David Dunlop

Tirapazamine Plus Cisplatin Versus Cisplatin in Advanced Non–Small-Cell Lung Cancer: A Report of the International CATAPULT I Study Group

PURPOSE A phase III trial, Cisplatin and Tirapazamine in Subjects with Advanced Previously Untreated Non-Small-Cell Lung Tumors (CATAPULT I), was designed to determine the efficacy and safety of tirapazamine plus cisplatin for the treatment of non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Patients with previously untreated NSCLC were randomized to receive either tirapazamine (390 mg/m(2) infused over 2 hours) followed 1 hour later by cisplatin (75 mg/m(2) over 1 hour) or 75 mg/m(2) of cisplatin alone, every 3 weeks for a maximum of eight cycles. RESULTS A total of 446 patients with NSCLC (17% with stage IIIB disease and pleural effusions; 83% with stage IV disease) were entered onto the study. Karnofsky performance status (KPS) was >/= 60 for all patients (for 10%, KPS = 60; for 90%, KPS = 70 to 100). Sixty patients (14%) had clinically stable brain metastases. The median survival was significantly longer (34.6 v 27. 7 weeks; P =.0078) and the response rate was significantly greater (27.5% v 13.7%; P <.001) for patients who received tirapazamine plus cisplatin (n = 218) than for those who received cisplatin alone (n = 219). The tirapazamine-plus-cisplatin regimen was associated with mild to moderate adverse events, including acute, reversible hearing loss, reversible, intermittent muscle cramping, diarrhea, skin rash, nausea, and vomiting. There were no incremental increases in myelosuppression, peripheral neuropathy, or renal, hepatic, or cardiac toxicity and no deaths related to tirapazamine. CONCLUSION The CATAPULT I study shows that tirapazamine enhances the activity of cisplatin in patients with advanced NSCLC and confirms that hypoxia is an exploitable therapeutic target in human malignancies.

Overcoming CYP1A1/1A2 mediated induction of metabolism by escalating erlotinib dose in current smokers.

PURPOSE Cigarette smoking induces CYP1A1/1A2 and is hypothesized to alter erlotinib pharmacokinetics. This study aimed to determine the maximum tolerated dose (MTD) of erlotinib in advanced non-small-cell lung cancer (NSCLC) patients who smoke and compare the pharmacokinetics of erlotinib at the MTD in current smokers with 150 mg. PATIENTS AND METHODS Cohorts of NSCLC patients currently smoking > or = 10 cigarettes per day for > or = 1 year received escalating doses of erlotinib for 14 days until dose-limiting toxicity (DLT). A separate cohort of patients was then randomly assigned to erlotinib at either MTD or 150 mg daily with pharmacokinetics assessed at day 14. Erlotinib was continued until progression or intolerable toxicity. RESULTS Four dose levels were evaluated in 22 patients: 200, 250, 300, and 350 mg. DLT was observed in one of six patients at 300 mg (rash) and two of five patients at 350 mg (acneiform dermatitis and fatigue/decreased Eastern Cooperative Oncology Group performance status). Thirty-five patients were randomly assigned to 150 mg or 300 mg. Common adverse events (all grades) were: skin toxicity (150 mg, 29%; 300 mg, 67%), diarrhea (150 mg, 18%; 300 mg, 50%), and fatigue (150 mg, 12%; 300 mg, 17%). Erlotinib exposure was dose-proportional within dose range tested. Median steady-state trough erlotinib plasma concentrations were 0.375 and 1.22 microg/mL for 150 mg and 300 mg, respectively. CONCLUSION The MTD of erlotinib in NSCLC patients who smoke was 300 mg. Steady-state trough plasma concentrations and incidence of rash and diarrhea in smokers at 300 mg were similar to those in former or never smokers receiving 150 mg in previous studies. The potential benefit of higher erlotinib doses in current smokers warrants further evaluation.

Combination Therapy With Gefitinib and Rofecoxib in Patients With Platinum-Pretreated Relapsed Non–Small-Cell Lung Cancer

PURPOSE In non-small-cell lung cancer (NSCLC), the epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) play major roles in tumorigenesis. This phase I/II study evaluated combined therapy with the EGFR tyrosine kinase inhibitor (TKI) gefitinib and the COX-2 inhibitor rofecoxib in platinum-pretreated, relapsed, metastatic NSCLC (n = 45). PATIENTS AND METHODS Gefitinib 250 mg/d was combined with rofecoxib (dose escalated from 12.5 to 25 to 50 mg/d through three cohorts, each n = 6). Because the rofecoxib maximum-tolerated dose was not reached, the 50 mg/d cohort was expanded for efficacy evaluation (n = 33). RESULTS Among the 42 assessable patients, there was one complete response (CR) and two partial responses (PRs) and 12 patients with stable disease (SD); disease control rate was 35.7% (95% CI, 21.6% to 52.0%). Median time to tumor progression was 55 days (95% CI, 47 to 70 days), and median survival was 144 days (95% CI, 103 to 190 days). In a pilot study, matrix-assisted laser desorption/ionization (MALDI) proteomics analysis of baseline serum samples could distinguish patients with an objective response from those with SD or progressive disease (PD), and those with disease control (CR, PR, and SD) from those with PD. The regimen was generally well tolerated, with predictable toxicities including skin rash and diarrhea. CONCLUSION Gefitinib combined with rofecoxib provided disease control equivalent to that expected with single-agent gefitinib and was generally well tolerated. Baseline serum proteomics may help identify those patients most likely to benefit from EGFR TKIs.

DHA-Paclitaxel (Taxoprexin) as First-Line Treatment in Patients with Stage IIIB or IV Non-small Cell Lung Cancer: Report of a Phase II Open-Label Multicenter Trial

Introduction: This prospective, open-label, non-randomized, multi-institutional phase II study was undertaken to assess the antitumor activity and safety of docosahexaenoic acid–paclitaxel (Taxoprexin) as first-line treatment of patients with advanced non-small cell lung cancer. Patients and Methods: Chemotherapy-naive patients were eligible if they had measurable stage IIIB or IV non-small cell lung cancer. Forty-four patients received docosahexaenoic acid–paclitaxel by intravenous infusion every 21 days. Two doses were evaluated: 1100 mg/m2 and 900 mg/m2. Patients were monitored for toxicity and tumor response. Results: Patients received between one and seven (median, two) cycles of treatment. Twenty-eight courses were administered in the cohort starting at 1100 mg/m2 and 109 courses at 900 mg/m2. The starting dose was reduced to 900 mg/m2 because of toxicity in the first 13 patients. Subsequently, the most severe toxicity was neutropenia (grade III/IV in 68% of patients treated with 900 mg/m2). Forty patients were eligible for assessment of tumor response. Two partial responses (4.5%) were documented, and a further 16 patients (36.4%) had stable disease based on an intent-to-treat analysis. The median duration of survival for all patients was 243 days (range, 154–359) and the 1-year survival rate was 35%. Conclusion: As a single-agent, docosahexaenoic acid–paclitaxel has little activity in patients with advanced non-small cell lung cancer, with 18 patients (40.1%) achieving either stable disease or a partial response after treatment. Despite the low objective response rate, treatment was associated with survival comparable to that seen with standard platinum-based combination chemotherapy. The dose-limiting toxicity was myelosuppression.