Intercalated erlotinib-docetaxel dosing schedules designed to achieve pharmacodynamic separation: results of a phase I/II trial.

INTRODUCTION: Epidermal growth factor receptor tyrosine kinase inhibitors given concurrently with chemotherapy do not improve patient outcomes compared with chemotherapy alone in advanced non-small cell lung cancer (NSCLC). On the basis of preclinical models, we hypothesized pharmacodynamic separation, achieved by intermittent delivery of epidermal growth factor receptor tyrosine kinase inhibitors intercalated with chemotherapy, as a reasonable strategy to deliver combination therapy. METHODS: A phase I dose-escalating trial using two scheduling strategies (arms A and B) was conducted in patients with advanced solid tumors to determine the feasibility of intermittent erlotinib and docetaxel. Phase II efficacy evaluation was conducted in an expanded cohort of patients with previously treated advanced NSCLC using arm B scheduling. Docetaxel was given every 21 days (70-75 mg/m intravenously) in both arms. In arm A, erlotinib was administered on days 2, 9, and 16 (600-1000 mg); in arm B, erlotinib was delivered on days 2 through 16 (150-300 mg). Patients without progression or unacceptable toxicity after six cycles continued erlotinib alone. RESULTS: Eighty-one patients were enrolled in this study (17 arm A; 25 arm B; and 39 at phase II dose). Phase I patients had advanced solid tumors and 22 with NSCLC (10 and 12 patients for arms A and B, respectively). Treatment was well tolerated for both arms, with dose-limiting toxicities including grade 3 infection and febrile neutropenia in arm A (maximum tolerated dose [MTD] of erlotinib 600 mg/docetaxel 70 mg/m) and grade 4 rash, febrile neutropenia, grade 3 mucositis, and grade 3 diarrhea in arm B (MTD of erlotinib 200 mg/docetaxel 70 mg/m). The MTD for arm B was chosen for phase II evaluation given the feasibility of administration, number of responses (one complete response and three partial responses), and achievement of pharmacodynamic separation. The response rate for patients treated at the phase II dose was 28.2%, and the disease control rate was 64.1%. Median progression-free and overall survival were 4.1 and 18.2 months, respectively. Common grade ≥3 toxicities were neutropenia (36%) and diarrhea (18%). CONCLUSIONS: Pharmacodynamic separation using intercalated schedules of erlotinib delivered on an intermittent basis together with docetaxel chemotherapy is feasible and tolerable. Further studies using this approach together with interrogation of relevant molecular pathways are ongoing.

Intermittent erlotinib in combination with pemetrexed: phase I schedules designed to achieve pharmacodynamic separation.

INTRODUCTION: Epidermal growth factor receptor tyrosine kinase inhibitors given concurrently with chemotherapy do not improve patient outcomes compared with chemotherapy alone in advanced non-small cell lung cancer (NSCLC). Pharmacodynamic separation by intermittent delivery of epidermal growth factor receptor tyrosine kinase inhibitors with chemotherapy may increase efficacy by overcoming hypothesized antagonism. METHODS: Two dose-escalating phase I trials (arm A and arm B) were conducted simultaneously. Pemetrexed was given every 21 days (500 mg/m intravenously). In arm A, erlotinib was given weekly on days 2, 9, and 16 (800-1400 mg). In arm B, erlotinib was given on days 2 to 16 (150-250 mg). Patients continued therapy until disease progression or unacceptable toxicity. RESULTS: Forty-two patients with advanced solid tumors, including 16 NSCLC, were treated. Patient characteristics included median age of 63 (range, 29-77), 19 males, and Karnofsky performance status >or=90/<90 = 27/15. The median number of cycles was 2. Treatment was well tolerated. Planned dose escalation was completed without reaching a maximum tolerated dose. Dose-limiting toxicities included grade 3 infection/fever (arm A: 500/1200) and grade 3 infection/neutropenia (arm B: 500/150). Rash frequency was 55% in arm A and 90% in arm B. There were six partial responses (four lung, one head and neck, one breast) and 16 stable diseases. Four patients with NSCLC remained on therapy for 9, 16, 16, and 22 cycles. CONCLUSIONS: We report the first clinical trial to test intermittent erlotinib plus pemetrexed. Pemetrexed 500 mg/m and weekly erlotinib 1400 mg (arm A) or pemetrexed 500 mg/m and erlotinib 250 mg on days 2 to 16 (arm B) are feasible and well tolerated. Arm B efficacy is being examined in a randomized phase II trial for second-line NSCLC.