title: A phase I dose escalation trial of AXP107-11, a novel multi-component crystalline form of genistein, in combination with gemcitabine in chemotherapy-naive patients with unresectable pancreatic cancer.
abstract: BACKGROUND
  AXP107-11 is a novel, multi-component crystalline form of the naturally occurring compound genistein. AXP107-11 has improved physiochemical properties and oral bioavailability compared to the natural form of genistein, and it is possible that combining AXP107-11 with chemotherapy may increase the effect and reduce chemoresistance. The purpose of this dose escalation phase Ib study was to assess the safety, maximum tolerated dose (MTD) and pharmacokinetics (PK) of AXP107-11 in combination with gemcitabine in treatment-naïve patients with inoperable pancreatic carcinoma.
  
  
  METHODS
  AXP107-11 was given orally in escalating doses (400 mg-1600 mg daily) in combination with standard gemcitabine treatment (1000 mg/m(2)/week) for the first seven of eight weeks and thereafter for a maximum of four × four-week treatment cycles. PK, safety, MTD and efficacy of AXP107-11 in combination with gemcitabine were evaluated.
  
  
  RESULTS
  Sixteen patients were enrolled and received AXP107-11. The maximum concentration in serum of unconjugated (free) genistein was 1 μM. Neither dose-limiting toxicities (DLTs) nor signs of hematological or non-hematological toxicities related to AXP107-11 were observed over a period ranging from 0.7 to 13.2 months. The median overall survival time was 4.9 months (range 1.5-19.5 months). Seven patients (44%) survived longer than six months and 19% were alive at the one-year follow-up.
  
  
  CONCLUSIONS
  Treatment of pancreatic cancer patients with AXP107-11 in combination with gemcitabine resulted in a favorable PK-profile with high serum levels without signs of either hematological or non-hematological toxicity. Accordingly, we suggest further studies with AXP107-11 in pancreatic cancer patients.
authors.affiliation: Center for Digestive Diseases, Stockholm, Sweden; CLINTEC, Karolinska Institutet, Stockholm, Sweden. Electronic address: matthias.lohr@ki.se.
authors.forename: Johannes-Matthias
authors.initials: JM
authors.lastname: Löhr
authors.affiliation: Dept of Oncology at Radiumhemmet, Stockholm, Sweden.
authors.forename: Masoud
authors.initials: M
authors.lastname: Karimi
authors.affiliation: Center for Allogenic Stem Cell Transplantation (CAST), Stockholm, Sweden.
authors.forename: Brigitta
authors.initials: B
authors.lastname: Omazic
authors.affiliation: Dept. of Radiology, Stockholm, Sweden; CLINTEC, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Kartalis
authors.affiliation: Dept. of Pathology, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Caroline Sabine
authors.initials: CS
authors.lastname: Verbeke
authors.affiliation: Axcentua Pharmaceuticals AB, Stockholm, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Berkenstam
authors.affiliation: Dept of Oncology at Radiumhemmet, Stockholm, Sweden.
authors.forename: Jan-Erik
authors.initials: JE
authors.lastname: Frödin
mesh_terms: D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D019833:Genistein / Q000008:administration & dosage / Q000493:pharmacokinetics; D006801:Humans; D017567:Karnofsky Performance Status; D008113:Liver Neoplasms / Q000556:secondary; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D016019:Survival Analysis; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D003841:Deoxycytidine; D019833:Genistein; D000093542:Gemcitabine
keywords: Chemosensitization; Chemotherapy; Gemcitabine; Genistein; Multi-targeted therapy; Pancreatic cancer