Phase I study of nelfinavir in liposarcoma

Abstract

Purpose: HIV protease inhibitors are associated with HIV protease inhibitor-related lipodystrophy syndrome. We hypothesized that liposarcomas would be similarly susceptible to the apoptotic effects of an HIV protease inhibitor, nelfinavir.

Methods: We conducted a phase I trial of nelfinavir for liposarcomas. There was no limit to prior chemotherapy. The starting dose was 1,250 mg twice daily (Level 1). Doses were escalated in cohorts of three to a maximally evaluated dose of 4,250 mg (Level 5). One cycle was 28 days. Steady-state pharmacokinetics (PKs) for nelfinavir and its primary active metabolite, M8, were determined at Levels 4 (3,000 mg) and 5.

Results: Twenty subjects (13 males) were enrolled. Median (range) age was 64 years (37-81). One subject at Level 1 experienced reversible, grade 3 pancreatitis after 1 week and was replaced. No other dose-limiting toxicities were observed. Median (range) number of cycles was 3 (0.6-13.5). Overall best responses observed were 1 partial response, 1 minor response, 4 stable disease, and 13 progressive disease. Mean peak plasma levels and AUCs for nelfinavir were higher at Level 4 (7.3 mg/L; 60.9 mg/L × h) than 5 (6.3 mg/L; 37.7 mg/L × h). The mean ratio of M8:nelfinavir AUCs for both levels was ~1:3.

Conclusions: PKs demonstrate auto-induction of nelfinavir clearance at the doses studied, although the mechanism remains unclear. Peak plasma concentrations were within range where anticancer activity was demonstrated in vitro. M8 metabolite is present at ~1/3 the level of nelfinavir and may also contribute to the anticancer activity observed.

Fig. 1

Current model of nelfinavir in liposarcoma. SREBP and ATF6 are synthesized as ER transmembrane proteins and transported to the Golgi upon appropriate stimulus. Luminal S1P cleaves first, followed by intramembrane S2P to liberate the transcriptionally active amino-terminal segments of nSREBP and nATF6 from the Golgi membrane to migrate to the nucleus to active transcription of lipogenic target genes such as FASN or UPR target genes (solid arrow); NFV inhibits liposarcoma proliferation and promotes apoptosis through inhibition of RIP processing of SREBP and ATF6. Inhibition of S2P cleavage by NFV leads to retention of precursor SREBP and ATF6 proteins in the ER or Golgi and block of transcriptional activation of target genes (FASN). Accumulation of unprocessed SREBP and ATF6 induces ER stress, which leads to caspase-dependent apoptosis (dotted arrow). NFV, nelfinavir; ER, endoplasmic reticulum; nSREBP-1, nuclear active SREBP; nATF6, nuclear active ATF6; FASN, fatty acid synthase; UPR, unfolded protein response; S1P, site-1 protease; S2P, site-2 protease; RIP, regulated intramembrane proteolysis (Adapted from Guan et al. [15])

Fig. 2

Pharmacokinetic data for nelfinavir and active metabolite M8. Pharmacokinetic results of dosing nelfinavir 3000 and 4250 mg BID demonstrate higher mean peak nelfinavir and M8 concentrations and corresponding AUC values. BID, twice daily (Elsevier, license# 2982560891165)

Fig. 3

Serial chest CT scans of a patient in a clinical trial of nelfinavir for liposarcoma: Partial remission was documented in a 64-year-old male with a dedifferentiated liposarcoma unresponsive to combination chemotherapy treated with nelfinavir 1500 mg orally twice daily beginning February 8, 2007 (Adapted from Chow et al. [32])