title: A phase I trial of the HIV protease inhibitor nelfinavir in adults with solid tumors.
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.
authors.affiliation: Medical Oncology Branch, National Cancer Institute, Bethesda, MD.
authors.forename: Gideon M
authors.initials: GM
authors.lastname: Blumenthal
authors.affiliation: Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Joell J
authors.initials: JJ
authors.lastname: Gills
authors.affiliation: Medical Oncology Branch, National Cancer Institute, Bethesda, MD.
authors.forename: Marc S
authors.initials: MS
authors.lastname: Ballas
authors.affiliation: Medical Oncology Branch, National Cancer Institute, Bethesda, MD.
authors.forename: Wendy B
authors.initials: WB
authors.lastname: Bernstein
authors.affiliation: Medical Oncology Branch, National Cancer Institute, Bethesda, MD.
authors.forename: Takefumi
authors.initials: T
authors.lastname: Komiya
authors.affiliation: Medical Oncology Branch, National Cancer Institute, Bethesda, MD.
authors.forename: Roopa
authors.initials: R
authors.lastname: Dechowdhury
authors.affiliation: Medical Oncology Branch, National Cancer Institute, Bethesda, MD.
authors.forename: Betsy
authors.initials: B
authors.lastname: Morrow
authors.affiliation: Medical Oncology Branch, National Cancer Institute, Bethesda, MD.
authors.forename: Hyejeong
authors.initials: H
authors.lastname: Root
authors.affiliation: Medical Oncology Branch, National Cancer Institute, Bethesda, MD.
authors.forename: Guinevere
authors.initials: G
authors.lastname: Chun
authors.affiliation: Medical Oncology Branch, National Cancer Institute, Bethesda, MD.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Helsabeck
authors.affiliation: Biostatistics and Data Management Section, National Cancer Institute, Bethesda, MD.
authors.forename: Seth M
authors.initials: SM
authors.lastname: Steinberg
authors.affiliation: Medical Oncology Branch, National Cancer Institute, Bethesda, MD.
authors.forename: Jaclyn
authors.initials: J
authors.lastname: LoPiccolo
authors.affiliation: Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kawabata
authors.affiliation: Medical Oncology Branch, National Cancer Institute, Bethesda, MD.
authors.forename: Erin R
authors.initials: ER
authors.lastname: Gardner
authors.affiliation: Medical Oncology Branch, National Cancer Institute, Bethesda, MD.
authors.forename: William D
authors.initials: WD
authors.lastname: Figg
authors.affiliation: Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Phillip A
authors.initials: PA
authors.lastname: Dennis
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D005260:Female; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008396:Maryland; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D019888:Nelfinavir / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013997:Time Factors; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D017320:HIV Protease Inhibitors; D019888:Nelfinavir