Pralatrexate with vitamin supplementation in patients with previously treated, advanced non-small cell lung cancer: safety and efficacy in a phase 1 trial.

Abstract

INTRODUCTION:

Pralatrexate is an antifolate designed for preferential tumor cell uptake and accumulation and received accelerated Food and Drug Administration approval in relapsed/refractory peripheral T-cell lymphoma. Pralatrexate 135 to 150 mg/m(2) every 2 weeks without vitamin supplementation was active in non-small cell lung cancer (NSCLC) although mucositis was dose limiting. This phase 1 study evaluated the safety of higher pralatrexate doses with vitamin supplementation to minimize toxicities.

METHODS:

Patients with stage IIIB/IV NSCLC received pralatrexate 150 to 325 mg/m(2) every 2 weeks with folic acid and vitamin B12 supplementation. Outcomes measured included adverse events (AEs), pharmacokinetics, and radiologic response.

RESULTS:

Thirty-nine patients were treated for a median of two cycles (range 1-16+). Common treatment-related grade 3 and 4 AEs by dose (≤190 mg/m(2) and >190 mg/m(2)) included mucositis (33 and 40%) and fatigue (11 and 17%). Treatment-related serious AE (SAE) rates for doses ≤190 and >190 mg/m(2) were 0 and 20%, respectively. The response rate was 10% (95% confidence interval: 1-20%), including two patients with complete response (26+ and 32+ months) and two with partial response. Serum pralatrexate concentrations increased dose dependently up to 230 mg/m(2).

CONCLUSIONS:

Pralatrexate with vitamin supplementation was safely administered to patients with previously treated NSCLC, and durable responses were observed. The recommended starting dose for phase 2 is 190 mg/m(2). A similar safety profile was observed in patients treated at 230 mg/m(2), although a higher serious AE rate was evident. Mucositis remains the dose-limiting toxicity of pralatrexate, and this study failed to demonstrate that vitamin supplementation prevents mucositis and failed to identify clinical predictors of mucositis. Individualized dose-modification strategies and prospective mucositis management will be necessary in future trials.

• Authors: Christopher G Azzoli, Jyoti D Patel, Lee M Krug, Vincent Miller, Leonard James, Mark G Kris, Michelle Ginsberg, Sara Subzwari, Leslie Tyson, Megan Dunne, Jennifer May, Martha Huntington, Michael Saunders, F M Sirotnak
• Journal: Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer (J Thorac Oncol) Vol. 6 Issue 11 Pg. 1915-22 (Nov 2011) ISSN: 1556-1380 [Electronic] United States
• PMID: 21841501 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• 10-propargyl-10-deazaaminopterin
• Folic Acid Antagonists
• Vitamin B Complex
• Folic Acid
• Aminopterin
• Vitamin B 12

Topics

• Adenocarcinoma (drug therapy, mortality, pathology)
• Aged
• Aminopterin (analogs & derivatives, pharmacokinetics, therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols
• Carcinoma, Non-Small-Cell Lung (drug therapy, mortality, pathology)
• Carcinoma, Squamous Cell (drug therapy, mortality, pathology)
• Dietary Supplements
• Female
• Folic Acid (administration & dosage)
• Folic Acid Antagonists (pharmacokinetics, therapeutic use)
• Humans
• Lung Neoplasms (drug therapy, mortality, pathology)
• Male
• Maximum Tolerated Dose
• Middle Aged
• Prognosis
• Tissue Distribution
• Vitamin B 12 (administration & dosage)
• Vitamin B Complex (administration & dosage)