A Phase I, Dose Escalation Study of Lapatinib in Combination with Carboplatin, Paclitaxel, with or without Trastuzumab in Patients with Metastatic Breast Cancer: An Update.
Authors: A. Storniolo, G. Magrinat, P. Rubin, B. Parker, A. Rush-Taylor, V. Sheidler, S. Aranjo, C. Shaw, N. Eldreth, G. Lott, J. Brechlin, J. Loftiss, N. Arya, R. Fleming
Journal: Cancer Research (2009)

Abstract 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, the feasibility, safety, and early clinical activity of paclitaxel, carboplatin, lapatinib with or without trastuzumab in patients (pts) with MBC was assessed.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 (Dose Level 0). A standard 3 + 3 Phase I design was used to determine the optimally tolerated regimen (OTR) dose level.Results: Twenty-seven pts (Grp A n=15, Grp B n=12) have been enrolled in the study (median age 45 yrs, range 27-74). A median of 5 cycles (range 1-21) in Grp A and 5.5 (range 2-15) in Grp B have been administered. Drug-related toxicities were reported in 14 pts (93%) in Grp A and 11 pts (92%) in Grp B. In Grp A, drug-related grade 3 toxicities ≥ 10% include neutropenia (47%), diarrhea (33%), and rash (20%). Two drug-related grade 4 toxicities were reported (urinary tract infection and hypocalcemia). In Grp B, drug-related grade 3 toxicities ≥ 10% include diarrhea (17%), fatigue (17%), and rash (17%). Drug-related grade 4 toxicity (neutropenia) occurred in 3 pts in Grp B. In Grp A, there were two patients with dose-limiting toxicity (DLT) (Gr 3 diarrhea, Gr 3 rash) at lapatinib 1000 mg (Dose Level +1). The OTR (Dose Level 0) was identified as lapatinib 750 mg, paclitaxel 80 mg/m2, carboplatin AUC 2, and trastuzumab 2 mg/kg. In Grp B, two patients had DLT (one with Gr 4 neutropenia, one with Gr 3 rash and hypokalemia) at Dose Level 0 (lapatinib 1000 mg). At Dose Level -1 (paclitaxel reduced to 70 mg/m2), one pt had a DLT (Gr 4 neutropenia) and this dose level will be expanded to 6 pts. Clinical activity to date in Grp A (12 pts) includes 2 CR, 8 PR, and 1 SD and in Grp B (11 pts) 5 PR and 5 SD. Two pts in Grp B were ErbB2+, both had PR. Response assessments were not available for 4 pts (3 pts were awaiting response assessment and 1 pt was removed from the study prior to response assessment due to toxicity (neutropenia, catheter infection)).Conclusions: Lapatinib may be administered safely in combination with carboplatin, paclitaxel, with or without trastuzumab at known effective doses. Clinical activity has been observed. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3097.