title: Safety, Tolerability, and Preliminary Activity of LB-100, an Inhibitor of Protein Phosphatase 2A, in Patients with Relapsed Solid Tumors: An Open-Label, Dose Escalation, First-in-Human, Phase I Trial.
abstract: Purpose:To determine the MTD and to assess the safety, tolerability, and potential activity of LB-100, a first-in-class small-molecule inhibitor of protein phosphatase 2A (PP2A) in adult patients with progressive solid tumors.Experimental Design:LB-100 was administered intravenously daily for 3 days in 21-day cycles in a 3 + 3 dose escalation design.Results:There were 29 patient entries over 7 dose escalations. One patient stopped treatment after one dose because of an acute infection and was reenrolled after recovery; each course was analyzed as a separate patient entry. Two patients had dose-limiting toxicity (reversible increases in serum creatinine or calculated serum creatinine clearance) at the 3.1 mg/m2level. Probable or possible study drug-related grade 3 adverse events occurred in 6 (20.7%) patients [anemia (n= 2), decreased creatinine clearance, dyspnea, hyponatremia, and lymphopenia]. Ten (50%) of 20 response-evaluable patients had stable disease for four or more cycles. One patient with pancreatic adenocarcinoma had a partial response noted after 10 cycles, which was maintained for five additional cycles. The other patients achieving stable disease had one of the following: fibrosarcoma, chondrosarcoma, thymoma, atypical carcinoid of lung, or ovarian, testicular, breast (n= 2), and prostate cancer. The recommended phase II dose of LB-100 is 2.33 mg/m2daily for 3 days every 3 weeks.Conclusions:The safety, tolerability, preliminary evidence of antitumor activity, and novel mechanism of action of LB-100 support its continued development alone and in combination with other therapies.Clin Cancer Res; 23(13); 3277-84. ©2016 AACR.
authors.affiliation: City of Hope, Duarte, California.
authors.forename: Vincent
authors.initials: V
authors.lastname: Chung
authors.affiliation: Mayo Clinic, Rochester, Minnesota.
authors.forename: Aaron S
authors.initials: AS
authors.lastname: Mansfield
authors.affiliation: Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada.|US Oncology Research, The Woodlands, Texas.
authors.forename: Fadi
authors.initials: F
authors.lastname: Braiteh
authors.affiliation: US Oncology Research, The Woodlands, Texas.|Texas Oncology, Tyler, Texas.
authors.forename: Donald
authors.initials: D
authors.lastname: Richards
authors.affiliation: Theradex Systems Inc., Princeton, New Jersey.
authors.forename: Henry
authors.initials: H
authors.lastname: Durivage
authors.affiliation: Theradex Systems Inc., Princeton, New Jersey.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Ungerleider
authors.affiliation: Chem-Master International, Inc. Stony Brook, New York.
authors.forename: Francis
authors.initials: F
authors.lastname: Johnson
authors.affiliation: Lixte Biotechnology Holdings, Inc., East Setauket, New York. jkovach@lixte.com.
authors.forename: John S
authors.initials: JS
authors.lastname: Kovach
mesh_terms: D000328:Adult; D000368:Aged; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage* / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D064420:Drug-Related Side Effects and Adverse Reactions / Q000145:classification / Q000473:pathology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010879:Piperazines / Q000008:administration & dosage* / Q000009:adverse effects; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; C000708580:LB100; D010879:Piperazines; D054648:Protein Phosphatase 2