Effects of dexamethasone (Dex) pretreatment on toxicity and efficacy of carboplatin and gemcitabine (Carbo/Gem) in patients with non-small cell lung cancer (NSCLC)

18124 Background: Our preclinical data showed that treating mice with Dex 4 days prior to chemotherapy increased efficacy and decreased toxicity of Carbo/Gem in nude mice bearing human NSCLC by increasing drug concentration in tumors, and decreasing drug concentration in normal tissue without altering plasma pharmacokinetics (PK). Thus, we undertook a Phase I/II trial to determine the optimal dose of Dex, and the effect of Dex on Carbo/Gem plasma PK. Methods: Patients (n=30) with untreated, stage IV NSCLC and PS =2 received Gem, 1g/m2 days 1&8, and Carbo, AUC 5.5 on day 1. Patients were randomized (1:2:2) to receive no Dex (arm 1), or Dex at 8 and 16 mg bid po 4 days before and on day 1 (arms 2 and 3). Dex was administered in courses 2, 3, and 4 (only) to allow course 1 vs course 2 intra-patient toxicity and Carbo/Gem plasma PK assessment. Plasma samples were analyzed by HPLC for Carbo/Gem. Plasma PK analysis was performed with NONMEM v5 using a 5-compatment or 2-compartment structural models for Gem and Carbo. Results: Patients in arms 1, 2, and 3 were similar in PS, age, gender, and histology. In arms 1, 2, and 3, patients completing 4 planned courses of therapy: 1/6, 6/12, 9/12; partial responses (RECIST): 2/6, 7/12, and 8/12. Hematologic toxicity in arms 1 (no Dex), 2, and 3 (Dex) was compared. Platelet nadirs (course2÷course1): 0.6±0.2, 3.77±2.0, 3.4±0.72 (p<0.02); AGC nadirs: 1.1±0.3, 2.32±0.4, 4.95±1.04 (p< 0.01); Change in median time to recovery from day 1 (course 2-course 1) of AGC to 1,500 mm3 in days: +9, -15, -19; Change in median time to recovery of platelets to 100,000 mm3: +5, -1, -1.5. Comparison of nadir AGC and platelets between courses 2, 3, and 4 consistently demonstrated superiority of arm 3 over arm 2. No significant differences in non-hematologic toxicities were seen between arms 1, 2 and 3. Gem and Carbo clearance values were not significantly different among arms or courses. Area under the time-concentration curves (course2÷course1): 0.91±0.18, 0.77±0.15, 0.80±0.16. Conclusions: Dex pretreatment appears to reduce toxicity and improve efficacy of Carbo/Gem in NSCLC patients, with arm 3>2. These effects are not due to alteration of plasma PK since no significant decrease in chemotherapy exposure was observed in arms 2 and 3. [Table: see text]