Phase I pharmacokinetic and pharmacodynamic study of the pan-PI3K/mTORC vascular targeted pro-drug SF1126 in patients with advanced solid tumours and B-cell malignancies

Abstract

Background 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. Patients and methods SF1126 was administered IV days 1 and 4, weekly in 28 day-cycles. Dose escalation utilised modified Fibonacci 3+3. Samples to monitor PK and PD were obtained. Results Forty four patients were treated at 9 dose levels (90–1110 mg/m2/day). Most toxicity was grade 1 and 2 with a single DLT at180 mg/m2 (diarrhoea). Exposure measured by peak concentration (Cmax) and area under the time-concentration curve (AUC0-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/m2. The protocol was amended to enrol patients with CD20+ B-cell malignancies at 1110 mg/m2. 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. Conclusion SF1126 is well tolerated with SD as the best response in patients with advanced malignancies.

MDM2 Regulates Hypoxic Hypoxia-inducible Factor 1α Stability in an E3 Ligase, Proteasome, and PTEN-Phosphatidylinositol 3-Kinase-AKT-dependent Manner

“…BEZ-235, BKM 120, PF4691502, GDC-0941, and TGX-221 were purchased from Selleck Chemicals. SF1126 was obtained from SignalRx Pharmaceuticals (40). Drugs were diluted into medium to the appropriate concentration before adding to cells to ensure that all treated dishes received the same concentration of DMSO that was added to control or untreated dishes at a final dilution of 1:1000.…”

“…1 and 2) led us to investigate the effects of different clinically relevant PI3K inhibitors (SF1126, BEZ235, PF4691502, BKM120, GDC0941, and TGX221) on the hypoxic induction of HIF1␣ in glioma models. SF1126 is a vascular RGDS/integrin targeted prodrug derivative of LY294002 that it has recently completed phase I clinical trials (40). SF1126 inhibits all isoforms of PI3K (pan-PI3K inhibitor), mTOR, ATM, PIM1, and PLK2.…”

A Macrophage-Dominant PI3K Isoform Controls Hypoxia-Induced HIF1α and HIF2α Stability and Tumor Growth, Angiogenesis, and Metastasis

“…1) led us to investigate the effects of different clinically relevant PI3K inhibitors (SF1126, PF4691502, PI-103, and BKM120) on the hypoxic induction of HIFa in macrophages. SF1126, a pan-PI3K inhibitor, is a vascular RGDS/ integrin targeted prodrug derivative of LY294002 and is entering phase II clinical trials (29). The other inhibitors used in early-phase clinical trials include: PI-103, a dual PI3K/mTOR inhibitor; PF4691502, a pan-PI3K inhibitor; and BKM120, a pan-PI3K inhibitor (33)(34)(35).…”

“…PI-103, BKM120, and PF4691502 were purchased from Selleck chemicals. SF2523 and SF1126 were obtained from SignalRx Pharmaceuticals (29,30 0 -diamidino-2-phenylindole (DAPI), hyaluronidase type V, and DNase I were from Sigma.…”

Chemical inhibition of DNA repair kinases as a promising tool in oncology

“…SF1126 was well tolerated and did not affect PI3-K activity in the normal tissue. An increase in late apoptosis, a decrease in phosphorylation of AKT and a cleavage of PARP correlating with late apoptosis was apparent 55 . NU7026, an inhibitor from chromenone library, is a cell permeable, ATP-competitive inhibitor of DNA-PK and ATM, but predominantly affects DNA-PK with IC 50 : 0,23 μM, IC 50 for ATM is more than 100 μM (ref.…”