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/m² 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.

Patients with stage IIIB/IV NSCLC received pralatrexate 150 to 325 mg/m² every 2 weeks with folic acid and vitamin B₁₂ supplementation. Outcomes measured included adverse events (AEs), pharmacokinetics, and radiologic response.

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/m² and >190 mg/m²) included mucositis (33 and 40%) and fatigue (11 and 17%). Treatment-related serious AE (SAE) rates for doses ≤190 and >190 mg/m² 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/m².

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/m². A similar safety profile was observed in patients treated at 230 mg/m², 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.