Conditions: Advanced Cancers
Keywords: Advanced Cancers Mucositis Esophagitis mTOR Inhibitor-based Regimen Radiation to the Esophagus Thoracic malignancies Placebo Glutamine Enterex Glutapak-10 NutreStore Resource GlutaSolve Sympt-X G.I. Sympt-X Questionnaires Surveys
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 77
Healthy volunteers: no

Brief summary:
The goal of this clinical research study is to learn if glutamine can help control and prevent sores, blisters, or inflammation in your mouth or esophagus due to your current treatment.

In this study, glutamine will be compared to a placebo. A placebo is not a drug. It looks like the drug but is not designed to treat any disease or illness. It is designed to be compared with a study drug to learn if the study drug has any real effect.

Detailed description:
Study Groups:

If you are found to be eligible to take part in this study, you will be randomly assigned (as in the flip of a coin) to 1 of 2 study groups. You will have an equal chance of being assigned to either group:

* If you are in Group 1, you will receive glutamine.
* If you are in Group 2, you will receive a placebo.

Neither you nor the study staff will know if you are receiving the study drug or the placebo. However, if needed for your safety, the study staff will be able to find out what you are receiving.

Study Drug Administration:

Glutamine or the placebo will be taken as a sugary drink by mouth. You will take the drink twice daily starting the day you first receive your anti-cancer therapy or radiation treatment.

You will mix one scoop of powder with 25-100 milliliters (about 2-6 tablespoons) of water. If you are in the chemotherapy group, you will swish the drink for 10 seconds and swallow. If you are in the radiation group, you will swallow the drink in small amounts several times.

Study Visits:

At every visit, you will be asked about any side effects you may be having and about any other drugs you may be taking.

Chemotherapy Group:

On Days 1, 8, and 22 of Cycle 1:

* You will have a mouth exam.
* Your weight will be recorded.

On Day 15 of Cycle 1:

* You will have a mouth exam.
* Your weight will be recorded.
* You will complete a quality of life questionnaire.

On Day 1 of Cycle 2 and beyond:

* You will have a mouth exam.
* Your weight will be recorded.
* If the doctor thinks it is needed, blood (about 2 teaspoons) will be drawn for routine tests.
* You will complete a quality of life questionnaire.
* You will complete a survey about how you feel about the study drug. This should take about 5-10 minutes to complete.
* If the doctor thinks it is needed, you will have a photograph of your mouth taken.

After 3 months of chemotherapy:

* You will complete a quality of life questionnaire.

After 6 months of chemotherapy:

* Your weight will be recorded.
* You will complete a quality of life questionnaire.

Follow-Up:

For your follow-up questionnaires at Day 1 of every Cycle, at 3 and 6 months, and during the End-of-Study visit, you may be called by the study team. This call should last about 5-10 minutes.

Radiation Therapy Group:

On Weeks 1, 2, 4, and 6 of Radiation:

* You will be asked if you have inflammation of your esophagus.
* Your weight will be recorded.
* If the doctor thinks it is needed, blood (about 2 teaspoons) will be drawn for routine tests.

On Weeks 3 and 5 of Radiation:

* You will be asked if you have inflammation of your esophagus.
* Your weight will be recorded.
* If the doctor thinks it is needed, blood (about 2 teaspoons) will be drawn for routine tests.
* You will complete a quality of life questionnaire.
* You will complete a survey about how you feel about the study drug.

On Week 7 of Radiation:

* You will be asked if you have inflammation of your esophagus.
* Your weight will be recorded.
* If the doctor thinks it is needed, blood (about 2 teaspoons) will be drawn for routine tests.
* You will complete a quality of life questionnaire.
* You will complete a survey about how you feel about the study drug.

  1 month after your radiation has ended:
* You will be asked if you have inflammation of your esophagus.
* Your weight will be recorded.
* If the doctor thinks it is needed, blood (about 2 teaspoons) will be drawn for routine tests.
* You will complete a quality of life questionnaire.
* You will complete a survey about how you feel about the study drug.

  3 months after your radiation has ended:
* You will complete a quality of life questionnaire.

Follow-Up:

For your follow-up questionnaires at 1 and 3 months and during the End-of-Study visit, you may be called by the study team. This call should last about 5-10 minutes.

Length of Study:

You may continue taking the study drug for as long as the doctor thinks it is in your best interest.

You will continue taking the glutamine or placebo for 4 weeks after the completion of your anti-cancer therapy or radiation treatment. If you stop chemotherapy or radiation before completion of the intended study period, you will continue to take the study drug for 4 weeks.

If you develop severe sores, blisters, or inflammation in your mouth or esophagus, you will be removed from the study, and the doctor will give you another medication for your sores and blisters.

Your participation on the study will be over 6 months after completion of your therapy.

End-of-Study Visit:

After you are off study, you will have an end-of-study visit. For the radiation group, this will be 6 months after radiation therapy. For the chemotherapy group, this is 4 weeks after the last dose.

* Your weight will be recorded.
* If the doctor thinks it is needed, blood (about 2 teaspoons) will be drawn for routine tests.
* You will complete a quality of life questionnaire.
* If you are in the chemotherapy group, you will have a mouth exam.

This is an investigational study. Glutamine is FDA approved and commercially available for the treatment of short bowel syndrome. Its use to treat mouth sores and inflammation of the esophagus is investigational.

Up to 180 patients will take part in this study. All will be enrolled at MD Anderson.

Arms:
arm 1: Participants receive placebo beginning on Day 1 of an mTOR inhibitor based therapy. Placebo taken as a sugary drink by mouth. Participant will take the drink twice daily starting first day anti-cancer therapy received. Participant to swish the drink for 10 seconds and swallow. Four weeks of treatment constitute 1 cycle for participants on mTOR inhibitor therapy. arm 2: Glutamine taken as a sugary drink by mouth. Participant will take the drink twice daily starting first day anti-cancer therapy received. Participant to swish the drink for 10 seconds and swallow. Four weeks of treatment constitute 1 cycle for participants on mTOR inhibitor therapy. arm 3: Placebo taken as a sugary drink by mouth. Participant will take the drink twice daily starting first day radiation therapy to the esophagus received. Participant to swallow the drink in small amounts several times. arm 4: Glutamine taken as a sugary drink by mouth. Participant will take the drink twice daily starting first day radiation therapy to the esophagus received. Participant to swallow the drink in small amounts several times.

Interventions: intervention 1: Placebo intervention 2: Glutamine intervention 3: Questionnaires
Intervention descriptions: intervention 1: mTOR Inhibitor Patient Group: Participants receive placebo beginning on Day 1 of an mTOR inhibitor based therapy. Placebo taken as a sugary drink by mouth. Participant will take the drink twice daily starting first day anti-cancer therapy received. Participant to swish the drink for 10 seconds and swallow. Four weeks of treatment constitute 1 cycle for participants on mTOR inhibitor therapy. intervention 2: mTOR Inhibitor Patient Group - Glutamine taken as a sugary drink by mouth. Participant will take the drink twice daily starting first day anti-cancer therapy received. Participant to swish the drink for 10 seconds and swallow. Four weeks of treatment constitute 1 cycle for participants on mTOR inhibitor therapy. intervention 3: Questionnaire completion for mTOR Inhibitor Patient Group: At baseline, Day 1 of cycle 2 and beyond, after 6 months of chemotherapy, and at end of study visit.

Protocol document:
Prot_SAP_000.pdf: 
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TITLE:  Randomized, Double Blinded Placebo-Controlled Study of Glutamine 
in Patients with Oral Mucositis on an mTOR Inhibitor-based Regimen or 
Esophagitis on a Regimen Receiving Radiation to the Esophagus 
  
 
 
Principal Investigator:     Aung Naing, MD 
Associate Professor,  
Department of Investigational Cancer Therapeutics 
1515 Holcombe Blvd., Unit 455 
Houston, TX 77030 
Phone: 713-792-2950 
Email: anaing@mdanderson.org 
 


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Co-Principal Investigators: 
 
Funda Meric-Bernstam, MD 
Siqing Fu, MD, PHD 
David S. Hong, MD  
Filip Janku, MD 
Daniel Karp, MD 
Sarina Piha-Paul, MD  
Vivek Subbiah, MD 
Apostolia Tsimberidou, MD, PHD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collaborators:  
 
Radiation Oncology: 
James Welsh, MD 
Melenda Jeter, MD, MPH 
Michael O’Reilly, MD 
Joe Chang, MD, PhD 
Zhongxing Liao, MD 
Steven Lin, MD, PhD 
Quynh Nhu Nguyen, MD 
 
Biostatistics: 
Carla Warneke 
 
Palliative Care: 
Akhila S. Reddy, MD 
 
Investigational Cancer 
Therapeutics: 
Shubham Pant, MD 
 
Symptom Research: 
Tito Mendoza, PhD 
 
Endocrine Neoplasia and HD: 
Mouhammed Habra, MD


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Table of Contents 
1.0 
Objectives and Endpoints ....................................................................................................... 5 
1.1 
Primary Objectives:.............................................................................................................. 5 
1.2 
Secondary Objectives: ........................................................................................................ 5 
2.0 
Background ............................................................................................................................... 5 
2.1 
Introduction ........................................................................................................................... 5 
2.1.1 mTOR Inhibitors and Mucositis .................................................................. 5 
2.1.2 Radiation and Esophagitis ......................................................................... 6 
2.2 
Rationale ............................................................................................................................... 7 
3.0 
Background Drug Information ................................................................................................ 8 
3.1 Preparation: .............................................................................................................................. 10 
3.2 Method/Route of Administration:........................................................................................... 10 
4.0 
Patient Eligibility ..................................................................................................................... 10 
4.1 
Inclusion Criteria ................................................................................................................ 10 
4.2 
Exclusion Criteria ............................................................................................................... 10 
5.0 
Treatment Plan ....................................................................................................................... 11 
5.1 
Drug Administration and Treatment Schedule .............................................................. 11 
5.1.1 mTOR Inhibitor Therapy .......................................................................... 11 
5.1.2 Radiation to the Esophagus ..................................................................... 11 
Figure 3. Treatment Regimen (Schema) ........................................................... 12 
5.2 Evaluation of Response ......................................................................................................... 13 
5.3 
Study Assessments and Procedures .............................................................................. 13 
5.3.1 Assessment of Improvement in Quality of Life ......................................... 13 
5.3.2 Pretreatment Evaluations: ........................................................................ 14 
5.3.3 Evaluation during Study: .......................................................................... 14 
5.3.4 End of Study Visit..................................................................................... 15 
6.0 
Study Calendar ....................................................................................................................... 16 
6.1 Study Assessment for Patients Receiving mTOR Inhibitor Therapy ............................... 17 
6.2 Study Assessment for Patients Receiving Radiation to the Esophagus ........................ 19 
7.0 
Concomitant medications ..................................................................................................... 20 
8.0 
Criteria for Removal from the Study .................................................................................... 20 


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9.0 
Criteria for Evaluation ............................................................................................................ 20 
10.0 
Reporting Requirements ....................................................................................................... 21 
10.1 Serious Adverse Event (SAE) Reporting........................................................................... 21 
10.2 Data Collection ...................................................................................................................... 23 
10.3 Investigator Reporting Responsibilities ............................................................................. 23 
11.0 
Study Monitoring .................................................................................................................... 24 
12.0 
Statistical Considerations ..................................................................................................... 24 
12.1 Study Objectives ................................................................................................................... 24 
12.2 Study Endpoints .................................................................................................................... 25 
12.3 Sample Size ........................................................................................................................... 26 
12.4 Statistical Analysis Plan ....................................................................................................... 26 
12.5 Randomization and Blinding ................................................................................................ 27 
Appendix A: Guidelines for Best Supportive Therapy .................................................................. 29 
13.0 
References .............................................................................................................................. 30 
 


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1.0 Objectives and Endpoints 
 
1.1 Primary Objectives: 
• To determine whether glutamine decreases the severity of mucositis in 
patients on an mTOR inhibitor-based regimen or esophagitis in patients 
receiving radiation to the esophagus. 
  
1.2 Secondary Objectives: 
• To assess whether glutamine regimen improves quality of life (QOL) in 
patients during mTOR inhibitor containing regimen and esophagitis 
during radiation to esophagus. 
• To assess whether glutamine improves other measures of 
mucositis/esophagitis including incidence of any mucositis/esophagitis, 
incidence of grade 3 or higher mucositis/esophagitis, duration of 
mucositis/esophagitis, delay in onset of mucositis/esophagitis, and 
interruption of cancer treatment due to mucositis/esophagitis. 
• To assess whether glutamine affects weight loss after six months of 
treatment for mTOR inhibitor patients and after completion of radiation 
therapy for esophagus radiation patients. 
• To assess toxicity profile of glutamine. 
• To assess whether glutamine affects muscle breakdown. 
 
 
 
2.0 Background 
 
2.1 Introduction 
 
2.1.1 mTOR Inhibitors and Mucositis 
 
Temsirolimus (Torisel; Wyeth Pharmaceuticals, PA) is a mammalian target of 
rapamycin (mTOR) inhibitor that gained FDA approval in 2007 for the treatment of 
advanced renal cell carcinoma.1 Another mTOR inhibitor, everolimus, has been 
approved for renal cell carcinoma, breast cancer, and neuroendocrine tumors.2 In 
addition, mTOR inhibitors have demonstrated encouraging efficacy results in patients 
with a range of advanced malignancies, alone or in combination with other 
chemotherapy agents or targeted therapies in trials for multiple forms of 
malignancies.3-6  As a central regulator of key pathways important in the proliferation 
of cancers, the mTOR inhibitor blocks the aberrant activation of phosphoinositide 3-
kinase (PI3K)/Akt signaling pathway, resulting in growth arrest of cancer cells halting 
in the G1 phase of the cell cycle. 7 
 
In general, mucositis is among the most common side effects reported from mTOR 
inhibitor-based treatment, which seems to be dose-related and occurs mostly in earlier 
cycles.7-9  It has been identified repeatedly as one of the most common dose-limiting 
toxicities.10  The mucositis incidence related to temsirolimus treatment as a single 


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agent was 41% in patients with solid tumors with 3% of grade 3 or above.1,11  However, 
2 recent reviews of temsirolimus-based treatment demonstrated that the mucositis 
incidence rate ranged from 60-65% with 5-10% of patients developing Grade 3.9,12  
The treatment that Investigational Cancer Therapeutics generally uses for the 
management 
of 
mucositis 
uses 
the 
following: 
xyloxylin 
(1:1:1 
ratio 
of 
diphenhydramine, Maalox, lidocaine; 10 milliliters (mL) swish/ swallow every 6 hours 
as needed).13 This treatment is not used prophylactically, but used when patient 
develops mucositis. There is no standard mucositis treatment; therefore, it is important 
to improve mucositis treatment for patients on therapy with mTOR inhibitors. 
 
2.1.2 Radiation and Esophagitis  
 
More than 1.5 million new cases of cancer are expected to occur in the United 
States in 2010, including more than 200,000 new cases of lung cancer and 16,000 
new cases of esophageal cancer.14,15 The primary aim of thoracic radiotherapy 
(TRT) in both NSCLC and esophageal cancer is to maximize the therapeutic ratio in 
order to deliver an effective dose to the tumor while maintaining an acceptable dose 
to the neighboring normal tissues.  However, complications such as acute radiation-
induced esophagitis (ARIE) may cause significant morbidity, unplanned treatment 
delays, and a decreased chance to escalate the dose to more effective levels. 
These issues may reduce tumor control and survival rates, as well as the patients’ 
quality of life (QOL). 
 
ARIE is often the dose-limiting complication that is reported in 5–100% of patients 
treated with TRT.16-18  Clinical and dosimetric factors that may be related to the 
incidence and severity of ARIE include: age, tumor and nodal stage, concurrent 
chemoirradiation, mean esophageal dose and maximal dose point, and esophageal 
volume receiving >35 Gray (Gy) (V35), V45, V50, V60, percent length of esophagus 
receiving >40 Gy, and >66 Gy full circumferences.19-24  Most of these factors are 
closely associated with the total radiation dose received by a certain volume of 
esophagus.  Thus, to prevent ARIE, the dose to the esophagus must be kept under 
the organ tolerance level, which can possibly be achieved by complete exclusion of 
the esophagus from the RT field by using novel RT techniques, such as intensity 
modulated RT (IMRT).  However, often this approach is not feasible due to the 
organ’s central position in the mediastinum, and the proximity of involved lymph 
nodes relative to the esophagus.  Therefore, the primary strategies in controlling 
ARIE currently revolve around identifying an effective radioprotective agent.  Based 
on the significant prior data, review below (section 2.2 and 3.0) we believe that 
glutamine will prove to be a safe and effective radioprotector of the esophagus.  
 
The rate of grade three esophagitis ranges between 15-30% in modern studies.  The 
rate seen in most recent NSCLC trial using concurrent chemo/radiation at MD 
Anderson was 16%. This compares favorable compared to the historic rates of other 
institutions such as the CALGB 9781 which has a 27% rate.25  For patients 
developing Grade 3 esophagitis, radiotherapy can be continued with pain 
management and IV support, or radiotherapy can be held for </= 5 days until 
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2.2 Rationale  
 
2.2.1 Rationale in mTOR Treatment Patients 
Anti-cancer agents damage cells in the intestine and oropharynx, which leads to 
mucositis.  Mucositis induced by anti-cancer treatment may be the result of multiple 
factors.  Anti-cancer agents inhibit the DNA synthesis of rapidly proliferating cells in 
the mucosa, and it hinders the renewal capacity of basal epithelium.  Subsequently, 
that results in mucosal atrophy and collagen breakdown thus leading to ulceration.26-
29 
Mucositis is a notable side effect and dose-limiting toxicity for patients in mTOR-
based regimens.9  Mucositis is further associated with dehydration and weight loss 
among patients undergoing temsirolimus-based trials.  In a recent study, mucositis 
was noted to be the most frequent adverse event overall (73.4%) among 2,822 
patients who received a temsirolimus-based, everolimus-based, or ridaforolimus-
based regimens.9  In a study of single-agent temsirolimus treatment in patients with 
advanced renal cell carcinoma, mucositis was 41.3%.11 
 
In a recent data review, we assessed the incidence and severity of mucositis in 87 
patients who received one of 3 temsirolimus-based combination trials.  Overall, the 
incidence of any grade of mucositis in our temsirolimus-based combination trials 
was 64.4%.  The incidence rate of mucositis greater than grade 2 was higher at 
9.2%.12  We also examined the effectiveness of our mucositis management, which 
included one or more of the following: xyloxylin (1:1:1 ratio of diphenhydramine, 
Maalox, lidocaine; 10 milliliters (mL) swish/ swallow every 6 hours as needed), 
Caphosol (sodium phosphate; 15 mL swish/spit every 4 hours as needed), 
valacyclovir (500 mg per os 3 times daily), Biotene mouth wash (every 4 hours as 
needed), and Carafate (1 gram (gm)/ 10 mL; 10 mL swish/swallow or spit every 6 
hours as needed) as previously described by Naing et al., 2011.13  However, there 
was no standard protocol to treat mucositis.  Based on physician discretion, there 
were some patients who received one or more of our mucositis regimens.12 
 
A better regimen for mucositis is indeed warranted. Although not utilized in our 3 
trials, oral glutamine may be a promising regimen for mucositis treatment.  Use of 
oral glutamine during and after the anti-cancer treatment has been shown to reduce 
the duration and severity of mucositis.30,31 
 
In mTOR based combination therapy, mucositis is a major obstacle.  By optimizing 
treatment for mucositis through the use of glutamine, it will enable patients to continue 
to have an effective treatment while maintaining good quality of life.  Hence, it is of 
great importance to devise an optimal regimen in both prophylactic and treatment 
settings. The primary objective of the current study is to prospectively demonstrate 
that oral glutamine use decreases the severity of mucositis in patients receiving 
mTOR-based therapy. 
 
 


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2.2.2 Rationale in Radiation Treatment Patients 
An agent with potential radioprotective properties is glutamine, which is the primary 
oxidative fuel of the gut epithelium and is necessary for maintenance of the integrity 
of the gut structure during normal and stress conditions.32-35  Significant amounts of 
glutamine are provided by skeletal muscles during hypercatabolic states such as 
cancer, however marked glutamine depletion develops over time, which cannot be 
compensated for by increased synthesis.  Glutamine depletion under conditions of 
stress compromises the acid–base balance, immune functions, epithelial integrity, 
and facilitated bacterial translocation in the gut.35  Furthermore, because of its 
protective functions against oxidative injury in normal tissues, depletion of 
glutathione (GSH), a byproduct of glutamine metabolism, may increase the extent of 
tissue damage caused by RT and/or chemotherapy (Ctx).36-38  In this setting, 
glutamine supplementation not only normalizes the levels in the body, but also 
selectively increases normal tissue GSH levels, which may explain its selective 
radioprotective actions on normal tissues.36,39 
 
In cancer patients, there is a tendency for progressive depletion of glutamine from 
muscle, which is a key factor in cancer-induced cachexia.  As muscle depots are the 
immediate source of glutamine for gut epithelium, glutamine depletion in such 
conditions may lead to reduced radiation tolerance.32,40  Additionally, ARIE and 
related complications such as nausea, vomiting, pain, dysphagia, or odynophagia 
may further worsen the tolerance of normal tissues to radiation.  Therefore, it is 
reasonable to assume that glutamine supplementation may be beneficial in 
prevention of ARIE and related complications in patients undergoing TRT.  This 
evidence suggests a selective radioprotective role for glutamine, and in the radiology 
department, we use glutamine in all patients with NSCLC in whom mediastinal 
irradiation is indicated.  The primary objective of the current study is to prospectively 
demonstrate that oral glutamine use in the prevention of ARIE and weight loss in 
thoracic cancer patients during TRT.  
 
3.0 Background Drug Information  
 
Drug Name: Glutamine + disaccharide suspension (Healios) 
 
Classification: Amino Acid, carbohydrates; Generally Recognized As Safe (GRAS) 
enteral nutrition and flavoring supplement 
 
Description: Glutamine, a precursor for glutathione, plays a pivotal role in 
regulating the intracellular redox potential, and clinical investigations indicate that 
glutamine inhibits other mediators of mucosal barrier injury by reducing the 
production of proinflammatory cytokines and cytokine-related apoptosis. Other 
experimental evidence suggests that glutamine may improve mucosal barrier wound 
healing by increasing fibroblasts and collagen synthesis. Glutamine is also critically 
important to meet demands for tissue repair during times of high cellular replication. 
In these times of increased glutamine demand caused by physiologic stress (e.g., 
during and after cytotoxic chemotherapy), the requirements for glutamine may 


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exceed the body’s ability to produce sufficient concentrations and exogenous 
glutamine may be needed.41  
 
Glutamine suspension in combination with the disaccharide sucrose has vastly 
improved uptake by mucosal cells (Figure 1). It takes <10 seconds for this effect to 
be completed.  
 
Figure 1. Glutamine 
transport into cells is 
facilitated by disaccharides. 
(from Peterson et al, ASCO 
plenary session 2008) 
 
 
 
 
 
 
 
 
 
 
Until recently trehalose, a glucose-glucose disaccharide with cell membrane and 
protein stabilizing properties was expensive.  It is now made from starch for mass 
production and is available as a good tasting sweetener (Treha, Cargill). Figure 2 
shows the similar structures of sucrose and trehalose. 
 
 
Figure 2. Sucrose is Glucose + fructose; trehalose is Glucose+Glucose (source: 
Google images) 
 
Use of a glutamine + disaccharide suspension has been safe and effective in 
reducing mucositis pain and oral discomfort in 1 pilot study and 3 randomized, 
placebo double blind clinical trials.30,31,42,43  Since trehalose is now commercially 
available, an improved orange-flavored formulation with all three generally 
recognized as safe components (glutamine, sucrose, trehalose) has been developed 
by Labrada Nutrition in Houston and given the brand name Healios. 
 
 


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3.1 Preparation:  
 
The drug and placebo will be provided by Healios Oncology Nutrition. 
 
Glutamine (Active): supplied as a powder. 1 scoop provides the individual serving 
of 4 grams glutamine (other components include 5 grams (gms) sucrose, 1.3 gm 
trehalose, 130 mg suspending agent to prevent quick settling, and 0.7 gm flavoring). 
One scoop is suspended with 25-100 milliliters (mL) water. 
 
Glycine (Placebo): supplied as a powder. 1 scoop provides the individual serving of 
4 grams glycine (other components include 5 grams (gms) sucrose, 1.3 gm 
trehalose, 130 mg suspending agent to prevent quick settling, and 0.7 gm flavoring). 
One scoop is suspended with 25-100 milliliters (mL) water 
 
3.2 Method/Route of Administration:  
Oral Administration 
• mTOR-based Therapy Cohort: The suspension is swished for 10 seconds, 
then swallowed.  
• Espophageal Radiation Patients: The suspension is swallowed in several 
small boluses. 
 
 
4.0 Patient Eligibility 
 
4.1 Inclusion Criteria 
 
1) Patients who will be initiating therapy with any investigator-initiated mTOR 
inhibitor based therapy in the Department of Investigational Cancer 
Therapeutics (Phase I Program) or initiating radiation therapy to the esophagus. 
2) For the esophagitis arm, any patient with thoracic malignancies, which will 
receive radiation alone or concurrent chemo/radiation. Radiation dose must be 
≥ 45 Gy. For the esophagitis arm, induction chemotherapy is allowed. 
3) Ability to understand and the willingness to sign a written informed consent.  A 
signed informed consent must be obtained prior to any study specific 
procedures. 
4) Patients must be >/= 17 years of age.  
5) Women of child-bearing potential MUST have a negative serum or urine 
pregnancy test unless prior hysterectomy or menopause (defined as 12 
consecutive months without menstrual activity).  Patients should not become 
pregnant or breastfeed while on this study.  Sexually active patients must agree 
to use contraception prior to study entry, for the duration of study participation, 
and for 30 days after the last dose. 
 
 
4.2 Exclusion Criteria  
 
1) Patients currently receiving therapy for mucositis. 


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5.0 Treatment Plan 
 
There will be a total of 180 patients in this study. There will be a cohort of 100 patients 
on mTOR-based regimens (Phase I or Phase II) which will be enrolled in the 
Department of Investigational Cancer Therapeutics. There will be a cohort of 80 
patients on radiation regimen which will be enrolled in the Department of Radiation 
Oncology. 
 
 
5.1 Drug Administration and Treatment Schedule 
 
This is randomized, double blinded, placebo-controlled trial examining Glutamine in 
patients receiving therapy with either mTOR inhibitor based therapy or radiation to the 
esophagus.  Patients will be randomly assigned to receive Glutamine or Placebo. The 
study will be conducted in the Department of Investigational Cancer Therapeutics and 
the Department of Radiation Oncology at The University of Texas MD Anderson 
Cancer Center in Houston, Texas.   
 
Patients will take 1 scoop (4 grams) of glutamine or placebo mixed with water twice 
each day. 
Caution: New Drug-Limited by Federal Law to Investigational Use. 
Patients will be randomized to glutamine or placebo by the MDACC Investigational 
Pharmacy (Section 12.5). Patients will be dispensed the study drug (glutamine or 
placebo) in a plastic bottle. Each bottle will contain 30 doses (scoops), which will be 
enough study drug for 15 days. A monthly supply (2 bottles) will be dispensed to 
patients. 
Per MDACC policy, any unused or expired drug will be disposed of by the 
Investigational Pharmacy. 
5.1.1 mTOR Inhibitor Therapy 
Four weeks of treatment constitute 1 cycle for patients on mTOR inhibitor therapy.  
Glutamine will start on day 1 of mTOR inhibitor treatment.  Patients may be allowed 
to continue the treatment if there is clinical response (to include prevention or 
resolution) of any mucositis. Patients will be treated on the double, blinded placebo-
controlled trial for as long as they are on mTOR inhibitor therapy. If the patient stops 
the mTOR inhibitor based therapy, mucositis treatment should continue for 4 weeks 
after the last dose of mTOR-inhibitor-based regimen to prevent further mucositis 
complications. 
 
5.1.2 Radiation to the Esophagus  
Radiation must be ≥45 Gy delivered alone or with concurrent chemotherapy. The 
type of concurrent chemo will be determined by the treating physician. For the 
esophagitis arm, induction chemotherapy is allowed. XRT must be given using 


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conventional daily fraction dose from 180-240 cGy per day. Radiation technique may 
include: 3D conformal, IMRT, and or protons. Glutamine will start on the first day of 
radiation, or within 10 days of the start of radiation and will be continued for 4 weeks 
after the last day of radiation. Radiation will be given daily (Monday through Friday) 
for 5 days per week. The number of weeks of radiation therapy will be determined by 
the treating physician. The end of treatment week will vary based on the number of 
weeks of radiation that the patient receives. 
 
 
Figure 3. Treatment Regimen (Schema) 
 
 
For patients who will receive mTOR inhibitor based therapy: the patients will be 
randomized to receive either placebo or Glutamine beginning on Day 1 of an mTOR 
inhibitor based therapy.  
 
For patients who will receive radiation to the esophagus: the patients will be 
randomized to receive either placebo or Glutamine beginning on Day 1 of radiation 
treatment, or within 10 days of the start of radiation. 


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5.2 Evaluation of Response 
For patients receiving mTOR inhibitor-based therapy, the patients will be evaluated 
weekly during the first 4 weeks of treatment for signs and symptoms of mucositis in 
the clinic using the CTCAE version 4.03 (Section 9.0).  After four weeks of therapy, 
mucositis symptoms may be assessed by in person interview or phone call to the 
patient. If mucositis symptoms are ≥ grade 2, the patient will be asked to visit clinic 
for oral examination. 
For patients receiving radiation therapy, the patients will be evaluated weekly based 
on the number of weeks of radiation therapy as determined by the treating 
physician, at end of treatment (or final week of radiation treatment based on number 
of weeks of radiation), 1 month, and 6 month post radiation therapy for signs and 
symptoms of esophagitis using the CTCAE version 4.03 (Section 9.0).  Esophagitis 
symptoms may be assessed by in person interview or phone call to the patient.  
 
5.3 Study Assessments and Procedures 
Evaluation will take place as per protocol schedule unless patient/logistical/medical 
reasons intervene. 
 
5.3.1 Assessment of Improvement in Quality of Life 
 
MD Anderson Symptom Inventory (MDASI-HN) 
MDASI was designed to assist in the assessment of 13 symptoms common in 
cancer patients (dry mouth, fatigue, pain, disturbed sleep, drowsiness, feeling of 
being distressed, anorexia, sadness, numbness/tingling, dyspnea, difficulty 
remembering, nausea, and vomiting) during the previous 24 hours.  In addition, 9 
head and neck cancer specific items are included in MDASI-HN which are mouth 
sores, taste, constipation, teeth/gum problems, skin pain, difficulty with voice, 
choking/coughing, difficulty swallowing, and problem with mucus. The severity at the 
time of assessment of each symptom is rated from 0 to 10 on a numerical scale, 0 
meaning that symptom is absent and 10 meaning that it is of the worst possible 
severity. The instruments and techniques are both valid and reliable in the 
assessment of the intensity of symptoms in cancer populations.12 
 
For patients receiving mTOR inhibitor-based therapy, the MDASI-HN will be 
administered at baseline, Day 15, Day 1 of Cycle 2 and beyond, end of study visit 
and 3 months (+/-14 days) and 6 months (+/-21 days) post end of mTOR inhibitor-
based therapy. These questionnaires may be administered over the phone. 
 
For patient receiving radiation, the MDASI-HN will be given at baseline, Week 3, 
Week 5, Week 7, end of treatment (or final week of radiation treatment based on 
number of weeks of radiation), at 1 month (+/-7 days), 3 months (+/-14 days), and 6 
months (+/-21days) after radiation.   These questionnaires may be administered 
over the phone. 
 
 
 


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Measure of Patient Satisfaction with Study Medication Satisfaction Scale  
The Study Medication Satisfaction Scale is a short, 7-item scale, that asks patients 
about several areas of satisfaction. The scale includes questions about ease or 
difficulty of taking the medication in general and in its current form, convenience of 
taking the study medications as instructed and patient confidence that the study 
medication is of benefit. 
For the patients receiving mTOR inhibitor-based therapy, the patient satisfaction 
scale will be given on Day 1 of Cycle 2 and beyond. 
For the patients receiving radiation, the patient satisfaction scale will be given at 
Week 3, Week 5, Week 7, end of treatment (or final week of radiation treatment 
based on number of weeks of radiation), and 1 month post radiation therapy. 
 
These surveys may be administered over the phone. 
 
 
5.3.2 Pretreatment Evaluations: 
 
To be completed within 4 weeks prior to initiation of therapy: 
• Medical history including list of current concomitant medications and history of 
mucositis and esophagitis with prior therapy (mucositis and esophagitis history 
may be obtained by retrospective medical record review). 
• Examination of oral mucosa. 
• Informed consent  
• Weight 
• ALC (absolute lymphocyte count) 
• Quality of life Questionnaire: MDASI-HN for all patients. 
• Medical photograph of oral mucosa for patients receiving therapy with an mTOR 
inhibitor containing regimen. Attempts to perform medical photographs will be 
made at this timepoint, but if unsuccessful, will not be considered a deviation to 
the protocol since it is not a safety assessment. 
• Women of childbearing potential will have a pregnancy test using urine and/or 
blood, and periodically as clinically indicated 
 
 
5.3.3 Evaluation during Study: 
 
• Examination of oral mucosa and grading of oral mucositis weekly during cycle 1 
and monthly in subsequent cycles for patients receiving mTOR inhibitor therapy. 
For patients receiving radiation to the esophagus signs and symptoms of 
esophagitis (ie: dysphagia, weight loss) are to be evaluated in the routine 
monitoring weekly visits during therapy, as per the study calendar below.  
• Weights to be obtained weekly during cycle 1 and monthly in subsequent cycles 
for patients receiving mTOR inhibitor therapy. For patients receiving radiation to 
the esophagus weights are to be obtained weekly during XRT. 
• Concomitant medications to be reviewed weekly during cycle 1 and monthly in 
subsequent cycles for patients receiving mTOR inhibitor therapy and weekly, 4 


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weeks post last radiation and at 6 months post last radiation for patients 
receiving radiation to the esophagus .  
• Quality of life questionnaire. MDASI-HN for patients receiving mTOR inhibitor 
therapy on day 15 and day 1 of Cycle 2 and beyond, end of study visit, and 3 
months (+/-14 days) and 6 months (+/-21 days) post end of mTOR inhibitor-
based therapy. Patients receiving radiation to the esophagus should complete 
the questionnaires at the Week 3, Week 5 and Week 7, end of treatment (or final 
week of radiation treatment based on number of weeks of radiation), as well as 1 
month (+/-7 days) and 3 months (+/-14 days), and 6 months (+/-21days) after 
treatment.  
• Patient Satisfaction Survey will be given on Day 1 of Cycle 2 and beyond for 
patients receiving mTOR inhibitor therapy and given at Week 3,Week 5, Week 7, 
end of treatment (or final week of radiation treatment based on number of weeks 
of radiation), and 1 month post treatment for patients receiving radiation to the 
esophagus. 
• For patients on mTOR inhibitor-based therapy, ALC may be obtained at 
screening and Day 1 of Cycles 2 and beyond. Attempts to perform ALC labs will 
be made at this timepoint, but if unsuccessful, will not be considered a deviation 
to the protocol since it is not a safety assessment. 
• For patients on radiation therapy, ALC may be weekly during radiation. Attempts 
to perform ALC labs will be made at these timepoints, but if unsuccessful, will not 
be considered deviations to the protocol since these are not safety assessments. 
• Medical Photograph of oral mucosa at the worst grade of mucositis and at cycle 
1 day 29 (prior to cycle 2) for patients receiving therapy with an mTOR inhibitor 
containing regimen. Attempts to obtain medical photographs will be made at this 
timepoint, but if unsuccessful, will not be considered a deviation to the protocol 
since it is not a safety assessment. 
 
 
5.3.4 End of Study Visit  
 
End of study for patients receiving mTOR inhibitor therapy will be within 4 weeks 
after the last dose of the mTOR inhibitor that they received. End of study for patients 
receiving radiation to the esophagus will be 6 months (+/- 21 days) after the last day 
of radiation. The following procedures will be completed at this time: 
 
• Examination of oral mucosa and grading of oral mucositis for patients who 
received mTOR inhibitor therapy. For patients who received radiation to the 
esophagus signs and symptoms of esophagitis are to be evaluated. 
• Weight 
• Concomitant Medications 
• ALC may be obtained. Attempts to perform ALC labs will be made at this 
timepoint, but if unsuccessful, will not be considered a deviation to the protocol 
since it is not a safety assessment. 
• Quality of life questionnaires: MDASI-HN  
 


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6.0 Study Calendar 
• Baseline evaluations are to be conducted within 28 days prior to start of protocol 
therapy.  
• Study Assessments will take place as per protocol schedule unless 
patient/logistical/medical reasons intervene. 


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6.1 Study Assessment for Patients Receiving mTOR Inhibitor Therapy 
All evaluations will have a +/- 2 day window. Cycle 1 Day 1 of the study drug will be Day 1 of the 
mTOR treatment.  
 
a Mucositis grading according to CTCAE v4.03 to be documented with the oral mucosa exam for 
patients receiving mTOR inhibitor therapy.  
b Weight loss to be calculated at each study assessment visit. 
Study 
Assessment 
Screening 
Cycle 1 
Cycle 
2 and 
Beyond 
End of 
Studyh 
3 months 
Post 
EOTh  
(+/- 14 
days)f 
6 months 
Post EOTh 
(+/- 21 
days)f 
 
Within 28 
Days of 
Cycle 1  
Day 1 (+1 
Day Prior 
to Dosing) 
Day 
1 
Day 
8 
Day 
15 
Day 
22 
Day 1 
 
 
 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
Medical 
History 
Review 
X 
 
 
 
 
 
 
 
 
Mucositis 
History 
X 
 
 
 
 
 
 
 
 
Oral Mucosa 
Exama 
X 
X 
X 
X 
X 
Xi. 
Xi. 
 
 
Mucositis 
Gradinga 
X 
X 
X 
X 
X 
X i. 
X i. 
 
 
Weight & 
Weight Lossb 
X 
X 
X 
X 
X 
X 
X 
 
X 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
 
 
ALCg 
X 
 
 
 
 
X 
X 
 
 
Pregnancy 
Test 
X 
 
 
 
 
 
 
 
 
Quality of Life 
Questionnaire 
c 
X 
 
  
X 
  
X 
X 
X 
X 
Patient 
Satisfaction  
with Study 
Medication 
 
 
 
 
 
X 
 
 
 
Medical 
Photographye 
X 
 
 
 
 
X 
 
 
 


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c QOL questionnaires will be performed at 3 months and 6 months if patients are still on mTOR 
inhibitor-based regimen 
d To be done only on Cycle 1 day 29 (prior to receiving Cycle 2 Day 1) 
e Medical Photography of the patient’s oral mucosa at screening, worst grade of mucositis 
experienced, and cycle 1 day 29 (prior to beginning cycle 2). Attempts to obtain photographs will be 
made at these timepoints, but if unsuccessful, will not be considered deviations to the protocol since 
these are not safety assessments. 
f This visit is for patients who remain on mTOR inhibitor containing therapy up to 3 or 6 months. 
g. The ALC may be obtained. Attempts to perform ALC labs will be made at these timepoints, but if 
unsuccessful, will not be considered deviations to the protocol since these are not safety 
assessments. 
h. The End of Study visit will be within 4 weeks after last dose of mTOR inhibitor therapy. The 3-month 
and 6-month follow-up visit will occur post end of treatment (EOT). 
i. After 4 weeks of therapy, mucositis symptoms, weight (weight loss), concomitant medications, and 
questionnaires may be assessed by phone call to the patient. 
 
 
 
The investigators are aware that the combination of mTOR inhibitors and glutamine, 
including sucrose and trehalose, may further increase mTOR inhibitor-induced 
hyperglycemia. The investigators will work closely with the endocrine collaborator.


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6.2 Study Assessment for Patients Receiving Radiation to the Esophagus 
All evaluations will have a +/- 2 day window. 
 
a Esophagitis grading will be according to CTCAE v4.03.  
b. The ALC may be obtained. Attempts to perform ALC labs will be made at these timepoints, but if unsuccessful, 
will not be considered deviations to the protocol since these are not safety assessments. If the patient does not 
return to clinic at 6 month post treatment visit, ALC can be done at the first visit after 6 month post radiation 
treatment. 
c Weight loss to be calculated at each study assessment visit. 
d. Number of weeks is based on number of weeks of therapy that patient receives as determined by the treating 
physician. Radiation will be given daily (Monday through Friday) for 5 days per week. 
e. End of Treatment visit will occur at the appropriate timepoint based on the number of weeks of radiation 
therapy that the patient receives as determined by the physician.  
f. For the 1-month, 3-month, and/or 6-month visits, the assessments of esophagitis grading, weight (weight loss), 
concomitant medications, and questionnaires may be assessed by phone call to the patient if patient is not 
returning to clinic.
Study 
Assessment 
Screening 
Weeks of Radiationd 
End of 
Radiation 
Treatmente 
 Post Radiation 
Therapy 
 
End of 
Study 
 
Within 28 
Days of 
Day 1 of 
Protocol 
Therapy 
1 
2 
3 
4 
5 
6 
7 
 
1 month 
(+/- 7 
days) f. 
3 Months 
(+/- 14 
days) f. 
 
6 Months 
(+/- 21 
days) f. 
 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical 
History Review 
X 
 
 
 
 
 
 
 
 
 
 
 
Esophagitis  
Historya 
X 
 
 
 
 
 
 
 
 
 
 
 
Esophagitis  
Gradea 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
ALCb  
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X b 
Weight & 
Weight Lossc 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
Pregnancy 
Test 
X 
 
 
 
 
 
 
 
 
 
 
 
Quality of Life 
Questionnaire 
X 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Patient 
Satisfaction 
with Study 
Medication  
 
 
 
X 
 
X 
 
X 
X 
X 
 
 


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7.0 Concomitant medications  
 
Concomitant medications that are being used to treat mucositis will be recorded at 
each visit.  
 
8.0 Criteria for Removal from the Study 
 
Patients may be removed from the study for the following reasons: 
1. Patient withdraws consent for continued participation or refuses further treatment 
with the study medication. 
2. If the patient develops grade 4 mucositis. 
3. Completion of study medication: 4 weeks post the last dose of the mTOR inhibitor 
(or after completion of 6 Cycles) or post 6 months after completion of radiation.  
 
9.0 Criteria for Evaluation 
 
CTCAE version 4.03 will be used to assess the grade of mucositis and 
esophagitis.44  The principal investigator will train physicians and mid-level providers 
on the interpretation and grading of mucositis and esophagitis to ensure uniformity 
and appropriate grading of oral exams. 
For oral mucositis, Grade 3 includes the use of opiates for severe mouth pain, IV fluids 
needed for decreased oral intake, or hold of mTOR inhibitor-based therapy due to severe 
mouth pain.  
Grade 
Adverse 
Event 
1 
2 
3 
4 
5 
Mucositis 
Oral 
Asymptomatic 
or mild 
symptoms; 
intervention not 
indicated 
Moderate pain; not 
interfering with oral 
intake; modified diet 
indicated 
Severe pain; 
interfering with 
oral intake 
Life-
threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Definition: A disorder characterized by inflammation of the oral mucosal. 
Grade 
Adverse 
Event 
1 
2 
3 
4 
5 
Esophagitis 
Asymptomatic; 
clinical or 
diagnostic 
observations 
only; 
intervention not 
indicated 
Symptomatic; 
altered 
eating/swallowing; 
oral supplements 
indicated 
Severely altered 
eating/swallowing; 
tube feeding, TPN 
or hospitalization 
indicated 
Life-
threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Definition: A disorder characterized by inflammation of the esophageal wall. 


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For esophagitis, Grade 2 will be when patients start xyloxylin. Grade 3 is when they start 
lortab or other narcotics. Grade 3 is defined as feeding tube required secondary to 
swallowing difficulty rather than uncontrolled nausea. 
 
If patients develop mucositis or esophagitis of grade 1 for more than 5 days or grade 
2 or above, the attending physician may have the option to initiate the patient on a 
best supportive therapy (See Appendix A). The study coordinator or research nurse 
will record the type and time of treatment of any additional supportive therapy that 
patients may be given while on the study which will be included in the data analysis.  
 
10.0 Reporting Requirements  
 
Safety Monitoring 
The principal investigator is responsible for monitoring the safety of patients who 
enroll in the study.  All adverse events (AEs) occurring after any administration of 
the study drug will be followed until resolution, stabilization, death, loss to follow up, 
or commencement of new therapy. 
 
10.1 Serious Adverse Event (SAE) Reporting 
 
Adverse Event Definition 
The CTEP active version of NCI Toxicity Criteria may be used by the Investigator as 
a guide in determining the severity of adverse events. 
Clinically significant adverse events (AEs) and Serious Adverse Events (SAEs) 
occurring during the study that are thought to be related to Glutamine or Best 
Supportive Care should be documented in the medical record. 
 
Toxicities of all grades that are felt to be related to Glutamine or Best Supportive 
Care, and all grades of mucositis, esophagitis, and weight loss will be documented 
in the patient electronic medical record.  Unless otherwise documented in the 
electronic medical record as clinically significant and study drug related, all lab 
abnormalities will be assumed to be related to the patient’s other co-morbid 
conditions, prior therapies, other concomitant therapies/medications, or underlying 
cancer. In this study, only adverse events related to the study drug, not related to 
mTOR inhibitor therapy or radiation therapy will be recorded. 
 
 
 
Serious Adverse Event (SAE) 
 
An adverse event or suspected adverse reaction is considered “serious” if, in the 
view of either the investigator or the sponsor, it results in any of the following 
outcomes: 
 
• Death 
• A life-threatening adverse drug experience – any adverse experience that places 
the patient, in the view of the initial reporter, at immediate risk of death from the 


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adverse experience as it occurred. It does not include an adverse experience that, 
had it occurred in a more severe form, might have caused death. 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
• A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based 
upon appropriate medical judgment, they may jeopardize the patient or subject and 
may require medical or surgical intervention to prevent one of the outcomes listed in 
this definition. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse (21 CFR 312.32). 
 
• Important medical events as defined above, may also be considered serious 
adverse events. Any important medical event can and should be reported as an 
SAE if deemed appropriate by the Principal Investigator or the IND Sponsor, IND 
Office. 
• All events occurring during the conduct of a protocol and meeting the definition of 
a SAE must be reported to the IRB in accordance with the timeframes and 
procedures outlined in “The University of Texas M. D. Anderson Cancer Center 
Institutional Review Board Policy for Investigators on Reporting Serious 
Unanticipated Adverse Events for Drugs and Devices”.  Unless stated otherwise in 
the protocol, all SAEs, expected or unexpected, must be reported to the IND 
Office, regardless of attribution (within 5 working days of knowledge of the event). 
• All life-threatening or fatal events, that are unexpected, and related to the study 
drug, must have a written report submitted within 24 hours (next working day) of 
knowledge of the event to the Safety Project Manager in the IND Office.   
• Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for 
safety reporting to the IND Office and MDACC IRB.  
• Serious adverse events will be captured from the time of the first protocol-specific 
intervention, until 30 days after the last dose of drug, unless the participant 
withdraws consent. Serious adverse events must be followed until clinical recovery 
is complete and laboratory tests have returned to baseline, progression of the 
event has stabilized, or there has been acceptable resolution of the event. 
• Additionally, any serious adverse events that occur after the 30 day time period 
that are related to the study treatment must be reported to the IND Office. This 
may include the development of a secondary malignancy. 
 
Reporting to FDA: 
• Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety 
Project Manager IND Office) according to 21 CFR 312.32. 
 


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It is the responsibility of the PI and the research team to ensure serious 
adverse events are reported according to the Code of Federal Regulations, 
Good Clinical Practices, the protocol guidelines, the sponsor’s guidelines, and 
Institutional Review Board policy. 
 
10.2 Data Collection 
 
All patients who meet eligibility criteria and are enrolled in this trial will be registered 
in Clinical Oncology Research Database (CORe) at the University of Texas MD 
Anderson Cancer Center at Houston.  Data will be collected and stored in the MD 
Anderson Protocol Data Management System (PDMS).   Only adverse events 
related to the study drug will be captured in PDMS. Data from the MDASI and 
patient satisfaction survey will be stored in a Microsoft Access database that will be 
created and managed by Dr. Akhila Reddy’s group. 
 
Data Protection and Confidentiality 
All patients who meet eligibility criteria and are enrolled in this trial will be registered 
in CORe at the University of Texas MD Anderson Cancer Center at Houston. All 
protocol participants must be registered in the CORE. The date in the current 
informed consent document is displayed to ensure only the most current IRB 
approved version is used.  Consent date, registration date, off study date, and 
evaluability data are required for all registrants. 
 
The principal investigator agrees to keep all information and results concerning the 
study confidential. The confidentiality obligation applies to all personnel involved with 
this clinical trial.  The Investigator must ensure that each participant’s anonymity will 
be maintained in accordance with applicable laws.  The principal investigator should 
keep a separate log of ID numbers, names and addresses.  Documents that contain 
the names associated with these ID numbers (e.g., written consent/assent forms), 
should be maintained by the Investigator in strict confidence except to the extent 
necessary to allow auditing by regulatory authorities, auditing or monitoring by the 
IRB. 
 
The Principal Investigator shall obtain all such permissions and authorizations as 
may be necessary or desirable to allow the collection and use of information 
protected under federal privacy laws and state privacy laws, including 
permission/authorization for monitoring and analysis (including re-analysis in 
combination with results of other studies), for regulatory submission purposes and 
for applicable reporting (if any). 
 
10.3 Investigator Reporting Responsibilities 
 
The conduct of the study will comply with all FDA safety reporting requirements.   
The Investigator or physician designee is responsible for verifying and providing 
source documentation for all adverse events and assigning the attribution for each 
event for all subjects enrolled on the trial 
 


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IND Annual Reports 
If the FDA has granted an IND number, it is a requirement of 21 CFR 312.33, that an 
annual report is provided to the FDA within 60-days of the IND anniversary date.  21 
CRF 312.33 provides the data elements that are to be submitted in the report.  The 
Annual Report should be filed in the study's Regulatory Binder. 
 
 
All adverse experience reports must include the patient number, age, sex, weight, 
severity of reaction (mild, moderate, severe), relationship to drug (probably related, 
unknown relationship, definitely not related), date and time of administration of test 
medications and all concomitant medications, and medical treatment provided.   The 
investigator is responsible for evaluating all adverse events to determine whether 
criteria for “serious” and as defined above are present.   
 
11.0 Study Monitoring 
 
This study will be monitored by the MD Anderson IND Office and a protocol-specific 
monitoring plan will be followed. 
 
Regulatory monitoring will be provided by the principal investigator, the Institutional 
Review Board, and the Data Safety and Monitoring Board (DSMB). 
 
 
12.0 Statistical Considerations 
 
Dr. Kenneth Hess (Professor, Department of Biostatistics) will perform all statistical 
analyses.  
 
12.1 Study Objectives 
 
Primary Objectives: 
• To determine whether glutamine decreases the severity of mucositis in 
patients on an mTOR inhibitor-based regimen or esophagitis in patients 
receiving radiation to the esophagus. 
  
Secondary Objectives: 
• To assess whether glutamine regimen improves quality of life (QOL) in 
patients during mTOR inhibitor containing regimen and esophagitis 
during radiation to esophagus. 
• To assess whether glutamine improves other measures of 
mucositis/esophagitis including incidence of any mucositis/esophagitis, 
incidence of grade 3 or higher mucositis/esophagitis, duration of 
mucositis/esophagitis, delay in onset of mucositis/esophagitis, and 
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• To assess whether glutamine affects weight loss after six months of 
treatment for mTOR inhibitor patients and after completion of radiation 
therapy for esophagus radiation patients. 
• To assess toxicity profile of glutamine. 
• To assess whether glutamine affects muscle breakdown. 
 
12.2 Study Endpoints 
 
Primary Endpoints 
• For mTOR inhibitor patients, the severity of oral mucositis will be taken as 
the maximum grade observed during the 6-month study period. For 
esophagus radiation patients, the severity of esophagitis will be taken as 
the highest grade observed by week six. 
 
Secondary Endpoints 
• For mTOR inhibitor patients, oral mucositis grade will be assessed at the 
following times: baseline, weekly during Cycle 1, and Day 1 of Cycle 2 
and beyond, and end of study. For esophagus radiation patients, 
esophagitis grade will be assessed at the following times: baseline, 
weekly during radiation, end of treatment (or final week of radiation 
treatment based on number of weeks of radiation), and 1 month and 6 
months post radiation therapy. 
• For mTOR inhibitor patients, QOL will be assessed by MDASI-HN at the 
following times: baseline, Day 15 of Cycle 1, Day 1 of Cycles 2 and 
beyond, end of study, and 3 months and 6 months post end of treatment. 
For esophagus radiation patients, QOL will be assessed by MDASI-HN at 
the following times: baseline, Weeks 3, 5, and 7 of radiation, end of 
treatment (or final week of radiation treatment based on number of weeks 
of radiation), 1 month, 3 months, and 6 months post radiation therapy. 
For mTOR inhibitor patients, Patient Satisfaction with Study Medication 
will be assessed at Day 1 of Cycles 2 and beyond. For esophagus 
radiation patients, Patient Satisfaction with Study Medication will be 
assessed at Weeks 3, 5, and 7, end of treatment (or final week of 
radiation treatment based on number of weeks of radiation), and 1 month 
post radiation therapy. 
• For mTOR inhibitor patients, body weight will be assessed at the 
following times baseline, weekly during Cycle 1, and Day 1 of Cycle 2 and 
beyond, and end of study. For esophagus radiation patients, body weight 
will be assessed at the following times: baseline, weekly during radiation, 
1 month and 6 months post radiation therapy. 
• For esophagus radiation patients, muscle breakdown will be assessed at 
baseline, weekly during radiation, 1 month and 6 months post radiation 
therapy. 
 
 
 


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12.3 Sample Size  
 
There will be a total of 180 patients in this study. The cohort of patients on mTOR-
based regimens will be 100, and the cohort of patients on radiation regimen will be 
80.  
 
For esophagus radiation, published data indicate that the distribution of patients by 
esophagitis grade is 0-1: 26%, 2: 37%, 3: 37% for patients not given glutamine45. If 
we target a modest treatment effect (0-1: 50%, 2: 38%, 3: 12%) then 40 patients per 
treatment arm would give us 81% power (assuming a two-sided 5% alpha and use 
of the Wilcoxon rank sum test for analysis). 
  
For mTOR inhibitor patients, we have unpublished data from 87 patients indicating 
that the distribution of patients by oral mucositis grade is 0-1: 69%, 2: 22%, 3: 9% for 
patients not given glutamine. If we target (0-1: 95%, 2: 5%, 3: 0%) as the results in 
the glutamine arm, then 50 patients per arm would give us 94% power (assuming a 
two-sided 5% alpha, and use of the Wilcoxon rank sum test for analysis). 
 
These calculations were made using nQuery Advisor 7.0.  
 
12.4 Statistical Analysis Plan  
 
Note: Analyses will be performed separately for patients treated with mTOR 
inhibitors and patients with esophagus radiation.   
  
  
For the primary objective, we will use the Wilcoxon rank sum test to compare the 
ordered categories of mucositis/esophagitis severity between treatment arms. A 
patient must complete at least 60% of the planned doses of placebo or glutamine to 
be considered evaluable in the statistical analysis. As a sensitivity analysis for the 
appropriateness of 60% dosing cut-off, we will analyze the outcome according to the 
proportion of drug taken.  The proportional of drug taken will be computed as the 
ratio of number of doses taken to the total number of doses prescribed. For the 
mTOR inhibitor group, the denominator will reflect the total time that each patient is 
on the study. For the esophagus radiation group, the denominator will reflect the 
total number of doses that are prescribed during the delivery of radiation. 
 
 
For the secondary objectives/endpoints, we will compare between treatment arms 
(1) the trajectories of the mucositis/esophagitis scores over time using linear mixed 
effects; (2) the proportion of patients developing mucositis/esophagitis using a 
Pearson chi-squared test; (3) the proportion of patients developing grade 3 or higher 
mucositis/esophagitis using a Pearson chi-squared test; (4) the duration of 
mucositis/esophagitis using the Wilcoxon rank sum test; (5) the time to develop 
mucositis/esophagitis using Kaplan-Meier estimates and the log rank test (due to 
right censoring in patients not developing mucositis/esophagitis); (6) the proportion 
of patients having treatment interruptions using a Pearson chi-squared test; (7) the 


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weight change using the Wilcoxon rank sum test; and (8) the QOL survey scores 
using the Wilcoxon rank sum test. 
 
For the secondary objective of describing the toxicity profile, descriptive statistics will 
be provided on the grade and type of toxicity by treatment arm. 
 
For the secondary objective of assessing the muscle breakdown in the esophagus 
radiation group, we will compare the muscle breakdown between the patients that 
received glutamine versus placebo. Muscle breakdown will be assessed by 
reviewing patient CTs pre-treatment, during weeks of radiation, 1 month post 
treatment, and 6 months post treatment. The CT image at the level of the third 
lumbar vertebra will be auto-segmented using Pinnacle software. One cross section 
will highlight the skeletal muscle mass while the other cross section will highlight the 
adipose tissue surrounding the vertebra. LBM (lean body mass) and FM (fat mass) 
will be estimated from skeletal muscle and adipose cross-sectional area (cm2) at the 
third lumbar vertebra using the formulae described by Chamchod et al.47  
 
LBMCT (kg) = 0.3 x [skeletal muscle at L3 (cm2)] + 6.06 
 
FMCT (kg) = 0.042 x [total adipose tissue at L3 (cm2)] +11.2 
 
 
 
Stopping Rules 
We will perform semi-annual futility analyses using Bayesian predictive probability 
methods.46  These analyses would be timed to occur at the time of our annual 
DSMB review as well as mid-way in between the meetings. The more frequent 
interim futility analysis will allow us to determine in a more timely fashion when and if 
there is sufficient evidence that it is unlikely that we would conclude that one 
treatment was better than the other if we completed planned enrollment. 
Consideration should be given to stopping the trial early for futility if the predicted 
probability that a significant difference between glutamine and placebo would be 
observed in the trial if it were continued to completion is < 5%.   
 
Separate analyses will be performed for the mTOR inhibitor patients and for the 
esophagus radiation patients.  
The study statisticians will conduct the analyses and send the results to the DSMB 
for consideration. The PI will not be notified of the results of these analyses unless 
the DSMB determines to recommend that study enrollment be stopped.  
 
 
12.5 Randomization and Blinding  
 
Patients will be equally randomized between treatment arms using permuted blocks 
within strata separately for the two groups of patients. For patients who will receive 
mTOR inhibitor based therapy, randomization will be stratified by: prior mucositis 
(Y/N), and prior radiation therapy to the head and neck (Y/N). For patients who will 


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receive radiation to the esophagus, randomization will be stratified based on the 
volume of esophagus receiving 40 Gy: (1) 20-40%; (2) 41-60%; (3) 61-80%. 
 
CORe will set up a Randomization website and the Investigational Pharmacy 
personnel will perform the randomization assignment.  
 
Both patients and the research staff conducting the assessment will be blinded to 
the treatment assignment. Placebo powder identical to glutamine powder in 
appearance and taste will be compounded by Healios Nutrition Oncology, and both 
will be dispensed by Investigational Pharmacy at MD Anderson. At the end of the 
blinded phase, we will assess blinding by asking patients which study arm they 
believe they have been randomized to. 
 
Unblinding Procedure: 
1. The Statistician and the investigational pharmacist will have access to the 
codes/assignments. 
2. The codes will be revealed only if there is a safety issue and the treating 
physician needs to be aware of the treatment assignment. 
3. The PI should be contacted regarding the patient’s circumstances. 
4. Prior to unblinding a patient, the investigator or research team will inform the IND 
Office Medical Monitor.   
5. The Investigator will then give permission for the unblinding to the statistician and 
the investigational pharmacist. 
6. The investigator or research team will notify the DSMB and IRB of the unblinding. 
 
 


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Appendix A: Guidelines for Best Supportive Therapy 
 
If patients develop mucositis or esophagitis of grade 1 for more than 5 days or grade 
2 or above, the attending physician may have the option to initiate the patient on a 
best supportive therapy. The treatment that the Department of Investigational 
Cancer Therapeutics generally uses for the management of mucositis is the 
following13:  
• Xyloxylin- 1:1:1 ratio of diphenhydramine, Maalox, lidocaine; 10 milliliters 
(mL) swish/ swallow every 6 hours as needed)  
• Caphasol (sodium phosphate; 15 mL swish/spit every 4 hours as needed) 
• Valacyclovir (500 mg po TID for treatment)  
• Biotene (MW every 4 hours as needed) 
• Carafate (1 gm/10 mL; 10 mL swish/swallow or spit QID as needed) 
 
 


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