Weber, J., Thompson, J.A., Hamid, O., Minor, D., Amin, A., Ron, I., . . . O'Day, S.J. (2009). A randomized, double-blind, placebo-controlled, phase II study comparing the tolerability and efficacy of ipilimumab administered with or without prophylactic budesonide in patients with unresectable stage III or IV melanoma. Clinical Cancer Research, 15, 5591–5598. 

To determine the usefulness of budesonide as a premedication to ipilimumab in the prevention of diarrhea caused by immune response to this agent

Double-blind, randomized study to receive or not to receive budesonide (placebo) with ipilimumab. Patients were randomized 1:1 to receive concomitant oral budesonide or placebo with open-label ipilimumab administered 10 mg/kg by 90-minute infusions at weeks 1, 4, 7, and 10. Oral budesonide 9 mg or placebo was self-administered daily until week 12, then tapered until discontinuation at week 16. Patients who developed grade 2 diarrhea or greater or other immune-related adverse events discontinued budesonide/placebo and commenced open-label budesonide/steroids. Patients with grade 2 diarrhea lasting for two weeks despite concomitant therapy or with grade 3 or 4 diarrhea discontinued ipilimumab.

• N = 135 enrolled, 115 randomized patients received at least one dose of ipilimumab (58 in group with budesonide, 57 in placebo group)
• MEDIAN AGE = 58 years (budesonide) 61 years (placebo)
• MALES: 74%(budesonide), 67% (placebo); FEMALES: 26% (budesonide), 33% (placebo)
• CURRENT TREATMENT: Immunotherapy
• KEY DISEASE CHARACTERISTICS: Unresectable and measurable stage III or IV melanoma
• OTHER KEY SAMPLE CHARACTERISTICS: Patients with ocular melanoma were excluded. Patients could be previously treated or previously untreated. Patients with a life expectancy of four months or more and performance status of Eastern Cooperative Oncology Group (ECOG) 0 or 1. Excluded patients had active untreated central nervous system metastasis, other malignancies from which they were disease free for less than five years, autoimmune disease (including history of inflammatory bowel disease), receipt of investigational drugs within four weeks of stating protocol therapy, previous treatment with an anti-CTLA-4 antibody, and had used immunosuppression.

• SITE: Not stated/unknown   
• SETTING TYPE: Outpatient    
• LOCATION: Not stated

PHASE OF CARE: Active antitumor treatment

Common Terminology Criteria for Adverse Events (CTCAE), version 3.0

CTCAE, version 3.0

The rate of grade 2 or greater diarrhea was similar between the two groups. Twenty-eight percent of the group with budesonide and 32% of the group with placebo experienced one event of grade 2 or greater diarrhea. No patients experienced more than two events. The side effects were similar in the budesonide and placebo arms. Ninety percent of patients with budesonide and 95% of those with placebo had drug-related adverse events of any grade. Diarrhea and autoimmune hepatitis were the most common adverse events. Adverse events in 26% with budesonide and 32% with placebo lead to treatment discontinuation.

Budesonide did not alter the rate of grade 2 or greater diarrhea, nor did it improve tolerability in patients receiving ipilimumab. The conclusion of the authors was that budesonide should not be used to prevent grade 2 or greater diarrhea. Systemic steroids were used to treated immune-related adverse events. No evidence showed that systemic steroids altered the activity of ipilimumab.

Ipilimumab is an immunotherapy that has immune-related side effects, which are managed differently than the side effects of chemotherapy agents. Nurses need to be aware of these side effects and report them to practitioners (physician or advanced practice providers) for management (most commonly steroid management).