Phase I study of the antifolate pralatrexate given with vitamin B12 and folic acid supplementation in patients (pts) with advanced non-small cell lung cancer (NSCLC)

Abstract

13006 Background: Pralatrexate is a novel antifolate that has shown promising activity in the treatment of pts with previously- treated NSCLC at doses of 135–150 mg/m2 IV every other week (q2w). [Krug, Clin Cancer Res 9(6), 2003; 6(9), 2000] The addition of vitamin B12 and folic acid supplementation may mitigate toxicity from pralatrexate and improve efficacy by allowing higher doses to be delivered. Methods: This study is designed to determine the maximum tolerated dose (MTD) of pralatrexate in combination with vitamin B12 and folic acid supplementation in pts with NSCLC. Key eligibility criteria include confirmed stage IIIB or IV NSCLC; at least 1 prior chemotherapy regimen; Karnofsky performance status (KPS) = 70%; and no other active concurrent malignancy. Using a rapid escalation design, pralatrexate was initially administered at a dose of 150 mg/m2 IV q2w, escalating by 40 mg/m2 increments in successive cohorts, with one patient per cohort if no dose limiting toxicity (DLT) is encountered. All pts receive vitamin B12 1 mg intramuscular q 8–10 weeks and folic acid 1 mg by mouth once a day beginning at least 7 days prior to pralatrexate. All patients undergo pharmacokinetic testing following their first and second dose of pralatrexate. Results: Between 1/05–12/06, a total of 9 pts have been treated at the following dose levels: 150 (n=1), 190 (n=1), 230 (n=1), and 270 (n=6). Patient characteristics include: 2 male/7 female; median age 63 (range 52–73); KPS 80–90%; all pts had stage 4 NSCLC; 5 pts received 1 prior regimen and 4 pts received 2 or more prior regimens. Grade 3 esophagitis was a DLT in one patient at the 270 mg/m2 dose. Three other patients experienced grade 1–2 mucositis at this dose level without limiting drug delivery. The trial is ongoing, and enrollment is planned at 310 mg/m2 q2w to determine the MTD. Conclusions: When given in combination with vitamin B12 and folic acid supplementation, pralatrexate has been well tolerated in this pt population, with an MTD at least twice as high as achieved in previous phase 1 testing without supplementation. We plan to conduct a phase 2 trial of pralatrexate with vitamin B12 and folic acid supplementation to see if a higher dose will improve efficacy. No significant financial relationships to disclose.