Polyglutamate-Paclitaxel Controls Recurrent Ovarian Cancer

ORLANDO—Interim results from a phase I/II clinical trial of patients with recurrent ovarian, fallopian tube, or peritoneal cancer show that polygutamate (PG)-paclitaxel (CT-2103, Xyotax) controlled disease in about half of the evaluable patients.

Less Toxic, More Selective

Paul Sabbatini, MD, of Memorial Sloan-Kettering Cancer Center, presented the interim findings in a poster at the 38th Annual Meeting of the American Society of Clinical Oncology (abstract 871). The investigators concluded that CT-2103, a less-toxic, more-selective form of paclitaxel (Taxol), is active as a single agent in recurrent ovarian cancer and warrants further study.

"We have stable disease in patients who progressed on Taxol therapy," Dr. Sabbatini told ONI. He emphasized that most of the 89 patients in the trial had been heavily pretreated, failing as many as nine prior chemotherapy regimens.

Among 43 patients evaluable for response, CT-2103 was more effective in the 22 patients with platinum-sensitive disease. It produced a partial response in five of these patients (23%) and stable disease in eight (36%), providing disease control in 59% of patients. Of the 21 patients who were platinum resistant or refractory, one patient (5%) had a partial response, and eight (38%) had stable disease. In all, 51% of patients evaluated for response achieved disease control with the experimental agent.

Median progression-free survival at 9.5 months of follow-up was 4.0 months for platinum-sensitive patients and 3.1 months for platinum-resistant/refractory patients.

Cell Therapeutics Inc. in Seattle supported the ongoing phase I/II study. It is being conducted at seven cancer centers, and 29 of the 88 patients who began treatment were still receiving treatment at the time of the ASCO presentation.

The median number of prior chemotherapy regimens was two for patients with platinum-sensitive disease (31 patients), four for those with platinum-resistant disease (19 patients), and six for those with platinum-refractory disease (16 patients). Patients ranged in age from 33 to 81 (median, 57). The study regimen delivers a CT-2103 dose equivalent to 175 mg/m² of paclitaxel every 3 weeks in a 10-minute intravenous infusion.

The new agent consists of paclitaxel bound to a biodegradable polyglutamate polymer. Blood vessels in tumor tissues, unlike blood vessels in normal tissue, are porous to molecules like polyglutamate. Based on preclinical studies, it appears that CT-2103 is preferentially trapped in the tumor blood vessels allowing significantly more of the chemotherapy dose to localize in the tumor. As a result, Dr. Sabbatini said, the patient receives more of the drug at the site of the tumor and less in normal organs, reducing toxicity.

None of the patients had any hair loss, and no grade 4 toxicities were reported in 88 patients evaluated for safety. The most common grade 3 toxicities were neutropenia, occurring in 10 patients, and neuropathy in 4. Only two patients were removed from the study because of neuropathy. One patient had grade 3 fatigue, and two experienced a grade 3 hypersensitivity reaction. Eight patients required premedication in cycles subsequent to occurrences of grade 2 hypersensitivity.

"Because of the side effect profile, it’s possible to continue for a period of time until either toxicity finally intervenes or progression occurs," Dr. Sabbatini said. For patients who have failed numerous prior chemotherapy regimens, he added, "if you have stable disease and a reasonably tolerated treatment, that would be considered a successful intervention."

Other investigators are currently studying CT-2103 as a first-line therapy for stage III or IV ovarian cancer in a phase III trial. This study, involving more than 950 patients, will evaluate carbo-platin (Paraplatin) plus either standard paclitaxel (175 mg/mg2) or CT-2103 (210 mg/m²) every third week.

After six cycles of treatment, patients who achieve partial remission or stable disease will remain on paclitaxel or CT-2103 once every 4 weeks until toxicity or disease progression. Patients who achieve complete remission will go on to a consolidation arm that consists of single-agent CT-2103 (175 mg/m²) or paclitaxel (175 mg/m²) once a month for 12 months.

In addition, Dr. Sabbatini said, a second, more tightly controlled phase II trial will be conducted with the Gynecology Oncology Group (GOG). This trial will be restricted to patients who have failed no more than two prior chemotherapy regimens for recurrent ovarian cancer. It will also use a higher dose, he said.

"If we make the population more homogenous, we can be more definitive," he said. "We had patients in this study with a wide variety of prior treatments who had responses."

CT-2103 is also being studied in non-small-cell lung cancer and colorectal cancer, and Cell Therapeutics, Inc. has announced the start of the first phase II study of the agent in breast cancer. Professor A. Hilary Calvert, MD, of New-castle General Hospital, will serve as coordinating investigator for the trial, which will be conducted by Cancer Research UK in the United Kingdom.