Entry Detail
| General information | |
| Database: | DB00450 |
| Objective: | To explore the activity of lapatinib with a novel trial design focused on the drug target rather than on histology. |
| Authors: | Galsky MD, et al |
| Title: | Targetspecific, histologyindependent, randomized discontinuation study of lapatinib in patients with human epidermal growth factor receptor 2amplified solid tumors. |
| Journal: | Invest New Drugs. |
| Year: | 2012 |
| PMID: | 20857170 |
| Trial Design | |
| Clinical Trial Id: | NCT00447226 |
| Agent: | lapatinib |
| Target: | Epidermal growth factor receptor Receptor proteintyrosine kinase erbB2 |
| Cancer Type: | advanced solid tumors |
| Cancer Subtype: | human epidermal growth factor receptor 2amplified solid tumors |
| Therapy Type: | mono |
| Therapeutic Combination Type: | NA |
| Therapeutic Combination Content: | NA |
| Study Type: | a phase II, multicenter (III communitybasedresearch sites), placebocontrolled, doubleblind, randomized discontinuation study |
| Key Patients Feature: | patients with metastatic gastroesophageal, bladder, uterine papillary serous, or ovariancancer that had progressed despite standard therapy hadarchival formalin fixed paraffin embedded tumor tissueanalyzed in a central laboratory (Caris Molecular ProfilingInstitute, Phoenix, Arizona) for human epidermal growth factor receptor 2 status by FISHanalysis (Stage 0). Patients with human epidermal growth factor receptor 2 amplification (aFISH probe ratio of >2.0) were eligible for participation inthe trial provided that the following eligibility criteria weremet: measurable disease per RECIST 1.0 [19], EasternCooperative Oncology Group performance status 1-2, andadequate cardiac (baseline ejection fraction on echocardiogram or multigated acquisition scan within institutionalnormal limits), hepatic [hepatic transaminases less than and equal to 3 X upperlimit of normal (ULN) in the absence of liver metastases orless than and equal to 5 X ULN in the presence of hepatic metastases; totalbilirubin less than and equal to 1.25 X ULN], renal (serum creatinine less than and equal to 2.0 mg/dlor calculated creatinine clearance more than and equal to 40 ml/min), and bonemarrow function (absolute neutrophil count more than and equal to 1.5¡Á109/L, hemoglobin more than and equal to 9 g/dL, platelets more than and equal to 75¡Á109/L). |
| Biomarker: | human epidermal growth factor receptor 2 amplifications |
| Biomark Analysis: | While human epidermal growth factor receptor 2 amplifications appear to be prevalent in select nonbreast tumors, lapatinib monotherapy is associated with modest activity. |
| Control Group Info: | A:lapatinib B: placebo |
| Treatment Info: | pts were enrolled into a doubleblinded randomized discontinuation study of lapatinib 1, 500 mg PO daily. The planned sample size was 250 patients with human epidermal growth factor receptor 2 amplified tumors, with the goal of randomizing 100 patients with stable disease (SD) at week 12 to either lapatinib or placebo. Patients responding after 12 weeks continued on lapatinib; those who progressed were discontinued from study. |
| Primary End Point: | (1) to determine the response rate to lapatinib during Stage 1 (openlabel)treatment and (2) to determine the percentage of patients that remained progression free 12 weeks after randomization between lapatinib and placebo in Stage 2 |
| Secondary End Point: | NA |
| Patients Number: | 141 |
| Trial Results | |
| DLT_MTD: | The most common adverse events reported in this studywere diarrhea (17 patients, 53%), fatigue (10 patients, 31%)and anorexia (9 patients, 28%) and nausea (9 patients, 28%) |
| Objective Response Rate: | 1 (3%) patienthad a complete response, 9 (28%) had stable disease, 20(63%) had progressive disease, and 2 (6%) were unknown.Only 7 patients with SD underwent randomization |
| Disease Control Rate: | 0.31 |
| Median Time to Progression: | 78 days [(95% CI, 42, 118)] |
| Median PFS A vs. C: | NA |
| Median OS A vs. C: | NA |
| Adverse Event(agent arm): | The most common adverse events reported in this study were diarrhea (17 patients, 53%), fatigue (10 patients, 31%) and anorexia (9 patients, 28%) and nausea (9 patients, 28%) The majority of adverse events were of grade 1-2 in severity; grades 3 and 4 toxicities were rare (grade 3 nausea and diarrhea were the only grade >3 adverse events to occur in >5% of patients). The side effect profile was similar to that previously reported in patients taking lapatinib for breast cancer. None of the deaths that occurred on study were attributed to study drug treatment. |
| Conclusions: | Basing trial eligibility on the presence of a genetic target, versus histologic classification, is challenging. While human epidermal growth factor receptor 2 amplifications appear to be prevalent in select nonbreast tumors, lapatinib monotherapy is associated with modest activity. The targetspecific histologyindependent randomized discontinuation design still merits consideration for targets clearly implicated in oncogene addiction. |