Entry Detail
| General information | |
| Database: | DB00654 |
| Objective: | This study evaluated the toxicity and efficacy of lapatinib in combination with chemotherapy among patients with human epidermal growth factor receptor 2positive, progressive brain metastases. |
| Authors: | Lin NU, et al |
| Title: | Randomizedphase II study of lapatinib plus capecitabine or lapatinib plus topotecan for patients with human epidermal growth factor receptor 2positive breast cancer brain metastases. |
| Journal: | J Neurooncol. |
| Year: | 2011 |
| PMID: | 21706359 |
| Trial Design | |
| Clinical Trial Id: | NCT00437073 |
| Agent: | lapatinib |
| Target: | Epidermal growth factor receptor Receptor proteintyrosine kinase erbB2 |
| Cancer Type: | advanced cancer with brain metastasis |
| Cancer Subtype: | brain metastases from human epidermal growth factor receptor 2-positive breast cancerhuman epidermal growth factor receptor 2positive breast cancer |
| Therapy Type: | com |
| Therapeutic Combination Type: | 2 |
| Therapeutic Combination Content: | lapatinib plus capecitabine or lapatinib plus topotecan |
| Study Type: | Randomizedphase II study |
| Key Patients Feature: | Eligible patients had human epidermal growth factor receptor 2positivebreast cancer (defined as 3 immunohistochemistry orevidence of gene amplification by fluorescence in situhybridization) and unequivocal radiographic evidence ofnew and/or progressive metastases in the brain despite priorstandard treatment with WBRT and/or SRS. Prior trastuzumab exposure was also required. Patients had at leastone measurable brain lesion (C10 mm on T1 weighted gadoliniumenhanced magnetic resonance imaging [MRI]).Other eligibility criteria included age C18 years, EasternCooperative Oncology Group [ECOG] performance status 0or 1, life expectancy [12 weeks, cardiac ejection fractionwithin institutional normal range, ability to swallow andretain oral medications, and adequate organ function. Allradiotherapy, chemotherapy, hormonal therapy, and/ortrastuzumab had to be discontinued at least 2 weeks beforeinitiation of protocol treatment. Concurrent administrationof other antineoplastic agents, radiotherapy, or inducers orinhibitors of CYP3A4 were not permitted, with the exception of corticosteroids as clinically indicated. Concurrentuse of enzyme inducing antiepileptic agents was also notallowed. Patients with prior exposure to lapatinib, capecitabine, or topotecan were excluded, as were patients withevidence of leptomeningeal carcinomatosis at screening |
| Biomarker: | human epidermal growth factor receptor 2positive |
| Biomark Analysis: | NA |
| Control Group Info: | single arm |
| Treatment Info: | Patients on the lapatinib plus capecitabine arm received lapatinib 1, 250 mg orally once daily and capecitabine2, 000 mg/m2 orally divided twice daily on days 1-14 of a 21day cycle. Patients on the lapatinib plus topotecan arm received lapatinib 1, 250 mg orally once daily and topotecan 3.2 mg/m2 intravenously on days 1, 8, and 15 of a 28day cycle. Lapatinib could be delayed for up to 2 weeks to allow for resolution of toxicity. In the event of toxicity, one dose reduction to 1, 000 mg once daily was allowed. |
| Primary End Point: | CNS objective response |
| Secondary End Point: | NA |
| Patients Number: | 110 |
| Trial Results | |
| DLT_MTD: | the most commonly reported AEson the lapatinib plus capecitabine arm were diarrhea, PPE, and fatigue. Grade 3 or 4 diarrhea was observed in 4 (31%)patients; grade 3 PPE was reported in 2 patients. Onepatient was withdrawn from the study for grade 3 hyperbilirubinemia.Other grade 3/4 toxicities were rare |
| Objective Response Rate: | Among the 13patients randomized to lapatinib plus capecitabine, 5 CNSPRs were observed (ORR 38%, exact 95% CI 13.9-68.4).Of patients with PR, time on study was 58, 86, 164, 166, and 252 days, respectively. No objective responses wereobserved among the 9 patients treated with lapatinib plustopotecan. |
| Disease Control Rate: | NA |
| Median Time to Progression: | NA |
| Median PFS A vs. C: | NA |
| Median OS A vs. C: | NA |
| Adverse Event(agent arm): | the most commonly reported AEs on the lapatinib plus capecitabine arm were diarrhea, PPE, and fatigue. Grade 3 or 4 diarrhea was observed in 4 (31%) patients; grade 3 PPE was reported in 2 patients. One patient was withdrawn from the study for grade 3 hyperbilirubinemia. Other grade 3/4 toxicities were rare. One fatal SAE of multiorgan failure was reported. Among patients treated with lapatinib plus topotecan, the most commonly reported AEs were diarrhea, nausea, fatigue, and thrombocytopenia. |
| Conclusions: | Although the study was stopped prior to full enrollment, some promising indications of CNS activity they were noted for lapatinib plus capecitabine. The combination of lapatinib plus topotecan was not active and was associated with excess toxicity. |