NATIONAL HARBOR, MD. (FRONTLINE MEDICAL NEWS) – Using either a polymerized formulation of paclitaxel or paclitaxel alone as maintenance therapy conferred no survival benefit for women with advanced ovarian, fallopian tube, or peritoneal cancer.

In a phase III randomized trial, patients survived a median 54.8 months with surveillance alone, 51.3 months with maintenance paclitaxel, and 60.0 months with maintenance paclitaxel poliglumex; these differences were not statistically significant.

In a presentation at the annual meeting of the Society of Gynecologic Oncology, Larry Copeland , MD, a professor of gynecologic oncology at Ohio State University, Columbus, said that treatment with surgery and chemotherapy yields a clinical complete response in many patients with these cancers. However, he said, recurrent progressive disease is still very common; the rationale behind maintenance chemotherapy is that it may “reduce the risk of recurrence and extend survival.”

There had been promising earlier data supporting this approach from a previous phase III comparison trial that evaluated the difference in clinical complete response between 3 or 12 cycles of paclitaxel, said Dr. Copeland. The results of a predefined interim analysis prompted the data monitoring committee to close that study ( J Clin Oncol. 2003;21[13]:2460-5 ) since the 12-cycle, 7-month arm of the study had better progression-free survival. However, the 12-cycle protocol did not confer a benefit in overall survival, the investigators later reported ( Gynecol Oncol 2009;114[2]:195-8 ).

The current stage III randomized trial enrolled women with stage III or IV ovarian, fallopian tube, or peritoneal cancer who had had five to eight cycles of chemotherapy and achieved clinical complete response. If patients had neuropathy, it could not exceed grade 1, and their cancer performance status scores could not exceed 2, Dr. Copeland said.

Patients were randomized 1:1:1 to a surveillance arm, to receive paclitaxel as a 3-hour infusion, or to receive paclitaxel poliglumex as a 10- to 20-minute infusion. Both study drugs were dosed at 35 mg/m2 every 28 days for 12 cycles.

The study ran from March 2005 to January 2014, enrolling 1,157 patients who were followed for a median of 71 months. Over 80% of patients in each study arm had ovarian cancer, and a similar number had stage III cancer and serous histology. Over 90% of patients in each arm had grade 2 or higher histology.

The study was designed as a superiority design, and patients were not to receive other cancer treatments until they had disease progression. Primary clinical endpoints for the study included overall survival, quality of life as measured by the Ovarian Specific Questionnaire Quality of Life–Cancer, and patient-reported neurotoxicity as reported on the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group/Neurotoxicity questionnaire.

The third scheduled interim analysis, in May 2016, examined the primary endpoint of overall survival, triggered when at least 200 deaths occurred in the surveillance group. The overall final analysis had been scheduled for the point at which at least 301 deaths happened in the surveillance group. In the abstract accompanying the presentation, Dr. Copeland wrote that the data at the point of this interim analysis indicated that “the relative death hazards passed the futility boundaries for both taxane regimens.”

“The log-rank statistic for each taxane regimen was below the interval specific in the study design, making it unlikely either of the taxane regimens has superior overall survival compared to surveillance,” said Dr. Copeland.

The hazard ratio for overall survival of the paclitaxel group compared to surveillance was 1.104, with a 97.5% confidence interval (CI) of 0.884-1.38. For the paclitaxel poliglumex group, the hazard ratio compared to surveillance alone was 0.979 (97.5% CI, 0.781-1.23).

Dr. Copeland and his colleagues also looked at progression-free survival, not a primary endpoint of the study. For the paclitaxel patients compared to surveillance, the HR for progression-free survival was 0.783 (95% CI, 0.666-0.921). For paclitaxel poliglumex, the HR was 0.847 (95% CI, 0.666-0.921).

Not unexpectedly, more patients who received taxane treatment than those in the surveillance arm experienced adverse events, said Dr. Copeland. The most common adverse events were hypersensitivity or allergic reactions, fatigue, alopecia, nausea, constipation, and sensory neuropathies. Grade 2 alopecia was experienced by about a quarter of the paclitaxel poliglumex cohort, and by a little less than half of the paclitaxel cohort. Neurologic adverse events were very common, reported by three quarters of the paclitaxel poliglumex cohort, four in five of the paclitaxel group, and by a little over half of the surveillance cohort.

Overall quality of life scores did not differ significantly among the treatment arms.

In an exploratory analysis, Dr. Copeland and his colleagues determined that patients with no residual disease (R0 patients) after initial cytoreductive surgery fared better, with a median 70 months of survival compared to a median 43.6 months for individuals with gross residual disease. When those patients were sorted out by treatment arm, there was no significant difference in OS for R0 patients who received any intervention or surveillance.

“Overall survival was not improved with taxane maintenance, though progression-free survival is slightly delayed,” Dr. Copeland concluded.

In discussion after the presentation, he said that he is not sure that further investigations will be pursued for paclitaxel poliglumex in the treatment of ovarian cancers.

Paclitaxel poliglumex (CT-2103; Opaxio) is paclitaxel conjugated to a polyglutamate polymer, a formulation that may enhance tumor penetration and retention, and that allows shorter infusion at a peripheral site. Previous work had shown that CT-2103’s structure enhanced pharmacokinetics and potentially decreased toxicity ( Expert Opin Investig Drugs. 2004 Nov;13[11]:1501-8 ).

Dr. Copeland reported receiving consulting or honoraria fees from Clovis, Advaxis, Janssen, and Tesaro, and is a stockholder or shareholder in Merck, Eli Lilly, and Cardinal Health. The study was sponsored by the Cancer Therapy Evaluation Program of the National Cancer Institute and by Cell Therapeutics, which plans to market paclitaxel poliglumex.

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