title: Rationally designed treatment for solid tumors with MAPK pathway activation: a phase I study of paclitaxel and bortezomib using an adaptive dose-finding approach.
abstract: In the preclinical setting, phosphorylation and subsequent proteosomal degradation of the proapoptotic protein BIM confers resistance to paclitaxel in solid tumors with RAS/RAF/MAPK pathway activation. Concurrent administration of the proteasome inhibitor bortezomib enables paclitaxel-induced BIM accumulation, restoring cancer cell apoptosis in vitro and producing tumor regression in mice in vivo. A phase I study was conducted to determine the maximum tolerated dose (MTD) of paclitaxel and bortezomib combinatorial treatment. Sixteen patients with refractory solid tumors commonly exhibiting mitogen-activated protein kinase (MAPK) pathway activation were treated weekly with paclitaxel and bortezomib. Starting doses were 40 mg/m(2) for paclitaxel and 0.7 mg/m(2) for bortezomib. A modified continual reassessment method adapted for 2-drug escalation was used for MTD determination with 3-patient cohorts treated at each dose level. MTD was reached at 60 mg/m(2) paclitaxel and 1.0 mg/m(2) bortezomib, the recommended phase II dose. Therapy was overall well tolerated. Most frequently observed toxicities included anemia (in 43.75% of patients, one grade 3 event), fatigue (in 43.75% of patients, one grade 3 event beyond cycle 1), and neuropathy (in 31.25% of patients, one grade 3 event after cycle 1). Of 15 evaluable patients, one non-small-cell lung carcinoma (NSCLC) patient with paclitaxel exposure at the adjuvant setting had a partial response and five patients had stable disease (SD); median disease stabilization was 143.5 days; three NSCLC patients had SD lasting 165 days or longer. Thus, rationally designed weekly treatment with paclitaxel and bortezomib in solid tumors with MAPK pathway activation, including previously taxane-treated malignancies, is a tolerable regimen with preliminary signals of antitumor activity worthy of further investigation.
authors.affiliation: Department of Medicine, Division of Medical Oncology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey, USA.
authors.forename: Janice M
authors.initials: JM
authors.lastname: Mehnert
authors.forename: Antoinette R
authors.initials: AR
authors.lastname: Tan
authors.forename: Rebecca
authors.initials: R
authors.lastname: Moss
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Poplin
authors.forename: Mark N
authors.initials: MN
authors.lastname: Stein
authors.forename: Mika
authors.initials: M
authors.lastname: Sovak
authors.forename: Kelly
authors.initials: K
authors.lastname: Levinson
authors.forename: Hongxia
authors.initials: H
authors.lastname: Lin
authors.forename: Michael
authors.initials: M
authors.lastname: Kane
authors.forename: Murugesan
authors.initials: M
authors.lastname: Gounder
authors.forename: Yong
authors.initials: Y
authors.lastname: Lin
authors.forename: Weichung Joe
authors.initials: WJ
authors.lastname: Shih
authors.forename: Eileen
authors.initials: E
authors.lastname: White
authors.forename: Eric H
authors.initials: EH
authors.lastname: Rubin
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Karantza
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D001897:Boronic Acids / Q000008:administration & dosage*; D000069286:Bortezomib; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage*; D011719:Pyrazines / Q000008:administration & dosage*; D016896:Treatment Outcome
chemical_list: D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib; D020928:Mitogen-Activated Protein Kinases; D017239:Paclitaxel