Aisner, Joseph

Background:Injectable azacitidine (AZA) has been evaluated in a variety of malignancies, including acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and solid tumors. CC‐486, the oral formulation of AZA, allows extended dosing schedules (>7 days per 28‐day treatment cycle) to increase AZA exposure to malignant cells over the course of the cycle. CC‐486 is under investigation in phase 3 clinical trials as maintenance therapy for patients with AML in first complete remission after induction chemotherapy (NCT01757535) and in lower‐risk MDS with concurrent thrombocytopenia and RBC transfusion dependence (NCT01566695). In these studies, patients receive CC‐486 300 mg QD administered in two 150 mg tablets. A single 300 mg CC‐486 tablet is in development for market approval.Aims:Evaluate the bioequivalence (BE) of a single 300 mg CC‐486 tablet relative to two 150 mg CC‐486 tablets, and the food effect (FE) on the bioavailability of the CC‐486 300 mg tablet.Methods:This was a phase 1, randomized, crossover study (NCT01519011). Adult patients had hematologic malignancies or solid tumors relapsed/refractory to prior therapy for which no standard treatments were available, and ECOG PS scores 0‐2. The BE phase assessed pharmacokinetic (PK) parameters of CC‐486 administered as two 150 mg tablets (formulation A) and as one 300 mg tablet (formulation B). Patients were randomized 1:1 to receive each formulation at least 48 hours apart. In the FE phase, patients were randomized to receive formulation B on each of 2 PK study days under fed (high fat, ∼800‐1000 calories) and fasted conditions. PK parameters, including area under the plasma concentration‐time curve from time 0 extrapolated to infinity (AUC∞), maximum plasma concentration (Cmax), time to Cmax (Tmax), terminal half‐life (t1/2), apparent total clearance (CL/F) and volume of distribution (Vz/F) were analyzed. BE of formulations A and B, and absence of FE on formulation B, were indicated when the 90% CI of the ratios of geometric means (RGM) based on log‐transformed data for AUC∞ and Cmax between formulations A and B, and between fed and fasted conditions, were within 80%>125%.Results:30 patients were enrolled in the BE phase (median age 68.5 yrs, range 46‐86); 3 patients (10%) had hematologic malignancies and 27 (90%) had solid tumors. Formulations A and B were bioequivalent: the Cmax RGM was 101.5% (90% CI 89.9, 114.7) and AUC∞ RGM was 105.7% (95.0, 117.6). Median Tmax was 1.0 hour for both formulations.57 patients enrolled in the FE phase (median age 62 yrs, 31‐88); all had solid tumors. Despite a lower Cmax under fed condition (RGM 78.9% [90%CI 68.6, 90.7]), overall drug exposure was similar (AUC∞ RGM 108.9% [90%CI 98.5, 120.5]) (Figure A). Consistent with an effect of gastric emptying, median Tmax was reached at 2 hrs and 1 hr post‐dose in fed and fasted states, respectively (Figure B) and mean t1/2 was 0.78 and 0.58 hr postdose. CL/F and Vz/F were comparable in fed and fasted states. Moderate to high intersubject variability was observed for all CC‐486 PK parameters (Figure A).Summary/Conclusion:A single oral CC‐486 300 mg tablet is bioequivalent to two 150 mg tablets. The PK profile for the CC‐486 300 mg tablet under fed and fasted conditions was comparable although Cmax occurred later and was decreased in fed vs. fasted condition. Systemic drug exposure (AUC∞) in fed and fasted states was similar and within the bioequivalence limits. Limited differences in other CC‐486 PK parameters between fed and fasted states are not expected to have a clinical impact.image

Abstract Purpose: This randomized phase II study was initially designed to test the activity of two dose schedules of lapatinib (GW572016H), an oral, reversible, dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) and human EGFR-2 (HER2/neu; HER2), in chemotherapy-naive patients with non–small cell lung cancer (NSCLC); it was later amended to target patients with bronchioloalveolar carcinoma or no smoking history. Experimental Design: Patients with good performance status and recurrent or metastatic NSCLC were randomized to lapatinib (orally, 1,500 mg once daily or 500 mg twice daily) until progression or intolerance. Patients could have had a maximum of one prior systemic therapy (chemotherapy or biological therapy) for NSCLC. Safety and activity were assessed every 4 and 8 weeks, respectively. Tumors were analyzed for EGFR and HER2 mutations and/or amplifications. Results: Of 75 patients in the nontargeted population, 1 (1.3%) had partial response and 16 (21%) had stable disease of ≥24 weeks. No complete or partial responses were observed in 56 patients in the targeted population; 14 (25%) had stable disease of ≥24 weeks. No responses were seen in three patients with EGFR mutations and five with EGFR gene amplification. No mutations in HER2 were found. One of two patients with HER2 amplification had a 51% decrease in tumor size; however, this response was unconfirmed. The most common adverse events were grade 1 or 2 diarrhea, rash, fatigue, nausea, and anorexia. Adverse events were similar across dosing regimens. Conclusions: Lapatinib was well tolerated, with no notable difference in toxicity between treatment groups. Lapatinib monotherapy did not induce a significant number of tumor regressions in NSCLC. Further studies may be warranted to determine whether lapatinib is active in combination with other agents in the treatment of NSCLC. Clin Cancer Res; 16(6); 1938–49