic lung adenocarcinoma patients who failed a first-line treatment.…”