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

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

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.

Study Overview

• Status: Terminated
• Conditions: Gastrointestinal Neoplasms
• Intervention / Treatment: Drug: Placebo; Drug: LGG

• Study Type: Interventional
• Enrollment (Actual): 23
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: LGG; 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; Other Names: Culturelle
Experimental: Placebo; 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
No Intervention: No intervention; 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?

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

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Investigators: Principal Investigator: Matthew Ciorba, M.D., Washington University School of Medicine

Publications and helpful links

General Publications

• Packey CD, Ciorba MA. Microbial influences on the small intestinal response to radiation injury. Curr Opin Gastroenterol. 2010 Mar;26(2):88-94. doi: 10.1097/MOG.0b013e3283361927.
• Ciorba MA, Stenson WF. Probiotic therapy in radiation-induced intestinal injury and repair. Ann N Y Acad Sci. 2009 May;1165:190-4. doi: 10.1111/j.1749-6632.2009.04029.x.
• Chitapanarux I, Chitapanarux T, Traisathit P, Kudumpee S, Tharavichitkul E, Lorvidhaya V. Randomized controlled trial of live lactobacillus acidophilus plus bifidobacterium bifidum in prophylaxis of diarrhea during radiotherapy in cervical cancer patients. Radiat Oncol. 2010 May 5;5:31. doi: 10.1186/1748-717X-5-31.
• Ciorba MA, Riehl TE, Rao MS, Moon C, Ee X, Nava GM, Walker MR, Marinshaw JM, Stappenbeck TS, Stenson WF. Lactobacillus probiotic protects intestinal epithelium from radiation injury in a TLR-2/cyclo-oxygenase-2-dependent manner. Gut. 2012 Jun;61(6):829-38. doi: 10.1136/gutjnl-2011-300367. Epub 2011 Oct 24.
• Riehl TE, Alvarado D, Ee X, Zuckerman A, Foster L, Kapoor V, Thotala D, Ciorba MA, Stenson WF. Lactobacillus rhamnosus GG protects the intestinal epithelium from radiation injury through release of lipoteichoic acid, macrophage activation and the migration of mesenchymal stem cells. Gut. 2019 Jun;68(6):1003-1013. doi: 10.1136/gutjnl-2018-316226. Epub 2018 Jun 22.

Helpful Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): August 19, 2014
• Primary Completion (Actual): January 12, 2017
• Study Completion (Actual): December 12, 2021

Study Registration Dates

• First Submitted: February 8, 2013
• First Submitted That Met QC Criteria: February 8, 2013
• First Posted (Estimate): February 12, 2013

Study Record Updates

• Last Update Posted (Actual): March 16, 2022
• Last Update Submitted That Met QC Criteria: March 1, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms
• Other Study ID Numbers: 201404101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No