A phase I/II study of pemetrexed with sirolimus in advanced, previously treated non-small cell lung cancer

Abstract

Background: Single-agent pemetrexed is a treatment for recurrent non-squamous non-small cell lung cancer (NSCLC) that provides limited benefit. Preclinical studies showed promising synergistic effects when the mammalian target of rapamycin (mTOR) inhibitor sirolimus was added to pemetrexed.

Methods: This was a single-institution phase I/II study of pemetrexed in combination with sirolimus. The primary endpoint for the phase I was to determine the maximum tolerated dose (MTD) and safety of the combination. The primary endpoint for the phase II portion was to determine the overall response rate at the MTD. Key eligibility criteria included recurrent, metastatic NSCLC, ECOG performance status of 0-2, and adequate organ function. Sirolimus was administered orally daily after an initial loading dose, and pemetrexed was given intravenously on day 1 of every 21-day cycle.

Results: Forty-two patients with recurrent, metastatic NSCLC were enrolled, 22 in phase I and 20 in phase II. The MTD was pemetrexed 500 mg/m² every 3 weeks, and sirolimus 10 mg on day 1, and 3 mg daily thereafter. Treatment-related adverse events (AEs) occurred in 38 (90.5%) patients. The most common grade 3-4 treatment-related AEs were lymphopenia (31%) and hypophosphatemia (19%). Two treatment-related deaths occurred due to febrile neutropenia and infection, respectively. Among 27 total patients treated at the MTD, 6 (22.2%) had a partial response (PR), 12 (44.4%) had stable disease (SD) and 5 (18.5%) had progressive disease. Median progression-free survival (PFS) was 18.4 weeks (95% CI: 7.0-29.4).

Conclusions: The combination of pemetrexed and sirolimus is active in heavily-pretreated NSCLC (ClinicalTrials.gov Identifier: NCT00923273).

Keywords: Lung cancer; pemetrexed; phase I/II, sirolimus; thymidylate synthase (TS).

Figure 1

Of the 27 patients at the MTD, seven developed progression (n=3), toxicities (n=3), or patient withdrawal (n=1) prior to completion of cycle 1. Two patients clinically progressed before completion of initial re-staging. (A) RECIST % for best response in evaluable patients who completed re-staging after 2 cycles (n=18). The dotted line indicates 30% reduction from the baseline. *, RECIST =0%; blue bars, adenocarcinoma; red bars, squamous cell carcinoma; shaded bars, prior pemetrexed exposure +. (B) Progression-free survival (PFS) in evaluable patients at the MTD (n=27). MTD, maximum tolerated dose.

Figure 2

Biomarker modulation in patients at the MTD. Protein derived from PBMC were obtained at baseline, cycle 1 day 8, and cycle 2 day 21 for immunoblotting of mTOR signaling (p-S6K, p-S6, 4E-BP1 and p-Akt) and Thymidylate synthase (TS). A representative western blotting result is shown. MTD, maximum tolerated dose; PBMC, peripheral blood mononuclear cell.

Figure S1

Difference in half-life (A) and clearance (B) between pemetrexed doses. There is a clear increasing trend with dose (Jonckheere-Terpstra trend test P=0.0013) when comparing C1D8 sirolimus trough blood concentrations on each dose level.

Figure S2

Difference in C_MAX (A) and AUCINF (B) between pemetrexed doses.

Figure S3

Increased C1D8 sirolimus trough levels with dose.

Figure S4

Lack of correlation between sirolimus trough levels and C_MAX (A) or AUCINF (B).

Figure S5

Biomarker analyses for additional patient samples at DL 1, 2, 4 and 5. (A) baseline; (B) cycle 1 day 8; (C) cycle 3 day 21. *, positive control (H460 cells treated with pemetrexed). Modulation of mTOR pathway was not observed at DL 1 and 2.