A randomized control trial of the probiotic LGG for prevention of side effects in patients undergoing chemoradiation for gastrointestional cancer 

Matt Ciorba, M.D.

Project Overview:
First-year funding from the Longer Life Foundation played a critical role in our achieving several project accomplishments and progress benchmarks. There was an initial delay in trial start up as we navigated our trial through the ins and outs of the FDA (Food and Drug Administration), Human studies research protection office (IRB) and cancer center protocols review committee. The FDA required product testing for purity, potency and identity. This required independent laboratory testing for each of these as well as genetic identity analysis in my lab. We persevered through and ultimately met each of these requirements. Consistent with FDA IND requirements, we ultimately changed our initial trial to a 20 patient Phase I clinical trial with patient safety and tolerability as a primary endpoint and clinical efficacy as a secondary endpoints. This pilot phase has been indispensably useful as it has allowed us to refine our trial protocol, patient recruitment procedures and bio-specimen collection techniques. Furthermore, the results will provide new insight in determining our calculations for a larger randomized phase 2 trial which we now anticipate to follow.

Additionally, in response to initial reviewer comments and in accordance with FDA/IRB suggestions we have:

  • Established a complete strategy for safety monitoring which is overseen by a Siteman cancer centered established Data Safety Monitoring Board.
  • Have a focused patient population including only patients with GI derived malignancies receiving radiation and a fluoropyrimidine based chemotherapy regimen.
  • Include CTCAE grade 3 diarrhea as an endpoint as it is at this level of toxicity that patients delay and/or cease therapy which can in turn affect cure rates and longevity.

An updated trial protocol and all amendments are attached. Trial results are listed below. We have also performed additional pre-clinical testing in collaboration with Dr William Stenson and found that LGG remains effective, intestinal specific and safe in animal models of fractionated abdominal only radiation that simulates human radiation therapy. These results as well as preliminary trial results are being presented at the FASEB Summer 2015 Gastrointestinal Pathobiology Meeting in Steamboat Springs, Colorado and are being written up for manuscript submission.

Initiating even a 20 patient phase 1 trial required additional funding to the $25,000 provided by the LLF. To supplement LLF funding, we submitted and received a developmental grant from the NCI funded Siteman cancer center to help develop this trial. My collaborator Dr. Parag Parikh was the principal investigator on this. It was one year of funding for clinical trial startup and played a very important role in allowing us to access to the cancer centers protocol development team and IRB submission. This funding ends June 30, 2015.

We have also submitted an RO1 grant to assist in furthering the preclinical studies of this work and to develop further the translational research studies. Dr. William Stenson was the PI on this grant, with doctors Ciorba and Parikh as co-investigators. Dr Ciorba submitted an R21 Application to the NCI in response to a call for applications on clinical trials in gastrointestinal health and nutritional supplements. This will be reviewed in October 2015. We have also established a new collaboration with Dr Christopher Hallemeier at the Mayo Clinic and have begun the process of seeking additional funding from the NCI’s Alliance for Clinical Trials in Oncology which funds large scale radioprotection human trials and to which Washington University belongs. The Alliance has submitted for a new IND for the larger trial base on our application. Our pilot trial has afforded us the understanding that a Phase II randomized trial will require multiple centers to  achieve more rapid completion. Together, we have co-authored a new article reviewing the current state of knowledge and how this field can move forward.