yingweiwo

Axitinib (AG-013736; Inlyta)

Alias: AG 013736; Axitinib; 319460-85-0; AG-13,736; axitinibum; C9LVQ0YUXG; UNII-C9LVQ0YUXG; NSC-757441; N-methyl-2-((3-((1E)-2-(pyridin-2-yl)ethenyl)-1H-indazol-6-yl)sulfanyl)benzamide; AG013736; Axitinib; AG-013736; Brand name: Inlyta
Cat No.:V0492 Purity: =99.93%
Axitinib (formerly AG013736; brand name Inlyta), is a potent, orally bioavailable, small molecule and multi-targeted kinase inhibitor with potential antitumor activity.
Axitinib (AG-013736; Inlyta)
Axitinib (AG-013736; Inlyta) Chemical Structure CAS No.: 319460-85-0
Product category: VEGFR
This product is for research use only, not for human use. We do not sell to patients.
Size Price Stock Qty
50mg
100mg
250mg
500mg
1g
2g
Other Sizes

Other Forms of Axitinib (AG-013736; Inlyta):

  • Axitinib-13C,d3 (AG-013736-13C,d3)
  • Axitinib-d3 (AG-013736-d3)
Official Supplier of:
Alternate Text
Alternate Text
Alternate Text
Alternate Text
Alternate Text
Alternate Text
Alternate Text
Alternate Text
Alternate Text
Alternate Text
Alternate Text
Alternate Text
Alternate Text
Alternate Text
Alternate Text
Alternate Text
Alternate Text
Alternate Text
Alternate Text
Alternate Text
Alternate Text
Alternate Text
Alternate Text
Alternate Text
Alternate Text
Alternate Text
Alternate Text
Alternate Text
Alternate Text
Alternate Text
Alternate Text
Alternate Text
Top Publications Citing lnvivochem Products
Purity & Quality Control Documentation

Purity: =99.93%

Product Description

Axitinib (formerly AG013736; brand name Inlyta), is a potent, orally bioavailable, small molecule that inhibits multiple kinases and has the potential to treat cancer. In porcine aorta endothelial cells, it inhibits several kinases, including PDGFRβ, VEGFR1, VEGFR2, VEGFR3, and c-Kit, with IC50 values of 0.1 nM, 0.2 nM, 0.1-0.3 nM, 1.6 nM, and 1.7 nM, respectively. Axitinib has an anti-angiogenic effect by inhibiting the proangiogenic cytokines PDGF and VEGF. On January 27, 2012, the FDA approved it as a treatment for renal cell carcinoma.

Biological Activity I Assay Protocols (From Reference)
Targets
VEGFR1/FLT1 (IC50 = 0.1 nM); VEGFR2/Flk1 (IC50 = 0.18 nM); VEGFR2/KDR (IC50 = 0.2 nM); VEGFR3 (IC50 = 0.1 nM-0.3 nM nM); PDGFRβ (IC50 = 1.6 nM)
ln Vitro
Axitinib may inhibit VEGF-mediated endothelial cell viability, tube formation, and downstream signaling in addition to cellular autophosphorylation of VEGFR. Variable cell lines with IC50 values of >10,000 nM (IGR-N91), 849 nM (IGR-NB8), 274 nM (SH-SY5Y), and 573 nM (non-VEGF stimulated HUVEC) are all inhibited by axitinib.[2]
Axitinib potently inhibits cellular VEGF RTK activities in vitro. [2]
In transfected or endogenous RTK-expressing cells, axitinib potently blocked growth factor-stimulated phosphorylation of VEGFR-2 and VEGFR-3 with average IC50 values of 0.2 and 0.1 to 0.3 nmol/L, respectively (Fig. 2A; Table 1). Cellular activity against VEGFR-1 was 1.2 nmol/L (measured in the presence of 2.3% bovine serum albumin), equivalent to an absolute IC50 of ∼0.1 nmol/L, based on protein binding of axitinib. The potency against murine VEGFR-2 (Flk-1) in Flk-1-transfected NIH-3T3 cells was 0.18 nmol/L, similar to that of its human homologue. Axitinib showed ∼8- to 25-fold higher IC50 against the closely related type III and V family RTKs, including PDGFR-β (1.6 nmol/L), KIT (1.7 nmol/L), and PDGFR-α (5 nmol/L; Table 1); nanomolar concentrations of axitinib blocked PDGF BB-mediated human glioma U87MG cell (PDGFR-β-positive) migration but not proliferation (data not shown). In contrast, axitinib had much weaker target and functional activity against FGFR-1 (Fig. 1A and B; Table 1). With up to 1 μmol/L concentrations, axitinib showed minimal activity against Flt-3 in RS;411 cells and RET in TT cells (data not shown). A similar trend was observed for enzymatic inhibitory activity (Ki) against recombinant tyrosine kinases of the aforementioned receptors (data not shown). Importantly, axitinib had little inhibition against “off-target” protein kinases; at a concentration of 1 μmol/L (∼1,000-fold of the Ki for VEGFR-2) across three kinase panels of ∼100 protein kinases (Pfizer in-house; Upstate and Dundee panels), axitinib inhibited only five protein kinases: Abl, Aurora-2, Arg, AMPK, Axl, and MST2 (≥60% inhibition). Finally, axitinib exhibited no significant activity in a broad protein kinase screen (Cerep; data not shown).
Axitinib inhibits VEGF-mediated endothelial cell survival, migration, and tube formation. [2]
Axitinib showed potent inhibition of VEGF-stimulated but not basic FGF-stimulated HUVEC survival with ∼1,000-fold selectivity for VEGFR-2 versus FGFR-1 receptors (Fig. 2B). The average IC50 value for VEGFR-2 derived from the functional assays (0.24 ± 0.09 nmol/L) was similar to that obtained in the cellular receptor phosphorylation assays (Table 1), confirming that receptor antagonism led to a functional inhibition by the compound. In addition, axitinib dose-dependently inhibited spheroidal endothelial tube formation in a three-dimensional fibrin matrix system (Fig. 2C; Supplementary Fig. S1). Higher compound concentrations than other types of assays were required to inhibit tube formation because of the presence of the higher serum level (4-8% FBS) in the system.
Axitinib inhibits intracellular signal transduction in endothelial cells. [2]
Axitinib rapidly and dose-dependently reduced the phosphorylation of Akt, endothelial nitric oxide synthase (eNOS), and extracellular signal-regulated kinase 1/2 (ERK1/2), key downstream signaling molecules of VEGF (Fig. 2D), with IC50 values similar to that of the inhibition of VEGFR-2. This suggests that the reduction in Akt, eNOS, and ERK1/2 phosphorylation may be due to antagonism of upstream VEGFRs by axitinib.
ln Vivo
Axitinib shows primary inhibition against orthotopically transplanted models of colon cancer (HCT-116), melanoma (M24met), and renal cell carcinoma (SN12C).[1] In IGR-N91 fenografts, axitinib reduces the Mean Vessels Density (MVD) to 21 from 49 in controls and delays the tumor growth by 11.4 days when compared to the controls (p.o. 30 mg/kg).[2] In the BT474 breast cancer model, axitinib at doses of 10-100 mg/kg dramatically suppresses growth and alters the tumor microvasculature.[3] In a variety of tumor types, such as melanoma, thyroid cancer, non-small cell lung cancer, and renal cell carcinoma, axitinib has demonstrated single-agent activity.
The present studies were designed to determine the pathophysiologic consequences of both single and combined treatments using fractionated radiotherapy plus Axitinib/AG-013736, a receptor tyrosine kinase inhibitor that preferentially inhibits vascular endothelial growth factor receptors. DU145 human prostate xenograft tumors were treated with (a) vehicle alone, (b) Axitinib/AG-013736, (c) 5x2 Gy/wk radiotherapy fractions, or (d) the combination. Automated image processing of immunohistochemical images was used to determine total and perfused blood vessel spacing, overall hypoxia, pericyte/collagen coverage, proliferation, and apoptosis. Combination therapy produced an increased tumor response compared with either monotherapy alone. Vascular density progressively declined in concert with slightly increased alpha-smooth muscle actin-positive pericyte coverage and increased overall tumor hypoxia (compared with controls). Although functional vessel endothelial apoptosis was selectively increased, reductions in total and perfused vessels were generally proportionate, suggesting that functional vasculature was not specifically targeted by combination therapy. These results argue against either an AG-013736- or a combination treatment-induced functional normalization of the tumor vasculature. Vascular ablation was mirrored by the increased appearance of dissociated pericytes and empty type IV collagen sleeves. Despite the progressive decrease in tumor oxygenation over 3 weeks of treatment, combination therapy remained effective and tumor progression was minimal. [1]
Target modulation in vivo by Axitinib. [2]
Acute axitinib treatment rapidly and significantly reduced retinal vascular VEGFR-2 phosphorylation. One hour after the second dose, retinal VEGFR-2 phosphorylation was reduced by 80% to 90% compared with that of the control tissues (Fig. 3A, left). Six and 24 to 32 h post-dose, the phospho-VEGFR-2 levels returned to ∼50% and 100% of the control, respectively. Levels of phospho-VEGFR-2 inversely correlated with axitinib plasma concentrations over the study time course. The EC50 value for the inhibition of VEGFR-2 phosphorylation was 0.49 nmol/L (or 0.19 ng/mL, the unbound value corrected for plasma protein binding; Fig. 3A, right). [2]
Axitinib also inhibited murine VEGFR-2 phosphorylation in angiogenic vessels of xenograft tumors of the M24met; M24met tumors secrete high VEGF-A, are highly vascularized, and do not express functional human VEGFR-2. A single oral dose of axitinib (100 mg/kg) markedly suppressed murine VEGFR-2 phosphorylation for up to 7 h compared with control tumors (Fig. 3B). Phosphorylation of downstream ERK1/2 was also measured from the same samples. Compared with the control, partial inhibition of ERK1/2 signal was observed in treated tissues as early as 30 min post-dose and remained inhibited for at least 7 h (Fig. 3C). [2]

Axitinib rapidly inhibited VEGF-induced vascular permeability in the skin of mice; the inhibition was dose-dependent and directly correlated with drug concentration in mice (Fig. 3D). Pharmacokinetic/pharmacodynamic analysis indicated an unbound EC50 of 0.46 nmol/L (Supplementary Fig. S2). Similar inhibitory effects were also shown in the skin of MV522 tumor-bearing mice without exogenous VEGF-A stimulation (data not shown). [2]

Taken together, the required in vivo pharmacologic concentration (Ctarget) based on the inhibition of vascular VEGFR-2 phosphorylation and VEGF-mediated permeability is ∼0.5 nmol/L (unbound), which translates to a Ctarget of ∼100 nmol/L (or 40 ng/mL, total concentration) in humans.
Axitinib inhibits tumor growth and angiogenesis in mice. [2]
Axitinib inhibited the growth of human xenograft tumors in mice (Table 2). Axitinib produced dose-dependent growth delay regardless of initial tumor size, model type, or implant site. Importantly, axitinib exhibited primary tumor inhibition and distant metastasis control in orthotopically implanted tumors such as M24met (melanoma), HCT-116 (colorectal cancer), and SN12C (renal cell carcinoma). A dose-dependent growth inhibition in the MV522 tumor model is shown (Fig. 4A). Tumor growth inhibition (TGI) was associated with central necrosis, reduction in microvessel density (CD31 staining) and Ki-67, and increased caspase-3 in the tumor (Fig. 4B; Supplementary Fig. S3). Similar effects were observed in all tumor types examined regardless of tumor type and RTK expression. In summary, axitinib treatment produced consistent antitumor efficacy across various tumor types and this activity is associated with reduction in vascular angiogenesis and tumor proliferation and increase in tumor apoptosis.
Determination of ED50 and Ceff. [2]
The efficacious dose resulting in 50% antitumor efficacy (ED50) was determined using the MV522 model. MV522 tumor cells do not express functional VEGF or PDGF RTKs. In addition, the tumors have a moderate growth rate, making it an ideal model to evaluate the antiangiogenesis-associated ED50 of axitinib. Based on the relationship between dose and the corresponding TGI (Fig. 4A), the ED50 was determined to be 8.8 mg/kg twice daily (Supplementary Fig. S4) and a 30 mg/kg twice daily dose level corresponded to an ED70 in this model. The range of in vivo efficacious concentration (Ceff) corresponding to a 50% TGI was determined by evaluating the relationship between TGI (Fig. 4A) and plasma concentrations. Based on Cmin (trough concentration), the estimated unbound Ceff was determined to be 0.28 nmol/L (or 0.11 ng/mL; Fig. 4C, left); based on Cave (average concentration across 24 h), the calculated unbound Ceff was determined to be 0.85 nmol/L (0.33 ng/mL; Fig. 4C, right). Thus, the Ceff value range (0.28-0.85 nmol/L) is in agreement with the Ctarget value (0.5 nmol/L) obtained from in vivo target modulation studies. [2]

The relationship between dose and target inhibition was further analyzed based on pharmacokinetic profiles, IC50 values, Ctarget, and Ceff. Plasma concentrations at 10 mg/kg (ED50 dose) and 30 mg/kg (ED70 dose) were both above and near Ctarget (for VEGFRs) and Ceff (TGI-based) during the majority of the day (Fig. 4D). However, the plasma concentrations at these doses only allowed a total of ∼5 and 12 h coverage over the cellular IC50 of PDGFR-β, respectively (anti-PDGFR-based Ctarget or Ceff from in vivo studies is not available). Based on this analysis, the antitumor efficacy at 10 mg/kg in the MV522 model (VEGFR-null, PDGFR-null) appeared to be mainly driven from vascular VEGFR inhibition by Axitinib. In the same model, infusions of axitinib achieved a near maximal antitumor efficacy (80%) that was associated with a steady-state plasma concentration greater than the cellular IC50 for VEGFRs but below the cellular IC50 for PDGFR-β (data not shown).
Axitinib enhances antitumor efficacy of chemotherapeutic agents in multiple tumor models. [2]
The antitumor efficacy of axitinib was assessed in combination with docetaxel (in LLC and human breast cancer models), carboplatin (in a human ovarian cancer model), or gemcitabine (in a human pancreatic cancer model). These models were chosen because they have only low or moderate sensitivity to chemotherapies in mice. [2]

In the LLC model, Axitinib (10 or 30 mg/kg orally twice daily) in combination with a maximally tolerated dose of docetaxel (40 mg/kg once a week) enhanced tumor growth delay, defined as the increase in the median time to the end point (TTE) in a treatment group compared with the control group. A TTE (a measure of disease progression) is defined as tumor size = 1,500 mm3 or animal moribund due to tumor burden or metastasis. A 54% or 100% tumor growth delay was obtained for docetaxel plus 10 or 30 mg/kg axitinib versus a 9%, 30%, and 60% for docetaxel alone and 30 and 60 mg/kg axitinib alone, respectively (data not shown). Docetaxel plus axitinib significantly delayed disease progression compared with docetaxel alone (Fig. 5A). In the MDA-MB-435/HAL-luc model, axitinib (30 mg/kg) and docetaxel (5 mg/kg; 25% of murine maximally tolerated dose) produced a robust tumor growth delay as shown by the reduction of tumor bioluminescent signal (Supplementary Fig. S5) and increase in the number of complete responders compared with either single agent alone (data not shown). [2]

The antitumor efficacy of Axitinib in combination with gemcitabine was investigated against various dosing schedules in the gemcitabine-resistant BxPC-3 human pancreatic cancer model (Fig. 5B). In one study, single-agent gemcitabine (140 mg/kg i.p., days 1, 4, 7, and 10, either one-cycle or three-cycle treatments) or axitinib (30 mg/kg orally twice daily) delayed tumor growth. In the groups receiving gemcitabine plus axitinib, the “early dosing” of axitinib (day 1, group 5) produced a greater tumor growth delay than “late dosing” [starting axitinib on day 11 (group 6) or 16 (group 7) after initiation of gemcitabine] regardless of the number of gemcitabine cycles; with the same axitinib regimen, three gemcitabine treatment cycles (group 8, 9, 10) produced a greater efficacy than one gemcitabine treatment cycle (group 5, 6, 7). Alternating dose of the two agents (group 12) or early termination of axitinib (group 11) resulted in a significant compromise in tumor growth delay compared with coadministration and continuous twice daily dosing of axitinib.
Combination of Axitinib and bevacizumab produced significant antimetastasis activity in M24met model. [2]
The ability of axitinib to enhance bevacizumab efficacy in the orthotopically implanted and spontaneous metastasis human melanoma M24met tumor model was investigated; M24met tumors do not express functional RTKs (data not shown). Most importantly, circulating human VEGF-A, the ligand for bevacizumab, was found to be >95% of total circulating VEGF-A in vivo in this model. [2]

In this study, both Axitinib (60 mg/kg orally twice daily) and bevacizumab (5 mg/kg i.v., 2xqw) exhibited moderate single-agent activity against lymph node tumor metastasis. The combination of the two agents significantly improved antimetastasis efficacy assessed based on reduction of lymph node tumor mass (Fig. 5C), antiangiogenesis (Supplementary Fig. S6), and proliferation index of metastatic lymph node tumors (Supplementary Fig. S7). In addition, the combination therapy significantly prolonged animal survival measured by reduction of time to progression (TTE), with a 13-day TTE for both single agents versus the control and a 20-day TTE for combination therapy versus the control (Fig. 5D). As expected, dosing with bevacizumab or bevacizumab plus axitinib, but not axitinib single-agent treatment, significantly reduced free plasma human VEGF-A (data not shown).
Enzyme Assay
Generated are porcine aorta endothelial (PAE) cells that overexpress full-length VEGFR2, PDGFRβ, Kit, and NIH-3T3 cells that overexpress murine VEGFR2 (Flk-1) or PDGFRα. To prepare ELISA capture plates, 100 μL/well of 2.5 μg/mL anti-VEGFR2 antibody, 0.75 μg/mL anti-PDGFRβ antibody, 0.25 μg/mL anti-PDGFRα antibody, 0.5 μg/mL anti-KIT antibody, or 1.20 μg/mL anti-Flk-1 antibody are coated on the 96-well plates. Next, an ELISA is used to measure RTK phosphorylation [2].
Cell Assay
A 96-well plate is seeded with 5 × 104 cells, and the cells are cultured for a full day. Concentrations of axitinib ranging from 1 nM to 10 μM are added to the cells. MTS tetrazolium substrate is used to measure cell viability after 72 hours, and IC50 values are computed.
Three-dimensional spheroidal tube formation assay [2]
Five hundred human microvascular endothelial cells were added to EGM-2 medium containing 0.24% methylcellulose and transferred to U-bottomed 96-well plates to form a spheroid overnight. Approximately 50 spheroids were collected and mixed with 2 mg/mL fibrinogen solution containing 4% to 8% fetal bovine serum (FBS) with or without compound in the 48-well plates coated with thrombin (5,000 units/mL). The resulting three-dimensional fibrin gel was covered with EGM-2 containing 4% to 8% FBS and incubated at 37°C. Endothelial tube formation was observed daily under an inverted microscope.
Immunoprecipitation and immunoblotting [2]
Endothelial or tumor cells were starved for 18 h in the presence of either 1% FBS (HUVEC) or 0.1% FBS (tumor cells). Axitinib was added and cells were incubated for 45 min at 37°C in the presence of 1 mmol/L Na3VO4. The appropriate growth factor was added to the cells, and after 5 min, cells were rinsed with cold PBS and lysed in the lysis buffer and a protease inhibitor cocktail. The lysates were incubated with immunoprecipitation antibodies for the intended proteins overnight at 4°C. Antibody complexes were conjugated to protein A beads and supernatants were separated by SDS-PAGE. The Super Signal West Dura kit was used to detect the chemiluminescent signal.
Animal Protocol
Mice and Rats: Mice bearing 400–600 mm3 M24met xenograft tumors receive either a single Axitinib dose or 0.5% carboxymethylcellulose/H2O as a control. Samples of blood and tumor tissue are obtained for VEGFR-2 and pharmacokinetic analyses. The Bradford colorimetric assay is used to measure the total protein concentrations in tumor tissues.
Axitinib (30 mg/kg) is injected intraperitoneally twice into six-day-old Sprague-Dawley rats. Retinal tissue is extracted and lysed, animals are sacrificed, and immunoprecipitation and immunoblotting experiments are carried out. The Alpha Imager 8800 is used for densitometry analysis, and ECL-Plus is used for detection.
In vivo target modulation [2]
VEGFR-2 phosphorylation inhibition in the rat development model. Six-day-old Sprague-Dawley rats were given two i.p. injections of Axitinib. Animals were sacrificed, retinas were collected and lysed, and immunoprecipitation/immunoblotting experiments were done as described above. ECL-Plus was used for detection and densitometry analysis was done using the Alpha Imager 8800.
VEGFR-2 phosphorylation inhibition in xenograft tumors. Mice with M24met xenograft tumors (400-600 mm3) were administered with a single dose of Axitinib or the control (0.5% carboxymethylcellulose/H2O). Blood and tumor tissue samples were collected for pharmacokinetic and VEGFR-2 measurements. Total protein concentrations in tumor tissues were determined using the Bradford colorimetric assay. Procedures for immunoprecipitation/immunoblotting and ELISA were as described above.
Axitinib pharmacokinetics [2]
Plasma concentrations of Axitinib were quantitatively determined by a triple-quadruple mass spectrometer equipped with a high-performance liquid chromatography system (Agilent 1100) using a Phenyl column (Zorbax Eclipse XDB, 5 μm particle size, 50 × 2.1 mm) under isocratic conditions of 60:40 water/acetonitrile containing 0.1% formic acid. Data were collected under multiple reaction monitoring mode of m/z 387.3→356.2 for axitinib and m/z 394.2→360.2 for the internal standard, Axitinib/AG-013736-d7. The method quantified for axitinib over the range of 1 to 1,000 ng/mL in mouse plasma. The area under the plasma concentration-time curve of axitinib was calculated using the linear trapezoidal rule.
Skin vascular permeability assay in naive or tumor-bearing mice [2]
The assay was done according to Miles and Miles with some modifications. nu/nu mice (n = 5-8) received a single oral dose of Axitinib followed by an injection of 30 μL Evan's blue dye through the tail vein. Thirty minutes later, murine VEGF-A (400 ng in 10 μL PBS) or PBS was injected into the trunk area posterior to the shoulder of the animal. Four hours later, the skin region immediately surrounding the blue color area was dissected and immersed in 1 mL formamide. Evan's blue was extracted by incubating the tissues in formamide at 56°C for 24 h. Vascular permeability was quantified by measuring light absorbance at 620 nm.
Mouse xenograft models [2]
In general, tumor cells in FBS-depleted medium were implanted s.c. into the right flank region of athymic mice, except for the following: the M24met cells were implanted intradermally in a 50 to 100 μL volume in BALB/C severe combined immunodeficient mice; the procedures for orthotopic implantation of HCT-116-GFP and SN12C-GFP tumors have been described elsewhere; the A375 cells were implanted in the presence of 10% Matrigel; the LLC tumors were inoculated either using the suspension cells or 2 × 2 mm viable tumor fragments via the Trocar needles. Unless otherwise specified, mice were randomized when the average tumor was ∼100 mm3 (9-12 per group). Tumor volumes were measured three times per week by electronic calipers and calculated according to the following equation: 0.5 × [length × (width)2]. Treatment usually lasted for 2 to 4 weeks or until tumors reached 1,500 mm3. The procedure for tumor bioluminescent imaging and quantification using the IVIS Imaging System has been reported elsewhere.
Treatments. Axitinib/AG-013736, a receptor kinase inhibitor of VEGFRs and, at higher doses, PDGFRs (IC50 = 0.1 nmol/L for VEGFR-1, 0.2 nmol/L for VEGFR-2, 0.1–0.3 nmol/L for VEGFR-3, and 1.6 nmol/L for PDGFRβ; ref. 18), was provided by Pfizer Global Research and given once daily by gavage in a volume of 0.13 mL. Control animals received 0.5% carboxymethylcellulose drug carrier. Irradiations were done on nonanesthetized mice using a 137Cs source operating at 2.4 Gy/min. Mice were confined to plastic jigs with tumor-bearing legs extended through an opening in the side, allowing local irradiations. Fractionated doses were given in five daily 2 Gy fractions per week (omitting weekends). For combination treatments, radiotherapy was delivered first, and Axitinib/AG-013736 was given within ∼4 h. Mice were sacrificed, and tumors were excised and then quick frozen (using liquid nitrogen) following 1, 2, or 3 weeks of treatment. [1]
ADME/Pharmacokinetics
Absorption, Distribution and Excretion
After one 5 mg dose of axitinib, it takes about 2.5 to 4.1 hours to reach maximum plasma concentration.
Axitinib is mainly eliminated unchanged in the feces (41%) with 12% of the original dose as unchanged axitinib. There is also 23% eliminated in the urine, most of which are metabolites.
The volume of distribution is 160 L.
The average clearance of axitinib is 38 L/h.
Metabolism / Metabolites
Axitinib undergoes mainly hepatic metabolism. CYP3A4 and CYP3A5 are the main hepatic enzymes while CYP1A2, CYP2C19, and UGT1A1 enzymes are secondary.
Biological Half-Life
Axitinib has a half life of 2.5 to 6.1 hours.
Toxicity/Toxicokinetics
Hepatotoxicity
In large clinical trials of axitinib, elevations in serum aminotransferase levels were common, occurring in up to 25% of patients. Values greater than 5 times the upper limit of normal (ULN), however, were uncommon, occurring in 1% to 2% of recipients. Furthermore, no instances of clinically apparent liver injury from axitinib were reported in prelicensure studies or during the more wide scale use since its approval. Nevertheless, periodic monitoring of liver tests during axitinib therapy is recommended.
Likelihood score: E* (unproven but suspected cause of clinically apparent liver injury).
Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the use of axitinib during breastfeeding. Because axitinib is more than 99% bound to plasma proteins, the amount in milk is likely to be low. The manufacturer recommends that breastfeeding be discontinued during axitinib therapy and for 2 weeks after the final dose of therapy. When axitinib is used in combination with avelumab or pembrolizumab, refer to those LactMed records.
◉ 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.
Protein Binding
Plasma protein binding for axitinib is high at over 99% with most protein binding to albumin followed by α1-acid glycoprotein.
References

[1]. The addition of AG-013736 to rractionated radiation improves tumor response without functionally normalizing the tumor vasculature. Cancer Res. 2007 Oct 15;67(20):9921-8.

[2]. Nonclinical antiangiogenesis and antitumor activities of axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor receptor tyrosine kinases 1, 2, 3. Clin Cancer Res. 2008 Nov 15;14(22):7272-83.

[3]. Metabolic Symbiosis Enables Adaptive Resistance to Anti-angiogenic Therapy that Is Dependent on mTOR Signaling. Cell Rep. 2016 May 10;15(6):1144-60.

Additional Infomation
Axitinib is an indazole substituted at position 3 by a 2-(pyridin-2-yl)vinyl group and at position 6 by a 2-(N-methylaminocarboxy)phenylsulfanyl group. Used for the treatment of advanced renal cell carcinoma after failure of a first line systemic treatment. It has a role as an antineoplastic agent, a tyrosine kinase inhibitor and a vascular endothelial growth factor receptor antagonist. It is a member of indazoles, a member of pyridines, an aryl sulfide and a member of benzamides.
Axitinib is a second generation tyrosine kinase inhibitor that works by selectively inhibiting vascular endothelial growth factor receptors (VEGFR-1, VEGFR-2, VEGFR-3). Through this mechanism of action, axitinib blocks angiogenesis, tumour growth and metastases. It is reported to exhibit potency that is 50-450 times higher than that of the first generation VEGFR inhibitors. Axitinib is an indazole derivative. It is most commonly marketed under the name Inlyta® and is available in oral formulations.
Axitinib is a Kinase Inhibitor. The mechanism of action of axitinib is as a Receptor Tyrosine Kinase Inhibitor.
Axitinib is an oral tyrosine kinase inhibitor selective for vascular endothelial growth factor (VEGF) receptors -1, -2 and -3 that is used in the therapy of advanced renal cell carcinoma. Axitinib therapy is commonly associated with transient elevations in serum aminotransferase that are generally mild and asymptomatic. Axitinib has yet to be linked to instances of clinically apparent acute liver injury.
Axitinib is an orally bioavailable tyrosine kinase inhibitor. Axitinib inhibits the proangiogenic cytokines vascular endothelial growth factor (VEGF) and platelet-derived growth factor receptor (PDGF), thereby exerting an anti-angiogenic effect.
A benzamide and indazole derivative that acts as a TYROSINE KINASE inhibitor of the VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR. It is used in the treatment of advanced RENAL CELL CARCINOMA.
Drug Indication
Used in kidney cell cancer and investigated for use/treatment in pancreatic and thyroid cancer.
FDA Label
Inlyta is indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC) after failure of prior treatment with sunitinib or a cytokine.
Mechanism of Action
Axitinib selectively blocks the tyrosine kinase receptors VEGFR-1 (vascular endothelial growth factor receptor), VEGFR-2, and VEGFR-3.
Pharmacodynamics
Axitinib prevents the progression of cancer by inhibiting angiogenesis and blocking tumor growth.
In conclusion, the current findings argue against a treatment-induced functional normalization of the tumor vasculature when applying combination therapy. Rather than tightening pericytes, AG-013736 and the combination treatment served instead to loosen pericyte-vessel and pericyte-basement membrane associations in this tumor model. Treatment substantially reduced total and functional vascular densities, but overall tumor hypoxia progressively increased, in contrast to the normalization hypothesis. Despite the reduction in oxygenation, tumor progression was minimal over 3 weeks of combination treatment, most likely due to continued vascular destruction and the prevention of new vessel growth. Further studies are essential to extend these measurements to additional tumor models and to determine whether alternative scheduling may also enhance treatment response. [1]
Purpose: Axitinib (AG-013736) is a potent and selective inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases 1 to 3 that is in clinical development for the treatment of solid tumors. We provide a comprehensive description of its in vitro characteristics and activities, in vivo antiangiogenesis, and antitumor efficacy and translational pharmacology data. Experimental design: The potency, kinase selectivity, pharmacologic activity, and antitumor efficacy of axitinib were assessed in various nonclinical models. Results: Axitinib inhibits cellular autophosphorylation of VEGF receptors (VEGFR) with picomolar IC(50) values. Counterscreening across multiple kinase and protein panels shows it is selective for VEGFRs. Axitinib blocks VEGF-mediated endothelial cell survival, tube formation, and downstream signaling through endothelial nitric oxide synthase, Akt and extracellular signal-regulated kinase. Following twice daily oral administration, axitinib produces consistent and dose-dependent antitumor efficacy that is associated with blocking VEGFR-2 phosphorylation, vascular permeability, angiogenesis, and concomitant induction of tumor cell apoptosis. Axitinib in combination with chemotherapeutic or targeted agents enhances antitumor efficacy in many tumor models compared with single agent alone. Dose scheduling studies in a human pancreatic tumor xenograft model show that simultaneous administration of axitinib and gemcitabine without prolonged dose interruption or truncation of axitinib produces the greatest antitumor efficacy. The efficacious drug concentrations predicted in nonclinical studies are consistent with the range achieved in the clinic. Although axitinib inhibits platelet-derived growth factor receptors and KIT with nanomolar in vitro potencies, based on pharmacokinetic/pharmacodynamic analysis, axitinib acts primarily as a VEGFR tyrosine kinase inhibitor at the current clinical exposure. Conclusions: The selectivity, potency for VEGFRs, and robust nonclinical activity may afford broad opportunities for axitinib to improve cancer therapy. [2]
Therapeutic targeting of tumor angiogenesis with VEGF inhibitors results in demonstrable, but transitory efficacy in certain human tumors and mouse models of cancer, limited by unconventional forms of adaptive/evasive resistance. In one such mouse model, potent angiogenesis inhibitors elicit compartmental reorganization of cancer cells around remaining blood vessels. The glucose and lactate transporters GLUT1 and MCT4 are induced in distal hypoxic cells in a HIF1α-dependent fashion, indicative of glycolysis. Tumor cells proximal to blood vessels instead express the lactate transporter MCT1, and p-S6, the latter reflecting mTOR signaling. Normoxic cancer cells import and metabolize lactate, resulting in upregulation of mTOR signaling via glutamine metabolism enhanced by lactate catabolism. Thus, metabolic symbiosis is established in the face of angiogenesis inhibition, whereby hypoxic cancer cells import glucose and export lactate, while normoxic cells import and catabolize lactate. mTOR signaling inhibition disrupts this metabolic symbiosis, associated with upregulation of the glucose transporter GLUT2.[3]
These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C22H18N4OS
Molecular Weight
386.47
Exact Mass
386.12
Elemental Analysis
C, 68.37; H, 4.69; N, 14.50; O, 4.14; S, 8.30
CAS #
319460-85-0
Related CAS #
Axitinib-13C,d3;1261432-00-1;Axitinib-d3;1126623-89-9
PubChem CID
6450551
Appearance
white to off-white solid powder
Density
1.4±0.1 g/cm3
Boiling Point
668.9±55.0 °C at 760 mmHg
Melting Point
213-215ºC
Flash Point
358.3±31.5 °C
Vapour Pressure
0.0±2.0 mmHg at 25°C
Index of Refraction
1.728
LogP
4.15
Hydrogen Bond Donor Count
2
Hydrogen Bond Acceptor Count
4
Rotatable Bond Count
5
Heavy Atom Count
28
Complexity
557
Defined Atom Stereocenter Count
0
SMILES
O=C(C1=C(SC2=CC3=C(C(/C=C/C4=CC=CC=N4)=NN3)C=C2)C=CC=C1)NC
InChi Key
RITAVMQDGBJQJZ-FMIVXFBMSA-N
InChi Code
InChI=1S/C22H18N4OS/c1-23-22(27)18-7-2-3-8-21(18)28-16-10-11-17-19(25-26-20(17)14-16)12-9-15-6-4-5-13-24-15/h2-14H,1H3,(H,23,27)(H,25,26)/b12-9+
Chemical Name
N-methyl-2-[[3-[(E)-2-pyridin-2-ylethenyl]-1H-indazol-6-yl]sulfanyl]benzamide
Synonyms
AG 013736; Axitinib; 319460-85-0; AG-13,736; axitinibum; C9LVQ0YUXG; UNII-C9LVQ0YUXG; NSC-757441; N-methyl-2-((3-((1E)-2-(pyridin-2-yl)ethenyl)-1H-indazol-6-yl)sulfanyl)benzamide; AG013736; Axitinib; AG-013736; Brand name: Inlyta
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: ~35 mg/mL (~90.5 mM)
Water: <1 mg/mL
Ethanol: <1 mg/mL
Solubility (In Vivo)
Solubility in Formulation 1: ≥ 2.08 mg/mL (5.38 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

Solubility in Formulation 2: 2.08 mg/mL (5.38 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C,1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

View More

Solubility in Formulation 3: ≥ 2.08 mg/mL (5.38 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly..


Solubility in Formulation 4: 0.5% CMC: 30mg/mL

Solubility in Formulation 5: 8.33 mg/mL (21.55 mM) in 20% HP-β-CD/10 mM citrate pH 2.0 (add these co-solvents sequentially from left to right, and one by one), clear solution; Need ultrasonic and adjust pH to 3 with H2O.

 (Please use freshly prepared in vivo formulations for optimal results.)
Preparing Stock Solutions 1 mg 5 mg 10 mg
1 mM 2.5875 mL 12.9376 mL 25.8752 mL
5 mM 0.5175 mL 2.5875 mL 5.1750 mL
10 mM 0.2588 mL 1.2938 mL 2.5875 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.

Calculator

Molarity Calculator allows you to calculate the mass, volume, and/or concentration required for a solution, as detailed below:

  • Calculate the Mass of a compound required to prepare a solution of known volume and concentration
  • Calculate the Volume of solution required to dissolve a compound of known mass to a desired concentration
  • Calculate the Concentration of a solution resulting from a known mass of compound in a specific volume
An example of molarity calculation using the molarity calculator is shown below:
What is the mass of compound required to make a 10 mM stock solution in 5 ml of DMSO given that the molecular weight of the compound is 350.26 g/mol?
  • Enter 350.26 in the Molecular Weight (MW) box
  • Enter 10 in the Concentration box and choose the correct unit (mM)
  • Enter 5 in the Volume box and choose the correct unit (mL)
  • Click the “Calculate” button
  • The answer of 17.513 mg appears in the Mass box. In a similar way, you may calculate the volume and concentration.

Dilution Calculator allows you to calculate how to dilute a stock solution of known concentrations. For example, you may Enter C1, C2 & V2 to calculate V1, as detailed below:

What volume of a given 10 mM stock solution is required to make 25 ml of a 25 μM solution?
Using the equation C1V1 = C2V2, where C1=10 mM, C2=25 μM, V2=25 ml and V1 is the unknown:
  • Enter 10 into the Concentration (Start) box and choose the correct unit (mM)
  • Enter 25 into the Concentration (End) box and select the correct unit (mM)
  • Enter 25 into the Volume (End) box and choose the correct unit (mL)
  • Click the “Calculate” button
  • The answer of 62.5 μL (0.1 ml) appears in the Volume (Start) box
g/mol

Molecular Weight Calculator allows you to calculate the molar mass and elemental composition of a compound, as detailed below:

Note: Chemical formula is case sensitive: C12H18N3O4  c12h18n3o4
Instructions to calculate molar mass (molecular weight) of a chemical compound:
  • To calculate molar mass of a chemical compound, please enter the chemical/molecular formula and click the “Calculate’ button.
Definitions of molecular mass, molecular weight, molar mass and molar weight:
  • Molecular mass (or molecular weight) is the mass of one molecule of a substance and is expressed in the unified atomic mass units (u). (1 u is equal to 1/12 the mass of one atom of carbon-12)
  • Molar mass (molar weight) is the mass of one mole of a substance and is expressed in g/mol.
/

Reconstitution Calculator allows you to calculate the volume of solvent required to reconstitute your vial.

  • Enter the mass of the reagent and the desired reconstitution concentration as well as the correct units
  • Click the “Calculate” button
  • The answer appears in the Volume (to add to vial) box
In vivo Formulation Calculator (Clear solution)
Step 1: Enter information below (Recommended: An additional animal to make allowance for loss during the experiment)
Step 2: Enter in vivo formulation (This is only a calculator, not the exact formulation for a specific product. Please contact us first if there is no in vivo formulation in the solubility section.)
+
+
+

Calculation results

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.
             (2) Be sure to add the solvent(s) in order.

Clinical Trial Information
Erlotinib in Combination With Select Tyrosine Kinase Inhibitors in Adult Patients With Advanced Solid Tumors
CTID: NCT06161558
Phase: Phase 1    Status: Not yet recruiting
Date: 2024-12-02
Axitinib + Ipilimumab in Advanced Melanoma
CTID: NCT04996823
Phase: Phase 2    Status: Recruiting
Date: 2024-11-29
Study to Evaluate the Efficacy and Safety of Immunotherapy With Axitinib in Advanced Collecting Duct Carcinoma
CTID: NCT06211114
Phase: Phase 2    Status: Recruiting
Date: 2024-11-26
A Phase II Study of Axitinib in Patients With Metastatic Renal Cell Cancer Unsuitable for Nephrectomy
CTID: NCT01693822
Phase: Phase 2    Status: Completed
Date: 2024-11-21
Talazoparib and Palbociclib, Axitinib, or Crizotinib for the Treatment of Advanced or Metastatic Solid Tumors, TalaCom Trial
CTID: NCT04693468
Phase: Phase 1    Status: Recruiting
Date: 2024-11-20
View More

Study to Evaluate the Efficacy and Safety of Pembrolizumab (MK-3475) in Combination With Axitinib Versus Sunitinib Monotherapy in Participants With Renal Cell Carcinoma (MK-3475-426/KEYNOTE-426)
CTID: NCT02853331
Phase: Phase 3    Status: Active, not recruiting
Date: 2024-11-18


A Study of AGS-16C3F vs. Axitinib in Metastatic Renal Cell Carcinoma
CTID: NCT02639182
Phase: Phase 2    Status: Completed
Date: 2024-11-18
Antiandrogen Therapy With or Without Axitinib Before Surgery in Treating Patients With Previously Untreated Prostate Cancer With Known or Suspected Lymph Node Metastasis
CTID: NCT01409200
Phase: Phase 2    Status: Active, not recruiting
Date: 2024-11-18
A Study to Evaluate the Bioavailability of Pembrolizumab (MK-3475) Via Subcutaneous (SC) Injection of MK-3475A (Pembrolizumab Formulated With MK-5180) In Advanced Solid Tumors (MK-3475A-C18)
CTID: NCT05017012
Phase: Phase 1    Status: Active, not recruiting
Date: 2024-11-18
A Study to Compare Treatments for a Type of Kidney Cancer Called TFE/Translocation Renal Cell Carcinoma (tRCC)
CTID: NCT03595124
Phase: Phase 2    Status: Active, not recruiting
Date: 2024-11-15
Combination of Toripalimab and JS004 Therapy for ccRCC
CTID: NCT06690697
Phase: Phase 2    Status: Recruiting
Date: 2024-11-15
Continued Access Study for Participants Deriving Benefit in Pfizer-Sponsored Avelumab Parent Studies That Are Closing
CTID: NCT05059522
Phase: Phase 3    Status: Active, not recruiting
Date: 2024-11-13
Canadian Profiling and Targeted Agent Utilization Trial (CAPTUR)
CTID: NCT03297606
Phase: Phase 2    Status: Recruiting
Date: 2024-11-12
NPC - AXEL Study : Axitinib-Avelumab
CTID: NCT04562441
Phase: Phase 2    Status: Active, not recruiting
Date: 2024-10-30
A Study of Avelumab With Axitinib Versus Sunitinib In Advanced Renal Cell Cancer (JAVELIN Renal 101)
CTID: NCT02684006
Phase: Phase 3    Status: Completed
Date: 2024-10-29
Study of Nivolumab and Axitinib in Patients With Advanced Renal Cell Carcinoma
CTID: NCT03172754
Phase: Phase 1/Phase 2    Status: Active, not recruiting
Date: 2024-10-26
A Study of Immune Checkpoint Inhibitor Combinations With Axitinib in Participants With Untreated Locally Advanced Unresectable or Metastatic Renal Cell Carcinoma
CTID: NCT05805501
Phase: Phase 2    Status: Active, not recruiting
Date: 2024-10-24
Neoadjuvant Pembrolizumab and Axitinib in Renal Cell Carcinoma with Inferior Vena Cava Tumor Thrombus
CTID: NCT05969496
Phase: Phase 2    Status: Recruiting
Date: 2024-10-23
Axitinib and Avelumab in Treating Patients With Recurrent or Metastatic Adenoid Cystic Carcinoma
CTID: NCT03990571
Phase: Phase 2    Status: Completed
Date: 2024-10-18
A Study to Evaluate MEDI5752 and Axitinib in Subjects With Advanced Renal Cell Carcinoma
CTID: NCT04522323
Phase: Phase 1    Status: Recruiting
Date: 2024-10-09
Pembrolizumab With or Without Axitinib for Treatment of Locally Advanced or Metastatic Clear Cell Kidney Cancer in Patients Undergoing Surgery
CTID: NCT04370509
Phase: Phase 2    Status: Recruiting
Date: 2024-10-04
Trial of X4P-001 in Participants With Advanced Renal Cell Carcinoma
CTID: NCT02667886
Phase: Phase 1/Phase 2    Status: Completed
Date: 2024-10-03
Registry For Temsirolimus, Sunitinib, And Axitinib Treated Patients With Metastatic Renal Cell Carcinoma (mRCC), Mantle Cell Lymphoma (MCL), And Gastro-Intestinal Stroma Tumor (GIST) [STAR-TOR]
CTID: NCT00700258
Phase:    Status: Completed
Date: 2024-09-23
Neoadjuvant Axitinib in Locally Advanced Renal Cell Carcinoma (RCC)
CTID: NCT01263769
Phase: Phase 2    Status: Completed
Date: 2024-09-19
A Study to Assess LBL-007 in Combination With Toripalimab and Axitinib Tablets Subjects With Advanced Melanoma
CTID: NCT04640545
Phase: Phase 1    Status: Recruiting
Date: 2024-09-19
Axitinib With or Without Anti-OX40 Antibody PF-04518600 in Treating Patients With Metastatic Kidney Cancer
CTID: NCT03092856
Phase: Phase 2    Status: Active, not recruiting
Date: 2024-08-28
Talazoparib and Axitinib for People With Previously Treated Advanced Kidney Cancer
CTID: NCT04337970
Phase: Phase 1/Phase 2    Status: Active, not recruiting
Date: 2024-08-21
SLM + Axitinib for Clear Cell RCC
CTID: NCT02535533
Phase: Phase 1    Status: Active, not recruiting
Date: 2024-08-09
Seleno-L Methionine (SLM)-Axitinib-Pembrolizumab
CTID: NCT05363631
Phase: Phase 1/Phase 2    Status: Recruiting
Date: 2024-08-07
Treatment Patterns With Targeted Therapies In Mrcc In Sweden - A Retrospective Analysis Of Data From National Registries
CTID: NCT04669366
Phase:    Status: Completed
Date: 2024-07-19
Axitinib and Pembrolizumab in Subjects With Advanced Alveolar Soft Part Sarcoma and Other Soft Tissue Sarcomas
CTID: NCT02636725
Phase: Phase 2    Status: Completed
Date: 2024-07-12
Study of Immunotherapy (Sasanlimab) in Combination With Targeted Therapies in People With Advanced Non-small Cell Lung Cancer (NSCLC) (Landscape 1011 Study)
CTID: NCT04585815
Phase: Phase 1/Phase 2    Status: Active, not recruiting
Date: 2024-07-10
Avelumab in Patients With MSS, MSI-H and POLE-mutated Recurrent or Persistent Endometrial Cancer and of Avelumab/Talazoparib and Avelumab/Axitinib in Patients With MSS Recurrent or Persistent Endometrial Cancer
CTID: NCT02912572
Phase: Phase 2    Status: Active, not recruiting
Date: 2024-07-05
A Study of INCB099280 in Combination With Axitinib in Adults With Advanced Solid Tumors
CTID: NCT05949632
Phase: Phase 1/Phase 2    Status: Active, not recruiting
Date: 2024-06-28
Study of Axitinib in Patients With Recurred or Metastatic Adenoid Cystic Carcinoma
CTID: NCT02859012
Phase: Phase 2    Status: Completed
Date: 2024-05-29
A Trial of AK104 or AK112 in Combination With Axitinib in Patients With Metastatic Mucosal Melanoma
CTID: NCT06424626
Phase: Phase 1    Status: Not yet recruiting
Date: 2024-05-22
Strata PATH™ (Precision Indications for Approved Therapies)
CTID: NCT05097599
Phase: Phase 2    Status: Active, not recruiting
Date: 2024-05-21
Nivolumab Plus Axitinib in Patients With Anti-PD1 Refractory Advanced Melanoma
CTID: NCT04493203
Phase: Phase 2    Status: Active, not recruiting
Date: 2024-05-07
Study of KN046 in Subjects With Advanced Non-Small Cell Lung Cancer
CTID: NCT05420220
Phase: Phase 2    Status: Recruiting
Date: 2024-05-01
TACE Plus Axitinib and Hydroxychlorquine for Liver-Dominant Metastatic Colorectal Cancer (CRC)
CTID: NCT04873895
Phase: Phase 1    Status: Terminated
Date: 2024-04-26
CARE1 Pragmatic Clinical Trial
CTID: NCT06364631
Phase: Phase 3    Status: Recruiting
Date: 2024-04-19
A Study of Avelumab in Combination With Axitinib In Non-Small Cell Lung Cancer (NSCLC) or Urothelial Cancer (Javelin Medley VEGF)
CTID: NCT03472560
Phase: Phase 2    Status: Terminated
Date: 2024-04-09
Study of PF-07265807 in Participants With Metastatic Solid Tumors.
CTID: NCT04458259
Phase: Phase 1    Status: Active, not recruiting
Date: 2024-04-03
Testing the Addition of Stereotactic Radiation Therapy With Immune Therapy for the Treatment of Patients With Unresectable or Metastatic Renal Cell Cancer, SAMURAI Study
CTID: NCT05327686
Phase: Phase 2    Status: Recruiting
Date: 2024-03-12
Post Marketing Surveillance Study to Observe Safety and Efficacy of Inlyta in South Korea
CTID: NCT02156895
Phase:    Status: Completed
Date: 2024-03-08
Upfront Immune Checkpoint Inhibitors With Deferred Cytoreductive Nephrectomy for Metastatic Renal Cell Carcinoma
CTID: NCT06279403
Phase: Phase 2    Status: Not yet recruiting
Date: 2024-02-28
A Study to Compare Bempegaldesleukin (BEMPEG: NKTR-214) Combined With Nivolumab and Tyrosine Kinase Inhibitor (TKI) to Nivolumab and TKI Alone in Participants With Previously Untreated Kidney Cancer That is Advanced or Has Spread
CTID: NCT04540705
Phase: Phase 1    Status: Completed
Date: 2024-02-28
Axitinib and Nivolumab for the Treatment of Mucosal Melanoma
CTID: NCT05384496
Phase: Phase 2    Status: Recruiting
Date: 2024-02-23
Axitinib +/- Pembrolizumab in First Line Treatment of mPRCC
CTID: NCT05096390
Phase: Phase 2    Status: Recruiting
Date: 2024-01-25
The Drug Rediscovery Protocol (DRUP Trial)
CTID: NCT02925234
Phase: Phase 2    Status: Recruiting
Date: 2024-01-24
Treatment Outcomes in Japanese RCC Patients Treated With Avelumab Plus Axitinib as First-line Therapy: Retrospective Study (J-DART2)
CTID: NCT05650164
Phase:    Status: Completed
Date: 2024-01-11
Survival Prolongation by Rationale Innovative Genomics
CTID: NCT03386929
Phase: Phase 1/Phase 2    Status: Terminated
Date: 2023-12-18
An Observational Chart Review Study To Describe The Real-World Outcomes And Use Of Avelumab In Combination With Axitinib For Treatment Of Patients With aRCC In The UK
CTID: NCT05394493
Phase:    Status: Completed
Date: 2023-12-06
Current Treatment Outcomes in Japanese RCC Patients Treated With Avelumab Plus Axitinib as First-line Therapy: Retrospective Study (J-DART)
CTID: NCT05012865
Phase:    Status: Completed
Date: 2023-12-06
Axitinib Therapy Management Study
CTID: NCT04555603
Phase:    Status: Withdrawn
Date: 2023-11-21
Continuing Access to Axitinib (A406- AG- 013736 ) For Patients Previously Receiving AG 013736 In Clinical Trials
CTID: NCT00828919
Phase: N/A    Status: Completed
Date: 2023-10-16
Avelumab With Axitinib in Persistent or Recurrent Cervical Cancer After Platinum-based Chemotherapy
CTID: NCT03826589
Phase: N/A    Status: Active, not recruiting
Date: 2023-10-03
A Study of AK104 Plus Axitinib in Advanced/Metastatic Special Pathological Subtypes of Renal Cell Carcinoma
CTID: NCT05808608
Phase: Phase 1/Phase 2    Status: Not yet recruiting
Date: 2023-09-25
A Study of AK104 Monotherapy or AK104 Plus Axitinib in Advanced/Metastatic Renal Cell Carcinoma
CTID: NCT05256472
Phase: Phase 2    Status: Recruiting
Date: 2023-09-21
Avelumab, Palbociclib and
A Phase 1b/2 Open Label Umbrella Study of Sasanlimab Combined with Anti-Cancer Therapies Targeting Multiple Molecular Mechanisms in Participants with Non-Small Cell Lung Cancer (NSCLC)
CTID: null
Phase: Phase 1, Phase 2    Status: Prematurely Ended, Completed
Date: 2021-06-01
Phase II study of avelumab plus intermittent axitinib in previously untreated patients with metastatic renal cell carcinoma (Tide-A study).
CTID: null
Phase: Phase 2    Status: Completed
Date: 2020-06-18
ProTarget
CTID: null
Phase: Phase 2    Status: Trial now transitioned
Date: 2020-04-28
A Phase II, single arm Study of avelumab In combination with Axitinib in Patients With unresectable/metastatic Gastrointestinal Stromal Tumor after failure of standard therapy - AXAGIST
CTID: null
Phase: Phase 2    Status: Ongoing
Date: 2019-04-03
A phase II study of Avelumab in combination with Axitinib in patients with advanced Thymic epithelial tumours (TET)
CTID: null
Phase: Phase 2    Status: Prematurely Ended
Date: 2019-02-20
A Phase 1b/2, study to evaluate safety and clinical activity of avelumab in combination with binimetinib with or without talazoparib in patients with locally advanced or metastatic RAS-Mutant Solid Tumors
CTID: null
Phase: Phase 1, Phase 2    Status: Completed
Date: 2019-02-19
A Phase 2 Study to Evaluate Safety and Anti-tumor Activity of Avelumab in Combination with Talazoparib In Patients with BRCA or ATM Mutant Tumors
CTID: null
Phase: Phase 2    Status: Ongoing, GB - no longer in EU/EEA, Completed
Date: 2019-02-19
A PHASE 2, OPEN LABEL STUDY TO EVALUATE SAFETY AND CLINICAL ACTIVITY OF AVELUMAB (BAVENCIO) IN COMBINATION WITH AXITINIB (INLYTA) IN PATIENTS WITH ADVANCED OR METASTATIC PREVIOUSLY TREATED NON-SMALL CELL LUNG CANCER OR TREATMENT NAÏVE CISPLATIN-INELIGIBLE UROTHELIAL CANCER.
CTID: null
Phase: Phase 2    Status: Ongoing, Completed
Date: 2018-09-26
A PHASE 1B/2 STUDY TO EVALUATE SAFETY AND ANTI-TUMOR ACTIVITY OF AVELUMAB IN COMBINATION WITH THE POLY (ADENOSINE DIPHOSPHATE [ADP]-RIBOSE) POLYMERASE (PARP) INHIBITOR TALAZOPARIB IN PATIENTS WITH LOCALLY ADVANCED OR METASTATIC SOLID TUMORS
CTID: null
Phase: Phase 1, Phase 2    Status: GB - no longer in EU/EEA, Completed
Date: 2018-05-31
A MULTICENTER, OPEN-LABEL, PHASE 1B/2 STUDY TO EVALUATE SAFETY AND EFFICACY OF AVELUMAB (MSB0010718C) IN COMBINATION WITH CHEMOTHERAPY WITH OR WITHOUT OTHER ANTI-CANCER IMMUNOTHERAPIES AS FIRST-LINE TREATMENT IN PATIENTS WITH ADVANCED MALIGNANCIES
CTID: null
Phase: Phase 1, Phase 2    Status: Ongoing, GB - no longer in EU/EEA, Completed
Date: 2018-03-28
A proof of concept study to explore safety and efficacy of tri-therapy approach in advanced/metastatic NSCLC and retrospectively assess the ability of integrated genomics and transcriptomics to match patients to the combination
CTID: null
Phase: Phase 1, Phase 2    Status: Ongoing, Prematurely Ended
Date: 2017-12-15
Phase II neoadjuvant study of Axitinib for reducing extent of venous tumour thrombus in clear cell renal cell cancer with venous invasion.
CTID: null
Phase: Phase 2    Status: GB - no longer in EU/EEA
Date: 2017-08-02
Phase II clinical trial on the combination of avelumab and axitinib for the treatment of patients with recurrent glioblastoma
CTID: null
Phase: Phase 2    Status: Completed
Date: 2017-05-04
A phase III study testing the role of PRoactivE coaching on PAtient REported outcome in advanced or metastatic renal cell carcinoma treated with sunitinib or a combination of pembrolizumab + axitinib or avelumab + axitinib in first line therapy
CTID: null
Phase: Phase 3    Status: Completed
Date: 2016-12-06
A Phase III Randomized, Open-label Study to Evaluate Efficacy and Safety of Pembrolizumab (MK-3475) in Combination with Axitinib versus Sunitinib Monotherapy as a First-line Treatment for Locally Advanced or Metastatic Renal Cell Carcinoma (mRCC) (KEYNOTE-426)
CTID: null
Phase: Phase 3    Status: Trial now transitioned, GB - no longer in EU/EEA, Ongoing
Date: 2016-12-01
A PHASE 3, MULTINATIONAL, RANDOMIZED, OPEN-LABEL, PARALLEL-ARM STUDY OF AVELUMAB (MSB0010718C) IN COMBINATION WITH AXITINIB (INLYTA®) VERSUS SUNITINIB (SUTENT®) ) MONOTHERAPY IN THE FIRST-LINE TREATMENT OF PATIENTS WITH ADVANCED RENAL CELL CARCINOMA
CTID: null
Phase: Phase 3    Status: Ongoing, Temporarily Halted, GB - no longer in EU/EEA, Completed
Date: 2016-08-05
Selecting cancer patients for treatment using Tumor Organoids, the SENSOR study
CTID: null
Phase: Phase 2    Status: Completed
Date: 2016-06-16
A RANDOMIZED PHASE 2 TRIAL OF AXITINIB AND TRC105 VERSUS AXITINIB ALONE (INCLUDING A LEAD-IN PHASE 1B DOSE-ESCALATION PORTION) IN PATIENTS WITH ADVANCED OR METASTATIC RENAL CELL CARCINOMA
CTID: null
Phase: Phase 2    Status: Prematurely Ended, Completed
Date: 2016-05-24
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
Phase II study on Inlyta® (axitinib) in recurrent and/or metastatic salivary gland cancers (SGCs) of the upper aerodigestive tract
CTID: null
Phase: Phase 2    Status: Ongoing
Date: 2014-10-21
Phase II Study of Axitinib in Advanced Solitary Fibrous Tumor
CTID: null
Phase: Phase 2    Status: Ongoing
Date: 2014-03-14
ADJUVANT AXITINIB TREATMENT OF RENAL CANCER: A RANDOMIZED DOUBLE-BLIND PHASE 3 STUDY OF ADJUVANT AXITINIB VS. PLACEBO IN SUBJECTS AT HIGH RISK OF RECURRENT RCC
CTID: null
Phase: Phase 3    Status: Prematurely Ended
Date: 2014-02-12
A prospective, open-label, multicenter, randomized phase II trial:
CTID: null
Phase: Phase 2    Status: Prematurely Ended
Date: 2012-06-25
Prediction of response to kinase inhibitors based on protein phosphorylation profiles in tumor tissue from advanced renal cell cancer patients
CTID: null
Phase: Phase 4    Status: Ongoing
Date: 2012-06-04
A Phase II Study of Axitinib in Patients with Metastatic Renal Cell Cancer Unsuitable for Nephrectomy
CTID: null
Phase: Phase 2    Status: GB - no longer in EU/EEA
Date: 2012-05-15
The AXitinib MicroBubble UltraSound in metastatic Colorectal cancer trial
CTID: null
Phase: Phase 2    Status: Completed
Date: 2012-04-23
A PHASE II TRIAL OF PF-04856884 (CVX-060), A SELECTIVE ANGIOPOIETIN 2 (ANG-2) INHIBITOR IN COMBINATION WITH AG-013736 (AXITINIB) IN PATIENTS WITH PREVIOUSLY TREATED METASTATIC RENAL CELL CARCINOMA
CTID: null
Phase: Phase 2    Status: Completed, Prematurely Ended
Date: 2012-02-02
A Phase II Trial of Metformin and Axitinib in BRAF Mutated Advanced Melanoma
CTID: null
Phase: Phase 2    Status: Completed
Date: 2011-10-31
A Phase II study of Axitinib as maintenance for patients with advanced colorectal carcinoma.
CTID: null
Phase: Phase 2    Status: Completed
Date: 2011-09-21
A Phase II randomized double-blind study of Santostatin LAR in combination with Axitinib versus Placebo in patients with progressive advanced well-differentiated neuroendocrine carcinomas of non-pancreatic origin (carcinoids)
CTID: null
Phase: Phase 2    Status: Ongoing, Completed
Date: 2011-08-11
AA randomized phase II clinical trial on the efficacy of axitinib as a monotherapy or in combination with lomustine for the treatment of patients with recurrent glioblastoma
CTID: null
Phase: Phase 2    Status: Completed
Date: 2011-05-05
MULTICENTER SECOND LINE STUDY OF AXITINIB IN PATIENTS WITH ADVANCED HEPATOCELLULAR CARCINOMA (HCC) PROGRESSED WITH SORAFENIB
CTID: null
Phase: Phase 2    Status: Ongoing
Date: 2011-04-19
A MULTICENTER, GLOBAL, RANDOMIZED, DOUBLE-BLIND STUDY OF AXITINIB PLUS BEST SUPPORTIVE CARE VERSUS PLACEBO PLUS BEST SUPPORTIVE CARE IN PATIENTS WITH ADVANCED HEPATOCELLULAR CARCINOMA FOLLOWING FAILURE OF ONE PRIOR ANTIANGIOGENIC THERAPY
CTID: null
Phase: Phase 2    Status: Completed
Date: 2011-01-03
AG-013736 (axitinib) for the treatment of metastatic renal cell cancer (mRCC)
CTID: null
Phase: Phase 3    Status: Completed
Date: 2010-12-21
A clinicopathological phase II study of axitinib in patients with advanced angiosarcoma and other soft tissue sarcomas
CTID: null
Phase: Phase 2    Status: Completed
Date: 2009-12-15
ESTUDIO EN FASE 2 ALEATORIZADO Y DOBLE CIEGO DE AXITINIB (AG-013736) CON O SIN AJUSTE DE LA DOSIS EN PACIENTES CON CANCER DE CELULAS RENALES METASTASICO
CTID: null
Phase: Phase 2    Status: Completed
Date: 2009-04-23
RANDOMIZED PHASE 2 STUDY OF CISPLATIN/PEMETREXED WITH OR WITHOUT AXITINIB (AG-013736) AS FIRST-LINE TREATMENT FOR PATIENTS WITH NON SQUAMOUS NON-SMALL CELL LUNG CANCER
CTID: null
Phase: Phase 2    Status: Completed
Date: 2008-12-16
PHASE 2 TRIAL OF AG-013736 AS FIRST-LINE TREATMENT FOR PATIENTS WITH SQUAMOUS NON-SMALL CELL LUNG CANCER RECEIVING TREATMENT WITH CISPLATIN AND GEMCITABINE
CTID: null
Phase: Phase 2    Status: Completed
Date: 2008-11-28
AXITINIB (AG-013736) AS SECOND LINE THERAPY FOR METASTATIC RENAL
CTID: null
Phase: Phase 3    Status: Completed
Date: 2008-06-18
Randomzied Phase 2 Trial of AG-013736 or Bevacizumab in Combination with Paclitaxel and Carboplatin as First Line Treatment For Patients with Advanced Non-small Cell Lung Cancer
CTID: null
Phase: Phase 2    Status: Completed
Date: 2008-03-20
Estudio aleatorizado en fase 2 de Folfox o Folfiri con AG-013736 o Bevacizumab en pacientes con cáncer colorrectal metastásico después del fracaso a una pauta de primera línea con irinotecan u oxaliplatino.
CTID: null
Phase: Phase 2    Status: Completed
Date: 2008-02-13
A randomized, double-blind phase 3 study of gemcitabine plus AG-013736 versus gemcitabine plus placebo for the first-line treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer
CTID: null
Phase: Phase 3    Status: Completed, Prematurely Ended
Date: 2007-08-27
A PHASE 2 STUDY OF THE ANTI-ANGIOGENESIS AGENT AG-013736 IN PATIENTS METASTATIC OR UNRESECTABLE LOCALLY-ADVANCED THYROID CANCER REFRACTORY TO, OR NOT SUITABLE CANDIDATES FOR 131I TREATMENT
CTID: null
Phase: Phase 2    Status: Completed
Date: 2006-11-24
Phase 2 Study of the Anti-Angiogenesis Agent AG-013736 as Second- or Later-Line Treatment in Patients with Advanced Non-Small Cell Lung Cancer
CTID: null
Phase: Phase 2    Status: Completed
Date: 2006-01-18
A randomized phase 2 study of the anti-angiogenesis agent AG-013736 in combination with gemcitabine in patients with chemotherapy-naïve advanced pancreatic cancer preceded by a phase 1 portion
CTID: null
Phase: Phase 2    Status: Completed
Date: 2005-07-21
Randomized, Placebo-Controlled, Double-Blind, Phase 2 Study of AG-013736 in Combination With Docetaxel Versus Docetaxel Alone in Patients With Metastatic Breast Cancer Preceded by a Phase 1 Evaluation of the Combination
CTID: null
Phase: Phase 2    Status: Completed
Date: 2004-09-24
Continuing Access to the Tyrosine Kinase Inhibitor of VEGFR-2, AG-013736 (A406) for Patients Previously Receiving AG-013736 in Clinical Trials
CTID: null
Phase: Phase 2    Status: Completed
Date:
Efficacy and Safety of Cytokines Versus Sunitinib as First-line Followed by Second-line Axitinib in the Treatment of Patients with Metastatic Renal Cell Carcinoma: A Phase III Randomized Sequential Open-Label Study
CTID: UMIN000012522
Phase: Phase III    Status: Complete: follow-up complete
Date: 2013-12-09
The exploratory study to determine optimum dosing of Axitinib (tyrosine kinase inhibitor) with pharmacokinetic analysis for patients with metastatic renal cell carcinoma
CTID: UMIN000011147
Phase:    Status: Pending
Date: 2013-07-10
A phase II study of axitinib for biliary tract cancer refractory to gemcitabine-based chemotherapy
CTID: UMIN000010520
Phase: Phase II    Status: Recruiting
Date: 2013-04-18
The evaluation of theraputic effects for advanced renal cell carcinoma patients using axitinib; dose intensity, gene polymorphism and micro vascular density
CTID: UMIN000009833
PhaseNot applicable    Status: Recruiting
Date: 2013-01-22
Phase II study of personalized titration of axitinib using therapeutic drug monitoring (TDM) in sunitinib-refractory metastatic or advanced renal cell carcinoma
CTID: UMIN000009579
Phase: Phase II    Status: Complete: follow-up complete
Date: 2012-12-19
Axitinib for the treatment of advanced hepatocellular carcinoma
CTID: jRCT2080221284
Phase:    Status:
Date: 2010-10-26

Biological Data
  • Cellular potency and selectivity of axitinib. Clin Cancer Res . 2008 Nov 15;14(22):7272-83
  • Axitinib showed in vivo target modulation and antiangiogenesis. Clin Cancer Res . 2008 Nov 15;14(22):7272-83
  • Antitumor efficacy and pharmacokinetic/pharmacodynamic correlation of axitinib. Clin Cancer Res . 2008 Nov 15;14(22):7272-83
  • Effect of axitinib in combination with chemotherapeutics and bevacizumab. Clin Cancer Res . 2008 Nov 15;14(22):7272-83
Contact Us