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Nintedanib (Vargatef; BIBF 1120)

Alias: BIBF1120; Nintedanib; BIBF-1120; Intedanib; BIBF 1120; trade name: Vargatef
Cat No.:V0530 Purity: =99.01%
Nintedanib (formerly BIBF-1120; trade name: Vargatef) is an orally bioavailable multi-kinase inhibitor with potential antineoplastic and anti-fibrotic activity.
Nintedanib (Vargatef; BIBF 1120)
Nintedanib (Vargatef; BIBF 1120) Chemical Structure CAS No.: 656247-17-5
Product category: VEGFR
This product is for research use only, not for human use. We do not sell to patients.
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Other Forms of Nintedanib (Vargatef; BIBF 1120):

  • Nintedanib esylate
  • Nintedanib D3 (BIBF 1120 D3)
  • Nintedanib-d8
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Purity & Quality Control Documentation

Purity: =99.01%

Product Description

Nintedanib (formerly BIBF-1120; trade name: Vargatef) is an orally bioavailable multi-kinase inhibitor with potential antineoplastic and anti-fibrotic activity. In cell-free experiments, it suppresses VEGFR1/2/3, FGFR1/2/3, and PDGFRα/β with IC50s of 34 nM/13 nM/13 nM, 69 nM/37 nM/108 nM, and 59 nM/65 nM. The FDA approved nitedanib in November 2014 to treat idiopathic pulmonary fibrosis (IPF).

Biological Activity I Assay Protocols (From Reference)
Targets
VEGFR1 (IC50 = 34 nM); VEGFR2 (IC50 = 13 nM); VEGFR3 (IC50 = 13 nM); FGFR1 (IC50 = 69 nM); FGFR2 (IC50 = 37 nM); FGFR3 (IC50 = 108 nM); PDGFRα (IC50 = 59 nM); PDGFRβ (IC50 = 65 nM)
ln Vitro
Nintedanib (BIBF 1120) attaches itself to the ATP-binding site of the kinase domain, which is located in the cleft between the amino and carboxy terminal lobes. With an EC50 of 79 nM in cell assays, neintedanib (BIBF 1120) inhibits the proliferation of PDGF-BB stimulated BRPs. After stimulation with 5% serum plus PDGF-BB, neintedanib (BIBF 1120) (100 nM) inhibits MAPK activation. In cultures of human vascular smooth muscle cells (HUASMC), neintedanib (BIBF 1120) inhibits PDGF-BB stimulated proliferation with an EC50 of 69 nM[1].
Kinase selectivity profile. [1]
Extensive biochemical testing revealed a distinctive, narrow range of kinases that are inhibited by Nintedanib/BIBF 1120 at pharmacologically relevant concentrations. The targeted kinases include all three VEGFR subtypes (IC50, 13–34 nmol/L), PDGFRα and PDGFRβ (IC50, 59 and 65 nmol/L), and FGFR types 1, 2, and 3 (IC50, 69, 37, and 108 nmol/L, respectively; Table 1). Comparable inhibition was seen for the corresponding human and rodent kinases. In addition, BIBF 1120 inhibits FLT3 (inhibition of acute myelogenous leukemia cell proliferation has been shown previously; ref. 29), as well as members of the Src-family (Src, Lyn, and Lck). By contrast, receptor tyrosine kinases, such as EGFR and HER2, InsR, IGF-IR, or the cell cycle kinases CDK1, CDK2, and CDK4 (Table 1) were not inhibited at concentrations below 1,000 nmol/L.

Signaling pathways, proliferation, and survival of endothelial cells. Treatment of VEGF-stimulated endothelial cells derived from umbilical veins (HUVEC) and skin microvessels (HSMEC) with NintedanibBIBF 1120 resulted in inhibition of cell proliferation and apoptosis (EC50, <10 nmol/L; Table 2) and was preceded by inhibition of MAPK and Akt phosphorylation (Fig. 2A). Inhibition of bFGF-stimulated HUVEC proliferation required higher drug concentrations (EC50, 290 nmol/L), although activation of both MAPK and Akt was at least partially suppressed at concentrations down to 100 nmol/L. The apoptosis marker cleaved caspase-3 was up-regulated in a concentration-dependent manner in both VEGF-stimulated and bFGF-stimulated HUVEC, and the proportion of apoptotic HUVEC cells as measured by TUNEL stain increased from 2% in control cells to 28% in the presence of 50 nmol/L BIBF 1120 (Supplementary Fig. S1A).
Effects on pericytes and smooth muscle cells. [1]
Pericytes, important for vessel maturation and stabilization, are known to express PDGFRs (30). Nintedanib/BIBF 1120 inhibited proliferation of PDGF-BB–stimulated BRPs with an EC50 of 79 nmol/L (Table 2), which is in general agreement with the biochemical kinase inhibition data. Signaling pathway analysis showed that activation of MAPK after stimulation with 5% serum plus PDGF-BB could be blocked by BIBF 1120 at concentrations down to 100 nmol/L. Stimulation of BRP with 5% serum plus bFGF blocked MAPK phosphorylation, but not concentration-dependently (Fig. 2B). Activation of Akt was clearly suppressed by BIBF 1120 after stimulation with PDGF-BB or bFGF down to a concentration of 100 nmol/L; interestingly, no increase in cleaved caspase-3 resulted from this pathway inhibition.

In cultures of human vascular smooth muscle cells (HUASMC), Nintedanib/BIBF 1120 inhibited PDGF-BB stimulated proliferation with an EC50 of 69 nmol/L (Table 2), and MAPK activation was inhibited at concentrations down to 100 nmol/L. Cell lysates of HUASMC stimulated with bFGF showed inhibition of MAPK activation above concentrations of 300 nmol/L. Phosphorylation of Akt was completely blocked in bFGF or PDGF-BB stimulated HUASMC at BIBF 1120 concentrations as low as 100 nmol/L. Furthermore, the apoptosis marker cleaved caspase-3 was up-regulated in bFGF-stimulated HUASMC treated with BIBF 1120 (Fig. 2C).
Sustained VEGFR blockade. [1]
To determine the duration of VEGFR-2 inhibition by Nintedanib/BIBF 1120, a pulse-chase experiment with VEGFR-2 transfected NIH3T3 cells (31) was performed. The cells were exposed for 1 hour to 50 nmol/L BIBF 1120, washed thoroughly with PBS, and incubated for 8, 24, or 32 hours in medium followed by stimulation with VEGF for 10 minutes. Western blot analysis of the cell lysates after immunoprecipitation revealed that inhibition of receptor phosphorylation was sustained for at least 32 hours after removal of BIBF 1120 (Supplementary Fig. S1B).
Combination effect of trifluridine and Nintedanib on colorectal cancer cell lines in vitro [2]
The isobologram plots were drawn using three isoeffect curves (mode I, mode IIa, and mode IIb) based on the 72-h growth inhibition curves for DLD-1, HT-29, and HCT116 cells (Fig. 1A-C) with trifluridine or nintedanib alone. Based on available dose-response curves, we analyzed the combined effect of the two drugs at the points of IC50. The IC50 values for trifluridine in DLD-1, HT-29, and HCT116 cells were 4.3×10−6, 3.8×10−6, and 1.8×10−6 M respectively, whereas the corresponding IC50 values for nintedanib were 3.4×10−6, 1.4×10−6 and 2.5×10−6 M, respectively. In the DLD-1 and HT-29 cells, a 72-h exposure to the combination treatment resulted in an additive effect (Fig. 1A and B). In the HCT116 cells the aforementioned combination treatment resulted in a sub-additive effect (Fig. 1C).
ln Vivo
Nintedanib (BIBF 1120) 25–100 mg/kg daily p.o. is very active in all tumor models, including a syngeneic rat tumor model and human tumor xenografts growing in nude mice. This is demonstrated by the tumor's perfusion on magnetic resonance imaging after three days, its decreased vessel integrity and density after five days, and its significant growth inhibition[1]. Orally administered nitedanib (BIBF 1120) is well tolerated and shows encouraging efficacy in in vivo tumor models[2].
BIBF 1120/Nintedanib affects tumor vessel density and pericytes. [1]
To confirm that BIBF 1120 affects the tumor vasculature, mice with established FaDu xenografts were treated for five consecutive days with either the vehicle control or BIBF 1120 at a dose of 100 mg/kg. After the last application, tumors were dissected and analyzed by immunohistochemistry using Meca 32 and PDGFRβ-specific antibodies to stain endothelial cells and pericytes (Fig. 3B). In comparison to control tumors, vessel density in xenografts from mice treated with BIBF 1120 was reduced by 76% (Fig. 3C; P < 0.001). Quantification of PDGFRβ-positive mural cells showed a reduction of 64% after 5 days of treatment with BIBF 1120 (Fig. 3C; P < 0.001). Double immunofluorescence staining with Meca 32 and PDGFRβ in tumor sections from control and BIBF 1120–treated mice show a clear association of Meca 32–positive endothelial cells and PDGFRβ-positive pericytes (Fig. 3D,, top) in the control mice, whereas in the BIBF 1120–treated mice, a marked reduction in both Meca 32–positive and PDGFRβ-positive cells was seen predominantly in the intratumoral compartment compared with the peritumoral tumor stroma separating the tumor nodules (Fig. 3D, area between the two dotted lines in the right bottom). At high magnification, a tight association between Meca 32–positive and PDGFRβ-positive cells can be seen in the tumor sample from a control mouse, but not in the BIBF 1120–treated tumor sample (Fig. 3D , arrow in left top and bottom). These data show not only the reduction of Meca 32–positive and PDGFRβ-positive cells upon BIBF 1120 treatment but also the loss of tight association between both cell types in the majority of the tumor vessels identified after 5 days of treatment.
In vivo antitumor activity associated with distinctive pharmacokinetic profile and favorable tolerability in mice. [1]
Continuous once daily p.o. treatment of mice with established FaDu tumor xenografts at 50 or 100 mg/kg resulted in a significant inhibition of tumor growth and treated versus control (T/C) values of 27% and 11%, respectively (Fig. 4A). BIBF 1120/Nintedanib was well tolerated even in the high-dose group, with no obvious weight loss over the treatment period. Marked inhibition of tumor growth was also observed in xenograft models of human renal cell carcinoma (Fig. 4B; Caki-1), colorectal (HT-29), ovarian (SKOV-3), non–small cell lung (Calu-6), and prostate carcinoma (PAC-120), as described in Supplementary Table S1. Moreover, in a syngeneic rat glioblastoma model (cell line GS-9L), efficacy was observed at 50, 25, and 10 mg/kg with T/C values of 30%, 45%, and 74%, respectively (Supplementary Table S1). Pharmacokinetic studies after p.o. application to mice (Fig. 4C) revealed a maximal plasma concentration of ∼1,000 nmol/L at 1 hour and trough plasma levels below 8 nmol/L at 24 hours postadministration. This distinctive pharmacokinetic profile can be explained by the rapid metabolization of BIBF 1120 by methyl ester cleavage, resulting in the generation of the main metabolite BIBF 1202 containing a free acid residue (data not shown).
Antitumor efficacy of TFTD/Nintedanib combination therapy in vivo [2]
The in vivo efficacy of TFTD monotherapy, Nintedanib monotherapy, and TFTD and nintedanib combination in human colorectal cancer xenograft models was evaluated. Nude mice bearing DLD-1 tumors were treated with 150 mg/kg TFTD, 40 mg/kg Nintedanib, or a combination of TFTD and nintedanib for 14 consecutive days. On day 15, TFTD monotherapy and nintedanib monotherapy resulted in a significant reduction in tumor growth in vivo (P<0.01) (Fig. 2A). In addition, the combination therapy exhibited greater antitumor activity than both monotherapies. The efficacy of the aforementioned treatments was evaluated in nude mice bearing tumors that were derived from 5-FU-resistant human colorectal cancer cells, DLD-1/5-FU (Fig. 2C). TFTD monotherapy and nintedanib monotherapy resulted in a significant reduction in tumor growth in vivo (P<0.01). The antitumor efficacy of both monotherapies was similar between the 5-FU-resistant DLD-1 cells and the parent DLD-1 cells. This indicated that no cross-resistance had occurred between DLD-1/5-FU and either of the monotherapies. The TFTD/nintedanib combination therapy exhibited greater antitumor activity against DLD-1/5-FU compared with the antitumor activity exhibited by both monotherapies. Thus, the combination therapy showed a similar antitumor effect against the DLD-1/5-FU (tumor growth inhibition rate 72.8%) and the DLD-1 (tumor growth inhibition rate 61.5%) tumors (data not shown). The efficacy of the above treatments was further evaluated in the HT-29 (Fig. 2E) and HCT116 (Fig. 2G) xenograft models. TFTD and nintedanib monotherapies both significantly suppressed tumor growth when compared with control (P<0.01). The combination therapy significantly suppressed tumor growth when compared to each monotherapy (P<0.01). Fig. 3 summarizes the antitumor effects of the administered therapies as evaluated by the mean RTV at day 15. The antitumor activity of the TFTD/nintedanib combination therapy, for all human colorectal cancer xenografts, was significantly greater than that of either monotherapy (P<0.01).
Enzyme Assay
In vitro kinase activity assays. [1]
The cytoplasmic tyrosine kinase domain of VEGFR-2 (residues 797–1355 according to sequence deposited in databank SWISS-PROT P35968) was cloned into pFastBac fused to GST and extracted as described in supplementary methods. Enzyme activity was assayed using standard conditions using a random polymer (Glu/Tyr 4:1) and in the presence of 100 μmol/L ATP (for details, see supplementary methods). For all other kinase assays, the entire cytoplasmic domains of the receptors (from the end of the transmembrane to the COOH terminus) were cloned into pFastBac vector containing GST and assayed under standard conditions.
In Vitro VEGFR-2 Kinase Assay [3]
The cytoplasmic kinase domain of VEGFR-2 (residues 797 to 1335 according to sequence deposited in databank SWISS-PROT P35968) was cloned into pFastBac fused to Glutathion-S-transferase (GST). The GST-fusion protein was expressed in SF-9 insect cells and extracted with HEPEX (20 mM HEPES pH 7.4, 100 mM NaCl, 10 mM ss-glycerophosphate, 10 mM para-nitro-phenylphosphate, 30 mM NaF, 5 mM EDTA, 5% glycerol, 1% Triton X-100, 1 mM Na3VO4, 0.1% SDS, 0.5 μg/mL pepstatin A, 2.5 μg/mL 3,4-dichloroisocoumarin, 2.5 μg/mL trans-epoxysuccinyl-l-leucyl-l-amido butane, aprotinin 20 KIU/mL, leupeptin 2 μg/mL, benzamidine 1 mM and 0.002% PMSF). Enzyme activity was assayed in the presence or absence of serial dilutions of the inhibitor performed in 25% DMSO. Each microtiter plate contained internal controls such as blank, maximum reaction, and historical reference compound. All incubations were conducted at room temperature on a rotation shaker. Ten μL of each inhibitor dilution was added to 10 μL of diluted kinase (0.8 μg/mL VEGFR-2, 10 mM Tris pH 7.5, 2 mM EDTA, 2 mg/mL BSA) and preincubated for 1 h. The reaction was started by addition of 30 μL of substrate mix containing 62.4 mM Tris pH 7.5, 2.7 mM DTT, 5.3 mM MnCl2, 13.3 mM Mg-acetate, 0.42 mM ATP, 0.83 mg/mL Poly-Glu-Tyr(4:1), and 1.7 μg/mL Poly-Glu-Tyr(4:1)-biotin and incubated for 1 h. The reaction was stopped by addition of 50 μL of 250 mM EDTA, 20 mM HEPES, pH 7.4. Then 90 μL of stopped solution was transferred to a streptavidin plate and incubated for 1−2 h. After three washes with PBS the EU-labeled antibody, PY20 was added (recommended dilution 1:2000 of 0.5 mg/mL labeled antibody in DELFIA assay buffer). Excessive detection antibody was removed by three washes of DELFIA washing buffer. Then 10 minutes before measurement on the multilabel reader VICTOR, each well was incubated with 100 μL of DELFIA enhancement solution. IC50 values were calculated by using a sigmoidal curve analysis program using the nonlinear regression analysis with variable slope.
The pFastBac clone containing the cytoplasmic tyrosine kinase domain of VEGFR2 (residues 797–1355 based on the sequence deposited in databank SWISS-PROT P35968) is fused to GST and extracted. The assay of enzyme activity is conducted in 25% DMSO with or without serial dilutions of Nintedanib/BIBF1120. There are internal controls on every microtiter plate, including blank, maximum reaction, and historical reference compound. On a rotating shaker, all incubations are carried out at room temperature. One hour is spent preincubating 10 μL of diluted kinase (0.8 μg/mL VEGFR2, 10 mM Tris pH 7.5, 2 mM EDTA, and 2 mg/mL BSA) with 10 μL of each BIBF1120 dilution. Addition of 30 μL of substrate mix containing 13.3 mM Mg-acetate, 6.2.4 mM Tris pH 7.5, 2.7 mM DTT, 5.3 mM MnCl2, 0.42 mM ATP, 0.83 mg/mL Poly-Glu-Tyr(4:1), and 1.7 μg/mL Poly-Glu-Tyr(4:1)-biotin initiates the reaction, which is then incubated for one hour. 90 μL of the reaction mix is placed on a streptavidin plate and incubated for one to two hours. The reaction is stopped by adding 50 μL of 250 mM EDTA, 20 mM HEPES, and pH 7.4. PY20 is added (recommended dilution 1:2000 of 0.5 mg/mL labeled antibody in DELFIA assay buffer) following three PBS washes with the EU-labeled antibody. Three DELFIA washing buffer washes are used to get rid of extra detection antibody. The DELFIA enhancement solution (100 μL) is then incubated in each well 10 minutes prior to measurement on the multilabel reader.
Cell Assay
For the assay, the cell lines BRP, HUASMC, and HUVEC are employed. The cultures are supplemented with BIBF1120 two hours prior to the addition of ligands. There are cell lysates produced. Standard SDS-PAGE techniques are used for western blotting, with 50–75 μg of protein loaded per lane. Improved chemiluminescence aids in detection. Monoclonal antibodies M3807 and M8159 are used to analyze total and phosphorylated mitogen-activated protein kinase (MAPK). The monoclonal antibody for phosphorylated Akt (Ser473) is used to analyze it, while the corresponding polyclonal antibody is used to detect total Akt. While a corresponding antibody is used to detect KDR (VEGFR2) protein, monoclonal antibodies are also utilized to detect cleaved caspase-3.
Inhibition of cell signaling cascades in drug-treated cells. [1]
HUVEC, HUASMC, and BRP were cultured as described above. Two hours before the addition of ligands, Nintedanib/BIBF 1120 was added to the cultures. Cell lysates were generated according to standard protocols. Western blotting was done using standard SDS-PAGE methods, loading 50 to 75 μg of protein per lane, with detection by enhanced chemiluminescence. Total and phosphorylated mitogen-activated protein kinase (MAPK) was analyzed using monoclonal antibodies.
Cytotoxicity assay and evaluation of the combination effect in vitro [2]
The drug cytotoxicity was measured with the crystal violet assay. The cells (2,000–4,000) were cultured in a 96-well microplate with 100 µl medium per well for 24 h. Trifluridine and Nintedanib were dissolved at the concentrations of 10 mM in dimethyl sulfoxide and the corresponding solutions were prepared using the culture medium under aseptic conditions. A total of 100 µl of the drug solution (trifluridine: 0.18–10 µM; nintedanib: 0.18–10 µM) were added into the culture medium. Following incubation of the plates for 72 h, the culture medium was removed and the cells were fixed with 4% glutaraldehyde for 30 min. The fixed cells were stained with 0.1% crystal violet for 2 min and washed and dissolved in 0.05 M NaH2PO4/50% ethanol. The absorbance was measured at a wavelength of 540 nm using a microplate reader.
The cytotoxic effects of the trifluridine and Nintedanib combination were analyzed using the isobologram method. A total of 3 isoeffect curves (modes I, IIa, and IIb), based on the growth inhibition curves of trifluridine alone and nintedanib alone, were drawn. The total area enclosed by the three curves represented an ‘envelope of additivity’. The combination of drug treatment was considered to show a supra-additive (synergistic) interaction, when the experimentally observed IC50 values were included in the left side of the envelope, whereas when the IC50 values were included in the envelope, the combination was considered as additive. The combination was considered to be sub-additive, when the IC50 values were included on the right side of the envelope and were within the dotted line square. Finally, when the IC50 values fell outside the square, the combination was considered to be protective.
Animal Protocol
For the assay, athymic NMRI-nu/nu female mice weighing between 21 and 33 grams are five to six weeks old. Following their acclimation, mice are injected with 1 to 5×106 (in 100 μL) of SKOV-3, FaDu, Caki-1, H460, HT-29, or PAC-120 cells subcutaneously into their right flank. Following their acclimation, 5×106 (in 100 μL) GS-9L cells are subcutaneously injected into the right flank of F344 Fischer rats. Blood is extracted from the retroorbital plexus of mice at predetermined intervals for pharmacokinetic analysis, and plasma is examined using high performance liquid chromatography-mass spectrometry methodology[1].
In vivo tumor models.[1]
Five-week-old to 6-wk-old athymic NMRI-nu/nu female mice (21–31 g) were used. After acclimatization, mice were inoculated with 1 to 5 × 106 (in 100 μL) FaDu, Caki-1, SKOV-3, H460, HT-29, or PAC-120 cells s.c. into the right flank of the animal. F344 Fischer rat were injected with 5 × 106 (in 100 μL) GS-9L cells s.c. into the right flank of the animal. For pharmacokinetic analysis, blood was isolated at indicated time points from the retroorbital plexus of mice and plasma was analyzed using high performance liquid chromatography–mass spectrometry methodology. [1]
TFTD was prepared by mixing trifluridine and TPI at a molar ratio of 1:0.5 in 0.5% HPMC solution. The dose of TFTD was expressed on the basis of the trifluridine content. TFTD was administered orally from day 1 to 14, twice a day at 6-h intervals at the reported effective dose (150 mg/kg/day). Nintedanib was administered orally from day 1 to 14, twice a day at 6-h intervals at the reported effective dose (40 mg/kg/day) (14,24). The vehicle solution that consisted of 0.5% HPMC solution was administered at 10 ml/kg to the control mouse group, following the same administration schedules as for the test drugs [2].
ADME/Pharmacokinetics
Pharmacokinetic studies after p.o. application to mice (Fig. 4C) revealed a maximal plasma concentration of ∼1,000 nmol/L at 1 hour and trough plasma levels below 8 nmol/L at 24 hours postadministration. This distinctive pharmacokinetic profile can be explained by the rapid metabolization of Nintedanib/BIBF 1120 by methyl ester cleavage, resulting in the generation of the main metabolite BIBF 1202 containing a free acid residue (data not shown). [1]
Rapid in vivo effects on tumor perfusion and permeability detected by DCE-MRI. [1]
Human FaDu (squamous cell carcinoma of the head and neck) xenografts growing in nude mice were analyzed by DCE-MRI using gadolinium contrast agent before and 72 hours after initiation of daily p.o. treatment with Nintedanib/BIBF 1120 at 100 mg/kg. Tumor perfusion and vascular permeability was readily visible in the initial MRI scan and clearly reduced after 3 days of treatment (Fig. 3A); quantitation of the KTRANS value showed a significant decrease in Nintedanib/BIBF 1120–treated tumors compared with both baseline values and untreated controls (Fig. 3A).
Because of their cellular potency and attractive selectivity profiles, compounds 2 and 3 were selected for in vivo testing. Both compounds yielded good plasma levels 2 h after oral administration to mice and were almost completely cleared from plasma 24 h after administration (Table 3). As shown for the lead structures, none of the compounds inhibited the proliferation of VEGF-independent cell lines at similar concentrations to those tested in HUVEC cells (EC50 > 1 μM), particularly HeLa, Calu-6, and FaDu tumor cell lines.
Preclinical Pharmacokinetics Relevant to Human Pharmacokinetics [4]
The pharmacokinetics and drug metabolism of nintedanib (dosed via intravenous [IV] infusion or oral gavage) were studied in several animal species. Mean plasma protein binding of nintedanib was > 97% in mice and rats, 91–93% in monkeys, and 98% in humans, over a concentration range of 50–2000 ng/mL [13, 17, 31]. Albumin was the major binding protein. Following administration of [14C]-radiolabelled nintedanib to rats, radioactivity was widely distributed into most of the tissues (except the central nervous system [CNS]). Repeated oral dosing ([14C]-radiolabelled nintedanib 30 mg/kg) for 13 days showed a slight accumulation in some tissues, although a similar accumulation in plasma concentrations was not apparent.
Clinical Pharmacokinetics [4]
The clinical pharmacokinetics of nintedanib monotherapy were investigated in healthy subjects, volunteers with hepatic impairment, and in patients with IPF or various advanced types of cancer. In healthy volunteers, only single-dose administration was performed. Key pharmacokinetic parameters following single and steady-state twice-daily dosing of nintedanib in patients with advanced cancer are presented in Table 2. The pharmacokinetics of nintedanib were further characterised by two successive population pharmacokinetic (PopPK) analyses, the first based on combined pharmacokinetic data from NSCLC (n = 849) and IPF (n = 342) patients and the second in IPF patients only (n = 933) enrolled in the phase II and III trials. For comparison, Table 3 gives key pharmacokinetic parameters after multiple dosing of nintedanib to typical patients with IPF or NSCLC based on the PopPK analyses. These results show that the key pharmacokinetic parameters are consistent across the two patient populations.
Toxicity/Toxicokinetics
Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the clinical use of nintedanib during breastfeeding. Because nintedanib is more than 97% bound to plasma proteins, the amount in milk is likely to be low. However, its half-life is about 9.7 hours and it might accumulate in the infant. The manufacturer recommends that breastfeeding be discontinued during nintedanib therapy.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.
In Vitro Drug–Drug Interaction Victim and Perpetrator Properties [4]
Several in vitro metabolism, transport and drug interaction studies were performed to quantitatively assess the drug–drug interaction potential of nintedanib. In vitro studies with human hepatocytes and/or human liver microsomes showed that nintedanib is a minor substrate for cytochrome P450 (CYP) 3A4 isoenzyme and has a very low potential (along with its two major metabolites [BIBF 1202 and BIBF 1202 glucuronide]) to inhibit or induce CYP isoenzymes, including those that are most relevant or genetically polymorphic for drug metabolism in humans (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 and CYP3A4). In human liver microsomes, nintedanib was rapidly hydrolysed by esterases (major mechanism) and demethylated by CYP3A4 (minor mechanism) to form the metabolites BIBF 1202 and BIBF 1053, respectively. CYP-dependent metabolism accounted for about 5% compared to about 25% ester cleavage. Thus, drug–drug interactions with nintedanib as a victim of CYP enzyme-modulating agents (e.g. with co-medication with CYP inhibitors or inducers) are considered very unlikely. Furthermore, drug–drug interactions with nintedanib as a perpetrator of CYP enzymes (e.g. nintedanib acting as a CYP enzyme inhibitor or inducer) are also considered very unlikely. Further in vitro data indicated that nintedanib, at clinically relevant concentrations, did not inhibit glucuronidation by uridine 5′-diphospho-glucuronosyltransferase (UDP-glucuronosyltransferase, UGT) 1A1 (UGT1A1) in human liver microsomes. UGT1A1 is responsible for the glucuronidation of the metabolite BIBF 1202 to BIBF 1202 glucuronide in human liver microsomes. In addition, BIBF 1202 was glucuronidated by several intestinal UGTs (UGT1A7, UGT1A8, UGT1A10). A clinically relevant drug–drug interaction based on inhibition of UGT after oral administration of nintedanib is considered less likely as all half-maximal inhibitory concentration (IC50) values are substantially higher than the therapeutic plasma concentrations. In vitro assays using transfected MDCK cells demonstrated that nintedanib is a substrate of the efflux transporter P-gp and weakly inhibits P-gp (Table 1). Studies using cell lines that express different drug transporters showed that nintedanib was not a substrate of organic anion-transporting polypeptide (OATP) 1B1, OATP1B3, OATP2B1, organic cation transporter (OCT) 2, multidrug resistance-associated protein 2 (MRP-2) or the efflux breast cancer resistance protein (BCRP), but was a weak substrate for OCT1. Nintedanib did not inhibit OATP1B1-, OATP1B3-, OATP2B1-, OCT1-, OCT2-, P-gp- or BRCP-mediated transport at clinically relevant concentrations.
References

[1]. BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res, 2008, 68(12), 4774-4782.

[2].Effect of a novel oral chemotherapeutic agent containing a combination of trifluridine, tipiracil and the novel triple angiokinase inhibitor nintedanib, on human colorectal cancer xenografts. Oncol Rep. 2016 Dec;36(6):3123-3130.

[3]. Design, synthesis, and evaluation of indolinones as triple angiokinase inhibitors and the discovery of a highly specific 6-methoxycarbonyl-substituted indolinone (BIBF 1120). J Med Chem, 2009, 52(14), 4466-4480.

[4]. Clinical Pharmacokinetics and Pharmacodynamics of Nintedanib. Clin Pharmacokinet. 2019 Sep;58(9):1131-1147.

Additional Infomation
Nintedanib is a member of the class of oxindoles that is a kinase inhibitor used (in the form of its ethylsulfonate salt) for the treatment of idiopathic pulmonary fibrosis and cancer. It has a role as an antineoplastic agent, a tyrosine kinase inhibitor, a vascular endothelial growth factor receptor antagonist, a fibroblast growth factor receptor antagonist and an angiogenesis inhibitor. It is an aromatic ester, a methyl ester, a member of oxindoles, an enamine, an aromatic amine, an aromatic amide and a N-alkylpiperazine. It is a conjugate base of a nintedanib(1+).
Nintedanib is a Kinase Inhibitor. The mechanism of action of nintedanib is as a Protein Kinase Inhibitor.
See also: Nintedanib (annotation moved to).
Drug Indication
Ofev is indicated in adults for the treatment of Idiopathic Pulmonary Fibrosis (IPF).
Inhibition of tumor angiogenesis through blockade of the vascular endothelial growth factor (VEGF) signaling pathway is a novel treatment modality in oncology. Preclinical findings suggest that long-term clinical outcomes may improve with blockade of additional proangiogenic receptor tyrosine kinases: platelet-derived growth factor receptors (PDGFR) and fibroblast growth factor receptors (FGFR). BIBF 1120 is an indolinone derivative potently blocking VEGF receptor (VEGFR), PDGFR and FGFR kinase activity in enzymatic assays (IC(50), 20-100 nmol/L). BIBF 1120 inhibits mitogen-activated protein kinase and Akt signaling pathways in three cell types contributing to angiogenesis, endothelial cells, pericytes, and smooth muscle cells, resulting in inhibition of cell proliferation (EC(50), 10-80 nmol/L) and apoptosis. In all tumor models tested thus far, including human tumor xenografts growing in nude mice and a syngeneic rat tumor model, BIBF 1120 is highly active at well-tolerated doses (25-100 mg/kg daily p.o.), as measured by magnetic resonance imaging of tumor perfusion after 3 days, reducing vessel density and vessel integrity after 5 days, and inducing profound growth inhibition. A distinct pharmacodynamic feature of BIBF 1120 in cell culture is sustained pathway inhibition (up to 32 hours after 1-hour treatment), suggesting slow receptor off-kinetics. Although BIBF 1120 is rapidly metabolized in vivo by methylester cleavage, resulting in a short mean residence time, once daily oral dosing is fully efficacious in xenograft models. These distinctive pharmacokinetic and pharmacodynamic properties may help explain clinical observations with BIBF 1120, currently entering phase III clinical development. [1]
Trifluridine/tipiracil (TFTD) is a combination drug that is used for the treatment of metastatic colorectal cancer and was formerly known as TAS-102. It is a combination of two active pharmaceutical compounds, trifluridine, an antineoplastic thymidine-based nucleoside analog, and tipiracil, which enhances the bioavailability of trifluridine in vivo. TFTD is used for the treatment of patients with unresectable advanced or recurrent colorectal cancer that is resistant to standard therapies. In the present study, the anticancer effects of trifluridine in combination with nintedanib, an oral triple angiokinase inhibitor, on human colorectal cancer cell lines were investigated. The cytotoxicity against DLD-1, HT-29, and HCT116 cell lines was determined by the crystal violet staining method. The combination of trifluridine and nintedanib exerted an additive effect on the growth inhibition of DLD-1 and HT-29 cells and a sub-additive effect on HCT116 cells, as determined by isobologram analyses. Subsequently, the human colorectal cancer cell lines were implanted subcutaneously into nude mice to allow the evaluation of the in vivo tumor growth inhibitory effects of TFTD and nintedanib combination therapy. TFTD (150 mg/kg/day) and/or nintedanib (40 mg/kg/day) were orally administered to the mice twice daily from day 1 to day 14. The tumor growth inhibition with combination therapy was 61.5, 72.8, 67.6 and 67.5% for the DLD-1, DLD-1/5-FU, HT-29, and HCT116 xenografts, respectively. This was significantly (P<0.05) higher than the effects of monotherapy with either TFTD or nintedanib. These results demonstrated the effectiveness of the combination of TFTD and nintedanib in the treatment of colorectal cancer xenografts. The concentration of trifluridine incorporated into DNA in the HT-29 and HCT116 tumors was determined by liquid chromatography-tandem mass spectrometry. The incorporation levels following treatment with TFTD and nintedanib for 14 consecutive days were higher than those associated with TFTD treatment alone. The preclinical findings indicate that the combination therapy with TFTD and nintedanib is a promising treatment option for colorectal cancer. [2]
Inhibition of tumor angiogenesis through blockade of the vascular endothelial growth factor (VEGF) signaling pathway is a new treatment modality in oncology. Preclinical findings suggest that blockade of additional pro-angiogenic kinases, such as fibroblast and platelet-derived growth factor receptors (FGFR and PDGFR), may improve the efficacy of pharmacological cancer treatment. Indolinones substituted in position 6 were identified as selective inhibitors of VEGF-, PDGF-, and FGF-receptor kinases. In particular, 6-methoxycarbonyl-substituted indolinones showed a highly favorable selectivity profile. Optimization identified potent inhibitors of VEGF-related endothelial cell proliferation with additional efficacy on pericyctes and smooth muscle cells. In contrast, no direct inhibition of tumor cell proliferation was observed. Compounds 2 (BIBF 1000) and 3 (BIBF 1120) are orally available and display encouraging efficacy in in vivo tumor models while being well tolerated. The triple angiokinase inhibitor 3 is currently in phase III clinical trials for the treatment of nonsmall cell lung cancer. [3]
Nintedanib is an oral, small-molecule tyrosine kinase inhibitor approved for the treatment of idiopathic pulmonary fibrosis and patients with advanced non-small cell cancer of adenocarcinoma tumour histology. Nintedanib competitively binds to the kinase domains of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF). Studies in healthy volunteers and in patients with advanced cancer have shown that nintedanib has time-independent pharmacokinetic characteristics. Maximum plasma concentrations of nintedanib are reached approximately 2-4 h after oral administration and thereafter decline at least bi-exponentially. Over the investigated dose range of 50-450 mg once daily and 150-300 mg twice daily, nintedanib exposure increases are dose proportional. Nintedanib is metabolised via hydrolytic ester cleavage, resulting in the formation of the free acid moiety that is subsequently glucuronidated and excreted in the faeces. Less than 1% of drug-related radioactivity is eliminated in urine. The terminal elimination half-life of nintedanib is about 10-15 h. Accumulation after repeated twice-daily dosing is negligible. Sex and renal function have no influence on nintedanib pharmacokinetics, while effects of ethnicity, low body weight, older age and smoking are within the inter-patient variability range of nintedanib exposure and no dose adjustments are required. Administration of nintedanib in patients with moderate or severe hepatic impairment is not recommended, and patients with mild hepatic impairment should be monitored closely and the dose adjusted accordingly. Nintedanib has a low potential for drug-drug interactions, especially with drugs metabolised by cytochrome P450 enzymes. Concomitant treatment with potent inhibitors or inducers of the P-glycoprotein transporter can affect the pharmacokinetics of nintedanib. At an investigated dose of 200 mg twice daily, nintedanib does not have proarrhythmic potential.[4]
These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C31H33N5O4
Molecular Weight
539.62
Exact Mass
539.253
Elemental Analysis
C, 69.00; H, 6.16; N, 12.98; O, 11.86
CAS #
656247-17-5
Related CAS #
Nintedanib esylate;656247-18-6;Nintedanib-13C,d3;Nintedanib-d3;1624587-84-3;Nintedanib-d8;1624587-87-6
PubChem CID
135423438
Appearance
Yellow solid powder
Density
1.3±0.1 g/cm3
Boiling Point
742.2±60.0 °C at 760 mmHg
Flash Point
402.7±32.9 °C
Vapour Pressure
0.0±2.5 mmHg at 25°C
Index of Refraction
1.658
LogP
2.59
Hydrogen Bond Donor Count
2
Hydrogen Bond Acceptor Count
7
Rotatable Bond Count
8
Heavy Atom Count
40
Complexity
892
Defined Atom Stereocenter Count
0
SMILES
O=C(C([H])([H])N1C([H])([H])C([H])([H])N(C([H])([H])[H])C([H])([H])C1([H])[H])N(C([H])([H])[H])C1C([H])=C([H])C(=C([H])C=1[H])/N=C(\C1C([H])=C([H])C([H])=C([H])C=1[H])/C1=C(N([H])C2C([H])=C(C(=O)OC([H])([H])[H])C([H])=C([H])C1=2)O[H]
InChi Key
CPMDPSXJELVGJG-UHFFFAOYSA-N
InChi Code
InChI=1S/C31H33N5O4/c1-34-15-17-36(18-16-34)20-27(37)35(2)24-12-10-23(11-13-24)32-29(21-7-5-4-6-8-21)28-25-14-9-22(31(39)40-3)19-26(25)33-30(28)38/h4-14,19,33,38H,15-18,20H2,1-3H3
Chemical Name
methyl 2-hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylate
Synonyms
BIBF1120; Nintedanib; BIBF-1120; Intedanib; BIBF 1120; trade name: Vargatef
HS Tariff Code
2934.99.9001
Storage

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Shipping Condition
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
Solubility Data
Solubility (In Vitro)
DMSO: ~6 mg/mL (~11.11mM)
Water: <1 mg/mL
Ethanol: ~3 mg/mL (~5.6 mM)
Solubility (In Vivo)
Solubility in Formulation 1: 10 mg/mL (18.53 mM) in 50% PEG300 50% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

Solubility in Formulation 2: 10 mg/mL (18.53 mM) in 1% CMC 0.5% Tween-80 (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.

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Solubility in Formulation 3: 30% PEG400+0.5% Tween80+5% propylene glycol: 30mg/mL


 (Please use freshly prepared in vivo formulations for optimal results.)
Preparing Stock Solutions 1 mg 5 mg 10 mg
1 mM 1.8532 mL 9.2658 mL 18.5316 mL
5 mM 0.3706 mL 1.8532 mL 3.7063 mL
10 mM 0.1853 mL 0.9266 mL 1.8532 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.

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g/mol

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Note: Chemical formula is case sensitive: C12H18N3O4  c12h18n3o4
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Working concentration mg/mL;

Method for preparing DMSO stock solution mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.

Method for preparing in vivo formulation:Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O,mix and clarify.

(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
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Clinical Trial Information
Correlation Between Changes in Lung Function and Changes in Cough and Dyspnoea in Nintedanib-treated Connective Tissue Disease Interstitial Lung Disease (CTD-ILD) Patients
CTID: NCT05503030
Phase:    Status: Recruiting
Date: 2024-11-26
Real-life-persistence to Antifibrotic Treatments
CTID: NCT06485635
Phase:    Status: Active, not recruiting
Date: 2024-11-26
A Study to Evaluate Long-term Safety of Nintedanib in Children and Adolescents With Interstitial Lung Disease (InPedILD®-ON)
CTID: NCT05285982
Phase: Phase 3    Status: Active, not recruiting
Date: 2024-11-21
Post-marketing Surveillance on Long Term Use of Ofev Capsules in Systemic Scleroderma Associated Interstitial Lung Disease (SSc-ILD) in Japan
CTID: NCT04325217
Phase:    Status: Active, not recruiting
Date: 2024-11-21
Study of the Efficacy of Nintedanib+Tocilizumab in Patients With Systemic Sclerosis and Interstitial Lung Disease
CTID: NCT06297096
Phase: Phase 3    Status: Not yet recruiting
Date: 2024-11-20
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Post-marketing Surveillance of Ofev Capsules in Chronic Fibrosing Interstitial Lung Diseases With a Progressive Phenotype in Japan
CTID: NCT04559581
Phase:    Status: Active, not recruiting
Date: 2024-11-18


INREAL - Nintedanib for Changes in Dyspnea and Cough in Patients Suffering From Chronic Fibrosing Interstitial Lung Disease (ILD) With a Progressive Phenotype in Everyday Clinical Practice: a Real-world Evaluation
CTID: NCT04702893
Phase:    Status: Completed
Date: 2024-11-18
A Study to Assess the Extent of Drug Interaction Between BMS-986278 and Ninetedanib, the Relative Bioavailability of BMS-986278 in Tablet and the Effect That Food Has on BMS-986278 in Tablet Formulations in Healthy Participants
CTID: NCT06568458
Phase: Phase 1    Status: Recruiting
Date: 2024-10-31
RCT of Nintedanib in Fibrotic Sarcoidosis
CTID: NCT06479603
Phase: Phase 4    Status: Recruiting
Date: 2024-10-23
Study of Oral Epigallocatechin-3-gallate (EGCG) in IPF Patients
CTID: NCT05195918
Phase: Phase 1    Status: Recruiting
Date: 2024-10-18
All-Case Surveillance of Ofev in Patients With IPF in Japan
CTID: NCT02607722
Phase:    Status: Completed
Date: 2024-10-15
Nintedanib Treatment in Unicentric Castleman Disease
CTID: NCT06643091
Phase: Phase 2    Status: Not yet recruiting
Date: 2024-10-15
A Study to Evaluate the Safety, Tolerability and Blood Levels of GSK3915393 Administered to Healthy Participants of Chinese, Japanese and European Ancestry and to Assess Effects of GSK3915393 on Nintedanib
CTID: NCT06625489
Phase: Phase 1    Status: Not yet recruiting
Date: 2024-10-03
Burden of Nintedanib Non-adherence Among Idiopathic Pulmonary Fibrosis (IPF) Patients
CTID: NCT05870956
Phase:    Status: Completed
Date: 2024-10-01
Drug-drug Interaction Study with GLPG4716 and Nintedanib and Pirfenidone in Healthy Subjects
CTID: NCT04971746
Phase: Phase 1    Status: Completed
Date: 2024-09-19
Nintedanib for the Prevention of Radiation Pneumonia in Unresectable NSCLC
CTID: NCT06570317
Phase:    Status: Recruiting
Date: 2024-08-26
Post Marketing Surveillance of Nintedanib in Indian Patients With Idiopathic Pulmonary Fibrosis
CTID: NCT03047031
Phase:    Status: Completed
Date: 2024-08-22
Myositis Interstitial Lung Disease Nintedanib Trial
CTID: NCT05799755
Phase: Phase 4    Status: Recruiting
Date: 2024-08-20
ENGOT-cx1/BGOG-cx1: 3 Weekly Carboplatin/Paclitaxel With or Without Nintedanib in Cervix Cancer
CTID: NCT02009579
Phase: Phase 2    Status: Completed
Date: 2024-08-07
Investigating Trends in Quality of Life in Patients With Idiopathic Pulmonary Fibrosis (IPF) Under Treatment With Nintedanib
CTID: NCT03710824
Phase:    Status: Completed
Date: 2024-07-31
The Study of the Use of Nintedanib in Slowing Lung Disease in Patients With Fibrotic or Non-Fibrotic Interstitial Lung Disease Related to COVID-19
CTID: NCT04619680
Phase: Phase 4    Status: Completed
Date: 2024-07-30
INCHANGE - Nintedanib for Changes in Cough and Dyspnea in Patients Suffering From Chronic Fibrosing Interstitial Lung Disease With a Progressive Phenotype in Everyday Clinical Practice: a Real-world Evaluation
CTID: NCT05151640
Phase:    Status: Active, not recruiting
Date: 2024-07-19
A Study to Find Out How Nintedanib is Taken up in the Body and How Well it is Tolerated in Children and Adolescents With Interstitial Lung Disease (ILD)
CTID: NCT04093024
Phase: Phase 3    Status: Completed
Date: 2024-07-09
Phase I/II Study of Nivolumab and Ipilimumab Combined With Nintedanib in Non Small Cell Lung Cancer
CTID: NCT03377023
Phase: Phase 1/Phase 2    Status: Active, not recruiting
Date: 2024-06-26
A Study to Test How Well a Medicine Called Nintedanib Helps People in China With Progressive Lung Fibrosis
CTID: NCT05065190
Phase: Phase 3    Status: Completed
Date: 2024-06-12
Study of Nintedanib and Chemotherapy for Advanced Pancreatic Cancer
CTID: NCT02902484
Phase: Phase 1/Phase 2    Status: Terminated
Date: 2024-06-03
Nintedanib in Lung Transplant Recipients With Bronchiolitis Obliterans Syndrome Grade 0p-1-2
CTID: NCT03283007
Phase: Phase 3    Status: Recruiting
Date: 2024-05-31
Nintedanib for the Treatment of SARS-Cov-2 Induced Pulmonary Fibrosis
CTID: NCT04541680
Phase: Phase 3    Status: Recruiting
Date: 2024-05-16
Cisplatin, Docetaxel, and Nintedanib Before Surgery in Treating Patients With Previously Untreated Stage IB-IIIA Non-small Cell Lung Cancer
CTID: NCT02225405
Phase: Phase 1    Status: Completed
Date: 2024-05-08
Adherence to Nintedanib Among Idiopathic Pulmonary Fibrosis Patients
CTID: NCT05022784
Phase:    Status: Completed
Date: 2024-04-19
Study to Evaluate the Efficacy and Safety of Nintedanib (BIBF 1120) + Prednisone Taper in Patients With Radiation Pneumonitis
CTID: NCT02496585
Phase: Phase 2    Status: Completed
Date: 2024-04-16
Nintedanib as Switch Maintenance Treatment of Pleural Malignant Mesothelioma
CTID: NCT02863055
Phase: Phase 2    Status: Active, not recruiting
Date: 2024-04-05
Nintedanib in Molecularly Selected Patients With Advanced Non-Small Cell Lung Cancer
CTID: NCT02299141
Phase: Phase 2    Status: Active, not recruiting
Date: 2024-03-13
Safety and Effectiveness of Nintedanib in Korean Patients
CTID: NCT04525547
Phase:    Status: Completed
Date: 2024-03-12
A Trial to Evaluate the Safety of Long Term Treatment With Nintedanib in Patients With Scleroderma Related Lung Fibrosis
CTID: NCT03313180
Phase: Phase 3    Status: Completed
Date: 2024-02-20
A Study to Assess the Effect of AZD5055 on the Pharmacokinetics (PK) of Nintedanib in Healthy Participants.
CTID: NCT05644600
Phase: Phase 1    Status: Terminated
Date: 2024-02-08
Nintedanib in Patients With Bronchiolitis Obliterans Syndrome Following Hematopoietic Stem Cell Transplantation
CTID: NCT03805477
Phase: Phase 2    Status: Recruiting
Date: 2024-02-01
A Treatment Protocol to Support the Care of Children and Adolescents With Fibrosing Interstitial Lung Disease (ILD)
CTID: NCT05624281
Phase:    Status: No longer available
Date: 2024-01-12
Safety of Nintedanib in Real World in China
CTID: NCT05676112
Phase:    Status: Withdrawn
Date: 2024-01-02
A Study in Healthy Men to Test Whether BI 1015550 Influences the Amount of Nintedanib and Pirfenidone in the Blood
CTID: NCT06070610
Phase: Phase 1    Status: Completed
Date: 2023-12-28
Nintedanib in Treating Patients With Locally Advanced or Metastatic Neuroendocrine Tumors
CTID: NCT02399215
Phase: Phase 2    Status: Completed
Date: 2023-12-26
Nintedanib and Azacitidine in Treating Participants With HOX Gene Overexpression Relapsed or Refractory Acute Myeloid Leukemia
CTID: NCT03513484
Phase: Phase 1    Status: Active, not recruiting
Date: 2023-12-22
Effect of Nintedanib on Biomarkers of Extracellular Matrix Turnover in Patients With Idiopathic Pulmonary Fibrosis and Limited Forced Vital Capacity Impairment
CTID: NCT02788474
Phase: Phase 4    Status: Completed
Date: 2023-12-21
A Drug-Drug Interaction Study of ENV-101 (Taladegib) on Nintedanib Pharmacokinetics in Healthy Subjects
CTID: NCT05817240
Phase: Phase 1    Status: Completed
Date: 2023-12-15
A Follow-up Study Investigating Long Term Treatment With Nintedanib in Patients With Progressive Fibrosing Interstitial Lung Disease (PF-ILD)
CTID: NCT03820726
Phase: Phase 3    Status: Completed
Date: 2023-09-13
Dose Reduction and Discontinuation With Anti-Fibrotic Medications
CTID: NCT05779007
Phase:    Status: Completed
Date: 2023-09-11
Vargatef in Addition to First Line Chemotherapy With Interval Debulking Surgery in Patients With Ovarian Cancer
CTID: NCT01583322
Phase: Phase 2    Status: Completed
Date: 2023-09-06
A Study in Healthy Men to Test Whether Four Capsules of 25 mg Nintedanib Are Taken up in the Body in the Same Way as One 100 mg Capsule
CTID: NCT04938453
Phase: Phase 1    Status: Completed
Date: 2023-07-17
Trial Of Pembrolizumab And Nintedanib
CTID: NCT02856425
Phase: Phase 1    Status: Recruiting
Date: 2023-04-25
Continuation of Nintedanib After Single Lung Transplantation in IPF Subjects
CTID: NCT03562416
Phase: Phase 2    Status: Terminated
Date: 2023-04-07
Prospective Clinical Study of Nintedanib to Inhibit Endometrial Fibrosis to Prevent Recurrence of Uterine Adhesions
CTID: NCT05635071
Phase: Phase 2/Phase 3    Status: Not yet recruiting
Date: 2022-12-02
Pirfenidone vs. Nintedanib for Fibrotic Lung Disease After Coronavirus Disease-19 Pneumonia
CTID: NCT04856111
Phase: Phase 4    Status: Unknown status
Date: 2022-10-03
A Study of Nintedanib for LymphAngioleioMyomatosis (LAM)
CTID: NCT03062943
Phase: Phase 2    Status: Completed
Date: 2022-09-28
An Expanded Access Program in Belgium to Provide Nintedanib to People With Lung Diseases Called Non-IPF ILDs Who Have no Alternative Treatment Options
CTID: NCT04739150
Phase:    Status: No longer available
Date: 2022-09-09
LCI-GI-APX-NIN-001: Nintedanib in Metastatic Appendiceal Carcinoma
CTID: NCT03287947
Phase: Phase 2    Status: Terminated
Date: 2022-08-09
Efficacy of Nintedanib for Treatment of Epistaxis in Hereditary Hemorrhagic Telangiectasia (HHT) Patients
CTID: NCT04976036
Phase: Phase 2    Status: Unknown status
Date: 2022-07-26
To Evaluate Drug-drug Interactions Between HEC585 and Pirfenidone or Nintedanib in Healthy Volunteers
CTID: NCT05383131
Phase: Phase 1    Status: Completed
Date: 2022-05-19
Dedicated Drug-Drug Interaction (DDI) Study in Healthy Volunteers
CTID: NCT04939467
Phase: Phase 1    Status: Completed
Date: 2022-04-15
Korean Cancer Study Group: Translational bIomarker Driven UMbrella Project for Head and Neck (TRIUMPH), Esophageal Squamous Cell Carcinoma- Part 1 (HNSCC)]
CTID: NCT03292250
Phase: Phase 2    Status: Completed
Date: 2022-03-29
Extension Trial of the Long Term Safety of BIBF 1120 in Patients With Idiopathic Pulmonary Fibrosis
CTID: NCT01619085
Phase: Phase 3    Status: Completed
Date: 2022-03-25
Doxorubicin + BIBF 1120 in Patients for Ovarian Cancer
CTID: NCT01485874
Phase: Phase 1    Status: Terminated
Date: 2022-02-15
Nintedanib in Treating Patients With Malignant Pleural Mesothelioma That Is Recurrent
CTID: NCT02568449
Phase: Phase 2    Status: Completed
Date: 2021-12-09
A Study Based on Medical Records That Looks at the Characteristics of Idiopathic Pulmonary Fibrosis Patients Grouped by the Type of Medication They Are Taking
CTID: NCT03958071
Phase:    Status: Completed
Date: 2021-11-15
Efficacy & Safety of Nintedanib in Patients With Progressive Fibrosing Coal Mine Dust-Induced Interstitial Lung Disease
CTID: NCT05067517
Phase: Phase 3    Status: Unknown status
Date: 2021-10-05
To Evaluate Drug-drug Interactions Between DWN12088 and Pirfenidone or Nintedanib in Healthy Volunteers
CTID: NCT04888715
Phase: Phase 1    Status: Completed
Date: 2021-09-23
Ph II Nintedanib vs. Ifosfamide in Soft Tissue Sarcoma
CTID: NCT02808247
Phase: Phase 2    Status: Terminated
Date: 2021-09-20
Compare Safety and Efficacy of BIBF 1120 Versus Sunitinib.
CTID: NCT01024920
Phase: Phase 2    Status: Completed
Date: 2021-07-19
Nintedanib and Capecitabine in Treating Patients With Refractory Metastatic Colorectal Cancer
CTID: NCT02393755
Phase: Phase 1/Phase 2    Status: Completed
Date: 2021-07-08
Study of Pulmonary Rehabilitation in Patients With Idiopathic Pulmonary Fibrosis (IPF)
CTID: NCT03717012
Phase: Phase 4    Status: Terminated
Date: 2021-06-09
-----------------------
A Multi-center, Randomised, Double-blind Trial of Nintedanib in Lung Tranplant (LTx) recipients with bronchiolitis obliterans sydrome (BOS) grade 1-2
CTID: null
Phase: Phase 3    Status: Ongoing
Date: 2019-04-09
An open-label extension trial of the long term safety of nintedanib in patients with Progressive Fibrosing Interstitial Lung Disease (PF-ILD)
CTID: null
Phase: Phase 3    Status: Ongoing, GB - no longer in EU/EEA, Completed
Date: 2019-01-31
An open-label extension trial to assess the long term safety of nintedanib in patients with ‘Systemic Sclerosis associated Interstitial Lung Disease’ (SSc-ILD)
CTID: null
Phase: Phase 3    Status: Ongoing, GB - no longer in EU/EEA, Completed
Date: 2017-11-06
A Phase II multicenter study comparing the efficacy of the oral angionenesis inhibitor nintedanib with the intravenous cytotoxis compound ifosfamide for treatment of patients with advanced metastatic soft tissue sarcoma after failure of systemic non-oxazaphosporine-based first line chemotherapy for inoperable disease 'ANITA'
CTID: null
Phase: Phase 2    Status: GB - no longer in EU/EEA, Completed
Date: 2017-07-04
Nintedanib as maintenance treatment of malignant pleural mesothelioma (NEMO): a double-blind randomized phase II study of the EORTC Lung Cancer Group
CTID: null
Phase: Phase 2    Status: GB - no longer in EU/EEA, Completed
Date: 2017-06-30
A PHASE I/II TRIAL OF COMBINATION NAB-PACLITAXEL AND NINTEDANIB OR NAB-PACLITAXEL AND PLACEBO IN RELAPSED NSCLC ADENOCARCINOMA
CTID: null
Phase: Phase 2    Status: Prematurely Ended
Date: 2017-05-09
A double blind, randomized, placebo-controlled trial evaluating the efficacy and safety of nintedanib over 52 weeks in patients with Progressive Fibrosing Interstitial Lung Disease (PF-ILD)
CTID: null
Phase: Phase 3    Status: Prematurely Ended, Completed
Date: 2017-02-28
INSTAGE(TM): A 24-week, double-blind, randomized, parallel-group study evaluating the efficacy and safety of oral nintedanib coadministrated with oral sildenafil, compared to treatment with nintedanib alone, in patients with idiopathic pulmonary fibrosis (IPF) and advanced lung function impairment
CTID: null
Phase: Phase 3    Status: Completed
Date: 2016-07-21
ENGOT-EN1/FANDANGO: A randomized phase II trial of first-line combination chemotherapy with nintedanib / placebo for patients with advanced or recurrent endometrial cancer.
CTID: null
Phase: Phase 2    Status: Prematurely Ended, Completed
Date: 2016-06-20
A 12-week, double blind, randomised, placebo controlled, parallel group trial followed by a single active arm phase of 40 weeks evaluating the effect of oral nintedanib 150 mg twice daily on change in biomarkers of extracellular matrix (ECM) turnover in patients with idiopathic pulmonary fibrosis (IPF) and limited forced vital capacity (FVC) impairment.
CTID: null
Phase: Phase 4    Status: Completed
Date: 2016-06-13
AN EXPLORATORY MULTICENTER, OPEN-LABEL, SINGLE ARM STUDY OF THE SAFETY AND TOLERABILITY OF PIRFENIDONE (ESBRIET®) IN COMBINATION WITH NINTEDANIB (OFEV®) IN PATIENTS WITH IDIOPATHIC PULMONARY FIBROSIS
CTID: null
Phase: Phase 4    Status: Completed
Date: 2016-02-25
A double blind, randomised, placebo-controlled trial evaluating efficacy and safety of oral nintedanib treatment for at least 52 weeks in patients with Systemic Sclerosis associated Interstitial Lung Disease (SSc-ILD)
CTID: null
Phase: Phase 3    Status: Prematurely Ended, Completed
Date: 2015-11-02
Nintedanib (BIBF 1120) plus docetaxel in NSCLC patients progressing after first-line CTX: angiogenic biomarker identification, phase II trial
CTID: null
Phase: Phase 2    Status: Prematurely Ended
Date: 2015-10-06
A twelve week, open-label, randomised, parallel-group study evaluating safety, tolerability and pharmacokinetics (PK) of oral nintedanib in combination with oral pirfenidone, compared to treatment with nintedanib alone, in patients with idiopathic pulmonary fibrosis (IPF)
CTID: null
Phase: Phase 4    Status: Completed
Date: 2015-08-26
Multicenter phase II trial of Nintedanib plus docetaxel in second line of treatment in patients with no squamous non small cell lung cancer refractory to first line chemotherapy (REFRACT study)
CTID: null
Phase: Phase 2    Status: Completed
Date: 2015-07-29
'Multicenter, prospective, open label study , in patients with non small cell
CTID: null
Phase: Phase 2    Status: Ongoing
Date: 2015-06-19
Molecular-biological tumor profiling for drug treatment selection in patients with advanced and refractory carcinoma
CTID: null
Phase: Phase 2    Status: Completed
Date: 2015-05-04
A Phase I/II, Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial Evaluating the Efficacy and Safety of Nintedanib/Vargatef in Combination With Paclitaxel Chemotherapy for Treatment of Patients with BRAF Wildtype Metastatic Melanoma
CTID: null
Phase: Phase 1, Phase 2    Status: Completed
Date: 2014-11-12
A phase II study exploring the safety and efficacy of nintedanib (BIBF1120) as second line therapy for patients with either differentiated or medullary thyroid cancer progressing after first line therapy.
CTID: null
Phase: Phase 2    Status: Completed
Date: 2014-10-08
A double-blind, randomised, placebo controlled Phase III study of nintedanib plus best supportive care (BSC) versus placebo plus BSC in patients with colorectal cancer refractory to standard therapies.
CTID: null
Phase: Phase 3    Status: Completed
Date: 2014-10-08
Phase II study with oral fibroblast growth factor-1 inhibitor BIBF1120 as second line treatment in lung carcinoma patients harboring fibroblast growth factor receptor-1 gene amplification (NVALT-15 study)
CTID: null
Phase: Phase 2    Status: Ongoing, Prematurely Ended
Date: 2014-06-02
Phase II randomised placebo controlled NEOadjuvant chemotherapy study of Nintedanib with Gemcitabine and Cisplatin in locally advanced muscle invasive BLADder cancEr
CTID: null
Phase: Phase 2    Status: GB - no longer in EU/EEA
Date: 2014-01-17
A Randomised Phase II Study of Nintedanib (BIBF1120) Compared to Chemotherapy in Patients with Recurrent Clear Cell Carcinoma of the Ovary or Endometrium
CTID: null
Phase: Phase 2    Status: Prematurely Ended, Completed
Date: 2013-11-14
ENGOT-cx1/BGOG-cx1: 'Randomized double-blind Phase II study comparing 3-weekly carboplatin (AUC 5) + paclitaxel 175 mg/m2 with or without concomitant and maintenance nintedanib (NINTEDANIB) in advanced or recurrent cervical carcinoma.'
CTID: null
Phase: Phase 2    Status: Ongoing, Completed
Date: 2013-10-28
Phase II, randomised, placebo controlled, multicentre, feasibility study of low dose (metronomic) cyclophosphamide with or without nintedanib (BIBF 1120) in advanced ovarian cancer (METRO-BIBF)
CTID: null
Phase: Phase 2    Status: Completed
Date: 2013-08-19
LUME-Meso: Double blind, randomised, multicentre, phase II/III study of nintedanib in combination with pemetrexed / cisplatin followed by continuing nintedanib monotherapy versus placebo in combination with pemetrexed / cisplatin followed by continuing placebo monotherapy for the treatment of patients with unresectable malignant pleural mesothelioma
CTID: null
Phase: Phase 2, Phase 3    Status: Prematurely Ended, Completed
Date: 2013-07-16
Randomized double blind placebo-controlled phase II trial of Vargatef® in addition to first line chemotherapy with interval debulking surgery in patients with adenocarcinoma of the ovary, the fallopian tube or serous adenocarcinoma of the peritoneum
CTID: null
Phase: Phase 2    Status: Completed
Date: 2013-06-11
A PHASE II RANDOMIZED STUDY OF DOCETAXEL WITH OR WITHOUT NINTEDANIB (BIBF-1120) IN PATIENT RECEIVING A SECOND-LINE OF CHEMOTHERAPY FOR HER NEGATIVE, METASTATIC OR LOCALLY RECURRENT BREAST CANCER
CTID: null
Phase: Phase 2    Status: Ongoing
Date: 2013-01-18
An open-label extension trial of the long term safety of oral BIBF 1120 in patients with Idiopathic Pulmonary Fibrosis (IPF)
CTID: null
Phase: Phase 3    Status: GB - no longer in EU/EEA, Completed
Date: 2012-05-02
A phase I/II, randomized, open-label, multi-centre study of BIBF1120 +
CTID: null
Phase: Phase 1, Phase 2    Status: Completed
Date: 2012-04-25
A randomized, placebo-controlled, multi-center phase I/II trial to assess the safety and efficacy of nintedanib (BIBF 1120) added to low-dose cytarabine in elderly patients with AML unfit for an intensive induction therapy
CTID: null
Phase: Phase 1, Phase 2    Status: Completed
Date: 2012-02-28
Ensayo clínico de fase I/II, aleatorizado, de paclitaxel neoadyuvante frente a imprimación con BIBF 1120 seguida por BIBF 1120 más paclitaxel en cáncer de mama HER-2 negativo con estudios correlativos proteómicos y de imagen dinámica.
CTID: null
Phase: Phase 2    Status: Completed
Date: 2011-09-19
A multicenter, randomized, phase II trial: BIBF 1120 vs. placebo in patients receiving oxaliplatin plus fluorouracil and leucovorin (mFOLFOX6) for advanced, chemorefractory metastatic colorectal cancer (mCRC)
CTID: null
Phase: Phase 2    Status: Ongoing
Date: 2011-05-20
A 52 weeks, double blind, randomized, placebo-controlled trial evaluating the effect of oral BIBF 1120, 150 mg twice daily, on annual Forced Vital Capacity decline , in patients with Idiopathic Pulmonary Fibrosis (IPF)
CTID: null
Phase: Phase 3    Status: Completed
Date: 2011-04-12
A 52 weeks, double blind, randomized, placebo-controlled trial evaluating the effect of oral BIBF 1120, 150 mg twice daily, on Forced Vital Capacity decline , in patients with Idiopathic Pulmonary Fibrosis (IPF)
CTID: null
Phase: Phase 3    Status: Completed
Date: 2011-04-01
LUME-Lung 3. A Phase I/II study of continuous oral treatment with BIBF 1120 added to standard gemcitabine/cisplatin therapy in first line NSCLC patients with squamous cell histology.
CTID: null
Phase: Phase 1, Phase 2    Status: Prematurely Ended, Completed
Date: 2010-12-14
Phase II study of BIBF 1120 in recurrent Glioblastoma multiforme
CTID: null
Phase: Phase 2    Status: Completed
Date: 2010-11-09
A phase II open label, roll over study of the long term tolerability,
CTID: null
Phase: Phase 2    Status: Completed
Date: 2010-04-28
A randomised, open label, parallel group Phase II study comparing the efficacy and tolerability of BIBF 1120 versus sunitinib in previously untreated patients with Renal Cell Cancer.
CTID: null
Phase: Phase 2    Status: Completed
Date: 2009-10-27
A multicenter, open label, phase I / II study to evaluate safety, pharmacokinetics and efficacy of BIBF 1120 in comparison with oral sorafenib for advanced hepatocellular carcinoma patients.
CTID: null
Phase: Phase 1, Phase 2    Status: Completed
Date: 2009-08-24
Multicentre, randomised, double-blind, Phase III trial to investigate the efficacy and safety of oral BIBF 1120 plus standard docetaxel therapy compared to placebo plus standard docetaxel therapy in patients with stage IIIB/IV or recurrent non small cell lung cancer after failure of first line chemotherapy
CTID: null
Phase: Phase 3    Status: Completed
Date: 2009-03-30
Multicenter, randomised, double-blind, Phase III trial to investigate the
CTID: null
Phase: Phase 3    Status: Temporarily Halted, Prematurely Ended, Completed
Date: 2009-02-27
A 12 month, double blind, randomized, placebo-controlled trial evaluating the effect of BIBF 1120 administered at oral doses of 50 mg qd, 50 mg bid, 100 mg bid and 150 mg bid on Forced Vital Capacity decline during one year, in patients with Idiopathic Pulmonary Fibrosis, with optional active treatment extension until last patient out.
CTID: null
Phase: Phase 2    Status: Completed
Date: 2007-07-06
A multicenter, randomized, open label phase II trial evaluating the efficacy and safety of mFOLFOX7 plus weekly alternating sequential oral administration of BIBF 1120 250 mg twice daily and BIBW 2992 50 mg once daily (BB) versus mFOLFOX7 alone as first-line therapy in patients with metastatic colorectal cancer.
CTID: null
Phase: Phase 2    Status: Completed, Prematurely Ended
Date: 2007-01-22
A multi-centre 3-arm randomized phase II trial of BIBF 1120 versus BIBW 2992 versus sequential administration of BIBF 1120 and BIBW 2992 in patients with hormone-resistant prostate cancer
CTID: null
Phase: Phase 2    Status: Completed
Date: 2006-02-16
A Randomised Placebo-Controlled Phase II Study of Continuous Maintenance Treatment with BIBF 1120 Following Chemotherapy in Patients with Relapsed Ovarian Cancer
CTID: null
Phase: Phase 2    Status: Completed
Date: 2005-11-28
Multicenter, randomised, double-blind Phase III trial to investigate the efficacy and safety of BIBF 1120 in combination with carboplatin and paclitaxel compared to placebo plus carboplatin and paclitaxel in patients with advanced ovarian cancer
CTID: null
Phase: Phase 3    Status: Completed
Date:
Long-term Effect of Pulmonary Rehabilitation under Nintedanib treatment in Idiopathic Pulmonary Fibrosis
CTID: UMIN000026376
Phase: Phase IV    Status: Complete: follow-up complete
Date: 2017-03-03
Nintedanib (BIBF 1120) in Mesothelioma
CTID: jRCT2080223319
Phase:    Status: completed
Date: 2016-09-14
The pilot study of Nintedanib and Carboplatin plus Paclitaxel for advanced non-small cell lung cancer with idiopathic interstitial pneumonia
CTID: UMIN000021591
Phase:    Status: Complete: follow-up complete
Date: 2016-04-01
None
CTID: jRCT2080223110
Phase:    Status: completed
Date: 2016-02-23
Prospective study of efficiency of fibrosis score in computed tomography as predictor after treatment with Nintedanib for idiopathic pulmonary fibrosis
CTID: UMIN000020722
PhaseNot applicable    Status: Recruiting
Date: 2016-01-25
The comparison of the efficacy and safety of pirfenidone and nintedanib in patients with idiopathic pulmonary fibrosis
CTID: UMIN000020682
PhaseNot applicable    Status: Complete: follow-up complete
Date: 2016-01-22
Randomized Phase 2 study of Nintedanib and Pirfenidone versus Nintedanib following a clinically meaningful decline in forced vital capacity in patients with idiopathic pulmonary fibrosis administering pirfenidone
CTID: UMIN000019436
Phase: Phase II    Status: Complete: follow-up complete
Date: 2015-10-21
Multicenter Phase 1b/2 Trial of Nintedanib with TAS-102 in Patients with Metastatic Colorectal Cancer (mCRC) who had the progression or intolerant to standard therapies.
CTID: UMIN000017114
Phase: Phase I,II    Status: Complete: follow-up complete
Date: 2015-04-13

Biological Data
  • Nintedanib (BIBF 1120)

    Cancer Res. 2008 Jun 15;68(12):4774-82.

  • Nintedanib (BIBF 1120)
  • Nintedanib (BIBF 1120)

    Cancer Res. 2008 Jun 15;68(12):4774-82.

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