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Clinical Trials |
Department of Medical Oncology, Vrije Universiteit Medical Center [B. C. K., K. H.], and NDDO Oncology [H. H.], 1081 HV Amsterdam, the Netherlands; Medical Oncology Service, Vall d’Hebron University Hospital, Barcelona, Spain [J. T., J. B.]; Ospedale San Giovanni, Bellinzona, Switzerland [F. C.]; U.O. Oncologica Medica, St. Chiari University Hospital, Pisa, Italy [E. P., P. F. C.]; Westdeutsches Tumorzentrum, Essen, Germany [S. S.]; ICRF Medical Oncology Unit, Oxford, United Kingdom [S. M., G. D., A. L. H.]; and Sugen, Inc., South San Francisco, California [P. S.]
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ABSTRACT |
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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.
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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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.
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PATIENTS AND METHODS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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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 x 109/liter, hemoglobin > 5.5 mmol/liter, platelet count 100 x 109/liter, bilirubin 1.25 x 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.
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RESULTS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. All patients, except 1, had previous tumor nephrectomy. Because of metastases, all patients, except 5, received previous immunotherapy (
-IFN and/or interleukin-2 and others), which was combined with chemotherapy in 17 patients (5-fluorouracil and others).
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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 (-IFN, interleukin-2, and others), hormonal treatment (tamoxifen and others), or combinations.
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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.
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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.
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. 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.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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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.
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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)
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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) .
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FOOTNOTES |
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2 To whom requests for reprints should be addressed, at Department of Medical Oncology, De Boelelaan 1117, 1081 HV Amsterdam, the Netherlands. Phone: 31 20 4444319; Fax: 31 20 4444355; E-mail: K.Hoekman{at}vumc.nl 
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.
Received 9/13/02; revised 11/15/02; accepted 10/ 2/02.
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REFERENCES |
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