title: Phase Ib Study of Safety and Pharmacokinetics of the PI3K Inhibitor SAR245408 with the HER3-Neutralizing Human Antibody SAR256212 in Patients with Solid Tumors.
abstract: Purpose:This phase Ib study was designed to determine the MTD, safety, preliminary efficacy, and pharmacokinetics of the HER3 (ErbB3) mAb SAR256212 in combination with the oral PI3K inhibitor SAR245408 for patients with metastatic or locally advanced solid tumors.Experimental Design:Patients received the combination of intravenous SAR256212 and oral SAR245408 in a 3 + 3 dose-escalation design until occurrence of disease progression or dose-limiting toxicity. Objective response rate, pharmacokinetics, pharmacodynamics, andPIK3CAmutational status were also evaluated.Results:Twenty-seven patients were enrolled. Thirteen of 20 patients tested (65%) had a hotspot-activating mutation inPIK3CAin their tumor. The MTD was determined to be SAR256212 at 40 mg/kg loading dose followed by 20 mg/kg weekly, plus SAR245408 200 mg daily. Dose-limiting toxicities included rash and hypotension; the most frequent treatment-related side effect was diarrhea (66.7%). Twenty-three patients were evaluable for efficacy, of which 12 patients (52.2%) had stable disease and 11 patients (47.8%) had progression of disease as best response. In this study with a limited sample size, there was no difference in best response between patients withPI3KCA-mutant versusPIK3CAwild-type tumors (P= 0.07). The concurrent administration of SAR245408 and SAR256212 did not appear to have an effect on the pharmacokinetics of either drug.Conclusions:The combination of SAR256212 and SAR245408 resulted in stable disease as the best response. Side effects seen in combination were similar to the profiles of each individual drug. Patient outcome was the same regardless of tumorPI3KCAmutation status.Clin Cancer Res; 23(14); 3520-8. ©2016 AACR.
authors.affiliation: Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.|Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Vandana G
authors.initials: VG
authors.lastname: Abramson
authors.affiliation: Clinical Pharmacology Laboratory, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts.
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Supko
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Tarah
authors.initials: T
authors.lastname: Ballinger
authors.affiliation: Early Drug Development Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: James M
authors.initials: JM
authors.lastname: Cleary
authors.affiliation: Early Drug Development Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: John F
authors.initials: JF
authors.lastname: Hilton
authors.affiliation: Early Drug Development Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.|Breast Oncology Program, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Sara M
authors.initials: SM
authors.lastname: Tolaney
authors.affiliation: Early Drug Development Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Nicole G
authors.initials: NG
authors.lastname: Chau
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Cho
authors.affiliation: Sanofi-Aventis US LLC, Cambridge, Massachusetts.
authors.forename: Joseph
authors.initials: J
authors.lastname: Pearlberg
authors.affiliation: Sanofi-Aventis US LLC, Cambridge, Massachusetts.
authors.forename: Joanne
authors.initials: J
authors.lastname: Lager
authors.affiliation: Early Drug Development Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. carlos.arteaga@vanderbilt.edu geoffrey_shapiro@dfci.harvard.edu.|Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Geoffrey I
authors.initials: GI
authors.lastname: Shapiro
authors.affiliation: Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee. carlos.arteaga@vanderbilt.edu geoffrey_shapiro@dfci.harvard.edu.|Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Carlos L
authors.initials: CL
authors.lastname: Arteaga
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects; D058534:Class I Phosphatidylinositol 3-Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D011810:Quinoxalines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D013449:Sulfonamides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing; D011810:Quinoxalines; D013449:Sulfonamides; C581157:XL147; C000589319:seribantumab; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C581292:ERBB3 protein, human; D020893:Receptor, ErbB-3