PURPOSE: The primary objective of this phase I study was to determine the maximum tolerated dose for
pemetrexed, alone and in combination with
carboplatin, with concurrent
radiotherapy. EXPERIMENTAL DESIGN: Patients with locally advanced or
metastatic non-small cell
lung cancer (
NSCLC) or
esophageal cancer were treated every 21 days for two cycles. Regimen 1 was
pemetrexed (200-600 mg/m(2)); regimen 2 was
pemetrexed (500 mg/m(2)) with escalating
carboplatin doses (AUC = 4-6). Both regimens included concurrent
radiation (40-66 Gy; palliative-intent doses were lower). RESULTS: Thirty patients (18 locally advanced and 12
metastatic with dominant local
symptoms) were enrolled, with an
Eastern Cooperative Oncology Group performance status of 0/1/2 (n = 8/21/1). All dose levels were tolerable for regimen 1 (n = 18: 15
NSCLC and 3
esophageal cancers) and regimen 2 (n = 12: all
NSCLC). In regimen 1, one dose-limiting
toxicity (grade 4
esophagitis/anorexia) occurred (500 mg/m(2)). Grade 3
neutropenia (3 of 18 patients) was the main
hematologic toxicity. In regimen 2, one dose-limiting
toxicity (grade 3
esophagitis) occurred (500 mg/m(2); AUC = 6); grade 3/4
leukopenia (4 of 12 patients) was the main
hematologic toxicity. Four complete responses (2
pathology proven) and eight partial responses were observed. When systemically active
chemotherapy doses were reached, further dose escalation was discontinued, and a phase II dose-range was established (
pemetrexed 500 mg/m(2) and
carboplatin AUC = 5-6). CONCLUSIONS: The combination of
pemetrexed (500 mg/m(2)) and
carboplatin (AUC = 5 or 6) with concurrent
radiation is well tolerated, allows for the administration of systemically active
chemotherapy doses, and shows signs of activity. To further determine efficacy, safety profile, and optimal
dosing, the Cancer and
Leukemia Group B study 30407 is currently evaluating this regimen in patients with unresectable stage III
NSCLC.
