title: A phase I/II study of decitabine in combination with panitumumab in patients with wild-type (wt) KRAS metastatic colorectal cancer.
abstract: OBJECTIVE
  KRAS mutations are predictive of lack of response to monoclonal antibodies (mAb) against EGFR in metastatic colorectal cancer (mCRC). Most wild-type KRAS patients, however, are also resistant. Retrospective data suggest that EGFR silencing play a role in resistance to therapy. We conducted a study to evaluate the safety and efficacy of decitabine (a hypomethylating agent) in combination with panitumumab (mAb against EGFR) in mCRC patients.
  
  
  METHODS
  20 patients with wild-type KRAS mCRC were included in this phase I/II study. Patients were treated with decitabine at 45 mg/m(2) IV over 2 h on day 1 and 15 and panitumumab 6 mg/kg IV over 1 h on day 8 and 22 every 28 days. Blood samples were collected at baseline, day 8, 15 and 22. Quantitative polymerase chain reaction was used to measure promoter-specific methylation in peripheral-blood cells (PBMCs).
  
  
  RESULTS
  The most common adverse events were grade 1-2 (rash and hypomagnesemia); 3 (16 %) patients had grade III-IV neutropenia including one patient with neutropenic fever. Two of 20 patients (10 %) had a partial response. Both had previously received cetuximab. Ten patients had stable disease (3 of them longer than 16 weeks). Decreased methylation of the MAGE promoter was not evidenced in PBMCs.
  
  
  CONCLUSIONS
  The combination of decitabine and panitumumab was well tolerated and showed activity in wild-type KRAS mCRC patients previously treated with cetuximab. Target modulation in surrogate tissues was not achieved and tumor biopsies were not available. Future studies evaluating hypomethylating agents in combination with EGFR mAb in patients with mCRC are warranted.
authors.affiliation: Department of Internal Medicine (Division of Oncology), Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA, ignacio.garrido-laguna@hci.utah.edu.
authors.forename: I
authors.initials: I
authors.lastname: Garrido-Laguna
authors.forename: K A
authors.initials: KA
authors.lastname: McGregor
authors.forename: M
authors.initials: M
authors.lastname: Wade
authors.forename: J
authors.initials: J
authors.lastname: Weis
authors.forename: W
authors.initials: W
authors.lastname: Gilcrease
authors.forename: L
authors.initials: L
authors.lastname: Burr
authors.forename: R
authors.initials: R
authors.lastname: Soldi
authors.forename: L
authors.initials: L
authors.lastname: Jakubowski
authors.forename: C
authors.initials: C
authors.lastname: Davidson
authors.forename: G
authors.initials: G
authors.lastname: Morrell
authors.forename: J D
authors.initials: JD
authors.lastname: Olpin
authors.forename: K
authors.initials: K
authors.lastname: Boucher
authors.forename: D
authors.initials: D
authors.lastname: Jones
authors.forename: S
authors.initials: S
authors.lastname: Sharma
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001374:Azacitidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors; D000077209:Decitabine; D066246:ErbB Receptors / Q000276:immunology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D000077544:Panitumumab; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins / Q000235:genetics
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D000077544:Panitumumab; D000077209:Decitabine; D015254:DNA Modification Methylases; C512478:EGFR protein, human; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D001374:Azacitidine