Abstract
Abstract Abstract #3121 Background: Lapatinib is a selective and highly potent dual, competitive inhibitor of erbB1 and erbB2 tyrosine kinases with clinical activity in erbB2-positive metastatic breast cancer (MBC). The combination of carboplatin, paclitaxel, and trastuzumab has been shown to have significant clinical activity in MBC as well as in the adjuvant setting. Given the synergy of dual inhibition with trastuzumab and lapatinib observed in both the preclinical and clinical settings, we assessed the feasibility, safety, and early clinical activity of paclitaxel, carboplatin, lapatinib with and without trastuzumab in patients (pts) with MBC.
 Methods: MBC pts previously untreated with trastuzumab or cytotoxic chemotherapy for metastatic or locally recurrent disease were enrolled into either Group (Grp) A (erbB2 positive) or B (erbB2 positive or negative). Escalating doses of lapatinib (planned range of 750-1500 mg/d) were administered in combination with (Grp A) or without (Grp B) trastuzumab (4 mg/kg followed by weekly 2 mg/kg infusions). Paclitaxel (80 mg/m2) and carboplatin (AUC 2 mg/ml*min) were administered on days 1, 8, 15 with cycles repeated every 28 days. Starting doses of lapatinib were 750 mg in Grp A and 1000 mg in Grp B. A standard 3 + 3 Phase I design is being used until the optimally tolerated regimen (OTR) dose level is determined. An additional 14 - 17 pts will be enrolled into each grp at the OTR dose level to further assess safety and tolerability.
 Results: Fourteen pts (Grp A n=8, Grp B n=6) have been enrolled in the study (median age 42 yrs, range 27-66). A median of 5.5 cycles (range 4-17) in Grp A and 3.5 (range 1-7) in Grp B have been administered. All pts had at least one adverse event (AE). In Grp A, grade 3 toxicities include neutropenia (50%), diarrhea (38%), rash (25%), vomiting (13%), hypokalemia (13%), and syncope (13%). No grade 4 toxicities were reported. In Grp B, grade 3 toxicities include fatigue (33%), hyponatremia (17%), menorrhagia (17%), dermatitis (17%), and rash (17%). One pt (in Grp B) had grade 4 neutropenia. No febrile neutropenia was observed. In Grp A, there was one DLT (Gr 3 diarrhea) at lapatinib 1000 mg. In Grp B, one DLT (Gr 4 neutropenia) at lapatinib 1000 mg has been observed. Clinical activity to date includes 8/8 objective responses in Grp A, (1 CR, 7 PR) and 2/6 objective responses (2 PR) in Grp B (all pts in Grp B were erbB2 negative). Dose escalation continues in both grps.
 Conclusions: Lapatinib may be administered safely in combination with carboplatin, paclitaxel, with and without trastuzumab at known effective doses for each. Clinical activity has been observed. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3121.
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