semaxinib and Head-and-Neck-Neoplasms

The institution of combined modality therapy for unresected solid tumors has resulted in significant improvements in tumor control and survival benefit compared with radiotherapy (RT) alone. A number of chemotherapy agents that can enhance the effectiveness of RT, such as cisplatin and 5-fluorouracil, are now considered standard treatment for patients with a number of cancer types. There is growing interest in a number of additional agents that have also been found to have radiosensitizing ability. These include paclitaxel, docetaxel, irinotecan, gemcitabine, and vinorelbine, as well as biologic agents. Other agents may be of value because they act to counter dose-limiting toxicities associated with RT. This article provides an update of some important, recently completed and ongoing clinical trials evaluating novel chemoradiation protocols, with examples taken primarily from studies conducted by the Radiation Therapy Oncology Group (RTOG). Theoretical approaches to the development of new agents and combined modality regimens are also discussed.

Topics: Alkyl and Aryl Transferases; Angiogenesis Inhibitors; Angiostatins; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Chemotherapy, Adjuvant; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dose Fractionation, Radiation; Drugs, Investigational; Endothelial Growth Factors; Enzyme Inhibitors; Esophageal Neoplasms; Farnesyltranstransferase; Female; Head and Neck Neoplasms; Humans; Indoles; Intercellular Signaling Peptides and Proteins; Isoenzymes; Laryngeal Neoplasms; Lung Neoplasms; Lymphokines; Male; Membrane Proteins; Neoplasms; Peptide Fragments; Plasminogen; Prostaglandin-Endoperoxide Synthases; Prostatic Neoplasms; Pyrroles; Radiotherapy, Adjuvant; Randomized Controlled Trials as Topic; Treatment Outcome; Uterine Cervical Neoplasms; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

SU5416 (semaxanib) is a synthetic small molecule inhibitor of the tyrosine kinase domain of vascular endothelial growth factor receptor 2 (VEGFR2). This Phase II study was conducted to determine the safety and efficacy of SU5416 in patients with recurrent or metastatic head and neck cancers.. This was an open label, single arm, Phase 2 study for patients who had received no more than 2 cytotoxic regimens. Thirty-five patients received intravenous SU5416 (145 mg/m(2)) twice per week by intravenous catheter. Radiologic imaging for response assessment was planned at the conclusion of each 8 week cycle. Serum VEGF levels and power Doppler ultrasound tumor imaging were explored as potential surrogate markers for SU5416 activity.. Thirty-two patients had received prior radiotherapy, including 18 patients who received prior concurrent chemoradiotherapy. Twelve patients had received prior chemotherapy in the recurrent disease setting. Thirty-one patients were evaluable for response. There was one partial response and one minor response. The median number of 8-week cycles received was 1 (range 1-4). Median overall survival was 6.25 months. The most common > or = grade 3 toxicity was headache (31%). There was one fatal carotid artery hemorrhage. Fatigue, nausea, and vomiting were common grade 1-2 adverse events. Power Doppler ultrasound demonstrated decreased tumor vascularity in 5 of 7 patients.. Treatment with SU5416 in patients with head and neck cancers is feasible, but objective responses are rare. Studies evaluating more potent anti-angiogenic agents in this disease are of interest.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Blood Pressure; Female; Head and Neck Neoplasms; Heart Rate; Humans; Indoles; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasms, Squamous Cell; Pyrroles; Regional Blood Flow; Ultrasonography; Vascular Endothelial Growth Factor A

SU5416 is a novel small organic molecule that non-competitively inhibits the phosphorylation of the VEGF tyrosine kinase receptor, Flk-1. This phase IB study was performed to determine the safety, pharmacokinetics, and preliminary efficacy of the combination of SU5416 and paclitaxel in recurrent or metastatic carcinoma of the head and neck.. Enrolled in the study were 12 patients with biopsy-proven recurrent or metastatic carcinoma of the head and neck. Six patients received intravenous SU5416 110 mg/m2 on days 1, 15, 18, 22 and 25, and paclitaxel 70 mg/m2 on days 8, 15 and 22. Since two patients experienced a dose-limiting toxicity (DLT) in cohort 1, the next six patients received identical treatment as above except the paclitaxel dose was reduced to 55 mg/m2 per week.. A total of 42 cycles at two different dose levels were given. In cohort 1 there were two deep venous thromboses that were DLTs. In the second cohort there was a DLT consisting of a transient ischemic attack after receiving SU5416. Most of the other toxicities seen were grade 1 or 2 in nature and consisted of headache, facial flushing, and fatigue. Two patients developed extensive ulcerative cavities at sites of prior radiation. There were no significant changes in the pharmacokinetic parameters of SU5416 given with paclitaxel. Four patients had prolonged freedom from progression of 18, 28, 42, and 60 weeks duration.. The combination of SU5416 with paclitaxel had a higher than expected incidence of thromboembolic events and prophylactic anticoagulation should be considered for future trials that combine an angiogenesis inhibitor with cytotoxic chemotherapy. Although the future development of SU5416 as a chemotherapeutic agent is unclear, there was a clinical benefit seen with this combination in 36% of the patients. This trial supports the use of developing antiangiogenic combinations, using molecular targeted agents, in head and neck carcinoma.

Topics: Adult; Aged; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Female; Head and Neck Neoplasms; Humans; Indoles; Maximum Tolerated Dose; Middle Aged; Neoplasm Recurrence, Local; Paclitaxel; Pyrroles

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Carcinoma, Squamous Cell; Cetuximab; Clinical Trials as Topic; Combined Modality Therapy; Head and Neck Neoplasms; Humans; Indoles; Platinum Compounds; Pyrroles; Recurrence