P5-19-11: Tesetaxel, an Oral Taxane, as First-Line Therapy for Women with Metastatic Breast Cancer.

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Abstract Background Parenteral taxanes (docetaxel, paclitaxel) are among the most active agents in treating metastatic breast cancer (MBC). However, their use is limited by inherent or acquired multidrug resistance, hypersensitivity, and neurotoxicity. Tesetaxel is an advanced-generation, orally available taxane that is formulated as a capsule for oral administration and has a long terminal half-life in plasma (∼180 hrs). Unlike standard taxanes, tesetaxel is not a substrate for P-glycoprotein (P-gp), a major cause of taxane resistance. The drug is highly concentrated in cells that overexpress P-gp. In taxane-resistant breast cancer xenografts (DU4475), tesetaxel induced a 94% reduction in tumor size, substantially exceeding the activity of docetaxel and paclitaxel (46% and 26%, respectively). Neurotoxicity was also substantially lower with tesetaxel compared with equi-myelotoxic doses of docetaxel. Among more than 350 patients (pts), there have been no occurrences of hypersensitivity reactions. An initial phase 2 study as 2nd-line therapy for pts with MBC who progressed after multidrug anthracycline-containing regimens showed a 38% partial response (PR) rate using tesetaxel Q3 wks at a dose of 27–35 mg/m2. We conducted a Phase 2, open-label, multicenter study of the efficacy and safety of tesetaxel as first-line therapy in women with MBC. Methods: Eligible pts have Stage IV, HER2−negative MBC; ECOG PS 0–1; and adequate organ function. No prior chemotherapy is allowed (other than 1 regimen in the adjuvant setting). Tesetaxel was administered orally Q3 wks at a starting dose of 27 mg/m2 with escalation to 35 mg/m2 as tolerated. No premedication for potential hypersensitivity was used. RECIST response rate was the primary endpoint. A Simon min-max two-stage design was used with a target response rate of 30% in 25 pts. Results: To date, 20 women have been enrolled and treated. The median age was 62 years (range, 45–78). Time from diagnosis was > 4 years in 5 pts and ≤ 4 years in 6; MBC was newly diagnosed in the remaining 9. Hormone receptor status was triple negative in 5 pts at diagnosis and 10 at the time of metastasis. The most common sites of metastasis were lung (13 pts) and bone (9). Prior treatment included hormonal therapy in 13 pts, adjuvant chemotherapy in 16 (most commonly, ACT), and radiotherapy in 9. Of 11 pts currently evaluable for response, PR was achieved in 6 (55%), with confirmation of response in 4 and an ongoing PR in 1 of the 2 pts with an unconfirmed PR. SD was observed in 2 and disease progression in 3. Neutropenia was the most common adverse event, affecting 50% of pts; Grade 3–4 occurrences were observed most often after escalation of the tesetaxel dose to 35 mg/m2. Single occurrences (Grade 1) of neuropathy and nail changes were reported. There were no occurrences of hypersensitivity. Conclusions: Tesetaxel overcomes multiple disadvantages of standard parenteral taxanes and is highly active in 1st- and 2nd-line MBC. To date, overall response rates in these settings are 55% and 38%, respectively. In view of this, we have amended the trial to expand the initial cohort. Potential schedule-dependency will be examined in a future cohort with a newly developed weekly-times-3 schedule. Updated results in both cohorts will be presented. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-19-11.