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

Eur J Cancer. 2012 Dec;48(18):3319-27. doi: 10.1016/j.ejca.2012.06.027. Epub 2012 Aug 23.

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 28day-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/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.

Conclusion: SF1126 is well tolerated with SD as the best response in patients with advanced malignancies.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Chromones / administration & dosage
  • Chromones / adverse effects
  • Chromones / pharmacokinetics
  • Chromones / pharmacology
  • Chromones / therapeutic use*
  • Dose-Response Relationship, Drug
  • Female
  • Gastrointestinal Diseases / chemically induced
  • Hematologic Diseases / chemically induced
  • Humans
  • Hypokalemia / chemically induced
  • Infusions, Intravenous
  • Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy
  • Leukemia, Lymphocytic, Chronic, B-Cell / enzymology
  • Lymphoma, Large B-Cell, Diffuse / drug therapy
  • Lymphoma, Large B-Cell, Diffuse / enzymology
  • Male
  • Maximum Tolerated Dose
  • Mechanistic Target of Rapamycin Complex 1
  • Middle Aged
  • Molecular Targeted Therapy
  • Multiprotein Complexes
  • Neoplasm Proteins / antagonists & inhibitors*
  • Neoplasms / drug therapy*
  • Neoplasms / enzymology
  • Oligopeptides / administration & dosage
  • Oligopeptides / adverse effects
  • Oligopeptides / pharmacokinetics
  • Oligopeptides / pharmacology
  • Oligopeptides / therapeutic use*
  • Phosphoinositide-3 Kinase Inhibitors*
  • Prodrugs / administration & dosage
  • Prodrugs / adverse effects
  • Prodrugs / pharmacokinetics
  • Prodrugs / pharmacology
  • Prodrugs / therapeutic use*
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / adverse effects
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use*
  • Proteins / antagonists & inhibitors*
  • Salvage Therapy
  • TOR Serine-Threonine Kinases
  • Young Adult

Substances

  • Antineoplastic Agents
  • Chromones
  • Multiprotein Complexes
  • Neoplasm Proteins
  • Oligopeptides
  • Phosphoinositide-3 Kinase Inhibitors
  • Prodrugs
  • Protein Kinase Inhibitors
  • Proteins
  • SF 1126
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1