A combination of the investigational treatment alisertib and weekly Taxol (paclitaxel) showed promising anti-tumor activity in ovarian cancer patients treated in a Phase 1/2 trial, warranting further studies of the combination.
Alisertib is an oral inhibitor of the aurora kinase A, a protein involved in cell division that is often overproduced in ovarian and breast cancers and linked with poor prognosis. In preclinical and Phase 1 studies, the treatment has shown potent anti-tumor activity with a manageable safety profile.
Taxol is a chemotherapy agent approved for several solid tumors, and is currently the standard of care for ovarian cancer patients who have failed platinum-based chemotherapies. But while the treatment is usually given in a three-week schedule, studies suggest that a weekly administration could improve patients’ outcomes.
Thus, researchers aimed to test a combination of alisertib and weekly Taxol in patients with advanced breast cancer and recurrent ovarian cancer.
The Phase 1/2 trial (NCT01091428) included 191 patients at 33 sites across the U.S., France, and Poland. During Phase 1, both breast and ovarian cancer patients were included, and researchers tested ascending doses of the combination to determine the safest and more efficacious dose.
Once this dose was determined, 142 patients with recurrent ovarian cancer were included in the Phase 2 part. There, patients were randomly assigned alisertib (40 mg twice daily) plus Taxol (60 mg/m2), or Taxol only (80 mg/m2).
Before randomization, patients had been stratified according to their responses to platinum-based chemotherapy and whether they had received a prior taxane treatment.
After a median follow-up of 7.2 months for the combination arm, 71% of patients had either died or seen their disease progress. The figure was 80% for those receiving Taxol, after a median follow-up of 4.6 months.
While the numbers didn’t reach statistical significance, researchers said that they favored the combination over Taxol only, making it worthy of further investigation.
There also was a trend toward more responses among patients receiving the combination (60% versus 52%), toward longer responses (6.6 months versus 5.6 months), and toward an extension in time to progression (6.7 months versus 4.7 months). Also, while overall survival could not be estimated, there had been only two deaths in the combination arm, compared to five in the Taxol group.
During the trial, the combination had no impact on patients’ quality of life, but caused more serious or life-threatening adverse events than Taxol only (86% versus 20%). Also, more patients discontinued treatment because of drug-related adverse events.
“Alisertib plus paclitaxel appeared less well-tolerated than paclitaxel alone, as evidenced by higher rates of dose reductions and discontinuations owing to toxic effects; this may be partly associated with a slightly greater duration of treatment exposure,” researchers said.
Nonetheless, “the combination of oral alisertib 40 mg twice daily plus weekly paclitaxel 60 mg/m2 showed promising antitumor activity with an increased but generally manageable safety profile in patients with recurrent ovarian cancer,” researchers concluded. “Future studies of alisertib in combination with paclitaxel and other taxanes are warranted.”