title: Phase I and II study of exisulind in combination with capecitabine in patients with metastatic breast cancer.
abstract: OBJECTIVE
  We studied the safety and clinical activity of exisulind in combination with capecitabine in 35 patients with metastatic breast cancer (MBC).
  
  
  METHODS
  All patients had received previous anthracycline and taxane chemotherapies. Two dose levels of exisulind were explored, 125 and 250 mg orally bid as continuous daily therapy, concomitant with capecitabine 2,000 mg/m2 for 14 days in 21-day cycles. In the phase I study, the dose-limiting toxicities were hand-foot syndrome and diarrhea. The 125-mg bid dose was selected for phase II testing.
  
  
  RESULTS
  The most common nonhematologic grade 2 to 3 adverse events were hand-foot syndrome (57%) and fatigue (48%). The most frequent grade 2 to 3 laboratory abnormality was granulocytopenia. No death, unexpected adverse events, or cumulative toxicity were encountered. One complete and four partial responses were achieved (objective response rate, 16%) in the 31 patients assessable for response. The median duration of response was 31 weeks; three patients experienced stable disease longer than 26 weeks. Overall clinical benefit (complete response, partial response, or stable disease > 26 weeks) was 23%. Fourteen specimens were available for immunohistochemical assessment of phosphodiesterase-5 isoenzyme (PDE-5) and PDE-2 expression, which are the targets of exisulind. Eighty percent of tumors showed some expression of PDE-5 in the invasive cancer cells including 35% that showed moderate or strong staining. PDE-2 showed moderate or strong staining in 78% of tumors. There was no apparent association between tumor response and staining intensity.
  
  
  CONCLUSIONS
  Exisulind (125 mg orally bid) in combination with capecitabine is well tolerated and the combination has anticancer activity similar to that of capecitabine alone in heavily pretreated patients with MBC.
authors.affiliation: Box 424, Department of Breast Medical Oncology, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030-4009, USA. lpusztai@mdanderson.org
authors.forename: Lajos
authors.initials: L
authors.lastname: Pusztai
authors.forename: Jim Hou
authors.initials: JH
authors.lastname: Zhen
authors.forename: Banu
authors.initials: B
authors.lastname: Arun
authors.forename: Edgardo
authors.initials: E
authors.lastname: Rivera
authors.forename: Clark
authors.initials: C
authors.lastname: Whitehead
authors.forename: W Joseph
authors.initials: WJ
authors.lastname: Thompson
authors.forename: Kimberly M
authors.initials: KM
authors.lastname: Nealy
authors.forename: Amy
authors.initials: A
authors.lastname: Gibbs
authors.forename: W Fraser
authors.initials: WF
authors.lastname: Symmans
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Esteva
authors.forename: Daniel
authors.initials: D
authors.lastname: Booser
authors.forename: James L
authors.initials: JL
authors.lastname: Murray
authors.forename: Vicente
authors.initials: V
authors.lastname: Valero
authors.forename: Terry L
authors.initials: TL
authors.lastname: Smith
authors.forename: Gabriel N
authors.initials: GN
authors.lastname: Hortobagyi
mesh_terms: D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology; D000069287:Capecitabine; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D005260:Female; D005472:Fluorouracil / Q000031:analogs & derivatives; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010727:Phosphoric Diester Hydrolases / Q000032:analysis; D011355:Prodrugs / Q000008:administration & dosage / Q000009:adverse effects; D013467:Sulindac / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives
chemical_list: D000964:Antimetabolites, Antineoplastic; D011355:Prodrugs; D003841:Deoxycytidine; D013467:Sulindac; D000069287:Capecitabine; D010727:Phosphoric Diester Hydrolases; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2; C517275:PDE2A protein, human; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human; C025463:sulindac sulfone; D005472:Fluorouracil