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Clinical Trial
. 2014 Sep 30;5(18):8161-72.
doi: 10.18632/oncotarget.2415.

A phase I trial of the HIV protease inhibitor nelfinavir in adults with solid tumors

Gideon M Blumenthal  1 , Joell J Gills  2 , Marc S Ballas  1 , Wendy B Bernstein  1 , Takefumi Komiya  1 , Roopa Dechowdhury  1 , Betsy Morrow  1 , Hyejeong Root  1 , Guinevere Chun  1 , Cynthia Helsabeck  1 , Seth M Steinberg  3 , Jaclyn LoPiccolo  1 , Shigeru Kawabata  2 , Erin R Gardner  1 , William D Figg  1 , Phillip A Dennis  2
Affiliations
Clinical Trial

A phase I trial of the HIV protease inhibitor nelfinavir in adults with solid tumors

Gideon M Blumenthal et al. Oncotarget. .

Abstract

Nelfinavir is an HIV protease inhibitor being repurposed as an anti-cancer agent in preclinical models and in small oncology trials, yet the MTD of nelfinavir has not been determined. Therefore, we conducted a Phase Ia study to establish the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of nelfinavir in subjects with advanced solid tumors. Adults with refractory cancers were given oral nelfinavir twice daily with pharmacokinetic and pharmacodynamic analyses. Twenty-eight subjects were enrolled. Nelfinavir was generally well tolerated. Common adverse events included diarrhea, anemia, and lymphopenia, which were mostly mild. The DLT was rapid-onset neutropenia that was reversible. The MTD was established at 3125 mg twice daily. In an expansion cohort at the MTD, one of 11 (9%) evaluable subjects had a confirmed partial response. This, plus two minor responses, occurred in subjects with neuroendocrine tumors of the midgut or pancreatic origin. Thirty-six percent of subjects had stable disease for more than 6 months. In peripheral blood mononuclear cells, Nelfinavir inhibited AKT and induced markers of ER stress. In summary, nelfinavir is well tolerated in cancer patients at doses 2.5 times the FDA-approved dose for HIV management and showed preliminary activity in tumors of neuroendocrine origin.

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Figures

Figure 1
Figure 1
Blood smear showing vacuolated monocytes and neutrophil from a patient that experienced DLT on nelfinavir DL5
Figure 2A
Figure 2A. C1D1 Nelfinavir (A) Cmax and (B) AUCinf, by dose
Each dot represents an individual patient
Figure 2B
Figure 2B. C2D1 Nelfinavir (A) Cmin (immediately prior to dose administration), (B) Cmax and (C) AUClast, by dose
Each dot represents an individual patient.
Figure 2C
Figure 2C
Pairwise comparison of midazolam clearance prior to the start of nelfinavir treatment (D-2) and at nelfinavir steady-state (D20).
Figure 3
Figure 3
PI3K/AKT inhibition and ER stress pathway induction by nelfinavir in PBMCs of two cancer patients at the MTD
Figure 4
Figure 4
Serial CT images from a subject who achieved a sustained PR response on nelfinavir in target lesion in liver
See this image and copyright information in PMC

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