5 research outputs found
Health Plan Competition For Medicaid Enrollees Based On Performance Does Not Improve Quality Of Care
Phase I dose-escalation study of 5-day intermittent oral lapatinib therapy in patients with human epidermal growth factor receptor 2-overexpressing breast cancer.
PurposeThe highly effective treatment of human epidermal growth factor receptor (HER) 2-amplified breast cancer has proven challenging because of a signal buffering capacity inherent in the functionally relevant HER2-HER3 target. HER2-HER3 signaling can be inactivated by doses of lapatinib that fully inactivate the HER2 kinase. In mouse models, such doses are not tolerable in continuous administration, but they are tolerable and highly effective in intermittent dosing. We pursued the clinical translation of this treatment hypothesis.Patients and methodsWe conducted a phase I dose-escalation study in women with advanced HER2-overexpressing breast cancer. Lapatinib was administered on days 1 through 5 of repeating 14-day cycles. Dose escalation was conducted using a 3+3 design with plasma lapatinib level monitoring.ResultsForty patients were evaluable for toxicity, and 34 patients were evaluable for dose-limiting toxicity (DLT). Lapatinib dose was escalated to 7,000 mg per day in twice-daily dosing with no DLTs; however, plasma lapatinib concentrations plateaued in this dose range. Additional cohorts evaluated strategies to increase lapatinib exposure, including the food effect, CYP3A4 inhibition, and dose fractionation. Of these, only ketoconazole was able to increase lapatinib exposure, despite highly variable lapatinib bioavailability. Intolerable exposure levels were not encountered. Eight patients (20%) experienced grade 3 diarrhea. Six patients achieved a response, and dramatic responses were seen in three patients with lapatinib concentrations approaching 10,000 ng/mL.ConclusionLapatinib exposure can be safely and significantly increased through intermittent dosing but reaches a ceiling that currently impedes clinical translation of the treatment hypothesis. Preliminary efficacy data suggest that exposures approaching those seen in mouse models can result in highly significant tumor responses
Phase I Dose-Escalation Study of 5-Day Intermittent Oral Lapatinib Therapy in Patients With Human Epidermal Growth Factor Receptor 2–Overexpressing Breast Cancer
PURPOSE: The highly effective treatment of human epidermal growth factor receptor (HER) 2–amplified breast cancer has proven challenging because of a signal buffering capacity inherent in the functionally relevant HER2-HER3 target. HER2-HER3 signaling can be inactivated by doses of lapatinib that fully inactivate the HER2 kinase. In mouse models, such doses are not tolerable in continuous administration, but they are tolerable and highly effective in intermittent dosing. We pursued the clinical translation of this treatment hypothesis. PATIENTS AND METHODS: We conducted a phase I dose-escalation study in women with advanced HER2-overexpressing breast cancer. Lapatinib was administered on days 1 through 5 of repeating 14-day cycles. Dose escalation was conducted using a 3+3 design with plasma lapatinib level monitoring. RESULTS: Forty patients were evaluable for toxicity, and 34 patients were evaluable for dose-limiting toxicity (DLT). Lapatinib dose was escalated to 7,000 mg per day in twice-daily dosing with no DLTs; however, plasma lapatinib concentrations plateaued in this dose range. Additional cohorts evaluated strategies to increase lapatinib exposure, including the food effect, CYP3A4 inhibition, and dose fractionation. Of these, only ketoconazole was able to increase lapatinib exposure, despite highly variable lapatinib bioavailability. Intolerable exposure levels were not encountered. Eight patients (20%) experienced grade 3 diarrhea. Six patients achieved a response, and dramatic responses were seen in three patients with lapatinib concentrations approaching 10,000 ng/mL. CONCLUSION: Lapatinib exposure can be safely and significantly increased through intermittent dosing but reaches a ceiling that currently impedes clinical translation of the treatment hypothesis. Preliminary efficacy data suggest that exposures approaching those seen in mouse models can result in highly significant tumor responses
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Time to Peak Glucose and Peak C-Peptide During the Progression to Type 1 Diabetes in the Diabetes Prevention Trial and TrialNet Cohorts
OBJECTIVE To assess the progression of type 1 diabetes using time to peak glucose or C-peptide during oral glucose tolerance tests (OGTTs) in autoantibody-positive relatives of people with type 1 diabetes. RESEARCH DESIGN AND METHODS We examined 2-h OGTTs of participants in the Diabetes Prevention Trial Type 1 (DPT-1) and TrialNet Pathway to Prevention (PTP) studies. We included 706 DPT-1 participants (mean ± SD age, 13.84 ± 9.53 years; BMI Z-score, 0.33 ± 1.07; 56.1% male) and 3,720 PTP participants (age, 16.01 ± 12.33 years; BMI Z-score, 0.66 ± 1.3; 49.7% male). Log-rank testing and Cox regression analyses with adjustments (age, sex, race, BMI Z-score, HOMA-insulin resistance, and peak glucose/C-peptide levels, respectively) were performed. RESULTS In each of DPT-1 and PTP, higher 5-year diabetes progression risk was seen in those with time to peak glucose >30 min and time to peak C-peptide >60 min (P < 0.001 for all groups), before and after adjustments. In models examining strength of association with diabetes development, associations were greater for time to peak C-peptide versus peak C-peptide value (DPT-1: χ2 = 25.76 vs. χ2 = 8.62; PTP: χ2 = 149.19 vs. χ2 = 79.98; all P < 0.001). Changes in the percentage of individuals with delayed glucose and/or C-peptide peaks were noted over time. CONCLUSIONS In two independent at-risk populations, we show that those with delayed OGTT peak times for glucose or C-peptide are at higher risk of diabetes development within 5 years, independent of peak levels. Moreover, time to peak C-peptide appears more predictive than the peak level, suggesting its potential use as a specific biomarker for diabetes progression