Introduction: Vascular endothelial growth factor (VEGF) is a key regulator in angiogenesis. Preclinical and clinical data support the role of VEGF and angiogenesis in renal cell carcinoma (RCC), melanoma (M), and soft tissue sarcoma (STS). The tyrosine kinase inhibitor SU5416 is a potent inhibitor of the VEGF receptors 1 and 2.

Experimental Design: We investigated 145 mg/m2 SU5416 twice weekly in patients with advanced or metastatic RCC, M, and STS. The primary objectives were efficacy and safety. Disease assessments were performed after 4 and 8 weeks of treatment and every 2 months thereafter. Documented stable disease (SD) lasting for ≥3 months was considered an antitumor response.

Results: A group of 29 patients was entered in the RCC trial, 20 patients in the M trial, and 31 patients in the STS trial. Response was observed in 6 (1 minor response and 5 SDs) of 24 evaluable patients (25%) in the RCC group, 6 (1 minor response and 5 SDs) of 26 patients (23%) in the STS group, and none of the patients in the M group. Progression-free survival ranged from 7 to 252 days (median 59 days) in the RCC group, from 7 to 260 days (median 60 days) in the STS group, and from 14 to 139 days (median 41 days) in the M group. Toxicities observed were those reported previously for SU5416.

Conclusion: SU5416 single agent is well tolerated. The antitumor response was low in patients with RCC and STS, whereas no responses were seen in patients with M.

Angiogenesis is essential for tumor growth and metastasis (1). VEGF,3 a key regulator of angiogenesis, exerts its effects through several receptors, of which VEGFR-2 (KDR human homologue; Flk-1 murine homologue) is the most important one (2). Several lines of evidence suggest that angiogenesis is important for the development and progress of RCC. VEGFRs have been found in fetal and adult endothelial renal cells, and VEGF is highly expressed both in von Hippel-Lindau-associated and sporadic RCC (3, 4, 5, 6, 7, 8). There is also substantial evidence that VEGF is important in growth and metastases of melanoma. Increased serum concentration of VEGF is correlated with tumor progression and survival, and the expression of VEGF in metastases is much higher than in primary melanomas (9, 10). In human melanoma xenografts, it has been shown that VEGF is one of the critical angiogenic factors and that anti-VEGF strategies have induced inhibition of melanoma growth (11, 12, 13, 14). Angiogenesis is involved in the progression of STSs, because it has been shown that sarcoma cells produce large amounts of VEGF in vitro and express VEGFRs. Furthermore, staining for VEGF in tissue samples is strongly positive, and fluid collections, which are often present inside STSs, contain large amounts of VEGF (15, 16, 17).

RCC is a chemotherapy-resistant tumor. Immunotherapy, based on interleukin-2 and/or IFN-containing regimens, has only modest benefits with response rates of 15–20% and median time-to-progression in the range of 3–4 months. Advanced melanoma has a very poor prognosis, and chemotherapy and/or immunotherapy offer very modest effects. The antitumor effect of chemotherapy (doxorubicin, ifosfamide) in advanced or metastatic STS is poor (20–40% transient responses), whereas toxicity is substantial.

Disruption of the VEGF/VEGFR pathway represents an attractive target for therapy. SU5416 (Z-3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]-2-indolinone) is a small lipophilic, highly protein-bound synthetic molecule that inhibits VEGFR-1 and -2 autophosphorylation induced on interaction of VEGF with its receptors by interfering with the tyrosine kinase domain (18, 19). In preclinical studies, SU5416 is a potent inhibitor of VEGF-mediated Flk-1 receptor signaling (20, 21, 22, 23). SU5416 is mainly metabolized via the cytochrome P-450 system. The maximum tolerated dose for i.v. administration of SU5416 in 69 patients with advanced malignancies was 145 mg/m2(24, 25, 26). The dose-limiting toxicities consisted of projectile vomiting, nausea, and severe headaches. Other adverse events included superficial and deep vein phlebitis, diarrhea, and fatigue. No hematological or organ toxicities were observed.

New strategies of treatment for patients with RCC, melanoma, and STS are badly needed. The pre and clinical evidence for the role of VEGF and angiogenesis in these tumors make them logical candidates for a therapy that inhibits VEGF signaling. Hence, we performed three Phase II trials with the angiogenesis inhibitor SU5416 as a single agent in patients with these tumors.

Three open-label, multicenter Phase II trials investigating SU5416 as a single agent were conducted in patients with advanced or metastatic RCC, melanoma, or STS. Primary objectives were response rate, response duration, and PFS. Secondary objectives included further characterization of SU5416 safety in these groups of patients.

Eligibility Criteria.

Entry in these Phase II trial was restricted to patients who met all of the following criteria: (a) age ≥ 18 years; (b) histologically proven; (c) stage III or IV; (d) RCC, M, or STS; (e) not amenable for standard therapy; and (f) progressive over the previous 8 weeks, with an Eastern Cooperative Oncology Group Performance Status ≤ 2. At least one bidimensionally measurable lesion according to WHO criteria was obliged. Previous treatment with immuno/chemotherapy was allowed, provided that the treatment-free interval was >4 weeks (6 weeks for Mitomycin C or nitrosoureas). Brain metastases were acceptable, provided that they were controlled by irradiation or medication, other than corticosteroids. Surgery within 4 weeks or treatment with erythropoietin, granulocyte colony-stimulating factor, or granulocyte macrophage colony-stimulating factor within 2 weeks before study entry was not allowed. Treatment with any investigational agent within 4 weeks of study entry or any previous angiogenesis-inhibiting agent, as well as concomitant steroid treatment for whatever reason, was not allowed. Patients had to have an absolute neutrophil count > 1.5 × 109/liter, hemoglobin > 5.5 mmol/liter, platelet count ≥ 100 × 109/liter, bilirubin ≤ 1.25 × upper normal limit, and a serum creatinine ≤ 150 μmol/liter or a creatinine clearance ≥ 40 ml/min.

Patients with cardiovascular disease, insulin-dependent diabetes, or significant comorbidity were excluded. A history of previous or concomitant other malignant disease, except basal cell carcinoma of the skin or in situ cervical carcinoma, was not allowed. Patients with history of allergic reactions to taxanes or a known allergy to Cremophor were excluded. Effective contraception by both male and female patients, and a negative urine pregnancy test within 4 days before receiving the first dose of SU5416 and every 8 weeks thereafter for all female patients at risk, was demanded. Protocols were approved by local human investigations committees, and written informed consent was obtained before study entry.

Drug Administration.

SU5416, supplied as a yellow-orange liquid formulation, was diluted 1:3 with 0.45% NaCl before administration. Components of the formulation include polyethylene glycol 400, polyoxyl 35 castor oil (Cremophor), benzyl alcohol, and dehydrated alcohol. Twice weekly 145 mg/m2 SU5416 was given i.v. over 90 min (in case of severe headache, slower). Each period of 4 weeks was considered as one treatment cycle.

To prevent allergic reactions to Cremophor, dexamethasone was administered p.o. 12 and 6 h before infusion. The dose of dexamethasone was 5 mg before the first two infusions, decreasing to 2 mg during the next two infusions and 1 mg thereafter, if no allergic reactions occurred. Furthermore, 2 mg of clemastine and 300 mg of cimetidine were given i.v. 0.5 h before each infusion.

Toxicity Evaluation.

Pretreatment evaluation was performed within 7 days before initiating therapy and included a complete history and physical examination, urinalysis, 12 lead electrocardiography, a complete blood cell count, serum chemistries, and tumor markers when indicated.

Each dose of SU5416 was closely monitored for toxicity. Vital signs were obtained before, during, and after every infusion. During the treatment period, screening for toxicity according to the NCI-CTC criteria (version 2), complete physical examination, performance status, complete blood cell count, and serum chemistries were obtained weekly. Twelve lead electrocardiography was performed every 4 weeks.

Any serious adverse or unexpected event had to be reported within 24 h of knowledge of the event, and a written report had to be submitted within one working day to New Drug Development Organization Oncology.

Response Evaluation.

Tumor staging was assessed with computed tomography or magnetic resonance imaging scans. All measurable lesions were followed for response evaluation, which was assessed after 4 and 8 weeks of treatment and every 2 months thereafter or in case of clinical suspicion of PD.

In contrast with response criteria normally used in chemotherapy trials, three major differences were present: (a) because the effect of SU5416 was not expected within one treatment cycle, PD ≤ 50% but without the development of new lesions was allowed at evaluation after 4 weeks of treatment; (b) this tumor assessment was taken as new baseline; and (c) SD lasting at least three treatment cycles was considered as a response. In case of SD or tumor regression, treatment would be continued, unless unacceptable toxicity occurred, to a maximum period of 1 year.

RCC.

Between July 1999 and November 2000, 20 male and 9 female patients, age 30–78 years (median 54), were entered in the RCC trial (Table 1). All patients, except 1, had previous tumor nephrectomy. Because of metastases, all patients, except 5, received previous immunotherapy (α-IFN and/or interleukin-2 and others), which was combined with chemotherapy in 17 patients (5-fluorouracil and others).

Five patients were considered not evaluable for response. Two patients (7 and 12) received less than one cycle, 1 because of rapid PD and 1 because of intestinal obstruction caused by tumor localization. Baseline tumor measurement in patient 6 was performed >14 days before day 1. Two patients (27 and 29) did not fulfill all in- or exclusion criteria; 1 patient suffered from diabetes mellitus with severe peripheral vascular disease and had no full tumor evaluation at baseline. Another used corticosteroids before and during the study.

A total of 24 patients was evaluable for response. SD was observed in 9 patients, which in 3 was not confirmed after 8 weeks of treatment because of development of a SAE in 2 patients (3 and 28) and discontinuation of treatment on patient’s request (14). Confirmed SD in the other 6 patients lasted from six to eight cycles. In 1 of these patients (5), an ongoing decrease of almost all lung metastases was observed during the first four cycles, cumulating in a 40% tumor reduction (MR). However, evaluation after six cycles showed evident increase of all lesions and the appearance of new lung metastases. Despite PD after seven cycles, patient 15 received two more cycles, because he was clinically not progressive and lack of alternative treatment. From cycles three up to six, patient 18 received once weekly infusions of SU5416.

In 15 patients, PD was documented during the first four cycles. However, patient 10 received five cycles, because the one measurable lesion, which was progressive after the first cycle, was irradiated during the second cycle, and the not measurable liver and lung lesions appeared stable until cycle five. Despite PD after four cycles in patient 23, six cycles were given, because target lesions were stable, and the new lesions that had appeared were <1 cm.

Hence, 6 patients of 24 evaluable patients (25%) had a confirmed response. This is 21% (6 of 29) of the intention-to-treat population. It is noteworthy that all patients experiencing a response, with the exception of 1, had an interval of >6 years between diagnosis of the primary tumor and inclusion in this trial. PFS ranged from 7 to 252 days (median 59 days) and OS from 21 to 511 days (median 276 days), including 10 patients who were still alive in October 2001. In 13 patients, treatment was discontinued because of the development of new lesions any time during treatment with SU5416.

Melanoma.

Between July 1999 and September 2001, 10 male and 10 female patients, median age 53.5 years (range 23–71), were entered in the melanoma trial (Table 2). All patients, except 2, had received previous surgery, and 5 received radiotherapy. Metastatic disease was in all patients, except 2, treated with systemic treatment, which consisted of chemotherapy (dacarbazine, cisplatin, and others), immunotherapy (α-IFN, interleukin-2, and others), hormonal treatment (tamoxifen and others), or combinations.

Three patients were considered not evaluable for response, because in 1 patient (1), no full tumor assessment was performed, and 2 other patients (9 and 11) received less than one cycle. Patient 9 discontinued treatment because of relapsing inflammatory pericarditis with pericardial effusions, which was considered not related to SU5416 or to tumor. Patient 11 developed rapid PD with the formation of ascites.

Hence, 17 patients were evaluable for response. No responses were observed. During cycles 1–4, PD was observed in 15 patients, which in 13 patients consisted, besides tumor increase of >50%, of development of new lesions. One patient (16), however, received seven cycles because SD was suspected, which after revision of tumor assessments, turned out to be PD after cycle 1. Two patients had an unconfirmed SD after one cycle but discontinued treatment because of drug-related hypersensitivity reactions. PFS ranged from 14 to 139 days (median 41 days), and OS ranged from 29 to 504 days (median 107.5 days), including 5 patients who were still alive in October 2001.

STS.

Between July 1999 and January 2001, 17 male and 14 female patients, median age 51 years (21–71), were entered in the STS trial (Table 3). Surgery of the primary tumor was performed in 25 patients. Radiotherapy, adjuvant or for metastatic disease, was given in 10 patients. Because of metastatic disease, 26 patients had received chemotherapy (doxorubicin and/or ifosfamide) before study entry. Four patients had also received an experimental treatment.

Five patients were considered not evaluable for response. Three patients (2, 6, and 8) received less than one cycle; 2 discontinued treatment because of rapid PD (2 and 8), and 1 died because of hepatic hemorrhage from a hepatic lesion of angiosarcoma (6), which was not considered to be related to SU5416. Two patients violated in- or exclusion criteria; patient 20 had no measurable lesion, and patient 28 used corticosteroids before and during treatment.

A total of 26 patients was evaluable for response. One patient (25) experienced an unconfirmed partial remission; after the first cycle, a tumor reduction of 51% was noted, which was 47% after the second cycle. However, after cycles 3 and 4, evident disease progression was documented. Confirmed SD was observed in 5 patients (5, 14, 19, 26, and 31). Patient 5 discontinued treatment during the fourth cycle because of weight loss grade III and a severe decline of his performance status (grade IV), which were both the result of a severe depression. Shortly thereafter, PD was noted. Patient 19 had PD after the fifth treatment cycle. End of study was the reason to stop treatment in the other 3 patients; 1 patient (31) continued treatment for another five cycles in a compassionate use protocol. One patient (18) had an unconfirmed SD; this patient decided to stop with SU5416 because of difficulty coming to the hospital twice weekly. PD during cycles 1–4 was the reason to stop treatment in 19 patients. Eleven patients developed new lesions at any time during the treatment.

Hence, 6 (1 MR and 5 SD) of 26 evaluable patients (23%) had a response. This is 19% (6 of 31) of the intention-to-treat population. PFS ranged from 7 to 260 days (median 60 days), and OS ranged from 7 to 505 days, including 15 patients who were still alive in October 2001.

We mention one observation separately because a remarkable phenomenon was observed at tumor assessment after 4 weeks of treatment in a 40-year-old woman (Table 3, patient 4) with a local-regional recurrence of a gastro-intestinal stroma cell tumor in the upper abdomen. The tumor was reduced in size only because of a decrease of centrally located tumor fluid (Fig. 1). At the next two tumor assessments after 8 and 12 weeks of treatment, PD was observed, but the fluid content of the tumor remained decreased.

Toxicity.

All 80 patients, who received a total of 230 cycles of SU5416, were included in the safety and toxicity analysis. The adverse events that were observed were mainly those reported before: (a) headache; (b) phlebitis; (c) nausea; (d) vomiting; (e) anorexia; (f) diarrhea; and (g) asthenia (Table 4). Seven patients died during treatment with SU5416. In 6 patients, this was considered not to be related to the treatment, because (rapid) PD was observed in 5 patients and massive bleeding from liver metastases, which occurred shortly after start of the treatment, in a patient with angiosarcoma. That necrosis of the liver metastases as a result of the treatment caused the bleeding seemed unlikely, although it could not be ruled out completely. A fatal myocardial infarction, occurring in the 5th week of treatment in patient 4 of the RCC group, was considered possibly related, because, besides obesity, this patient had no other cardiovascular risk factors. Other SAEs included four thromboembolic events, which were considered possibly related to SU5416, although these patients had other risk factors for thromboembolism, such as malignancy, previous radiotherapy (patient 16, STS group), and a central line (patient 6, RCC group). Three patients of the RCC group developed reversible renal insufficiency, which in 2 (patients 3 and 20) was considered as not related to SU5416 but attributable to the underlying disease in combination with infection and concomitant medication (nonsteroid anti-inflammatory drugs). The third renal insufficiency (patient 28) was caused by dehydration secondary to diarrhea. All symptoms recurred in patient 28 after rechallenge with SU5416 and was therefore considered probably related. Diarrhea with metabolic acidosis in patient 27 of the RCC group was attributable to an intercurrent infection. All other SAEs, besides two allergic reactions grade III, were considered not to be related to SU5416.

We investigated the safety and efficacy of the angiogenesis inhibitor SU5416 as a single agent in patients with advanced or metastatic RCC, melanoma, or STS. SU5416 twice weekly i.v. was well tolerated with similar toxicities as reported previously (headache, phlebitis, and asthenia). SAEs possibly related to SU5416 therapy consisted of five thromboembolic events (four deep venous thromboses and one fatal myocardial infarction). This incidence of 6.3% is similar as reported previously in a patient population with malignancy (27). We observed no efficacy in patients with melanoma and, in view of the response criteria used, low efficacy (Table 5) in patients with RCC and STS (25 and 23%, respectively). Besides two MRs, the efficacy consisted only of SDs, which, in the patients with RCC, could also be part of the natural history of their disease, because most of them had a long interval between primary diagnosis and start of SU5416 treatment. In a prospective, randomized, double-blind trial comparing placebo, low dose, and high dose of a neutralizing antibody to VEGF (bevacizumab), also no major responses were observed, but interim analysis showed a highly significant prolongation of time-to-progression of high-dose antibody versus placebo (28). Because of our trial design, we cannot draw any conclusion whether SU5416 did prolong time-to-progression.

The low efficacy is remarkable in view of the substantial evidence that VEGF is definitely involved in the development and progress of these three tumor types. Moreover, because SU5416 has proven its efficacy in human melanoma and sarcoma xenograft models, by which mechanisms could explain the lack of efficacy in humans bearing these tumors (20, 29). We will discuss seven possible mechanisms.

Patients with large tumors may have established mature vessels, instead of immature VEGF-dependent vessels. The vascular dependence of tumor cells may differ substantially inside tumors (30). However, the fact that ∼50% of the patients developed new tumor lesions during SU5416 therapy sharply demonstrates the inefficacy of this treatment and points to a primary resistance for this kind of treatment. Latent metastatic lesions in these patients made the angiogenic switch, and SU5416 could not change the balance of pro- and antiangiogenic factors in the right direction (1).

The bioavailability of SU5416 in tumors may be insufficient. The presence of very high local concentrations of VEGF in tumors may overcome the effects of SU5416. In vitro and in vivo data indicate that 145 mg/m2 SU5416 twice weekly reaches effective plasma and cellular concentrations and has long-lasting effects on VEGFR phosphorylation and function in animal models, but the effects in large human tumors are unknown, and the short plasma half-life could be significant (23).

The most probable explanations for the lack of efficacy and also pointing to primary resistance are the presence of many different pro-angiogenic factors in tumors and the redundancy of these pro-angiogenic factors. The process of angiogenesis is regulated by many different factors (complexity), which have overlapping activity (redundancy; Ref. 31). Tumor cells can produce, besides VEGF, many other angiogenesis stimulators, e.g., among others, basic fibroblast growth factors and hepatocyte growth factor, e.g., in preclinical models, it has been shown that basic fibroblast growth factor has an essential autocrine role and that VEGF has a beneficial but not essential role in human melanoma (32). Many pro-angiogenic growth factors may act as antiapoptotic regulators, via the up-regulation of, among others, bcl-2 and survivin in endothelial cells by nonoverlapping signaling pathways (33, 34, 35). Two possible mechanisms of secondary resistance are: (a) the selection of tumor cells that produce other or more different growth factors during treatment with an angiogenesis inhibitor, which targets one specific growth factor; and (b) a change of apoptotic responses caused by epigenetic modulation of expression of genes in endothelial cells, which encode antiapoptotic effector molecules (34, 35).

Receptor heterodimerization has been described for the platelet-derived growth factor receptor and epidermal growth factor receptor as a mechanism for transactivation (36). It is unknown whether heterodimerization is also occurring between the different VEGFRs or with other growth factor receptors, which may result in bypassing the effects of SU5416.

The observation of the decrease in tumor fluid in the STS patient described points to the fact that: (a) VEGF is a permeability factor and, this effect of VEGF can be blocked with SU5416; and (b) caution in defining a response is necessary.

In conclusion, the inhibition of one of the key players is probably not enough to inhibit angiogenesis entirely. New compounds that target several different growth factors, such as SU6668 and SU11248 (inhibitors of the VEGFR, platelet-derived growth factor receptor, and fibroblast growth factor receptor), and/or combinations of new biological compounds, which target different pathways involved in angiogenesis, such as matrix metalloproteinases, integrins, and cell adhesion molecules, have to be explored. Combinations with classical chemotherapy have to also be considered. Much is still unclear concerning dosages and optimal ways of administration of these new biological agents alone and in combination with chemotherapy. Unexpected toxicities have been observed, and caution must be paid in the combination of novel biological agents and chemotherapy (37).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1

Supported by Sugen, Inc.

3

The abbreviations used are: VEGF, vascular endothelial growth factor; RCC, renal cell carcinoma; MR, minor response; SD, stable disease; PD, progressive disease; STS, soft tissue sarcoma; SAE, serious adverse event; VEGFR, vascular endothelial growth factor receptor; PFS, progression-free survival; OS, overall survival.

Fig. 1.

Tumor assessments in a patient with a local-regional recurrence of a gastro-intestinal stroma cell tumor. A, before treatment start: tumor area 9050 mm2 (white line); fluid area 4601 mm2 (dark line). B, after 4 weeks of treatment: tumor area 8045 mm2; fluid area 3701 mm2.

Fig. 1.

Tumor assessments in a patient with a local-regional recurrence of a gastro-intestinal stroma cell tumor. A, before treatment start: tumor area 9050 mm2 (white line); fluid area 4601 mm2 (dark line). B, after 4 weeks of treatment: tumor area 8045 mm2; fluid area 3701 mm2.

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Table 1

Patient characteristics of RCCa

PatientAgeSexPSIntervalb (months)Site of metastasesPrevious treatmentNo. of cyclesResponseResponse durationReason off studySAE
52 16 lu S,RT,IT + CT PD  PD  
54 65 lu,pl PD  PD (nl)  
55 lu,li,lnn S,IT + CT PD  PD RI with metabolic acidosis 
56 19 lu S,IT SDnc 1 cycle SAE Fatal myocardial infarction 
77 185 lu,adre MR (40%) 6 cycles PD (nl)  
38 lu,lnn,bo S,IT + CT 1c NE  SAE Jugular vein thrombosis 
47 13 lu,pl S,IT <1 NE  rPD Death caused by PD 
60 57 lu S,IT PD  PD  
59 73 lnn S,IT + CT SD 8 cycles PD  
10 67 15 lu,li,lnn,bo S,IT 5c PD  PD (nl) DVT iliacal vein left 
11 47 12 lnn,bo S,RT,IT + CT PD  PD (nl)  
12 63 159 lu,li,lnn S,IT + CT <1c NE  SAE Intestinal obstruction 
13 53 17 lu,li,lnn S,RT,IT + CT 6c SD 6 cycles PD (nl)  
14 78 20 lu S,HT,IT 2c SDnc 2 cycles OR  
15 68 196 lu,li,bo S,RT,HT,IT + CT 9c SD 7 cycles PD  
16 30 160 li,lnn,bo S,RT,IT + CT 8c SD 8 cycles PD (nl)  
17 54 67 lu,lnn S,IT + CT 5c PD  PD (nl)  
18 49 77 lnn S,IT + CT 6c SD 6 cycles PD  
19 52 na lu None PD  PD (nl) Death caused by PD 
20 59 15 lnn S,CT PD  PD RI and urinary tract infection 
21 41 57 lu S,IT + CT 2c PD  PD (nl)  
22 51 33 rec,lnn,sk S,RT,IT + CT 2c PD  PD (nl) Death caused by PD 
23 49 28 lu,li,lnn,sp S,IT + CT 6c PD  PD (nl)  
24 51 lnn S,IT + CT 4c PD  PD  
25 40 12 lu,lnn S,IT PD  PD (nl)  
26 60 li,lnn,st S,IT + CT 3c PD  PD (nl)  
27 64 lu,lnn S,HT,IT + CT 1c NE  PD Diarrhea with metabolic acidosis 
28 74 75 lu,lnn,adre SDnc 1 cycle SAE Diarrhea with dehydration and RI 
29 59 lu,bo S,RT,IT 1c NE  PD (nl)  
PatientAgeSexPSIntervalb (months)Site of metastasesPrevious treatmentNo. of cyclesResponseResponse durationReason off studySAE
52 16 lu S,RT,IT + CT PD  PD  
54 65 lu,pl PD  PD (nl)  
55 lu,li,lnn S,IT + CT PD  PD RI with metabolic acidosis 
56 19 lu S,IT SDnc 1 cycle SAE Fatal myocardial infarction 
77 185 lu,adre MR (40%) 6 cycles PD (nl)  
38 lu,lnn,bo S,IT + CT 1c NE  SAE Jugular vein thrombosis 
47 13 lu,pl S,IT <1 NE  rPD Death caused by PD 
60 57 lu S,IT PD  PD  
59 73 lnn S,IT + CT SD 8 cycles PD  
10 67 15 lu,li,lnn,bo S,IT 5c PD  PD (nl) DVT iliacal vein left 
11 47 12 lnn,bo S,RT,IT + CT PD  PD (nl)  
12 63 159 lu,li,lnn S,IT + CT <1c NE  SAE Intestinal obstruction 
13 53 17 lu,li,lnn S,RT,IT + CT 6c SD 6 cycles PD (nl)  
14 78 20 lu S,HT,IT 2c SDnc 2 cycles OR  
15 68 196 lu,li,bo S,RT,HT,IT + CT 9c SD 7 cycles PD  
16 30 160 li,lnn,bo S,RT,IT + CT 8c SD 8 cycles PD (nl)  
17 54 67 lu,lnn S,IT + CT 5c PD  PD (nl)  
18 49 77 lnn S,IT + CT 6c SD 6 cycles PD  
19 52 na lu None PD  PD (nl) Death caused by PD 
20 59 15 lnn S,CT PD  PD RI and urinary tract infection 
21 41 57 lu S,IT + CT 2c PD  PD (nl)  
22 51 33 rec,lnn,sk S,RT,IT + CT 2c PD  PD (nl) Death caused by PD 
23 49 28 lu,li,lnn,sp S,IT + CT 6c PD  PD (nl)  
24 51 lnn S,IT + CT 4c PD  PD  
25 40 12 lu,lnn S,IT PD  PD (nl)  
26 60 li,lnn,st S,IT + CT 3c PD  PD (nl)  
27 64 lu,lnn S,HT,IT + CT 1c NE  PD Diarrhea with metabolic acidosis 
28 74 75 lu,lnn,adre SDnc 1 cycle SAE Diarrhea with dehydration and RI 
29 59 lu,bo S,RT,IT 1c NE  PD (nl)  
a

PS, performance status; lu, lung; li, liver; lnn, lymphnodes; pl, pleural; adre, adrenal; bo, bone; rec, recurrence primary site; sk, skin; sp, spleen; st, soft tissue; S, surgery; RT, radiotherapy; IT, immunotherapy; CT, chemotherapy; IT + CT, combined immunochemotherapy; HT, hormonal therapy; rPD, rapidly progressive disease; NE, not evaluable; OR, own request; nc, nonconfirmed; (nl), new lesion; DVT, deep venous thrombosis; RI, renal insufficiency.

b

Interval between diagnosis of primary tumor and start of SU5416 treatment.

c

SU5416 given via central line.

Table 2

Patient characteristics of melanomaa

PatientAgeSexPSPrimary siteIntervalb (months)Site of metastasesPrevious treatmentNo. of cyclesResponseReason off studySAE
58 Right foot 38 sk S,RT NE PD (nl) DVT left leg 
56 Back 58 lu,li,lnn,sk,bo,adre PD PD (nl)  
42 Back 130 lu,lnn,sk,pl S,RT,CT PD PD (nl) Pleuritis carcinomatosa 
55 Back 108 lu,li,lnn,pl S,IT + CT PD PD  
36 Right hand 28 li,lnn,adre S,RT,IT + CT PD PD (nl) Death caused by PD 
56 Right foot 35 lu,lnn,sk S,RT,IT + CT PD PD (nl)  
33 Unknown 26 lu,lnn,sk S,RT,IT + CT PD PD (nl)  
51 Right knee 105 lu,li S,IT + CT 5c PD PD (nl)  
49 Right shoulder 172 lu,sk S,CT,IT <1c NE SAE Pericardial effusion 
10 33 Unknown lu,li,lnn,sk,pl CT + HT 1c PD PD (nl) Infection central line 
11 58 Umbilicus 13 lu,li,bo,lnn,sk,per S,IT <1c NE rPD (nl) Ascites caused by tumor 
12 41 Right upper leg 35 lu,li,lnn,sk S,IT + CT PD PD (nl)  
13 40 Right knee 22 lu,li,lnn,sk,sp,adre S,CT PD PD (nl) Pneumonia 
14 71 Left foot 83 sk,lnn,per,st S,CT,IT PD PD (nl)  
15 52 Right middle finger 35 lu,lnn,sk S,CT + HT 2c PD PD (nl)  
16 59 Left lower leg 38 lu,lnn S,CT + HT 7c,d PD PD (nl)  
17 23 Back 71 lu,sk S,CT SDnc SAE Urticaria grade III 
18 64 Unknown lu,li CT 1c SDnc SAE Allergic reaction grade III 
19 67 Neck 56 lu,lnn S,CT + HT 1c PD PD (nl) Infection central line 
20 66 Vulva 13 lu,lnn S,IT 4c PD PD  
PatientAgeSexPSPrimary siteIntervalb (months)Site of metastasesPrevious treatmentNo. of cyclesResponseReason off studySAE
58 Right foot 38 sk S,RT NE PD (nl) DVT left leg 
56 Back 58 lu,li,lnn,sk,bo,adre PD PD (nl)  
42 Back 130 lu,lnn,sk,pl S,RT,CT PD PD (nl) Pleuritis carcinomatosa 
55 Back 108 lu,li,lnn,pl S,IT + CT PD PD  
36 Right hand 28 li,lnn,adre S,RT,IT + CT PD PD (nl) Death caused by PD 
56 Right foot 35 lu,lnn,sk S,RT,IT + CT PD PD (nl)  
33 Unknown 26 lu,lnn,sk S,RT,IT + CT PD PD (nl)  
51 Right knee 105 lu,li S,IT + CT 5c PD PD (nl)  
49 Right shoulder 172 lu,sk S,CT,IT <1c NE SAE Pericardial effusion 
10 33 Unknown lu,li,lnn,sk,pl CT + HT 1c PD PD (nl) Infection central line 
11 58 Umbilicus 13 lu,li,bo,lnn,sk,per S,IT <1c NE rPD (nl) Ascites caused by tumor 
12 41 Right upper leg 35 lu,li,lnn,sk S,IT + CT PD PD (nl)  
13 40 Right knee 22 lu,li,lnn,sk,sp,adre S,CT PD PD (nl) Pneumonia 
14 71 Left foot 83 sk,lnn,per,st S,CT,IT PD PD (nl)  
15 52 Right middle finger 35 lu,lnn,sk S,CT + HT 2c PD PD (nl)  
16 59 Left lower leg 38 lu,lnn S,CT + HT 7c,d PD PD (nl)  
17 23 Back 71 lu,sk S,CT SDnc SAE Urticaria grade III 
18 64 Unknown lu,li CT 1c SDnc SAE Allergic reaction grade III 
19 67 Neck 56 lu,lnn S,CT + HT 1c PD PD (nl) Infection central line 
20 66 Vulva 13 lu,lnn S,IT 4c PD PD  
a

PS, performance status; lu, lung; li, liver; lnn, lymphnodes; pl, pleural; adre, adrenal; bo, bone; rec, recurrence primary site; sk, skin; sp, spleen; st, soft tissue; S, surgery; RT, radiotherapy; IT, immunotherapy; CT, chemotherapy; IT + CT, combined immunochemotherapy; HT, hormonal therapy; rPD, rapidly progressive disease; NE, not evaluable; OR, own request; nc, nonconfirmed; (nl), new lesion; DVT, deep venous thrombosis; RI, renal insufficiency.

b

Interval between diagnosis of primary tumor and start of SU5416 treatment.

c

SU5416 given via central line.

d

After revision of evaluation, it was found that PD was present after cycle 1.

Table 3

Patient characteristics of soft tissue sarcomaa

PatientAgeSexPSDiagnosisPrimary siteIntervalb (months)Site of metastasesPrevious treatmentNo. of cyclesResponseResponse durationReason off studySAE
67 GIST Gastric li PD  PD (nl)  
36 Angiosarcoma Adrenal 32 lu,rec S,RT,CT,IT <1 NE  rPD Death caused by PD 
37 GIST Gastric prim,li,lnn CT PD  PD  
40 GIST Gastric rec PD  PD  
49 Schwannoma Flank 10 lu,lnn S,CT SD 4 cycles SAE Weight loss + decrease PS 
28 Angiosarcoma Breast 11 li,lnn,bo S,CT <1 NE  Death Bleeding liver metastases 
50 Leiomyosarcoma Retpet 42 lu,li S,RT,CT PD  PD (nl)  
60 Pleomorphic STS Breast lu,pl S,RT,CT <1c NE  rPD (nl) Pleuritis carcinomatosa 
55 Leiomyosarcoma Peroneal 10 lu,li,bo,sp S,CT PD  PD (nl)  
10 44 Leiomyosarcoma Abdom 36 lu PD  PD (nl)  
11 45 Leiomyosarcoma Abdom 31 rec,lu,per S,CT,ET PD  PD  
12 36 Sarcoma Gastric 19 li,lnn,ren S,CT 5c PD  PD (nl) Tachycardia (WPW) 
13 51 Leiomyosarcoma Kidney lu,sk S,CT PD  PD  
14 69 Leiomyosarcoma nk 13 li,sp CT 14c SD 12 cycles EoS  
15 59 Leiomyosarcoma Intestine 47 li S,IT,HT PD  PD  
16 62 MFH Shoulder 78 lu,rec S,RT,CT PD  SAE + PD (nl) DVT left subclavian vein 
17 62 Leiomyosarcoma Retpet 46 lu,li,rec,per S,CT 2c PD  PD  
18 21 Neurofibrosarcoma Sacral lnn,pl,rec None SDnc  OR  
19 71 Leiomyosarcoma Axilla 18 lu,retper S,CT SD 5 cycles PD  
20 57 nd Hemangiopericytoma Tentorium 334 li S,RT,CT,HT NE  PD (nl)  
21 51 Leiomyosarcoma Bladder 91 lu,li,lnn S,CT 3c PD  PD (nl)  
22 49 Histiocytoma Vas def 218 lu,rec,st S,RT,CT 2c PD  PD (nl)  
23 66 Leiomyosarcoma Uterus 233 li S,CT 2c PD  PD (nl)  
24 71 Leiomyosarcoma Gluteus lu,rec CT 3c PD  PD  
25 60 MFH Gastric 35 rec S,CT MR  PD  
26 49 Hemangiopericytoma Abdom li,rec,bo CT,RT 7c SD 7 cycles EoS Exogenous psychosis 
27 62 MFH Retpet 36 li,rec S,RT,CT PD  PD  
28 26 Neurofibrosarcoma Thigh 27 pl,st S,RT,CT,ET 2c NE  PD  
29 57 Liposarcoma Thigh 161 per S,RT,CT,ET 1c PD  PD  
30 44 Sarcoma Abdom 18 li S,CT,ET 1c PD  PD  
31 52 Hemangioendothelioma Bronchus 10 lu,rec CT 5 (+4cu)c SD 9 cycles EoS  
PatientAgeSexPSDiagnosisPrimary siteIntervalb (months)Site of metastasesPrevious treatmentNo. of cyclesResponseResponse durationReason off studySAE
67 GIST Gastric li PD  PD (nl)  
36 Angiosarcoma Adrenal 32 lu,rec S,RT,CT,IT <1 NE  rPD Death caused by PD 
37 GIST Gastric prim,li,lnn CT PD  PD  
40 GIST Gastric rec PD  PD  
49 Schwannoma Flank 10 lu,lnn S,CT SD 4 cycles SAE Weight loss + decrease PS 
28 Angiosarcoma Breast 11 li,lnn,bo S,CT <1 NE  Death Bleeding liver metastases 
50 Leiomyosarcoma Retpet 42 lu,li S,RT,CT PD  PD (nl)  
60 Pleomorphic STS Breast lu,pl S,RT,CT <1c NE  rPD (nl) Pleuritis carcinomatosa 
55 Leiomyosarcoma Peroneal 10 lu,li,bo,sp S,CT PD  PD (nl)  
10 44 Leiomyosarcoma Abdom 36 lu PD  PD (nl)  
11 45 Leiomyosarcoma Abdom 31 rec,lu,per S,CT,ET PD  PD  
12 36 Sarcoma Gastric 19 li,lnn,ren S,CT 5c PD  PD (nl) Tachycardia (WPW) 
13 51 Leiomyosarcoma Kidney lu,sk S,CT PD  PD  
14 69 Leiomyosarcoma nk 13 li,sp CT 14c SD 12 cycles EoS  
15 59 Leiomyosarcoma Intestine 47 li S,IT,HT PD  PD  
16 62 MFH Shoulder 78 lu,rec S,RT,CT PD  SAE + PD (nl) DVT left subclavian vein 
17 62 Leiomyosarcoma Retpet 46 lu,li,rec,per S,CT 2c PD  PD  
18 21 Neurofibrosarcoma Sacral lnn,pl,rec None SDnc  OR  
19 71 Leiomyosarcoma Axilla 18 lu,retper S,CT SD 5 cycles PD  
20 57 nd Hemangiopericytoma Tentorium 334 li S,RT,CT,HT NE  PD (nl)  
21 51 Leiomyosarcoma Bladder 91 lu,li,lnn S,CT 3c PD  PD (nl)  
22 49 Histiocytoma Vas def 218 lu,rec,st S,RT,CT 2c PD  PD (nl)  
23 66 Leiomyosarcoma Uterus 233 li S,CT 2c PD  PD (nl)  
24 71 Leiomyosarcoma Gluteus lu,rec CT 3c PD  PD  
25 60 MFH Gastric 35 rec S,CT MR  PD  
26 49 Hemangiopericytoma Abdom li,rec,bo CT,RT 7c SD 7 cycles EoS Exogenous psychosis 
27 62 MFH Retpet 36 li,rec S,RT,CT PD  PD  
28 26 Neurofibrosarcoma Thigh 27 pl,st S,RT,CT,ET 2c NE  PD  
29 57 Liposarcoma Thigh 161 per S,RT,CT,ET 1c PD  PD  
30 44 Sarcoma Abdom 18 li S,CT,ET 1c PD  PD  
31 52 Hemangioendothelioma Bronchus 10 lu,rec CT 5 (+4cu)c SD 9 cycles EoS  
a

PS, performance status; GIST, gastrointestinal stroma cell tumor; MFH, malignant fibrous histiocytoma; vas def, vas deferens; lu, lung; li, liver; lnn, lymphnodes; pl, pleural; adre, adrenal; bo, bone; rec, recurrence primary site; sk, skin; sp, spleen; st, soft tissue; retper, retro-peritoneal; per, peritoneal; prim, primary tumor; S, surgery; RT, radiotherapy; IT, immunotherapy; CT, chemotherapy; ET, experimental treatment; HT, hormonal therapy; rPD, rapidly progressive disease; SD, stable disease; NE, not evaluable; OR, own request; EoS, end of study; nc, nonconfirmed; (nl), new lesion; cu, compassionate use; DVT, deep venous thrombosis; WPW, Wolff-Parkinson-White syndrome.

b

Interval between diagnosis of primary tumor and start of SU5416 treatment.

c

SU5416 given via central line.

Table 4

Toxicities of all 80 patients (total of 230 cycles) during SU5416 therapy

ToxicityGrades
All (%)aIII (%)aIV (%)a
Headache 61.3 7.5  
Phlebitis 33.8 3.8  
Nausea 46.3 1.3  
Vomiting 42.5 7.5  
Anorexia 27.5 2.5  
Diarrhea 28.8 3.8  
Asthenia 57.5 10.0 1.3 
Pain injection site 17.5   
Somnolence 25.0 1.3  
Flu like syndrome 10.0   
Voice alteration 7.5 1.3  
Increased AF 11.3 5.0  
Increased γ-GT 12.5 8.8  
Increased liver transaminases 20.0 3.8  
Anemia 16.3 2.5  
Leucopenia 2.5 1.3  
Thrombocytopenia 2.5 1.3  
ToxicityGrades
All (%)aIII (%)aIV (%)a
Headache 61.3 7.5  
Phlebitis 33.8 3.8  
Nausea 46.3 1.3  
Vomiting 42.5 7.5  
Anorexia 27.5 2.5  
Diarrhea 28.8 3.8  
Asthenia 57.5 10.0 1.3 
Pain injection site 17.5   
Somnolence 25.0 1.3  
Flu like syndrome 10.0   
Voice alteration 7.5 1.3  
Increased AF 11.3 5.0  
Increased γ-GT 12.5 8.8  
Increased liver transaminases 20.0 3.8  
Anemia 16.3 2.5  
Leucopenia 2.5 1.3  
Thrombocytopenia 2.5 1.3  
a

Percentage of patients experiencing the event.

Table 5

Overview of response rates of SU5416 in RCC, melanoma, and soft tissue sarcoma

CRaPRMRSDSD ncPDNE
RCC   1/24 (4,2%) 5/24 (20,8%) 3/24 (12,5%) 15/24 (62,5%) 5/29 
Melanoma     2/17 (11,7%) 15/17 (88,3%) 3/20 
Soft tissue sarcoma   1/26 (3,8%) 5/26 (19,2%) 1/26 (3,8%) 19/26 (73,2%) 5/31 
CRaPRMRSDSD ncPDNE
RCC   1/24 (4,2%) 5/24 (20,8%) 3/24 (12,5%) 15/24 (62,5%) 5/29 
Melanoma     2/17 (11,7%) 15/17 (88,3%) 3/20 
Soft tissue sarcoma   1/26 (3,8%) 5/26 (19,2%) 1/26 (3,8%) 19/26 (73,2%) 5/31 
a

CR, complete remission; PR, partial remission; SD, Defined as no increase of ≥25% of all measurable tumor lesions for at least three treatment cycles; nc, nonconfirmed; NE, not evaluable.

1
Hanahan D., Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis.
Cell
,
86
:
353
-364,  
1996
.
2
Ferrara N. Molecular and biological properties of vascular endothelial growth factor.
J. Mol. Med.
,
77
:
527
-543,  
1999
.
3
Simon M., Rockl W., Hornig C., Grone E. F., Theis H., Weich H. A., Fuchs E., Yayon A., Grone H. J. Receptors of vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) in fetal and adult human kidney: localization and [125I]VEGF binding sites.
J. Am. Soc. Nephrol.
,
9
:
1032
-1044,  
1998
.
4
Gnarra J. R., Zhou S., Merrill M. J., Wagner J. R., Krumm A., Papavassiliou E., Oldfield E. H., Klausner R. D., Linehan W. M. Post-transcriptional regulation of vascular endothelial growth factor mRNA by the product of the VHL tumor suppressor gene.
Proc. Natl. Acad. Sci. USA
,
93
:
10589
-10594,  
1996
.
5
Nakagawa M., Emoto A., Hanada T., Nasu N., Nomura Y. Tubulogenesis by microvascular endothelial cells is mediated by vascular endothelial growth factor (VEGF) in renal cell carcinoma.
Br. J. Urol.
,
79
:
681
-687,  
1997
.
6
Nicol D., Hii S. I., Walsh M., Teh B., Thompson L., Kennett C., Gotley D. Vascular endothelial growth factor expression is increased in renal cell carcinoma.
J. Urol.
,
157
:
1482
-1486,  
1997
.
7
Pal S., Claffey K. P., Dvorak H. F., Mukhopadhyay D. The von Hippel-Lindau gene product inhibits vascular permeability factor/vascular endothelial growth factor expression in renal cell carcinoma by blocking protein kinase C pathways.
J. Biol. Chem.
,
272
:
27509
-27512,  
1997
.
8
Mukhopadhyay D., Knebelmann B., Cohen H. T., Ananth S., Sukhatme V. P. The von Hippel-Lindau tumor suppressor gene product interacts with Sp1 to repress vascular endothelial growth factor promoter activity.
Mol. Cell. Biol.
,
17
:
5629
-5639,  
1997
.
9
Ugurel S., Rappl G., Tilgen W., Reinhold U. Increased serum concentration of angiogenic factors in malignant melanoma patients correlates with tumor progression and survival.
J. Clin. Oncol.
,
19
:
577
-583,  
2001
.
10
Salven P., Heikkila P., Joensuu H. Enhanced expression of vascular endothelial growth factor in metastatic melanoma.
Br. J. Cancer
,
76
:
930
-934,  
1997
.
11
Danielsen T., Rofstad E. K. VEGF, bFGF and EGF in the angiogenesis of human melanoma xenografts.
Int. J. Cancer
,
76
:
836
-841,  
1998
.
12
Oku T., Tjuvajev J. G., Miyagawa T., Sasajima T., Joshi A., Joshi R., Finn R., Claffey K. P., Blasberg R. G. Tumor growth modulation by sense and antisense vascular endothelial growth factor gene expression: effects on angiogenesis, vascular permeability, blood volume, blood flow, fluorodeoxyglucose uptake, and proliferation of human melanoma intracerebral xenografts.
Cancer Res.
,
58
:
4185
-4192,  
1998
.
13
Yuan F., Chen Y., Dellian M., Safabakhsh N., Ferrara N., Jain R. K. Time-dependent vascular regression and permeability changes in established human tumor xenografts induced by an anti-vascular endothelial growth factor/vascular permeability factor antibody.
Proc. Natl. Acad. Sci. USA
,
93
:
14765
-14770,  
1996
.
14
Claffey K. P., Brown L. F., del Aguila L. F., Tognazzi K., Yeo K. T., Manseau E. J., Dvorak H. F. Expression of vascular permeability factor/vascular endothelial growth factor by melanoma cells increases tumor growth, angiogenesis, and experimental metastasis.
Cancer Res.
,
56
:
172
-181,  
1996
.
15
Masood R., Cai J., Zheng T., Smith D. L., Naidu Y., Gill P. S. Vascular endothelial growth factor/vascular permeability factor is an autocrine growth factor for AIDS-Kaposi sarcoma.
Proc. Natl. Acad. Sci. USA
,
94
:
979
-984,  
1997
.
16
Saenz N. C., Heslin M. J., Adsay V., Lewis J. J., Leung D. H., LaQuaglia M. P., Brennan M. F. Neovascularity and clinical outcome in high-grade extremity soft tissue sarcomas.
Ann. Surg. Oncol.
,
5
:
48
-53,  
1998
.
17
Verheul H. M., Hoekman K., Lupu F., Broxterman H. J., van der Valk P., Kakkar A. K., Pinedo H. M. Platelet and coagulation activation with vascular endothelial growth factor generation in soft tissue sarcomas.
Clin. Cancer Res.
,
6
:
166
-171,  
2000
.
18
Itokawa T., Nokihara H., Nishioka Y., Sone S., Iwamoto Y., Yamada Y., Cherrington J., McMahon G., Shibuya M., Kuwano M., Ono M. Antiangiogenic effect by SU5416 is partly attributable to inhibition of Flt-1 receptor signaling.
Mol. Cancer Ther.
,
1
:
295
-302,  
2002
.
19
Mendel D. B., Laird A. D., Smolich B. D., Blake R. A., Liang C., Hannah A. L., Shaheen R. M., Ellis L. M., Weitman S., Shawver L. K., Cherrington J. M. Development of SU5416, a selective small molecule inhibitor of VEGF receptor tyrosine kinase activity, as an anti-angiogenesis agent.
Anticancer Drug Des.
,
15
:
29
-41,  
2000
.
20
Fong T. A., Shawver L. K., Sun L., Tang C., App H., Powell T. J., Kim Y. H., Schreck R., Wang X., Risau W., Ullrich A., Hirth K. P., McMahon G. 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.
,
59
:
99
-106,  
1999
.
21
Shaheen R. M., Davis D. W., Liu W., Zebrowski B. K., Wilson M. R., Bucana C. D., McConkey D. J., McMahon G., Ellis L. M. Antiangiogenic therapy targeting the tyrosine kinase receptor for vascular endothelial growth factor receptor inhibits the growth of colon cancer liver metastasis and induces tumor and endothelial cell apoptosis.
Cancer Res.
,
59
:
5412
-5416,  
1999
.
22
Ellis L. M., Takahashi Y., Liu W., Shaheen R. M. Vascular endothelial growth factor in human colon cancer: biology and therapeutic implications.
Oncologist
,
5
:
11
-15,  
2000
.
23
Mendel D. B., Schreck R. E., West D. C., Li G., Strawn L. M., Tanciongco S. S., Vasile S., Shawver L. K., Cherrington J. M. The angiogenesis inhibitor SU5416 has long-lasting effects on vascular endothelial growth factor receptor phosphorylation and function.
Clin. Cancer Res.
,
6
:
4848
-4858,  
2000
.
24
Rosen L., Mulay M., Mayers A., Kabbinavar F., Rosen P., Cropp G., Hannah A. Phase 1 dose-escalating trial of SU5416, a novel angiogenesis inhibitor in patients with advanced malignancies.
Proc. Am. Soc. Clin. Oncol.
,
:
161a
abstract 618 
1999
.
25
Cropp G., Rosen L., Mulay M., Langecker P., Hannah A. Pharmacokinetics and pharmacodynamics of SU5416 in a phase I, dose escalating trial in patients with advanced malignancies.
Proc. Am. Soc. Clin. Oncol.
,
:
161a
abstract 619 
1999
.
26
Stopeck A., Sheldon M., Vahedian M., Cropp G., Gosalia R., Hannah A. Results of a phase I dose-escalating study of the antiangiogenic agent. SU5416, in patients with advanced malignancies.
Clin. Cancer Res.
,
8
:
2798
-2805,  
2002
.
27
Otten H. M., Prins M. H. Venous thromboembolism and occult malignancy.
Thromb. Res.
,
102
:
V187
-V194,  
2001
.
28
Yang J., Haworth L., Steinberg S., Rosenberg S., Novotny W. A randomized double-blind placebo-controlled trial of bevacizumab (anti-VEGF antibody) demonstrating a prolongation in time to progression in patients with metastatic renal cancer.
Proc. Am. Soc. Clin. Oncol.
,
:
5a
abstract 15 
2002
.
29
Angelov L., Salhia B., Roncari L., McMahon G., Guha A. Inhibition of angiogenesis by blocking activation of the vascular endothelial growth factor receptor 2 leads to decreased growth of neurogenic sarcomas.
Cancer Res.
,
59
:
5536
-5541,  
1999
.
30
Yu J. L., Rak J. W., Coomber B. L., Hicklin D. J., Kerbel R. S. Effect of p53 status on tumor response to antiangiogenic therapy.
Science
,
295
:
1526
-1528,  
2002
.
31
Jung Y. D., Ahmad S. A., Akagi Y., Takahashi Y., Liu W., Reinmuth N., Shaheen R. M., Fan F., Ellis L. M. Role of the tumor microenvironment in mediating response to anti-angiogenic therapy.
Cancer Metastasis Rev.
,
19
:
147
-157,  
2000
.
32
Graeven U., Rodeck U., Karpinski S., Jost M., Philippou S., Schmiegel W. Modulation of angiogenesis and tumorigenicity of human melanocytic cells by vascular endothelial growth factor and basic fibroblast growth factor.
Cancer Res.
,
61
:
7282
-7290,  
2001
.
33
Tran J., Master Z., Yu J. L., Rak J., Dumont D. J., Kerbel R. S. A role for survivin in chemoresistance of endothelial cells mediated by VEGF.
Proc. Natl. Acad. Sci. USA
,
99
:
4349
-4354,  
2002
.
34
Kerbel R. S., Yu J., Tran J., Man S., Viloria-Petit A., Klement G., Coomber B. L., Rak J. Possible mechanisms of acquired resistance to anti-angiogenic drugs: implications for the use of combination therapy approaches.
Cancer Metastasis Rev.
,
20
:
79
-86,  
2001
.
35
Benjamin L. E. The controls of microvascular survival.
Cancer Metastasis Rev.
,
19
:
75
-81,  
2000
.
36
Saito Y., Haendeler J., Hojo Y., Yamamoto K., Berk B. C. Receptor heterodimerization: essential mechanism for platelet-derived growth factor-induced epidermal growth factor receptor transactivation.
Mol. Cell. Biol.
,
21
:
6387
-6394,  
2001
.
37
Kuenen B. C., Rosen L., Smit E. F., Parson M. R., Levi M., Ruijter R., Huisman H., Kedde M. A., Noordhuis P., van Der Vijgh W. J., Peters G. J., Cropp G. F., Scigalla P., Hoekman K., Pinedo H. M., Giaccone G. Dose-finding and pharmacokinetic study of cisplatin, gemcitabine, and SU5416 in patients with solid tumors.
J. Clin. Oncol.
,
20
:
1657
-1567,  
2002
.