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Phase II Study of the Antiangiogenic Agent SU5416 in Patients with Advanced Soft Tissue Sarcomas

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Phase II Study of the Antiangiogenic Agent SU5416 in Patients with Advanced Soft Tissue Sarcomas 5732 Vol. 10, 5732–5740, September 1, 2004 Clinical Cancer Research Phase II Study of the Antiangiogenic Agent SU5416 in Patients with Advanced Soft Tissue Sarcomas John V. Heymach,1 Jayesh Desai,1 The most common grade 3 toxicities were headache and Judith Manola,1,2 Darren W. Davis,8 thrombosis. Other less serious toxicities included fatigue, David J. McConkey,8 David Harmon,4 nausea, and abdominal pain. The median systolic blood 4 1 pressure increased from 118 mmHg at baseline to 133 after Post-treatment tumor .(0.01 ؍ David P. Ryan, Geraldine Goss, 1 month of treatment (P 1 3 Travis Quigley, Annick D. Van den Abbeele, biopsies showed no significant decreases in VEGF receptor 7 5 Stuart G. Silverman, Susan Connors, phosphorylation compared with baseline in 3 evaluable pa- Judah Folkman,5 Christopher D. M. Fletcher,6 tients. One patient with gastrointestinal stromal tumor who and George D. Demetri1 had rapid progression during SU5416 treatment was subse- Departments of 1Medical Oncology, 2Biostatistical Science, and quently treated with another KIT inhibitor, imatinib mesy- 3Nuclear Medicine, Dana-Farber Cancer Institute, Boston, late, and had a partial response lasting >36 months. Massachusetts; 4Division of Hematology-Oncology, Massachusetts Conclusions: SU5416 was relatively well tolerated but 5 General Hospital, Boston, Massachusetts; Department of Surgery, did not demonstrate significant antitumor activity against Children’s Hospital, Boston, Massachusetts; Departments of advanced soft tissue sarcoma. Correlative studies suggest 6Pathology and 7Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts; and 8The University of that VEGF receptor or KIT inhibition was incomplete in at Texas M. D. Anderson Cancer Center, Houston, Texas least some cases, providing a possible explanation for the observed lack of activity. ABSTRACT Purpose: SU5416 (semaxanib) is a small molecule inhib- INTRODUCTION itor of the vascular endothelial growth factor (VEGF) The growth and metastatic spread of tumors are dependent receptor-2 and KIT receptor tyrosine kinases. This Phase II on angiogenesis, a multistep process regulated by the local study was conducted to investigate the safety and efficacy of balance of endogenous pro- and antiangiogenic factors (1). SU5416 for patients with soft tissue sarcomas. Among the known stimulators of tumor angiogenesis, vascular Experimental Design: Thirteen patients with locally ad- endothelial growth factor (VEGF) is thought to play a pivotal vanced or metastatic soft tissue sarcomas were treated with role. The activities of VEGF are primarily mediated by two SU5416 via intravenous infusion at a dose of 145 mg/m2 receptors, VEGF receptor-1 (VEGFR-1 and Flt-1) and twice weekly. In selected cases tumor biopsies were taken VEGFR-2 (KDR and Flk-1; ref. 2). VEGF-induced endothelial before and after 2 months of treatment. migration, proliferation, and vascular permeability appear to be Results: The median progression-free survival was 1.8 dependent on VEGFR-2 signaling via its tyrosine kinase do- months. Median overall survival was 22.8 months. No ob- main. In preclinical models, blockade of the VEGF pathway jective tumor responses were observed. There was evidence inhibits tumor growth as demonstrated by investigators using of shorter survival among patients with high baseline urine monoclonal antibodies that bind VEGF or VEGFR-2 or small No grade 4 toxicities were observed. molecule inhibitors of the VEGFR-2 tyrosine kinase domain .(0.04 ؍ VEGF levels (P (3–6). These approaches are currently being evaluated in human clinical trials. SU5416 (semaxanib) is a small molecule inhibitor of Received 1/26/04; revised 5/504; accepted 5/11/04. VEGFR-2 tyrosine kinase (3). In murine models, SU5416 re- Grant support: Biostatistics support provided by Grant CA-06516 duced tumor angiogenesis and inhibited the growth of a broad from the National Cancer Institute. J. Heymach is supported in part by range of tumor types (3, 7). Phase I and II clinical trials have American Society for Clinical Oncology Young Investigator Award and been conducted using a twice-weekly dosing schedule, with a American Association for Cancer Research-Amgen Research Fellow- ship. G. Demetri and J. Desai are supported in part by the Richard I. maximum tolerated dose of 145 mg/m2. Dose-limiting toxicities Kaner Ewing’s Sarcoma Research Fund, the Leslie’s Links Foundation, were observed including nausea, vomiting, and headache (8, 9). the Abraham J. and Phyllis Katz Foundation, the Quick Family Sarcoma A once-weekly schedule has also been tested, which also Research Fund, and the Ludwig Trust for Cancer Research at Harvard showed that doses up to 145 mg/m2 were well tolerated (10). Medical School. D. Davis is supported in part by the Commonwealth Evidence of antitumor activity has been observed in several Foundation for Cancer Research. The costs of publication of this article were defrayed in part by the studies (10–12). When SU5416 was given in combination with payment of page charges. This article must therefore be hereby marked gemcitabine and cisplatin, a high incidence of thromboembolic advertisement in accordance with 18 U.S.C. Section 1734 solely to complications was observed and was accompanied by labora- indicate this fact. tory evidence of endothelial cell perturbation, discouraging ad- Requests for reprints: George Demetri, Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, SW530, 44 Binney Street, ditional use of this combination (13). After initiation of this trial, Boston, MA 02115.E-mail: [email protected]. it was also reported that SU5416 also inhibits the KIT receptor ©2004 American Association for Cancer Research. tyrosine kinase (14, 15). Mutations causing constitutive activa- Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2004 American Association for Cancer Research. Clinical Cancer Research 5733 tion of the KIT receptor appear to play a critical role in the apy Evaluation Program of the National Cancer Institute. The pathogenesis of gastrointestinal stromal tumors and a KIT in- drug was administered via intravenous infusion in an outpatient hibitor, imatinib, is effective therapy for the treatment of gas- setting at a dose of 145 mg/m2 twice weekly. The first dose of trointestinal stromal tumor (16–19). SU5416 was administered at 100 mL/hour for the first 15 Soft tissue sarcomas are a diverse group of tumors of minutes before increasing to full speed (200 mL/hour). If the mesenchymal origin. For most histologic subsets of advanced or patient had any evidence of venous irritation, the infusion rate metastatic soft tissue sarcomas, chemotherapy is currently the was slowed to 100 mL/hour. Patients were observed for a treatment of choice. Unfortunately, these drugs carry substantial minimum of 3 hours after their first three doses. Components in toxicity, and resistance tends to arise quickly. The vast majority the formulation included Cremophor (poloxyl 35 castor oil), of soft tissue sarcomas were found to express VEGF, and polyethylene glycol 400, benzyl alcohol, and dehydrated alcohol elevated serum VEGF levels were found to correlate with higher (supplied by Sugen, Redwood City, CA). To prevent allergic histologic tumor grade (20, 21). VEGF receptor inhibitors reaction to Cremophor, premedication with dexamethasone and showed antitumor activity in preclinical models of sarcoma (3, an H1-receptor blocker were used. Patients also received pro- 7). Therefore, soft tissue sarcomas represent a rational target in phylaxis against thromboembolic disease with coumadin 1 mg/ which to perform therapeutic testing of VEGF pathway inhibi- day, Dalteparin 2,500 IU subcutaneously/daily, or Lovenox 30 tors. For this reason, we have conducted a Phase II study of mg subcutaneously/daily. SU5416 in patients with advanced or metastatic soft tissue Evaluations During Treatment. Pretreatment evalua- sarcoma. We have also explored potential markers of antiangio- tion was carried out within 14 days before treatment and in- genic activity including urine VEGF and basic fibroblast growth cluded informed consent, a complete history, and physical ex- factor (bFGF) levels and tumor endothelial cell VEGFR phos- amination. Baseline laboratory studies included complete blood phorylation assessed by laser scanning cytometry (22). count with differential, comprehensive coagulation profile, liver function tests, renal function, serum chemistries, urinalysis, and pregnancy test. Baseline electrocardiogram; chest X-ray; com- MATERIALS AND METHODS puted tomography scans of the chest, abdomen, and pelvis with Patient Eligibility. All of the patients were required to quantification of measurable disease; and bone scan (if relevant) have histologically documented soft tissue sarcoma with meas- were also performed. 2-Deoxy-2-[18F]fluoro-D-glucose positron urable disease that was metastatic or inoperable. This study was emission tomography (18FDG-PET) scans were also performed designed to include patients who were treated previously with to complete the baseline assessment. During treatment, patients chemotherapy and who had either not responded or had pro- were seen by a physician weekly and had a complete physical gression of disease after an initial response. All of the patients examination, assessment of performance status, complete blood had to have had prior chemotherapy. All of the patients were count, serum chemistries, coagulation profile, and urine and Ն18 years of age, signed a
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