Flk-1 (IC50 = 1.23 μM)

Semaxanib, with an IC50 of 1.04 μM, prevents Flk-1-overexpressing NIH 3T3 cells from phosphorylating the Flk-1 receptor in a VEGF-dependent manner. With an IC50 of 20.3 μM, semaxanib prevents PDGF-dependent autophosphorylation in NIH 3T3 cells. With an IC50 of 0.04 and 50 μM, respectively, semaxanib inhibits VEGF- and FGF-driven mitogenesis in a dose-dependent manner. The in vitro growth of C6 glioma, Calu 6 lung carcinoma, A375 melanoma, A431 epidermoid carcinoma, and SF767T glioma cells (all with IC50s > 20 μM) is unaffected by semaxanib treatment.[1]

Semaxanib dose-related suppresses the in vivo growth of the A375 tumor. Daily intraperitoneal administration of SU5416 in DMSO at Semaxanib results in a >85% inhibition of subcutaneous tumor growth with no detectable toxicity. Semaxanib exhibits a wide range of antitumor properties. With an average death rate of 2.5%, SU5416 significantly inhibits the subcutaneous growth of 8 out of 10 tumor lines tested (A431, Calu-6, C6, LNCAP, EPH4-VEGF, 3T3HER2, 488G2M2, and SF763T cells).[1] The tumor microvasculature's total and functional vascular densities are significantly reduced by semaxanib (25 mg/kg/day), which exhibits strong antiangiogenic activity.[2]

---

The Semaxanib/SU5416 + hypoxia (SuHx) rat model is a commonly used model of severe pulmonary arterial hypertension. While it is known that exposure to hypoxia can be replaced by another type of hit (e.g., ovalbumin sensitization) it is unknown whether abnormal pulmonary blood flow (PBF), which has long been known to invoke pathological changes in the pulmonary vasculature, can replace the hypoxic exposure. Here we studied if a combination of Semaxanib/SU5416 administration combined with pneumonectomy (PNx), to induce abnormal PBF in the contralateral lung, is sufficient to induce severe pulmonary arterial hypertension (PAH) in rats. Sprague Dawley rats were subjected to SuPNx protocol (SU5416 + combined with left pneumonectomy) or standard SuHx protocol, and comparisons between models were made at week 2 and 6 postinitiation. Both SuHx and SuPNx models displayed extensive obliterative vascular remodeling leading to an increased right ventricular systolic pressure at week 6 Similar inflammatory response in the lung vasculature of both models was observed alongside increased endothelial cell proliferation and apoptosis. This study describes the SuPNx model, which features severe PAH at 6 wk and could serve as an alternative to the SuHx model. Our study, together with previous studies on experimental models of pulmonary hypertension, shows that the typical histopathological findings of PAH, including obliterative lesions, inflammation, increased cell turnover, and ongoing apoptosis, represent a final common pathway of a disease that can evolve as a consequence of a variety of insults to the lung vasculature. [3]

---

A significant glycolytic shift in the cells of the pulmonary vasculature and right ventricle during pulmonary arterial hypertension (PAH) has been recently described. Due to the late complications and devastating course of any variant of this disease, there is a great need for animal models that reproduce potential metabolic reprograming of PAH. Our objective is to study, in situ, the metabolic reprogramming in the lung and the right ventricle of a mouse model of PAH by metabolomic profiling and molecular imaging. PAH was induced by chronic hypoxia exposure plus treatment with Semaxanib/SU5416, a vascular endothelial growth factor receptor inhibitor. Lung and right ventricle samples were analyzed by magnetic resonance spectroscopy. In vivo energy metabolism was studied by positron emission tomography. Our results show that metabolomic profiling of lung samples clearly identifies significant alterations in glycolytic pathways. We also confirmed an upregulation of glutamine metabolism and alterations in lipid metabolism. Furthermore, we identified alterations in glycine and choline metabolism in lung tissues. Metabolic reprograming was also confirmed in right ventricle samples. Lactate and alanine, endpoints of glycolytic oxidation, were found to have increased concentrations in mice with PAH. Glutamine and taurine concentrations were correlated to specific ventricle hypertrophy features. We demonstrated that most of the metabolic features that characterize human PAH were detected in a hypoxia plus Semaxanib/SU5416 mouse model and it may become a valuable tool to test new targeting treatments of this severe disease. [4]

Polystyrene ELISA plates precoated with a Flk-1-specific monoclonal antibody are then filled with soluble membranes from 3T3 Flk-1 cells. Serial dilutions of SU5416 are added to the immunolocalized receptor following an overnight incubation at 4 °C with lysate. The ELISA plate wells containing serially diluted solutions of SU5416 are filled with varying concentrations of ATP in order to cause autophosphorylation of the receptor. After 60 minutes at room temperature, EDTA is used to halt the autophosphorylation process. The immunolocalized receptor is incubated with a biotinylated monoclonal antibody that is directed against phosphotyrosine to measure the amount of phosphotyrosine on the Flk-1 receptors in each individual well. Homo sapiens conjugated with avidin is added to the wells following the extraction of the unbound anti-phosphotyrosine antibody. Three, three, five, nine tetramethyl benzidine dihydrochloride in stabilized form is added to each well along with H₂O₂. H₂SO₄ is used to halt the reaction after 30 minutes of allowing the assay's color readout to progress.

HUVECs are cultivated at 37 °C for 24 hours to quiesce the cells after plating them in 96-well flat-bottomed plates (1×10⁴ cells/100 μL/well) in F-12K media containing 0.5% heat-inactivated FBS. After adding serial dilutions of the compounds made in the medium containing 1% DMSO for two hours, the media are then supplemented with mitogenic concentrations of acidic fibroblast growth factor (0.5–5 ng/mL) or VEGF (5 ng/mL or 20 ng/mL). In the assay, the final DMSO concentration is 0.25%. After a full day, the cell monolayers are incubated for an additional 24 hours with the addition of either BrdUrd or [³H]thymidine (1 μCi/well). One can use a liquid scintillation counter or a BrdUrd ELISA to quantify the uptake of [³H]thymidine or BrdUrd into cells, respectively.

Mice: At 12 weeks of age, female BALB/c nu/nu mice weighing 20–22 g are utilized. In this surgical procedure, aseptic technique is applied. The abdominal wall just above the colon has a tiny 1 cm midline incision made in it. Applying a 27-gauge needle beneath the colon's serosa allows for the implantation of C6 cells (0.5×10⁶ cells/animal). All of the exposed intestine is reinserted into the abdominal cavity following implantation. Using a 6.0 surgical suture and wound clips, the peritoneum and skin are sealed. Seven days following surgery, the wound clips are extracted. Starting one day after implantation, the animals receive a 50 μL intraperitoneal bolus injection of either DMSO or Semaxanib (SU5416) once a day. The animals are put to sleep 13–16 days after implantation, and the amount of local tumor growth on the colon is measured using venier calipers or by weighing the tumors. The formula for calculating tumor volumes is length × width × height.

---

Rats: Five groups of sixty male Sprague Dawley rats (n = 60, 6–8 weeks) are randomly assigned to: control (Con), pneumonectomy (PNx), Semaxanib (SU), semaxinib+hypoxia (SuHx), and semaxinib+PNx (SuPNx). It uses the SuHx protocol. In short, animals receive an injection of 25 mg/kg of semaxinib dissolved in carboxymethylcellulose (CMC) and are then exposed to 10% hypoxia for four weeks before being returned to normoxia. Animals from PNx had a left pneumonectomy. A 25 mg/kg injection of semaxinib is given two days after PNx surgery. Con received only the CMC that was solvent. Echocardiography is used to assess the morphometry and function of the heart at baseline (prehypoxia/presurgery), week 2, and week 6. The animals are put to sleep and their left and right ventricles' (LV and RV) pressures are measured using catheterization two and six weeks after surgery or hypoxia.

---

Pharmacokinetics [5]
Semaxanib plasma and urine sampling [5]
Blood samples for semaxanib were collected on day 1 of the first and second course of treatment. Blood samples (5 ml) were collected in heparinized tubes predose and at 10, 35, and 45 min, 1, 1.5, 2, 4, 6, 8, and 24 h after the semaxanib infusion. Total urinary volume was collected from 0–8, 8–24, 24–48, and 48–72 h during the first week of course 1. Immediately after collection, all samples were centrifuged at 3,000 rpm for 15 min, transferred to labeled cryostorage tubes, and frozen at −80°C until analysis.

Pharmacokinetic analyses for Semaxanib [5]
Non-compartmental modeling and parameter estimation were performed using WinNonLin®. The area under the concentration–time curve from time zero to the time of the final quantifiable sample (AUC0–Tf) was calculated using the linear trapezoid method. The AUC was extrapolated to infinity (AUC0–inf) by dividing the last measured concentration by the terminal rate constant (k), which was calculated as the slope of the log-linear terminal portion of the plasma concentration–time curve using linear regression. The terminal phase half-life (t ½) was calculated as 0.693/k. The observed maximum plasma concentration (C max) and the time to maximum concentration (T max) were determined by inspection of the concentration–time curve.

---

Rats were randomly divided among five groups: control (Con), Semaxanib/SU5416 (SU), pneumonectomy (PNx), SU5416 + hypoxia (SuHx), and SU5416 +PNx (SuPNx) (Fig. 1). The SuHx protocol was employed as previously described (5). Briefly, animals were injected with SU5416 (25 mg/kg) dissolved in carboxymethylcellulose (CMC) and exposed to hypoxia (10%) for 4 wk followed by re-exposure to normoxia. PNx animals underwent a left pneumonectomy. Two days following PNx surgery an injection of SU5416 was administered (25 mg/kg). The Con group received only the solvent CMC. Echocardiography was utilized at baseline (prehypoxia/presurgery), week 2, and week 6 to determine cardiac morphometry and function. Two and six weeks postsurgery/posthypoxia animals were anesthetized and right ventricle (RV) and left ventricle (LV) pressure measurements via catheterization were performed. Animals were killed via exsanguination, and organs were weighed and processed for analysis.[3]

---

The study was performed using an established model of PAH in mice that is generated by hypoxia exposure combined with Semaxanib (SU5416) administration (HPX+SU model). Healthy normoxic mice (NMX group) and healthy hypoxic mice (HPX group) were used as controls. The HPX+SU murine PAH model has been well-characterized in previous studies. Briefly, ten-weak-old male C57BL/6 mice (Charles River Laboratories) were exposed to normobaric hypoxia (10% of oxygen) for 3 weeks (n = 25) and were only removed from the chamber once per week for the administration of subcutaneous injections of the VEGF inhibitor, Semaxanib/SU5416. SU5416 was suspended in carboxymethyl cellulose (CMC) (0.5% [w/v] CMC sodium, 0.9% [w/v] sodium chloride, 0.4% [v/v] polysorbate 80, 0.9% [v/v] benzyl alcohol in deionized water) and injected at 20 mg/kg. HPX mice (n = 12) were exposed to the same hypoxic conditions and weekly sham injections. NMX mice (n = 25) were maintained in a room with normal oxygen levels.[4]

Pharmacokinetics and pharmacodynamics [5]
All 12 patients had plasma sampling performed for Semaxanib in course 1, and 7 patients in course 2. The principal PK parameters for semaxanib are summarized in Table 5. C max ranged from 1.2 to 3.8 μg/ml in course 1 and 1.1 to 3.9 μg/mL in course 2; t 1/2 was 1.3 ( ± 0.31) h. The PK parameters from the first and second courses were similar, suggesting neither major drug accumulation nor drug interactions. Additionally, PK parameters of exposure were similar to those observed in single-agent phase II studies, further supporting the conclusion of absence of drug interactions. Scatterplots of C max and AUC values of semaxanib for the seven patients having PK sampling on course 1 and course 2 are depicted in Figs. 1 and 2. Comparison of the C max and AUC values between cycle 1 and 2 showed no significant differences over time for C max but a decrease in the AUC values in cycle 2 (not statistically significant).

Pharmacokinetic results demonstrate Semaxanib parameters of exposure comparable to those observed in single-agent phase I studies, suggesting the lack of major drug interactions between semaxanib and thalidomide. Comparison of the C max and AUC values between course 1 and 2 showed no significant differences for C max but a decrease in the AUC values in course 2. This is consistent with results from other studies reporting an induction of clearance of 50–60% for semaxanib on the daily or biweekly dosing schedule. The mechanism of the increase in clearance is not known but may be secondary to liver enzyme induction either by the drug or by the corticosteroids required for premedication. The PD analysis revealed a trend toward an increase in serum VEGF levels for the patients receiving more than four cycles of treatment. However, no statistical comparisons could be performed in this small patient population. This observation appears consistent with recent studies suggesting that high urinary and plasma levels of VEGF may correlate with clinical response to a VEGFR inhibitor. One possible explanation for these findings may be the decrease of internalized VEGF following receptor binding during the treatment with a VEGFR inhibitor thus leading to an increase in circulating VEGF levels.

Non-hematological toxicities of Semaxanib [5]
The principal non-hematological toxicities of the regimen were headache in eight patients, that reached grade 3–4 in three patients and grade 3–4 thrombosis in three patients. Patients who experienced severe headache were all female, aged 43–59, with a history of migraine (two patients) or anxiety (one patient). This side effect occurred predominantly after the first infusion of semaxanib and decreased to a grade 1 or 2 with premedication using non-steroidal anti-inflammatory drugs for subsequent infusions. One patient, however, decided to withdraw consent after experiencing a grade 3 headache in course 1.

One patient experienced a pulmonary embolism on day 20 of the first course. Two additional patients experienced grade 3 thrombosis of the internal jugular vein and subclavian vein, respectively. For both these patients, no extension to the vena cava and no sign of pulmonary embolism was detected on a spiral computerized tomography scan. These thromboembolic events were considered drug related and affected patients were discontinued from study as required by the protocol. Sensory neuropathy, described as intermittent tingling and numbness mainly in the upper and lower extremities was observed in eight patients but generally mild to moderate: grade 1 for five patients and grade 2 for two patients. Only one patient experienced grade 3 sensory neuropathy after the first course. The same patient experienced additional neurological symptoms including headache, vertigo, loss of balance and was diagnosed with brain metastases. Lower extremity edema was a frequent but tolerable side effect (grade 1 for two patients and grade 2 for three patients). The severity of the edema appeared to increase with the number of courses of treatment received.

Other toxicities were mild to moderate (grade 1 or 2) and included: asthenia (11 patients), constipation (3 patients), hypercholesterolemia (1 patient), and hyperglycemia (2 patients). One patient experienced asymptomatic grade 4 hypertriglyceridemia after four courses of treatment and received atorvastatin calcium with significant lowering of triglyceride levels permitting continued study participation at a lower dose level. Two patients experienced asymptomatic grade 4 hyperglycemia related to the corticosteroid therapy required as premedication for semaxanib. Of note, no significant changes were observed in serum cortisol levels or coagulation tests performed during treatment; however only six patients completed these laboratory tests according to the protocol. Principal non-hematological toxicities are summarized in Table 4.

---

Hematological toxicity of Semaxanib[5]
Hematological toxicity was minimal and included grade 1 anemia in three patients. No neutropenia, lymphopenia, or thrombocytopenia was observed.

---

We showed that the VEGFR-2 tyrosine kinase inhibitor Semaxanib/SU5416 is well tolerated at a dose of 65 mg/m2 twice weekly in combination with weekly cisplatin 30 mg/m2 and irinotecan 50 mg/m2 weeks 1-4 every 6 weeks. Toxicity was overall reversible, manageable, and consistent with the previously reported toxicity profile of SU5416. At DL2, we observed an increase in hematologic toxicity over what is expected for weekly cisplatin and irinotecan, suggesting that SU5416 at higher doses may exacerbate the hematologic toxicity of this regimen. Pharmacokinetic analyses were not performed in our study, which limits our ability to fully explain this finding, and we cannot exclude that pharmacokinetic interactions resulted in increased or overlapping toxicity at DL2. Our study population was heavily pre-treated with more than 3/4 of the patients having received 2 or more lines of prior therapy, which may have limited the patients' ability to tolerate the investigational treatment regimen.
Despite administration of low-dose antithrombotic prophylaxis, we observed an increase in treatment-related venous thromboembolic events over what is expected for Semaxanib/SU5416 (0-16%) alone. Both cisplatin and irinotecan are associated with venous thromboembolism, and the use of these agents in combination with SU5416 may have contributed to the incidence of venous thromboembolic events observed on our study. It has been hypothesized that the combination of SU5416 with agents that induce thrombocytopenia may lead to an increase in thromboembolic events due to a combined effect on platelets and endothelium, which may also explain our findings. [6]

[1]. SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk-1/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization, and growth of multiple tumor types. Cancer Res, 1999, 59(1), 99-106.

[2]. Inhibition of tumor growth, angiogenesis, and microcirculation by the novel Flk-1 inhibitor SU5416 as assessed by intravital multi-fluorescence videomicroscopy. Neoplasia, 1999, 1(1), 31-41.

[3]. Pneumonectomy combined with SU5416 induces severe pulmonary hypertension in rats.Am J Physiol Lung Cell Mol Physiol. 2016 Jun 1;310(11):L1088-97.

[4]. Metabolic Reprogramming in the Heart and Lung in a Murine Model of Pulmonary Arterial Hypertension. Front Cardiovasc Med. 2018 Aug 15;5:110.

[5]. A phase II, pharmacokinetic, and biologic study of semaxanib and thalidomide in patients with metastatic melanoma. Cancer Chemother Pharmacol. 2007 Feb;59(2):165-74.

[6]. A phase I dose escalation and pharmacodynamic study of SU5416 (semaxanib) combined with weekly cisplatin and irinotecan in patients with advanced solid tumors. Onkologie. 2013;36(11):657-60.

Semaxanib is an oxindole that is 3-methyleneoxindole in which one of the hydrogens of the methylene group is replaced by a 3,5-dimethylpyrrol-2-yl group. It has a role as an antineoplastic agent, a vascular endothelial growth factor receptor antagonist, an EC 2.7.10.1 (receptor protein-tyrosine kinase) inhibitor and an angiogenesis modulating agent. It is a member of pyrroles, a member of oxindoles and an olefinic compound. It is functionally related to a 3-methyleneoxindole.
Semaxanib is a quinolone derivative with potential antineoplastic activity. Semaxanib reversibly inhibits ATP binding to the tyrosine kinase domain of vascular endothelial growth factor receptor 2 (VEGFR2), which may inhibit VEGF-stimulated endothelial cell migration and proliferation and reduce the tumor microvasculature. This agent also inhibits the phosphorylation of the stem cell factor receptor tyrosine kinase c-kit, often expressed in acute myelogenous leukemia cells.

---

Drug Indication
Investigated for use/treatment in colorectal cancer and lung cancer.

---

SU5416, a novel synthetic compound, is a potent and selective inhibitor of the Flk-1/KDR receptor tyrosine kinase that is presently under evaluation in Phase I clinical studies for the treatment of human cancers. SU5416 was shown to inhibit vascular endothelial growth factor-dependent mitogenesis of human endothelial cells without inhibiting the growth of a variety of tumor cells in vitro. In contrast, systemic administration of SU5416 at nontoxic doses in mice resulted in inhibition of subcutaneous tumor growth of cells derived from various tissue origins. The antitumor effect of SU5416 was accompanied by the appearance of pale white tumors that were resected from drug-treated animals, supporting the antiangiogenic property of this agent. These findings support that pharmacological inhibition of the enzymatic activity of the vascular endothelial growth factor receptor represents a novel strategy for limiting the growth of a wide variety of tumor types.[1]

---

Vascular endothelial growth factor (VEGF) plays a fundamental role in mediating tumor angiogenesis and tumor growth. Here we investigate the direct effect of a novel small molecule inhibitor of the Flk-1-mediated signal transduction pathway of VEGF, SU5416, on tumor angiogenesis and microhemodynamics of an experimental glioblastoma by using intravital multifluorescence videomicroscopy. SU5416 treatment significantly suppressed tumor growth. In parallel, Semaxanib/SU5416 demonstrated a potent antiangiogenic activity, resulting in a significant reduction of both the total and functional vascular density of the tumor microvasculature, which indicates an impaired vascularization as well as significant perfusion failure in treated tumors. This malperfusion was not compensated for by changes in vessel diameter or recruitment of nonperfused vessels. Analyses of the tumor microcirculation revealed significant microhemodynamic changes after angiogenesis blockage such as a higher red blood cell velocity and blood flow in remnant tumor vessels when compared with controls. Our results demonstrate that the novel antiangiogenic concept of targeting the tyrosine kinase of Flk-1/KDR by means of a small molecule inhibitor represents an efficient strategy to control growth and progression of angiogenesis-dependent tumors. This study provides insight into microvascular consequences of Flk-1/KDR targeting in vivo and may have important implications for the future treatment of angiogenesis-dependent neoplasms.[2]

---

The SU5416/Semaxanib + hypoxia (SuHx) rat model is a commonly used model of severe pulmonary arterial hypertension. While it is known that exposure to hypoxia can be replaced by another type of hit (e.g., ovalbumin sensitization) it is unknown whether abnormal pulmonary blood flow (PBF), which has long been known to invoke pathological changes in the pulmonary vasculature, can replace the hypoxic exposure. Here we studied if a combination of SU5416 administration combined with pneumonectomy (PNx), to induce abnormal PBF in the contralateral lung, is sufficient to induce severe pulmonary arterial hypertension (PAH) in rats. Sprague Dawley rats were subjected to SuPNx protocol (SU5416 + combined with left pneumonectomy) or standard SuHx protocol, and comparisons between models were made at week 2 and 6 postinitiation. Both SuHx and SuPNx models displayed extensive obliterative vascular remodeling leading to an increased right ventricular systolic pressure at week 6 Similar inflammatory response in the lung vasculature of both models was observed alongside increased endothelial cell proliferation and apoptosis. This study describes the SuPNx model, which features severe PAH at 6 wk and could serve as an alternative to the SuHx model. Our study, together with previous studies on experimental models of pulmonary hypertension, shows that the typical histopathological findings of PAH, including obliterative lesions, inflammation, increased cell turnover, and ongoing apoptosis, represent a final common pathway of a disease that can evolve as a consequence of a variety of insults to the lung vasculature. [3]

---

Purpose: This phase II study evaluated the combination of Semaxanib, a small molecule tyrosine kinase inhibitor of vascular endothelial growth factor (VEGF) receptor-2, and thalidomide in patients with metastatic melanoma to assess the efficacy, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of the combination.
Patients and methods: Patients with metastatic melanoma, who had failed at least one prior biologic and/or chemotherapeutic regimen, were treated with escalating doses of thalidomide combined with a fixed dose of Semaxanib.
Results: Twelve patients were enrolled and received 44 courses of Semaxanib at the fixed dose of 145 mg/m2 intravenously twice-weekly in combination with thalidomide, commencing at 200 mg daily with intrapatient dose escalation as tolerated. Treatment with semaxanib was initiated 1 day before thalidomide in the first course, permitting the assessment of the PKs of semaxanib alone (course 1) and in combination with thalidomide (course 2). The principal toxicities included deep venous thrombosis, headache, and lower extremity edema. Of ten patients evaluable for response, one complete response lasting 20 months and one partial response lasting 12 months were observed. Additionally, four patients had stable disease lasting from 2 to 10 months. The PKs of semaxanib were characterized by drug exposure parameters comparable to those observed in single-agent phase II studies, indicating the absence of major drug-drug interactions. Maximum semaximib plasma concentration values were 1.2-3.8 microg/ml in course 1 and 1.1-3.9 microg/ml in course 2. The mean terminal half-life was 1.3 ( +/- 0.31) h. Biological studies revealed increasing serum VEGF concentrations following treatment in patients remaining on study for more than 4 months.
Conclusion: The combination of semaxanib and thalidomide was feasible and demonstrated anti-tumor activity in patients with metastatic melanoma who had failed prior therapy. Further evaluations of therapeutic strategies that target multiple angiogenesis pathways may be warranted in patients with advanced melanoma and other malignancies. [5]

---

Background: This phase I study evaluated the safety of Semaxanib/SU5416, a potent and selective inhibitor of the vascular endothelial growth factor (VEGF) receptor tyrosine kinase Flk-1, in combination with weekly cisplatin and irinotecan in patients with advanced solid tumors.
Methods: The patients received cisplatin 30 mg/m² and irinotecan 50 mg/m² weekly from week 1 to week 4, with SU5416 at either 65 mg/m² (dose level (DL)1) or 85 mg/m² (DL2) twice weekly for 6 weeks (1 cycle). Serial ¹⁸fluorodeoxyglucose-positron emission tomography (¹⁸FDG-PET) and ¹⁵O-H₂O-PET scans were obtained.
Results: 13 patients were treated (7 on DL1, 6 on DL2); 7 patients completed at least 1 cycle of treatment. 3 patients experienced dose-limiting toxicity (DLT) at DL2 (grade 3 neutropenia and grade 3 thrombocytopenia causing treatment delay, grade 3 nausea/vomiting). No objective responses were observed at DL1, which was determined to be the maximum tolerated dose (MTD). 1 partial response (PR) was observed at DL2. ¹⁸FDG-PET responses were documented but did not predict response according to the Response Evaluation Criteria in Solid Tumors (RECIST).
Conclusions: SU5416 at 65 mg/m² twice weekly combined with cisplatin and irinotecan weekly for 4 of 6 weeks is well tolerated but without evidence of clinical activity. ¹⁸FDG-PET may be a useful pharmacodynamic marker of SU5416 bioactivity but requires additional development.[6]

C15H14N2O

238.28

238.11

C, 75.61; H, 5.92; N, 11.76; O, 6.71

204005-46-9

(Z)-Semaxanib;194413-58-6; 204005-46-9; 1055412-47-9 (Semaxanib analog/chlorinated)

5329098

Yellow to orange solid powder

1.3±0.1 g/cm3

481.4±45.0 °C at 760 mmHg

244.9±28.7 °C

0.0±1.2 mmHg at 25°C

1.684

2.87

2

1

1

18

377

0

O=C1/C(=C(/[H])\C2=C(C([H])([H])[H])C([H])=C(C([H])([H])[H])N2[H])/C2=C([H])C([H])=C([H])C([H])=C2N1[H]

WUWDLXZGHZSWQZ-WQLSENKSSA-N

InChI=1S/C15H14N2O/c1-9-7-10(2)16-14(9)8-12-11-5-3-4-6-13(11)17-15(12)18/h3-8,16H,1-2H3,(H,17,18)/b12-8-

(3Z)-3-[(3,5-dimethyl-1H-pyrrol-2-yl)methylidene]-1H-indol-2-one

Sugen 5416; Sugen5416; Sugen-5416; semoxind; SU5416; SU-5416; SU 5416; Semaxanib; Semaxinib; 204005-46-9; 194413-58-6

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (10.49 mM) (saturation unknown) 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.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 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.

---

Solubility in Formulation 2: 2.25 mg/mL (9.44 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% 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 22.5 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.

---

View More

Solubility in Formulation 3: 1% DMSO+30% polyethylene glycol+1% Tween 80: 30 mg/mL

---

 (Please use freshly prepared in vivo formulations for optimal results.)