title: A phase I dose-escalation study of lenalidomide in combination with gemcitabine in patients with advanced pancreatic cancer.
abstract: OBJECTIVE
  Lenalidomide have both immunomodulatory and anti-angiogenic properties which could confer anti-cancer effects. The aim of this study was to assess the feasibility of combining lenalidomide with the standard treatment gemcitabine in pancreatic cancer patients with advanced disease.
  
  
  METHODS
  Eligible patients had locally advanced or metastatic adenocarcinoma of the pancreas. Patients received lenalidomide days 1-21 orally and gemcitabine 1000 mg/m2 intravenously (days 1, 8 and 15), each 28 day cycle. Three cohorts of lenalidomide were examined (Cohort I = 15 mg, Cohort II = 20 mg and Cohort III = 25 mg daily). The maximum tolerated dose (MTD) of lenalidomide given in combination with gemcitabine was defined as the highest dose level at which no more than one out of four (25%) subjects experiences a dose-limiting toxicity (DLT). Patients should also be able to receive daily low molecular weight heparin (LMWH) (e.g. dalteparin 5000 IU s.c. daily) as a prophylactic anticoagulant for venous thromboembolic events (VTEs). Twelve patients (n = 4, n = 3 and n = 5 in cohort I, II and III, respectively) were enrolled in this study.
  
  
  RESULTS
  Median duration of treatment was 11 weeks (range 1-66), and median number of treatment cycles were three (range 1-14). The only DLT was a cardiac failure grade 3 in cohort III. Frequent treatment-related adverse events (AEs) (all grades) included neutropenia, leucopenia and fatigue (83% each, but there was no febrile neutropenia); thrombocytopenia (75%); dermatological toxicity (75%); diarrhea and nausea (42% each); and neuropathy (42%).
  
  
  CONCLUSIONS
  This phase I study demonstrates the feasibility of the combination of lenalidomide and gemcitabine as first-line treatment in patients with advanced pancreatic cancer. The tolerability profile demonstrated in the dose escalation schedule of lenalidomide suggests the dosing of lenalidomide to be 25 mg daily on days 1-21 with standard dosing of gemcitabine and merits further evaluation in a phase II trial.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01547260.
authors.affiliation: Department of Radiology, Oncology and Radiation Science, Section of Oncology, Uppsala University, Uppsala, Sweden; Department of Oncology, Uppsala University Hospital, Entrance 78, 751 85 Uppsala, Sweden.
authors.forename: Gustav J
authors.initials: GJ
authors.lastname: Ullenhag
authors.affiliation: Department of Oncology and Pathology (Radiumhemmet), Cancer Centre Karolinska, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: Eva
authors.initials: E
authors.lastname: Rossmann
authors.affiliation: Department of Oncology and Pathology (Radiumhemmet), Cancer Centre Karolinska, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Liljefors
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000284:Administration, Oral; D000368:Aged; D000925:Anticoagulants / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D017985:Dalteparin / Q000627:therapeutic use; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D004334:Drug Administration Schedule; D005221:Fatigue / Q000139:chemically induced / Q000503:physiopathology; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D000077269:Lenalidomide; D007970:Leukopenia / Q000139:chemically induced / Q000503:physiopathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced / Q000503:physiopathology; D010179:Pancreas / Q000187:drug effects / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013792:Thalidomide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D000093542:Gemcitabine
chemical_list: D000925:Anticoagulants; D003841:Deoxycytidine; D013792:Thalidomide; D000077269:Lenalidomide; D017985:Dalteparin; D000093542:Gemcitabine
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