Prophylaxis of recurrent chemotherapy-induced oral mucositis: A phase II multicenter, randomized, placebo-controlled trial of recombinant human intestinal trefoil factor (rhITF)

Reviewer: Arpi Thukral, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 3, 2008

Presenter: N. P. Barker
Presenter's Affiliation: The GI Company Inc., Framingham, MA
Type of Session: Scientific


  • Oral mucositis is a common, debilitating symptom affecting many patients on high-dose chemotherapy. 
  • It is an inflammation of the mucous membranes of the mouth, and can often range from erythema and sores to severe ulcerations. 
    • It can be quite painful and often reduces QOL by preventing patients from eating, drinking, or talking for long periods of time.
  • It has been shown to affect 5-15% of patients undergoing cancer treatment in general, but with certain agents such as 5-florouracil (5FU), the rates are much higher, approaching 40-50%. 
  • Currently, there is no effective treatment approved to prevent oral mucositis or shorten its duration.
  • Intestinal Trefoil Factor (ITF), is an endogenous protein found mostly on mucosal surfaces throughout the gastrointestinal tract. 
    • In a paper by Taupin D., et. al. in 2003, ITF has been shown to promote mucosal protection, repair, and restitution. 
  • Therefore, it is hypothesized that therapy with recombinant human ITF (rhITF) can alleviate damage to the mucosa of the oral cavity and lessen the effects of oral mucositis. 
  • Preclinical studies on ITF have demonstrated compelling efficacy data in numerous in vivo models of mucosal damage. 
  • The purpose of this Phase II study was to evaluate the safety and efficacy of rhITF given topically as an oral spray to the oral cavity of colorectal cancer patients undergoing 5-FU chemotherapy, a group at high risk for developing oral mucositis.

Materials and Methods

  • This is a phase II randomized, double-blinded, multicenter, placebo-controlled trial. 
  • Stage I-IV colorectal patients undergoing 5-FU chemotherapy who reported a WHO (World Health Organization) grade >2 oral mucositis (OM) in the first cycle of chemotherapy were eligible for this study. 
  • 99 patients were randomized at the start of their second cycle of chemotherapy into 3 arms:
1)      treatment with placebo (n=33)
2)      rhITF 10 mg/mL (low dose) (n=33)
3)      rhITF 80 mg/mL (high dose) (n=33)
  • The rhITF was administered as an oral spray (300 microliters) 8 times a day. It was given for 14 consecutive days during the second cycle of chemotherapy.
  • Patients were assessed on days 1, 3, 5, 7, 10, 12, 14 and 21 +/- 2 for WHO and OMAS (Oral Mucositis Assessment Scale) grades of OM, and treatment-related effects.
  • The primary efficacy endpoint studied was reduction in proportion of patients developing WHO grade>2 OM. 
  • The secondary endpoints studied were safety and reduction in peak mean/median oral mucositis scores as defined by the WHO and OMAS scales. 


  • In terms of patient characteristics, the groups were fairly balanced.  There were no differences seen in age, gender, height, or weight between the 2 groups. Patients did have various stages of colorectal cancer. 
  • Patient-reported compliance rates were above 95%. 
  • TESSs (Treatment Emergent Signs and Symptoms) associated with treatment were reported in 4 patients (1 placebo, 2 low dose rhITF, and 1 high dose rhITF); however all were mild to moderate in intensity and resolved spontaneously. There were no serious adverse events or deaths reported in this study.
  • Frequency of WHO grade >2 OM:

Placebo group
Low dose rhITF
High dose rhITF
# of patients with grade ­2 OM

  • These data correspond to a reduction of OM of 81% (p<0.0001) in the low-dose group and 75% (p=0.002) in the high-dose group, when compared to the placebo.
  • The mean OMAS scores were significantly higher in the placebo group vs. the drug groups. 

Author's Conclusions

  • The authors concluded that they have met both their primary and secondary endpoints by showing a reduction in the proportion of patients developing WHO grade>2 OM, and by showing a decrease in the mean peak OM scores in the drug groups. 
  • rhITF oral spray is safe and well-tolerated when given concurrently with chemotherapy, and should be considered for treatment for prophylaxis of mucositis
  • This drug should be further tested in larger, phase III randomized trials. 

Clinical/Scientific Implications

  • Chemotherapy related oral mucositis is a debilitating symptom which affects many patients undergoing chemotherapy. There is currently no approved preventative therapy for OM. 
  • This phase II randomized trial provides valuable information about the use of rhITF, an endogenous protein involved in mucosal restitution and repair, for the reduction and prevention of oral mucositis. 
  • The study was well-designed and well-executed, and met its primary and secondary endpoints. 
    • This rhITF data shows a highly statistically significant reduction in the incidence of oral mucositis, and it appears that this treatment is safe and well-tolerated. 
  • Although the data seem promising, this is an underpowered phase II trial, and the clinical relevance of this hypothesis should optimally be tested in a Phase III randomized trial.  
  • Cost/benefit analysis must also be considered before this drug is widely used clinically.
  • Futures studies may explore the use of this drug not only topically, but systemically as well in order to decrease other GI tract mucosal inflammation caused by chemotherapy. In addition, this drug should also be studied in other cancer patient populations besides colorectal cancer.
  • Furthermore, it would be interesting to test the use of this drug in other diseases causing inflammation of the digestive tract in future studies. 

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