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Heat Shock Protein 70 Inducer Enhances Paclitaxel Benefit for Advanced Solid Tumours: Presented at AACR-NCI-EORTC

By Paula Moyer

BOSTON, MA -- November 21, 2003 -- A novel compound that induces heat shock protein 70 appears to enhance the benefit of paclitaxel in patients with advanced solid tumours, according to Anna Berkenblit, MD.

Dr. Berkenblit, a medical oncologist at Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States, noted that she and her co-investigators observed no adverse effects related to the investigative drug, known for now as STA-4783. She reported their findings here November 18^th at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics.

The investigative team recruited 15 patients with advanced solid tumours who had adequate organ and haematologic function. The 11 men and four women were a median of 55 years old (range, 33-72). The patients had received previous treatment with a median of two chemotherapy regimens (range, 1-3). In six patients (40%), the regimens included paclitaxel. Among these patients, three had Kaposi's sarcoma, five had metastatic melanoma, and one patient each had and angiosarcoma, oesophageal squamous carcinoma, gallbladder cancer, acinar cell cancer, breast cancer, and colon cancer.

The participants received treatment consisting of intravenous administration of STA-4783 and paclitaxel over a three-hour infusion period on a weekly basis every three weeks. The initial doses were STA-4783 44 mg/m² and paclitaxel 135 mg/m². The paclitaxel was increased to 175 mg/m², followed first by an increase of STA-4783 to 88 mg/m². The dose for STA-4783 was then increased in similar increments afterward. The investigators conducted pharmacokinetic studies during the first cycle using liquid chromatography-mass spectrometry (LC/MS) to measure both compounds in the patients' plasma.

The investigators evaluated cohorts of three patients at each of the following dose levels: STA-4783 44 mg/m² and paclitaxel 135 mg/m²; STA-4783 44 mg/m² and paclitaxel 175 mg/m²; STA-4783 88 mg/m² and paclitaxel 175 mg/m²; STA-4783 175 mg/m² and paclitaxel 175 mg/m²; and STA-4783 263 mg/m² and paclitaxel 175 mg/m².

Dr. Berkenblit and her co-investigators observed no dose-limiting toxicities or other toxicities that could be linked to STA-4783. They also documented no allergic reactions or any evidence of neuropathy exceeding grade 1. Among the 10 patients whose responses were evaluable, the investigators observed partial responses in two patients with Kaposi's sarcoma. Additionally, one patient with rapidly progressing angiosarcoma who had had prior treatment with paclitaxel quit forming new lesions immediately and had symptomatic improvement and stabilisation of disease after two cycles.

The investigative agent cleared rapidly from plasma with a half-life (t_1/2,z) of 0.85±0.10 hours and a clearance rate of 28.4±7.3 L/h/m². The volume of distribution at steady-state (V_ss) was comparable to total body water, at 20.8±7.2 L/m². The pharmacokinetic parameters for STA-4783 at 44 mg/m² were similar to those that have been seen in patients who received paclitaxel at doses of 135 mg/m² or 175 mg/m². The maximal drug concentration (C_max) for STA-4783 was 3.0±0.3 microM at the 88 mg/m² dose level. The pharmacokinetic parameters for paclitaxel at a dose of 175 mg/m² were unaffected by co-administration with STA-4783 and were consistent with prior data, the investigators stated.


[Study title: A Phase I Study of STA-4783, an Inducer of Heat Shock Protein 70, Combined With Paclitaxel in Patients With Advanced Solid Tumors. Abstract A254]

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