sf-1126 and Lymphoma--Large-B-Cell--Diffuse

SF1126 is a peptidic pro-drug inhibitor of pan-PI3K/mTORC. A first-in-human study evaluated safety, dose limiting toxicities (DLT), maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of SF1126, in patients with advanced solid and B-cell malignancies.. SF1126 was administered IV days 1 and 4, weekly in 28day-cycles. Dose escalation utilised modified Fibonacci 3+3. Samples to monitor PK and PD were obtained.. Forty four patients were treated at 9 dose levels (90-1110 mg/m(2)/day). Most toxicity was grade 1 and 2 with a single DLT at180 mg/m(2) (diarrhoea). Exposure measured by peak concentration (C(max)) and area under the time-concentration curve (AUC(0-)(t)) was dose proportional. Stable disease (SD) was the best response in 19 of 33 (58%) evaluable patients. MTD was not reached but the maximum administered dose (MAD) was 1110 mg/m(2). The protocol was amended to enrol patients with CD20+ B-cell malignancies at 1110 mg/m(2). A CLL patient who progressed on rituximab [R] achieved SD after 2 months on SF1126 alone but in combination with R achieved a 55% decrease in absolute lymphocyte count and a lymph node response. PD studies of CLL cells demonstrated SF1126 reduced p-AKT and increased apoptosis indicating inhibition of activated PI3K signalling.. SF1126 is well tolerated with SD as the best response in patients with advanced malignancies.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Chromones; Dose-Response Relationship, Drug; Female; Gastrointestinal Diseases; Hematologic Diseases; Humans; Hypokalemia; Infusions, Intravenous; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Large B-Cell, Diffuse; Male; Maximum Tolerated Dose; Mechanistic Target of Rapamycin Complex 1; Middle Aged; Molecular Targeted Therapy; Multiprotein Complexes; Neoplasm Proteins; Neoplasms; Oligopeptides; Phosphoinositide-3 Kinase Inhibitors; Prodrugs; Protein Kinase Inhibitors; Proteins; Salvage Therapy; TOR Serine-Threonine Kinases; Young Adult