Phase 2 Trial of Paclitaxel Polyglumex with Capecitabine for Metastatic Breast Cancer

Background: Capecitabine and paclitaxel are established effective treatments, alone and combined with other cytotoxic and targeted agents, for metastatic breast cancer (MBC). Paclitaxel polyglumex (a macromolecular conjugate of paclitaxel bound to poly-l-glutamic acid) has potential advantages over conventional paclitaxel, including little alopecia, short infusion time with no premedication, enhanced tumor permeability/retention effect, and improved tolerability. We therefore examined tolerability and efficacy of paclitaxel polyglumex with capecitabine in patients with MBC. Patients and Methods: This was a single-stage phase 2 study, with interim analysis conducted with endpoints of tumor response, adverse events (toxicities), time to progression, and overall survival. The main eligibility criteria were: age > 18 years, no prior MBC chemotherapy, Eastern Cooperative Oncology Group performance score < 2, disease measurable by RECIST criteria, no HER2 overexpression or amplification, no brain metastases or peripheral sensory neuropathy. Treatment consisted of paclitaxel polyglumex (135 mg/m(2)) by intravenous infusion on day 1+capecitabine (825 mg/m(2)) orally twice daily on days 1 to 14, repeated on a 3-week cycle. Forty-one evaluable patients were required to test the null hypothesis that the complete and partial tumor response rate (CR+PR) was at the most 40% against the alternative of at least 60%. Paclitaxel polyglumex+capecitabine would be considered promising in this population if >= 21 responses were observed among first 41 evaluable patients. Results: Forty-eight patients were enrolled between April 2006 and April 2007; all patients were evaluable. The median number of treatment cycles administered was 6. Eighteen patients [38%; 95% confidence interval (CI), 24%-53%] had a confirmed tumor response (2 CR, 16 PR) by RECIST criteria. Fifteen (38%; 95% CI, 23%-53%) responses occurred in first 41 patients, falling short of prespecified goal of 21 responses. Median duration of tumor response was 13.2 months. Three of the responders were progression free at last follow-up with a median follow-up of 43 months. Median progression-free survival was 5.1 months (95% CI, 4.0-7.6 mo). Six-month progression-free survival was 42% (95% CI, 30%-58%). Median dose level administered was paclitaxel polyglumex (135 mg/m(2)) and capecitabine (825 mg/m(2)) for cycles 1 to 7. Most common severe (grade 3/4) toxicities (at least possibly related to study drug) were: leukopenia 9 (19%), neutropenia 8 (17%), neurosensory 4 (8%), skin reaction-hand/foot 4 (8%), and dyspnea 2 (4%). Forty-six percent (22/47) of patients experienced grade >= 3 toxicity and 8% (4/48) experienced grade >= 4 toxicity. No alopecia was reported. Conclusions: Although the trial failed to reach goal of 21 confirmed tumor responses among the first 41 evaluable patients, paclitaxel polyglumex and capecitabine is well tolerated and effective in MBC.