ABSTRACT
PURPOSE: 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. EXPERIMENTAL DESIGN: 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.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/drug therapy , Adult , Aged , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/adverse effects , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Azacitidine/administration & dosage , Azacitidine/adverse effects , Azacitidine/analogs & derivatives , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , DNA Methylation , DNA Modification Methylases/antagonists & inhibitors , Decitabine , ErbB Receptors/immunology , Female , Humans , Male , Middle Aged , Mutation , Neoplasm Metastasis , Panitumumab , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins p21(ras) , ras Proteins/geneticsABSTRACT
The present study was designed to assess whether 5% aluminium chloride hexahydrate in absolute alcohol exerted any effect on sebaceous gland excretory activity. Eleven acne patients controlled with long-term antibiotics applied active and placebo solutions in a double-blind trial. The sebum excretion rate was measured on two control visits and thereafter at fortnightly intervals for a further 6 weeks. Patients preferred the 'active' solution, many claiming increased dryness of their skin. However, neither the 'active' nor 'placebo' solution had a significant demonstrable effect on sebum excretion rate. The beneficial effect of topical aluminium chloride hexahydrate is therefore assumed to be due to factors other than an alteration in sebum excretion.
