Purpose: This phase I study assessed the safety, optimally tolerated regimen (OTR), pharmacokinetics, pharmacodynamics, and preliminary clinical activity of lapatinib and docetaxel in patients with advanced solid tumors.
Patients and methods: Doses of lapatinib (oral once daily, continuous) and docetaxel (intravenous, every 3 weeks) were escalated in cohorts of at least three patients based on dose-limiting toxicities in the first treatment cycle until the OTR was reached. The protocol was amended to include pegfilgrastim because of dose-limiting toxicity (neutropenia), and a second dose-escalation phase was conducted to determine the OTR for the combination of docetaxel, lapatinib, and pegfilgrastim. After the determination of the OTR, the pharmacokinetics of lapatinib and docetaxel were determined to estimate the potential for an interaction between docetaxel and lapatinib at the OTR dose level.
Results: Fifty-two patients with advanced solid tumors were enrolled. The OTR dose level for lapatinib and docetaxel with pegfilgrastim was 1,250 mg (once daily) and 75 mg/m(2) (once every 3 weeks), respectively. Overall, adverse events (AEs) were mild to moderate in severity. The drug-related AEs reported by most patients (>or= 25%) were diarrhea (56%), rash (52%), fatigue (27%), and nausea (25%). Of 43 patients assessable for clinical response, two patients had confirmed partial responses. The pharmacokinetics of lapatinib (area under the curve, maximum serum concentration) and docetaxel (area under the curve, clearance) in combination were not significantly different than when the drugs are administered separately.
Conclusion: The combination of docetaxel and lapatinib with pegfilgrastim was well tolerated. No pharmacokinetic interaction was observed. Clinical activity was seen in this phase I drug combination trial.