sf-1126 and Leukemia--Lymphocytic--Chronic--B-Cell

The activation of the PI3K/AKT/mTOR pathway is a main driver of cell growth, proliferation, survival, and chemoresistance of cancer cells, and, for this reason, represents an attractive target for developing targeted anti-cancer drugs. There are plenty of preclinical data sustaining the anti-tumor activity of dual PI3K/mTOR inhibitors as single agents and in combination in lymphomas. Clinical responses, including complete remissions (especially in follicular lymphoma patients), are also observed in the very few clinical studies performed in patients that are affected by relapsed/refractory lymphomas or chronic lymphocytic leukemia. In this review, we summarize the literature on dual PI3K/mTOR inhibitors focusing on the lymphoma setting, presenting both the three compounds still in clinical development and those with a clinical program stopped or put on hold.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Chromones; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma; Molecular Targeted Therapy; Oligopeptides; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Quinoxalines; Signal Transduction; Sulfonamides; TOR Serine-Threonine Kinases

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