Prevention Elusive With Ipilimumab Diarrhea

Prophylactic budesonide did not significantly decrease the risk of grade 2 or higher diarrhea that is common in patients who have unresectable melanoma treated with the investigational drug ipilimumab, a phase II trial found.

Ipilimumab is a human monoclonal antibody directed against CTL antigen-4, which is a key negative regulator of the T-cell immune response. In clinical studies, immune-related adverse events associated with ipilimumab most commonly have involved the gastrointestinal tract or the skin.

Dr. Jeffrey Weber and his associates hypothesized that oral budesonide, which is used to treat grade 2 diarrhea when it accompanies ipilimumab therapy, might work as prophylaxis to prevent diarrhea without affecting any antitumor activity from ipilimumab.

They randomized 115 patients with unresectable stage III or IV melanoma to treatment with open-label IV ipilimumab (10 mg/kg every 3 weeks for four doses), plus blinded oral budesonide or placebo. The once-daily budesonide dose was 9 mg through week 12, then tapered until discontinuation at week 16.

Grade 2 or higher diarrhea occurred in 19 (33%) of the 58 patients in the budesonide group and 20 (35%) of the 57 patients in the placebo group, Dr. Weber and colleagues reported in an online article to appear in the Sept. 1, 2009, issue of Clinical Cancer Research (doi:10.1158/1078-0432.CCR-09-1024

Budesonide should not be used prophylactically for grade 2 or higher diarrhea associated with ipilimumab therapy, concluded Dr. Weber of the Moffitt Cancer Center and Research Institute, Tampa. Prompt treatment of diarrhea or colitis, however, seemed to be effective in preventing serious complications such as gastrointestinal perforations, he added.

Patients who developed grade 2 or higher diarrhea or other immune-related adverse events discontinued the blinded drug and started open-label therapy with budesonide or other steroids. If the diarrhea lasted 2 weeks or there was grade 3 or 4 diarrhea, they stopped ipilimumab. None of the patients developed gastrointestinal or colonic perforations.

Bristol-Myers Squibb, which is developing ipilimumab with Medarex, sponsored the study and funded editorial and writing assistance for the investigators. Dr. Weber and three of his associates have received funds for speaking, advising, and research for Bristol-Myers Squibb. Dr. Weber owns part of a patent with Medarex on CT2A-4 antibodies. The journal marked the article as an advertisement because page charges were levied to defray the costs of publication.

Grade 3–4 immune-related adverse events occurred in 46 (40%) of all patients, compared with rates of 25% and 22% in other studies that used the same dosing regimens of ipilimumab, the investigators noted. Unlike some of the earlier studies, the current trial included many patients with poor prognostic markers.

Immune-related adverse events affecting the skin, gastrointestinal system, liver, endocrine system, or other area were seen in 47 patients (81%) in the budesonide group and 48 patients (84%) in the placebo group.

Secondary end points in the study included multiple measures of the efficacy of ipilimumab in treating melanoma. A complete response or partial response was seen in seven patients (12%) in the budesonide group and in nine patients (16%) in the placebo group. In addition, the disease stabilized in 11 patients (19%) in each group.

With a median follow-up of over 12 months, the median overall survival rate was 18 months in the budesonide group and 19 months on placebo.

Prophylactic budesonide did not significantly decrease the risk of grade 2 or higher diarrhea that is common in patients who have unresectable melanoma treated with the investigational drug ipilimumab, a phase II trial found.

Ipilimumab is a human monoclonal antibody directed against CTL antigen-4, which is a key negative regulator of the T-cell immune response. In clinical studies, immune-related adverse events associated with ipilimumab most commonly have involved the gastrointestinal tract or the skin.

Dr. Jeffrey Weber and his associates hypothesized that oral budesonide, which is used to treat grade 2 diarrhea when it accompanies ipilimumab therapy, might work as prophylaxis to prevent diarrhea without affecting any antitumor activity from ipilimumab.

They randomized 115 patients with unresectable stage III or IV melanoma to treatment with open-label IV ipilimumab (10 mg/kg every 3 weeks for four doses), plus blinded oral budesonide or placebo. The once-daily budesonide dose was 9 mg through week 12, then tapered until discontinuation at week 16.

Grade 2 or higher diarrhea occurred in 19 (33%) of the 58 patients in the budesonide group and 20 (35%) of the 57 patients in the placebo group, Dr. Weber and colleagues reported in an online article to appear in the Sept. 1, 2009, issue of Clinical Cancer Research (doi:10.1158/1078-0432.CCR-09-1024

Budesonide should not be used prophylactically for grade 2 or higher diarrhea associated with ipilimumab therapy, concluded Dr. Weber of the Moffitt Cancer Center and Research Institute, Tampa. Prompt treatment of diarrhea or colitis, however, seemed to be effective in preventing serious complications such as gastrointestinal perforations, he added.

Patients who developed grade 2 or higher diarrhea or other immune-related adverse events discontinued the blinded drug and started open-label therapy with budesonide or other steroids. If the diarrhea lasted 2 weeks or there was grade 3 or 4 diarrhea, they stopped ipilimumab. None of the patients developed gastrointestinal or colonic perforations.

Bristol-Myers Squibb, which is developing ipilimumab with Medarex, sponsored the study and funded editorial and writing assistance for the investigators. Dr. Weber and three of his associates have received funds for speaking, advising, and research for Bristol-Myers Squibb. Dr. Weber owns part of a patent with Medarex on CT2A-4 antibodies. The journal marked the article as an advertisement because page charges were levied to defray the costs of publication.

Grade 3–4 immune-related adverse events occurred in 46 (40%) of all patients, compared with rates of 25% and 22% in other studies that used the same dosing regimens of ipilimumab, the investigators noted. Unlike some of the earlier studies, the current trial included many patients with poor prognostic markers.

Immune-related adverse events affecting the skin, gastrointestinal system, liver, endocrine system, or other area were seen in 47 patients (81%) in the budesonide group and 48 patients (84%) in the placebo group.

Secondary end points in the study included multiple measures of the efficacy of ipilimumab in treating melanoma. A complete response or partial response was seen in seven patients (12%) in the budesonide group and in nine patients (16%) in the placebo group. In addition, the disease stabilized in 11 patients (19%) in each group.

With a median follow-up of over 12 months, the median overall survival rate was 18 months in the budesonide group and 19 months on placebo.

Prophylactic budesonide did not significantly decrease the risk of grade 2 or higher diarrhea that is common in patients who have unresectable melanoma treated with the investigational drug ipilimumab, a phase II trial found.

Ipilimumab is a human monoclonal antibody directed against CTL antigen-4, which is a key negative regulator of the T-cell immune response. In clinical studies, immune-related adverse events associated with ipilimumab most commonly have involved the gastrointestinal tract or the skin.

Dr. Jeffrey Weber and his associates hypothesized that oral budesonide, which is used to treat grade 2 diarrhea when it accompanies ipilimumab therapy, might work as prophylaxis to prevent diarrhea without affecting any antitumor activity from ipilimumab.

They randomized 115 patients with unresectable stage III or IV melanoma to treatment with open-label IV ipilimumab (10 mg/kg every 3 weeks for four doses), plus blinded oral budesonide or placebo. The once-daily budesonide dose was 9 mg through week 12, then tapered until discontinuation at week 16.

Grade 2 or higher diarrhea occurred in 19 (33%) of the 58 patients in the budesonide group and 20 (35%) of the 57 patients in the placebo group, Dr. Weber and colleagues reported in an online article to appear in the Sept. 1, 2009, issue of Clinical Cancer Research (doi:10.1158/1078-0432.CCR-09-1024

Budesonide should not be used prophylactically for grade 2 or higher diarrhea associated with ipilimumab therapy, concluded Dr. Weber of the Moffitt Cancer Center and Research Institute, Tampa. Prompt treatment of diarrhea or colitis, however, seemed to be effective in preventing serious complications such as gastrointestinal perforations, he added.

Patients who developed grade 2 or higher diarrhea or other immune-related adverse events discontinued the blinded drug and started open-label therapy with budesonide or other steroids. If the diarrhea lasted 2 weeks or there was grade 3 or 4 diarrhea, they stopped ipilimumab. None of the patients developed gastrointestinal or colonic perforations.

Bristol-Myers Squibb, which is developing ipilimumab with Medarex, sponsored the study and funded editorial and writing assistance for the investigators. Dr. Weber and three of his associates have received funds for speaking, advising, and research for Bristol-Myers Squibb. Dr. Weber owns part of a patent with Medarex on CT2A-4 antibodies. The journal marked the article as an advertisement because page charges were levied to defray the costs of publication.

Grade 3–4 immune-related adverse events occurred in 46 (40%) of all patients, compared with rates of 25% and 22% in other studies that used the same dosing regimens of ipilimumab, the investigators noted. Unlike some of the earlier studies, the current trial included many patients with poor prognostic markers.

Immune-related adverse events affecting the skin, gastrointestinal system, liver, endocrine system, or other area were seen in 47 patients (81%) in the budesonide group and 48 patients (84%) in the placebo group.

Secondary end points in the study included multiple measures of the efficacy of ipilimumab in treating melanoma. A complete response or partial response was seen in seven patients (12%) in the budesonide group and in nine patients (16%) in the placebo group. In addition, the disease stabilized in 11 patients (19%) in each group.

With a median follow-up of over 12 months, the median overall survival rate was 18 months in the budesonide group and 19 months on placebo.