Pazopanib (GW 786034, GlaxoSmithKline) is a potent selective, multitargeted tyrosine kinase inhibitor of vascular endo-thelial growth factor receptor VEGF-R1, VEGF-R2, and VEGF-R3; platelet-derived growth factor receptor PDGF-Ra/в; and the c-kit receptor, which block tumor growth and inhibit angio-genesis.

To determine the effects of pazopanib on tumor growth, researchers conducted a phase 2 randomized, double-blind trial of cytokine-naive patients with advanced or metastatic renal cell carcinoma and patients with refractory disease who had not responded to a prior regimen containing a cytokine or bevacizumab (Avastin, Genentech).

Oral pazopanib 800 mg was administered once daily. At week 12, patients’ responses were assessed according to parameters of the Response Evaluation Criteria in Solid Tumors (RECIST). Patients with stable disease were randomly assigned to continue receiving pazopanib or to receive placebo in a blinded fashion. Patients with partial and complete responses were assigned to continue taking pazopanib.
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Responses for the first 60 patients at week 12 were determined by an independent review. Twenty-four patients had partial responses (40%); 25 patients had stable disease (42%); five patients had progressive disease (8%); responses were unknown in two patients (3%); and four patients withdrew from the study before week 12 for reasons other than progressive disease or adverse events (7%).

Twenty-seven patients (45%) were randomly assigned to receive pazopanib, based on an investigator review at week 12. The total disease-control rate was 82%, consisting of partial responses and stable disease.

Sixty-seven percent of patients were new to treatment; 33% of the patients had failed to respond to one prior treatment regimen; 23% did not respond to cytokines, 8% did not respond to bevacizumab, and 2% did not respond to either agent. This group of 161 patients consisted of 71% men and 29% women, with a mean age of 60.3 years; 81% were Caucasian.

The most common adverse events and laboratory abnormalities in all patients were liver enzyme elevations, diarrhea, fatigue, nausea, hair depigmentation, and hypertension.
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The interim analysis of this phase 2 study demonstrated that pazopanib at week 12 resulted in acceptable toxicity and a partial response rate of 40% among patients with advanced or metastatic renal cell carcinoma. Based on these results, the Independent Data Monitoring Committee recommended discontinuing the randomization of patients to placebo.

A phase 3 trial of pazopanib has completed its accrual of patients .

Initial Trials with Next-Generation Trastuzumab DM1 (Herceptin)

Presenter: Howard A. Burris III, Sarah Cannon Research Institute, Nashville, Tenn.

Trastuzumab-DM1 (T-DM1) is a novel antibody-drug conjugate in development for human epithelial growth factor re-ceptor-2 (HER-2)-positive. It is designed to combine the antitumor activity of trastuzumab (Herceptin, Genentech) with targeted delivery of highly potent chemotherapy to HER-2-expressing cells. Focusing the delivery of such agents to tumor cells via high-specificity monoclonal antibodies that bind unique or overexpressed cell-surface tumor antigens is intended to create a more favorable therapeutic window for these agents, compared with those given as free drug (not conjugated to DM1, the cell-killing agent).

T-DM1 binds to the HER-2 position with an affinity similar to that of trastuzumab, and it undergoes internalization via the normal HER-2 internalization cycle. T-DM1 inhibits tubulin polymerization; it binds to tubulin competitively with vinca alkaloids (which stop cell division), but it is 20 to 100 times more potent than vincristine. T-DM1 is active in trastuzumab-sensitive and trastuzumab-insensitive HER-2-positive pre-clinical models. kamagra soft tablets

A phase 1 trial using an every-three-week dosing schedule is under way. In the first 18 patients with HER-2 and metastatic breast cancer who previously received trastuzumab, grade 2 and higher adverse events have been infrequent and manageable with no cardiac toxicity observed. Rapidly reversible grade 4 thrombocytopenia is dose-limiting at 4.8 mg/kg. The maximum tolerated dose of T-DM1 every three weeks is 3.6 mg/kg.

At the maximum tolerated dose, no neuropathy has been observed, and thrombocytopenia is generally grade 1 and rapidly reversible. T-DM1 shows antitumor activity (with four ongoing partial responses) at doses at or below the maximum tolerated dose on this every-three-week schedule. A weekly dosing schedule is also being evaluated.