title: Cediranib in patients with malignant mesothelioma: a phase II trial of the University of Chicago Phase II Consortium.
abstract: BACKGROUND
  Malignant mesothelioma (MM) is an aggressive disease with limited therapeutic options. In preclinical models, vascular endothelial growth factor (VEGF) stimulates MM proliferation. In MM patients, higher plasma VEGF levels correlate inversely with survival. Cediranib is an orally administered tyrosine kinase inhibitor of VEGF receptors-1, -2, and -3.
  
  
  METHODS
  We conducted a multi-center phase II trial of cediranib in patients with unresectable, histologically-confirmed MM who had received ≤1 prior regimen of chemotherapy. The primary endpoint was objective response rate. Initial cediranib dosing was 45 mg daily during a 28-day cycle. Due to substantial toxicity, the starting dose was subsequently lowered to 30 mg daily.
  
  
  RESULTS
  Fifty-one patients enrolled at 9 centers; 50 were evaluable for response. Partial responses were observed in 10% of patients; stable disease was seen in 34%. Disease control (PR+SD) was higher at the 45 mg cediranib dose level (67% vs. 34%, p=0.04). Median progression-free survival was 1.8 months (95% CI 0.1, 14.2); median overall survival (OS) was 4.4 months (95% CI 0.9, 41.7). The 1-year survival rate was 15%. Grade 3/4 toxicities were more frequent in the 45 mg dose level group (87% vs. 43%, p=0.002). These included fatigue, hypertension, pulmonary embolism, angioedema, and reversible posterior leukoencephalopathy. Median OS was superior in patients who developed ≥grade 3 hypertension (8.5 vs. 4.1 months, p=0.024).
  
  
  CONCLUSIONS
  This trial did not meet its pre-specified response endpoint. A higher cediranib dose level was associated with improved disease control, but this dose was poorly tolerated.
authors: Section of Hematology/Oncology, University of Chicago, Chicago, IL 60637, USA.
authors: Nicholas P
authors: NP
authors: Campbell
authors: Rangesh
authors: R
authors: Kunnavakkam
authors: Natasha
authors: N
authors: Leighl
authors: Mark D
authors: MD
authors: Vincent
authors: David R
authors: DR
authors: Gandara
authors: Marianna
authors: M
authors: Koczywas
authors: Barbara J
authors: BJ
authors: Gitlitz
authors: Edem
authors: E
authors: Agamah
authors: Sachdev P
authors: SP
authors: Thomas
authors: Walter M
authors: WM
authors: Stadler
authors: Everett E
authors: EE
authors: Vokes
authors: Hedy L
authors: HL
authors: Kindler
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D008654:Mesothelioma / Q000188:drug therapy* / Q000401:mortality; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome; D007211:Indoles
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C500926:cediranib; D007211:Indoles