nintedanib and Pancreatic-Neoplasms

This Phase I study evaluated continuous- and intermittent-dosing (every other week) of afatinib plus nintedanib in patients with advanced solid tumours.. In the dose-escalation phase (n=45), maximum tolerated doses (MTDs) were determined for continuous/intermittent afatinib 10, 20, 30 or 40 mg once daily plus continuous nintedanib 150 or 200 mg twice daily. Secondary objectives included safety and efficacy. Clinical activity of continuous afatinib plus nintedanib at the MTD was further evaluated in an expansion phase (n=25).. The most frequent dose-limiting toxicities were diarrhoea (11%) and transaminase elevations (7%). Maximum tolerated doses were afatinib 30 mg continuously plus nintedanib 150 mg, and afatinib 40 mg intermittently plus nintedanib 150 mg. Treatment-related adverse events (mostly Grade⩽3) included diarrhoea (98%), asthenia (64%), nausea (62%) and vomiting (60%). In the dose-escalation phase, two patients had partial responses (PRs) and 27 (60%) had stable disease (SD). In the expansion phase, one complete response and three PRs were observed (all non-small cell lung cancer), with SD in 13 (52%) patients. No pharmacokinetic interactions were observed.. MTDs of continuous or intermittent afatinib plus nintedanib demonstrated a manageable safety profile with proactive management of diarrhoea. Antitumour activity was observed in patients with solid tumours.

Topics: Adult; Afatinib; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Drug Administration Schedule; Female; Humans; Indoles; Lung Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Pancreatic Neoplasms; Quinazolines; Treatment Outcome

Angiogenesis remains a sensible target for pancreatic ductal adenocarcinoma (PDAC) therapy. VEGF, PDGF, FGF and their receptors are expressed at high levels and correlate with poor prognosis in human PDAC. Nintedanib is a triple angiokinase inhibitor that targets VEGFR1/2/3, FGFR1/2/3 and PDGFRα/β signaling. We investigated the antitumor activity of nintedanib alone or in combination with the cytotoxic agent gemcitabine in experimental PDAC. Nintedanib inhibited proliferation of cells from multiple lineages found in PDAC, with gemcitabine enhancing inhibitory effects. Nintedanib blocked PI3K/MAPK activity and induced apoptosis in vitro and in vivo. In a heterotopic model, net local tumor growth compared to controls (100%) was 60.8 ± 10.5% in the gemcitabine group, -2.1 ± 9.9% after nintedanib therapy and -12.4 ± 16% after gemcitabine plus nintedanib therapy. Effects of therapy on intratumoral proliferation, microvessel density and apoptosis corresponded with tumor growth inhibition data. In a PDAC survival model, median animal survival after gemcitabine, nintedanib and gemcitabine plus nintedanib was 25, 31 and 38 days, respectively, compared to 16 days in controls. The strong antitumor activity of nintedanib in experimental PDAC supports the potential of nintedanib-controlled mechanisms as targets for improved clinical PDAC therapy.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Cell Proliferation; Deoxycytidine; Gemcitabine; Humans; Indoles; Neoplasms, Experimental; Neovascularization, Pathologic; Pancreatic Neoplasms; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Receptors, Fibroblast Growth Factor; Receptors, Platelet-Derived Growth Factor; Receptors, Vascular Endothelial Growth Factor; Xenograft Model Antitumor Assays

Pancreatic neuroendocrine tumors (PNET) represent a rare but challenging heterogeneous group of cancers with an increasing incidence over the last number of decades. Herein, we report an in-depth evaluation of the new antiangiogenic small-molecule tyrosine kinase inhibitor (TKI) nintedanib in the preclinical Rip1Tag2 transgenic mouse model of neuroendocrine carcinoma of the pancreas (insulinoma).. We have assessed the antiangiogenic and antitumor activity of nintedanib, in comparison with other antiangiogenic TKI, by treating Rip1Tag2 transgenic mice with different treatment schedules complemented with histopathologic, cell biologic, and biochemical analyses.. Prolonged nintedanib treatment of Rip1Tag2 mice has led to a strong suppression of angiogenesis, accompanied by a reduced tumor burden, which translated into a significant prolongation of survival. Despite nintedanib's inhibitory action on perivascular cells, the blood vessels remaining after therapy displayed a considerably mature phenotype with tight perivascular cell coverage and preserved perfusion. Nintedanib treatment did not increase local tumor invasiveness or metastasis to the liver and pancreatic lymph nodes--a phenomenon that has been observed with antiangiogenic treatments of Rip1Tag2 transgenic mice in other laboratories. In contrast with the strong reduction in blood microvessel densities, nintedanib did not have any impact on tumor lymphangiogenesis.. Based on our findings, we propose the clinical evaluation of the antiangiogenic drug nintedanib as a new treatment modality for PNET patients, notably in a direct comparison with already established therapeutic regimens, such as sunitinib.

Topics: Animals; Antigens, Polyomavirus Transforming; Antineoplastic Agents; Apoptosis; Carcinoma, Neuroendocrine; Disease Models, Animal; Drug Evaluation, Preclinical; Female; Humans; Indoles; Insulin; Mice; Mice, Transgenic; Neoplasm Metastasis; Neoplasm Staging; Neovascularization, Pathologic; Pancreatic Neoplasms; Phenotype; Promoter Regions, Genetic; Signal Transduction; Tumor Burden; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factor Receptor-3

Signaling from other angiokinases may underlie resistance to VEGF-directed therapy. We evaluated the antitumor and biologic effects of BIBF 1120 (nintedanib), a tyrosine kinase inhibitor that targets VEGF receptor, platelet-derived growth factor receptor, and fibroblast growth factor receptor in preclinical models of lung and pancreatic cancer, including models resistant to VEGF-targeted treatments. In vitro, BIBF 1120 did not show antiproliferative effects, nor did it sensitize tumor cells to chemotherapy. However, in vivo BIBF 1120 inhibited primary tumor growth in all models as a single agent and in combination with standard chemotherapy. Analysis of tumor tissue posttreatment revealed that BIBF 1120 reduced proliferation (phospho-histone 3) and elevated apoptosis (cleaved caspase-3) to a greater extent than chemotherapy alone. Furthermore, BIBF 1120 showed potent antiangiogenic effects, including decreases in microvessel density (CD31), pericyte coverage (NG2), vessel permeability, and perfusion, while increasing hypoxia. Despite the induction of hypoxia, markers of epithelial-to-mesenchymal transition (EMT) were not elevated in BIBF 1120-treated tumors. In summary, BIBF 1120 showed potent antitumor and antiangiogenic activity in preclinical models of lung and pancreatic cancer where it induced hypoxia but not EMT. The absence of EMT induction, which has been implicated in resistance to antiangiogenic therapies, is noteworthy. Together, these results warrant further clinical studies of BIBF 1120.

Topics: Apoptosis; Caspase 3; Drug Evaluation, Preclinical; Epithelial-Mesenchymal Transition; Humans; Hypoxia; Indoles; Lung Neoplasms; Neovascularization, Pathologic; Pancreatic Neoplasms; Protein Kinase Inhibitors; Receptors, Fibroblast Growth Factor; Receptors, Platelet-Derived Growth Factor; Receptors, Vascular Endothelial Growth Factor; Xenograft Model Antitumor Assays