A Study of Lapatinib in Combination With Caelyx in Patients With Advanced HER2 Positive Pretreated Breast Cancer

Title: A Phase Ib Study of Lapatinib in Combination with Caelyx in Patients with Advanced HER2 positive pretreated Breast Cancer. Protocol Code: IRST 174.01 Phase: Ib Study Design: open-label,single arm study in patients with advanced HER2 positive breast cancer. Treatment Plan: Lapatinib is given at escalating doses orally and continuously on days 1-21. Caelyx is administered at escalating doses in a 60-minute i.v. infusion on day 1. Each cycle is defined as 21 days. Four dose levels are planned. Dose level -1, Caelyx 30 mg/mq \& Lapatinib 1000 mg die; dose level 1, Caelyx 30 mg/mq \& Lapatinib 1250 mg die; dose level 2, Caelyx 30 mg/mq \& Lapatinib 1500 mg die; dose level 3, Caelyx 40 mg/mq \& Lapatinib 1500 mg die. Three patients will be initially enrolled in each dose level starting from level 1. If none of the first triplet of patients will develop DLT, the dose will be escalated to the next level for the subsequent three patients. If one of the first triplets of patients will develop first-course DLT, a maximum of 3 additional patients will be entered at the same dose level. The MTD is defined as the dose below that at which two patients have experienced DLT. Lapatinib will be self-administered by the patient in an outpatient setting at the dose of the assigned step. Patients will take the drug daily by mouth on days 1 to 21 of each cycle. Caelyx will be administered by intravenous infusion over an exact period of 1 hour (preferably by a pump to guarantee a constant speed of infusion) on day 1 of each cycle repeated every 21 days. Objectives: Primary: to define the MTD and the safety profile of Lapatinib (Tyverb) plus Caelyx. Secondary: to preliminarily explore the anti tumour activity, to determine the objective tumor response rate using RECIST criteria. Sample Size: No formal sample size estimation is performed as this is primarily a descriptive phase I trial of safety and tolerability. STATISTICAL METHODOLOGY: Evaluation of toxicity: all patients will be evaluable for toxicity from the time of their first treatment with Caelyx and Lapatinib. Evaluation of response: all patients included in the study must be assessed for response to treatment, even if there are major protocol treatment deviations or if they are ineligible. Each patient will be assigned one of the following categories: 1) complete response, 2) partial response, 3) stable disease, 4) progressive disease, 5) early death from malignant disease, 6) early death from toxicity, 7) early death because of other cause, or 9) unknown (not assessable, insufficient data). All of the patients who met the eligibility criteria (with the possible exception of those who received no study medication) should be included in the main analysis of the response rate. Patients in response categories 4-9 should be considered as failing to respond to treatment (PD). Thus, an incorrect treatment schedule or drug administration does not result in exclusion from the analysis of the response rate. All conclusions should be based on all eligible patients. Subanalyses may then be performed on the basis of a subset of patients, excluding those for whom major protocol deviations have been identified (e.g., early death due to other reasons, early discontinuation of treatment, major protocol violations, etc.). However, these subanalyses may not serve as the basis for drawing conclusions concerning treatment efficacy, and the reasons for excluding patients from the analysis should be clearly reported. The 95% confidence intervals should also be provided.