Unformatted text preview: UCD#171/GSK 104241 Lapatinib and Vinor elbine Phase I 2 .0 Objectives
There are clinic al and biologic al objectiv es for this phas e I study. 2.1 Primary Clinic al Objectiv e To evaluate the safety and feasibility of two different schedules of lapatinib in combination with vinorelbine in patients wit h adv anced s olid tumors. 2.2 Sec ondary Clinic al Objectiv es To define the maximum tolerated doses (MTD) of two different schedules of lapatinib in combination with vinorelbine in patients with advanced solid tumors. To assess for preliminary efficacy of the c ombination with t wo different schedules of administration. 2.3 Biological Objectives To perf orm laboratory correlativ e studies on patient tissue specimens to investigate potential predictors of res ponse. To assess pharmacokinetics of lapatinib and vinorelbine in ARM A at the MTD. 3 .0 Background/Rationale GW572016 (Lapatinib) acts as a dual inhibit or of both EGFR/ HER1 and ErbB2 tyrosine kinase activity. EGFR/ HER1 and ErbB-2 over-expression by tumor cells has been linked with aggressiv e tumor growth, dis ease progression, poor surviv al, and poor response to therapy. Over-ex pression of EGFR/ HER1 has been reported in a number of epitheliumderiv ed carcinomas including head and neck, colorectal, lung, es ophageal, gastric, and breast carcinoma. In a similar manner, ErbB2 has been report ed to be over-ex pressed in 15-30% of invasiv e ductal breast canc er and has been associated wit h increas ed proliferation, poor clinic al outcome, and altered responsiv eness to various adjuv ant therapies (Allred et al., 2001). Lapatinib has been shown to be a potent and s elective dual inhibit or of EGFR/ HER1 and ErbB2 tyrosine kinase activity (Rusnak et al., 2001). Lapatinib has demonstrated selectiv e growth inhibition of human cell lines (head and neck, breast, and gastric ) in vitro. Lapatinib is >300-fold more selective towards ErbB2 and EGFR than other EGFR kinas e directed therapy (erlotinib, gefitinib). Lapatinib demonstrated potent growt h inhibition of human breast ductal (BT474) and head and neck (HN5) tumor xenografts in mice. In a phase IB study, heavily pre-treated patients with metastatic dis eas e expressing EGFR or ErbB2 reported that lapatinib was well tolerat ed at all dos e lev els tested (5001600 mg/ day) (Spector et al., 2003). Tumor types in whic h objective response or stable disease were seen included: breast (7), colorect al (2), ovarian (2), lung (1), granular cell (1), and head and neck (1) carc inomas as well as adenoc arcinoma of unk nown primary (1). Objective responses were obs erved in ErbB2-expressing breast cancer patients
Version 2 : D ecember 26, 2005 4 UCD#171/GSK 104241 Lapatinib and Vinor elbine Phase I who had progress ed after rec eiving prior trast uzumab (Herceptin™)-based regimens. The most common adv erse events inc luded grade 1-2 ras h (25%), diarrhea (27%), and naus ea/vomiting (21%). Results from phas e I studies support the us e of 1500 mg po daily as achieving biologically active concentrations and target pathway inhibition with an accept able toxicity profile. Vinorelbine has activity in many solid tumors but it s primary use is in the treat ment of advanced breast canc er and non-s mall cell lung cancer. As a single agent, vinorelbine has res ponse rates ranging from 32-52% wit h a median duration of respons e of 7-10 months in heavily pretreated adv anc ed breast cancer patients (Terzoli et al., 2004). When combined with other agents res ponse rates as high as 75% have been reported but at the price of increased toxicity (Conti et al., 1998). Vinorelbine most commonly is used in the 3rd or 4th line s etting in breast canc er after the use of anthracyclines and taxanes (Estev a et al., 2001). In the setting of NSCLC, randomiz ed trials of weekly vinorelbine (25-30 mg/ m2) vers us vinorelbine/cisplatin have demonstrat ed decreased toxicity wit h vinorelbine alone, making single agent vinorelbine a reas onable alternative for PS 2 patients (Le Chevalier et al., 1994; Depierre et al., 1994) . Two randomized trials from Italy hav e targeted "poor-risk" patients and have demonstrated the potential feasibility and benefit of using single-agent vinorelbine in PS 2 patients. The ELVIS trial enrolled 191 older patients (age > 70) with stage IV or IIIB NSCLC and randomiz ed them to rec eive vinorelbine 30 mg/ m2 on days 1 and 8 ev ery 21 days for a maximum of 6 cycles or to supportiv e care alone (Gridelli et al., 2001). There were 24% PS 2 patients in each group. Treat ment was well tolerated in the vinorelbine group; only 3 patients experienced grade 3 toxicities. In addition, treat ment was associated with improved surviv al in this PS 2 subgroup (median s urvival 26 vs 8 weeks). The ability to combine vinorelbine with a less toxic therapy, such as lapatinib, is appealing in these particular groups of patients in whose disease we are palliating, partic ularly in advanced breast canc er in which phase I trials have demonstrated signific ant anti-tumor activity with lapatinib alone (Spector et al., 2003). While preclinical data s uggests synergis m when c ombining chemotherapy wit h the EGFR tyrosine kinase inhibitors (such as gefitinib) this has not been demonstrated clinically. Four large randomized phase III studies, two with erlotinib and two with gefitinib in combination with platinum-bas ed chemotherapy in advanced NSCLC have not res ulted in improv ements in res ponse rat es or surv ival (Herbst et al., 2004; Giacc one et al., 2004; Gatzemeier et al., 2004; Herbst et al., 2004) Based on pre-clinical data from the lab of Dr. Gumerlock at UC Dav is, it is hypothes ized that the intermittent use of the EGFR tyros ine kinase inhibitor, erlotinib, in combination with c hemotherapy would result in improved efficacy than either agent alone or concurrently (Kimura et al., ASCO 2004). This work suggests that the sequence in which chemotherapy and the EGFR-TK inhibitors are administered may influence efficacy, such that the drugs should not be administ ered together but in sequence. We have nearly complet ed enrollment on a phase I trial of intermittent EGFR inhibition with erlotinib and doc etaxel. In this study patients are simultaneously being accrued to two (2) arms of a phase I study (Arm A and Arm B). In Arm A patients receiv e q 3 weekly docet axel and intermittent high-dos e weekly erlotinib. In Arm B patients rec eive q 3 weekly docetax el and erlotinib day 2-16.
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- Winter '06
- Vinorelbine, lapatinib, breast canc er