Heidi H. Gillenwater

Multicenter, Phase II Trial of Sunitinib in Previously Treated, Advanced Non–Small-Cell Lung Cancer

PURPOSE Aberrant vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) signaling have been shown to play a role in non-small-cell lung cancer (NSCLC) pathogenesis and are associated with decreased survival. We evaluated the clinical activity and tolerability of sunitinib malate (SU11248), an oral, multitargeted tyrosine kinase inhibitor that blocks the activity of receptors for VEGF and PDGF, as well as related tyrosine kinases in patients with previously treated, advanced NSCLC. PATIENTS AND METHODS Patients with stage IIIB or IV NSCLC for whom platinum-based chemotherapy had failed received 50 mg/d of sunitinib for 4 weeks followed by 2 weeks of no treatment in 6-week treatment cycles. The primary end point was objective response rate (ORR); secondary end points included progression-free survival, overall survival, and safety. RESULTS Of the 63 patients treated with sunitinib, seven patients had confirmed partial responses, yielding an ORR of 11.1% (95% CI, 4.6% to 21.6%). An additional 18 patients (28.6%) experienced stable disease of at least 8 weeks in duration. Median progression-free survival was 12.0 weeks (95% CI, 10.0 to 16.1 weeks), and median overall survival was 23.4 weeks (95% CI, 17.0 to 28.3 weeks). Therapy was generally well tolerated. CONCLUSION Sunitinib has promising single-agent activity in patients with recurrent NSCLC, with an ORR similar to that of currently approved agents and an acceptable safety profile. Further evaluation in combination with other targeted agents and chemotherapy in patients with NSCLC is warranted.

Second-line chemotherapy with 96-hour infusional paclitaxel in refractory non-small cell lung cancer: report of a phase II trial.

Advanced metastatic non-small cell lung cancer (NSCLC) that has progressed on initial cisplatin-based chemotherapy has a poor prognosis. Although paclitaxel is an active agent in the first-line therapy of NSCLC, 24-hr infusion of paclitaxel in patients with NSCLC failing first-line cisplatin-based regimens has shown minimal activity. Prolonged infusions of paclitaxel have shown activity in breast cancer patients who have failed short infusions of paclitaxel. In this study, 13 patients with refractory NSCLC who progressed on or after initial chemotherapy were treated with 96-hr paclitaxel (140 mg/m2 over 96 hr every 3 weeks) infusions as outpatients using a CADD infusion pump via a central catheter. Nine patients received only one or two cycles of treatment because of disease progression and had a median survival of 3 months (range, 1-5 months). Four patients had stabilization of disease for two to six cycles of treatment and had a median survival of 8 months (range, 8-12+ months). Grade 3-4 hematologic and nonhematologic toxicity occurred in < 10% of cycles, and no treatment-related hospitalizations occurred. Quality of life (QOL) assessments using the Functional Assessment of Cancer Therapy-Lung questionnaire were performed at baseline and with each treatment cycle. In conclusion, although no objective responses were seen, disease stabilization occurred in 31% of patients. Overall toxicity was tolerable with no major negative impact on QOL in those patients receiving two or more cycles of treatment.

Measured versus estimated glomerular filtration rate in the Calvert equation: influence on carboplatin dosing

Abstract. Purpose: Carboplatin is frequently dosed to achieve a desired area under the plasma concentration-time curve (AUC) by using the Calvert or Chatelut equations to estimate carboplatin clearance. Accurate determination of glomerular filtration rate (GFR) is necessary to correctly calculate carboplatin clearance using the Calvert equation. In clinical practice, the Cockcroft-Gault formula is frequently used to estimate GFR, but this practice has been reported to under- and overestimate carboplatin clearance. The purpose of this trial was to compare determinations of carboplatin clearance using the Chatelut equation and four separate GFR determinations, including 99mTc-DTPA, the Cockcroft-Gault formula, a 24-h urine collection and a 2-h urine collection. Methods: Carboplatin clearance was estimated in 21 previously untreated extensive-stage small-cell lung cancer patients. GFR was determined using 99mTc-DTPA, the Cockcroft-Gault formula, 24-h urine collection and 2-h urine collection. Serum and urine creatinine concentrations were measured using enzymatic assays. The carboplatin clearance was then calculated by individually adding 25 to the four GFR determinations based on the Calvert equation, which states that carboplatin clearance equals GFR+25 (nonrenal clearance). The carboplatin clearance was also estimated using the Chatelut equation. The five determinations of carboplatin clearance were compared using Friedmans test and post-hoc Wilcoxon signed rank tests. Precision and bias for each carboplatin clearance determination were calculated assuming that 99mTc-DTPA provided the most accurate measure of GFR. Results: A statistically significant difference was found between the five methods of estimating carboplatin clearance (P<0.001). No difference was found between carboplatin clearance calculated using 99mTc-DTPA and the Chatelut equation, the Cockcroft-Gault formula or the 2-h urine collection. The Chatelut equation provided more precision and less bias than the 2-h urine collection (median precision 20% and 30%, median bias –1% and –18%, respectively). Conclusion: Compared to 99mTc-DTPA, the Chatelut equation more accurately estimates carboplatin clearance than the Cockcroft-Gault formula, the 2-h urine collection and the 24-h urine collection. The greater negative bias found for the latter three estimates of carboplatin clearance could result in underdosing of carboplatin.

Phase II trial of irinotecan, paclitaxel and carboplatin in patients with previously untreated Stage IIIB/IV nonsmall cell lung carcinoma

This Phase II multicenter, open‐label, single‐arm study evaluated the efficacy and safety of a three‐drug combination of irinotecan (CPT‐11), paclitaxel, and carboplatin in advanced nonsmall cell lung carcinoma (NSCLC).

Phase II Study of Continuous Daily Sunitinib Dosing in Patients with Previously Treated Advanced Non–Small-Cell Lung Cancer (NSCLC)

Background Sunitinib is an oral, multitargeted tyrosine kinase inhibitor of vascular endothelial growth factor receptors, platelet-derived growth factor receptors, KIT, RET, and FLT3. In a phase II trial, 11% of patients with recurrent advanced non–small-cell lung cancer (NSCLC) exhibited a partial response (PR) to sunitinib administered on a 4/2 schedule (4 weeks on treatment followed by 2 weeks off; Socinski, 2006). A planned extension of this phase II study, reported here, investigated the efficacy and safety of sunitinib given on a continuous dosing schedule. Patients and Methods Patient eligibility criteria included stage IIIB/IV NSCLC previously treated with 1-2 chemotherapy regimens, Eastern Cooperative Oncology Group performance status ≤ 1, and adequate organ function. Patients with brain metastases or recent gross hemoptysis were excluded. Treatment comprised oral sunitinib 37.5 mg per day continuously in repeated 4-week cycles. The primary endpoint was objective response rate per Response Evaluation Criteria in Solid Tumors; secondary endpoints included progression-free survival (PFS), overall survival, and safety. Results Forty-seven patients were treated on the continuous dosing schedule, starting a median of 3 cycles (range, 1-10 cycles). Baseline characteristics included median age of 60 years (range, 37-81 years); male sex, 57%; Eastern Cooperative Oncology Group performance status 0-2 (49%/49%/2%, respectively); 53% of patients had adenocarcinoma, 15% of patients had squamous cell carcinoma, and 32% of patients had “other”. One patient (2%) exhibited a PR, and 8 patients (17%) had stable disease > 3 months. Median PFS was 12.1 weeks (95% confidence interval, 8.6-13.7 weeks); median overall survival had not been reached at the time of analysis. Adverse events (AEs) were generally mild to moderate (grade 1/2) and the most common AEs were fatigue/asthenia, pain/myalgia, nausea/vomiting, diarrhea, dyspnea, and stomatitis/mucosal inflammation. Grade ≥ 3 AEs included fatigue/asthenia (15%), hypertension (6%), hypoxia (6%), dyspnea (4%), and hemoptysis (2%). Serious, treatment-related AEs included congestive heart failure (1 patient, who died after onset of this AE), gastrointestinal bleeding (n = 1), hypomagnesemia (n = 1), and hypoxic respiratory failure (n = 1). Conclusion Continuous daily sunitinib dosing has an acceptable safety profile in patients with previously treated, advanced NSCLC. Preliminary efficacy data show evidence of activity, with 1 PR and a median PFS of 12.1 weeks. Further study of sunitinib continuous dosing in combination with other treatments for NSCLC is planned.