Probiotic LGG for Prevention of Side Effects in Patients Undergoing Chemoradiation for Gastrointestinal Cancer

Study Overview
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Brief Summary
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Phase 3 placebo-controlled trial to determine efficacy of the probiotic LGG for reducing acute treatment related GI toxicity in patients with GI malignancy with phase 1 safety lead-in.

Official Title
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A Phase I and Randomized Controlled Phase II Trial of the Probiotic LGG for Prevention of Side Effects in Patients Undergoing Chemoradiation for Gastrointestinal Cancer

Conditions
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Gastrointestinal Neoplasms

Intervention / Treatment
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* Drug: LGG
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Current diagnosis of a gastrointestinal, abdominal, or pelvic cancer for which the use of continuous definitive or adjuvant external-beam RT to the abdomen or pelvis to a minimum dose of 4500 cGy is planned. Scheduled to receive concurrent administration of fluoropyrimidine chemotherapy (5-FU or capecitabine) during radiation therapy. Age ≥ 18 years. Life expectancy ≥ 6 months. Negative pregnancy test done ≤7 days prior to registration (for women of childbearing potential only). The following laboratory values obtained ≤ 28 days prior to registration: Hemoglobin ≥ 9.0 g/dL WBC ≥ 3,500 Absolute neutrophil count ≥ 1,500 Platelets ≥ 100,000 ECOG Performance Status (PS) of 0, 1, or 2. Willingness to abstain from ingestion of yogurt products and/or any product containing probiotics during study drug treatment. Ability to complete questionnaire(s) alone or with assistance. Ability to understand and willingness to sign informed consent. Exclusion Criteria: Previous bowel resection which, in the opinion of the investigator, would decrease the benefit of the probiotic. Patients who have undergone recent bowel surgeries which would not decrease the benefit of the probiotic are eligible provided they are more than 30 days from surgery with no serious complications. Known allergy to a probiotic preparation. Any history of inflammatory bowel disease. Grade 3 or 4 diarrhea, rectal bleeding, abdominal cramping, or incontinence of stool ≤7 days prior to registration. Any medical condition that may interfere with ability to receive protocol treatment. Prior abdominal or pelvic RT. Use of probiotics ≤ 2 weeks prior to registration. Use of antibiotics ≤ 3 days prior to registration. Planned continuous antibiotic treatment during RT. History of gastrointestinal or genitourinary obstruction or porphyria. History of irritable bowel syndrome (IBS). History of hypersensitivity to all of the following antibiotics: penicillin, erythromycin, clindamycin, and any fluoroquinolone.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LGG<br>LGG (containing 10^10 viable bacteria) taken by mouth twice daily beginning at baseline (but starting at least 3 days prior to the start of radiation) and continue during RT and for the 2 weeks following RT. | Drug: LGG<br> <br> * Other names: Culturelle;|
| Experimental: Placebo<br>Placebo taken by mouth twice daily beginning at baseline (but starting at least 3 days prior to the start of radiation) and continue during RT and for the 2 weeks following RT. | Drug: Placebo<br> <br> |
| No Intervention: No intervention<br>Patients who prefer not to receive LGG will not be randomized and will receive standard of care RT. These patients will serve as a non-intervention comparator cohort to the first 20 patients and will have specimens collected but will not receive the placebo. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy (randomized phase II trial) | Compare the proportion of patients receiving abdominal or pelvic chemoradiation with a fluoropyrimidine being treated with the probiotic LGG who develop CTCAE grade 2 or greater diarrhea to the proportion of patients receiving abdominal or pelvic chemoradiation with a fluoropyrimidine being treated with placebo who develop CTCAE grade 2 or greater diarrhea | Up to 6 months following the last dose of LGG or placebo | 
| Safety (phase I safety lead-in) | Determine the safety and tolerability of LGG in patients receiving abdominal or pelvic chemoradiation with a fluoropyrimidine The DSMC will review the data as part of an interim analysis when the last patient has had 30 days of follow-up. The DSMC will ensure that at least 18 patients have had follow-up at 30 days (with expected 10% drop-out). Accrual to the randomized portion of the trial will occur only if there are no episodes of lactobacillus associated septicemia. Additionally, if two or more serious adverse events of a similar nature occur and a causal relationship to the investigational product cannot be excluded, accrual to the randomized portion will not occur. | Up to 30 days following completion of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Diarrhea subscale score | The average AUC of the FACIT-D diarrhea subscale scores will be compared between the two treatment groups using a two-sample t-test. The FACIT-D will be completed at baseline, weekly during radiation treatment, for the two weeks following completion of radiation treatment, 12 months following the end of radiation treatment, and years 2-5 following the completion of radiation treatment. | Up to 5 years after completion of treatment. | 
| Need for antidiarrhea medication | Need for use of an antidiarrheal medication (Loperamide) will be evaluated at a binary endpoint (Use or No Use). Comparison will be made using Fisher's exact test as previously described (Chitapanarux 2010) | Up to 2 weeks after completion of treatment | 
| Grade 3 or greater diarrhea | In patients receiving abdominal or pelvic chemoradiation with a fluoropyrimidine, compare the proportion of patients who develop diarrhea of grade 3 or greater (by CTCAE version 4.0) in those treated with the probiotic LGG to the proportion in those receiving placebo | Up to 6 months following the last dose of LGG or placebo | 
| Fecal calprotectin | Determine whether fecal calprotectin correlates with onset, duration, and/or severity of diarrhea during chemoradiation | Up to 2 weeks following the completion of treatment | 
| Serum citrulline | Determine whether serum citrulline correlates with onset, duration, and/or severity of diarrhea during chemoradiation | Up to 2 weeks following the completion of treatment |