Clinical trial NCT02300727
Conditions: Mucositis
Keywords: Mucositis Neoplasms CANCER Curcumin Drug Therapy ANTINEOPLASTIC AGENTS
Sponsor: Amy Beres
Start date: 2015-02-01; Completion date: 2018-10-25
Enrollment: 6 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Oral mucositis is a common side effect from cancer treatment. Patients receiving chemotherapy and radiotherapy can get very painful sores in their mouth that compromise nutrition and oral hygiene as well as increase risk for infection, and can last for weeks. Currently, the only treatment for mucositis is oral hygiene to try to support recovery.

Curcumin (also known as Turmeric) is a frequently-used spice in India and Southeast Asia. Studies in cells and animals have shown that it can reduce the amount of bacteria and can prevent inflammation.

In this study, the investigators want to learn if a mouthwash made with curcumin is safe for people to use and if it can help their mucositis.

Detailed description:
This is a phase I/II study involving 2 parts; a dose escalation to determine the maximum tolerated dose (MTD) of curcumin and an expansion at the MTD.

Oral mucositis is a common and often debilitating complication associated with cancer treatment. Treatment of mucositis is mainly supportive - oral hygiene is the means of treatment. Curcumin (Turmeric), a frequently-used spice in India and Southeast Asia, can reduce bacterial load and prevent inflammation in cultured epithelial cells and prevent chemotherapy- and radiotherapy-induced mucositis in animal models.

The primary objective of this Phase I/II study is to determine the maximum tolerated dose (MTD) of oral curcumin in patients who have chemotherapy-induced mucositis. The secondary objectives of this study are to determine whether or not oral curcumin has an acceptable safety profile or impacts oral mucositis health outcomes.

Arms: arm 1: Standard mouth wash preparation administered by ingested mouth rinse three times per day.

The standard mouth rinse contains 40% Benadryl, 40% Maalox, and 20% of 1% Viscous Lidocaine. arm 2: Curcumin (BCM-95) administered by ingested mouth rinse three times per day. Subjects will be in this arm at the previously determine maximum tolerated dose (MTD). arm 3: Curcumin (BCM-95) administered by ingested mouth rinse. A total of 12-15 subjects will be in this arm to determine maximum tolerated dose (MTD).

There will be 3 participant at each of 4 does levels (0.33g, 1g, 2g, 3g) per rinse, three times daily for 4-6 weeks. (additional 3 subjects if a dose-limiting toxicity occurs)
Interventions: intervention 1: Curcumin-MTD intervention 2: Mouthwash-standard pharmacy preparation intervention 3: Curcumin
Intervention descriptions: intervention 1: 0.33g-3g by ingested mouth wash three times per day for 4-6 weeks until unacceptable toxicity develops- to determine the maximum tolerated does (MTD). intervention 2: Standard mouth wash preparation administered by ingested mouth rinse three times per day.

The standard mouth rinse contains 40% Benadryl, 40% Maalox, and 20% of 1% Viscous Lidocaine. intervention 3: After maximum tolerated dose (MTD) is determined, MTD by ingested mouth wash three times per day for 4-6 weeks until mucositis is resolved, disease progression, or unacceptable toxicity develops.

Protocol documents:
Prot_SAP_000.pdf: 
Page 1 of 23 
 
 
 
 
 
 
 
 
A PHASE I/II STUDY TO DETERMINE  
THE SAFETY AND EFFICACY OF CURCUMIN 
IN PATIENTS WITH ORAL MUCOSITIS 
SECONDARY TO CHEMOTHERAPY 
 
 
Principal Investigator:  
Dhimant Patel, MD 
Aurora BayCare Medical Center 
2845 Greenbrier Rd 
Green Bay, WI 54311 
Phone: 920-288-4180 
Fax: 920-288-4182 
Email: Dhimant.patel@aurora.org 
 
Sub-investigators:  
Nancy Davis, MD 
 
Umang Gautam, MD 
 
Ubaid Nawaz, MD 
 
Jessie Lawton, Pharm D, BCOP 
Nina Garlie, PhD 
John Richards, PhD  
 
 
Study Coordinators: 
Catherine Newbanks, RN 
 
Corrine Zipperer, RN 
 
Sarah Peterson, RN 
 
 
Sponsor:  
Aurora Health Care 
 
750 West Virginia Street  
 
Milwaukee, WI 53204 
 
 
 
Protocol version:  April 29, 2015 
 


Page 2 of 23 
 
PRECIS 
 
Background: 
Oral mucositis is a common and often debilitating complication associated with 
cancer treatment. Treatment of mucositis is mainly supportive - oral hygiene is the 
means of treatment. Curcumin (Turmeric), a frequently-used spice in India and 
Southeast Asia, can reduce bacterial load and prevent inflammation in cultured 
epithelial cells and prevent chemotherapy- and radiotherapy-induced mucositis in 
animal models.  
 
Objectives: 
The primary objective of this Phase I/II study is to determine the maximum 
tolerated dose (MTD) of oral curcumin in patients who have chemotherapy-
induced mucositis. The secondary objectives of this study are to determine 
whether oral curcumin: 
1. 
Decreases an objective measurement of oral mucositis 
2. 
Decreases the pain associated with oral mucositis 
3. 
Decreases the duration of mucositis 
4. 
Has an acceptable safety profile 
 
Eligibility: 
Inclusion Criteria: 
• ≥ 18 years of age  
• ≥ grade 2 oral mucositis related to chemotherapy for cancer 
Exclusion Criteria:  
• Current use of therapeutic doses of anticoagulants such as warfarin or 
antiplatelet agents (prophylactic doses and agents are acceptable) 
• Biliary tract obstruction or cholelithiasis 
 
Design: 
This is a phase I/II study involving 2 parts. The first part is a dose escalation to 
determine the maximum tolerated dose of curcumin. There will be 3 subjects at 
each dose level of curcumin and 4 dose levels of curcumin. Each dose will be 
given 3 times each day for 14 days. Each dose will be given as a mouth rinse 
containing curcumin and water. The mouth rinse will be used for 30 seconds and 
then swallowed. Subjects will be evaluated for dose-limiting toxicity until the MTD 
is determined. 
 
The second part of the study is an expansion at the MTD. Subjects will be 
randomized 1:1 to an experimental arm (curcumin) and a control arm (standard of 
care), with 23 subjects enrolled to each arm. Subjects on the experimental arm will 
use a mouth rinse containing the MTD of curcumin 3 times each day for 14 days. 
Subjects on the control arm will use a standard mouth rinse 3 times each day for 
14 days. Both mouth rinses will be used for 30 seconds and then swallowed. 
Subjects will be evaluated for response and toxicity. Statistical analysis of the 
response data will determine whether oral exposure to curcumin reduces 
mucositis.  


Page 3 of 23 
 
 
 
APPENDICES: 
A: DAILY LOG  
B: HEALTH CARE PROVIDER ASSESSMENT TOOL 
C: SUBJECT ASSESSMENT TOOL 
D: BIOSKETCH FOR DR. DHIMANT PATEL 
Section 
Contents 
Page 
1 
1. BACKGROUND AND SIGNIFICANCE 
4 
2 
OBJECTIVES / ENDPOINTS   
5 
3 
STUDY DESIGN 
5 
4 
SUBJECT SELECTION 
6 
4.1 
INCLUSION CRITERIA 
6 
4.2 
EXCLUSION CRITERIA 
6 
5 
STUDY PROCEDURES AND SCHEDULE 
6 
5.1 
STUDY VISITS 
7 
5.2 
STUDY CALENDAR 
10 
5.3 
PREPARATION OF STANDARD MOUTH RINSE 
11 
5.4 
PREPARATION OF STUDY MOUTH RINSE (CURCUMIN) 
11 
5.5 
STUDY DRUG (CURCUMIN) DOSE 
11 
5.6 
DETERMINATION OF MTD 
11 
6 
EXPECTED ADVERSE EVENTS 
12 
6.1 
DOSE-LIMITING TOXICITY 
12 
6.2 
CRITERIA FOR SUBJECT REMOVAL 
12 
6.3 
CRITERIA FOR STUDY DISCONTINUATION 
13 
6.4 
CRITERIA FOR DOSE REDUCTION 
13 
6.5 
SERIOUS ADVERSE EVENTS (SAEs) 
13 
7 
BENEFITS 
13 
8 
SAMPLE SIZE 
 13 
9 
MEASUREMENT OF EFFECT 
 14 
9.1 
DETERMINATION OF OBJECTIVE MEASUREMENT OF ORAL MUCOSITIS 
14 
9.2 
DETERMINATION OF SUBJECTIVE MEASUREMENT OF ORAL MUCOSITIS 
14 
9.3 
DETERMINATION OF PAIN ASSOCIATED WITH ORAL MUCOSITIS 
14 
9.4 
DETERMINATION OF DURATION OF MUCOSITIS 
15 
9.5 
DETERMINATION OF TOXICITY PROFILE 
15 
9.6 
CRITERIA TO BE EVALUABLE FOR EFFICACY AND SAFETY 
15 
10 
CORRELATIVE STUDIES (LABORATORY STUDIES) 
 15 
10.1 
SAMPLE COLLECTION 
15 
10.2 
EVALUATION OF PROINFLAMMATORY CYTOKINES 
15 
10.3 
FUTURE RESEARCH AND SAMPLE DISPOSITION 
16 
11 
DATA COLLECTION 
16 
12 
MONITORING PLAN 
16 
13 
REPORTING REQUIREMENTS 
17 
13.1 
REPORTING REQUIREMENT FOR SERIOUS ADVERSE EVENTS (SAEs)  
18 
14 
REGULATORY REQUIREMENTS 
18 
14.1 
INFORMED CONSENT 
18 
14.2 
INSTITUTIONAL REVIEW BOARD 
19 
14.3 
 SUBJECT CONFIDENTIALITY 
19 
15 
EXPERIENCE OF THE INVESTIGATORS 
20 
16 
REFERENCES 
21 


Page 4 of 23 
 
1.  Background and Significance 
 
Oral mucositis refers to erythematous and ulcerative lesions of the oral mucosa 
observed in patients with cancer being treated with chemotherapy, and/or with 
radiation therapy to fields involving the oral cavity. Oral and/or GI mucositis has 
been reported in 51% of patients receiving chemotherapy for solid tumors or 
lymphoma[1].  Clinically significant oral mucositis has been reported in an even 
higher percentage (approximately 75–80%) of patients who receive high-dose 
chemotherapy prior to hematopoietic cell transplantation[2]. Lesions of oral 
mucositis are often very painful and compromise nutrition and oral hygiene as well 
as increase risk for local and systemic infection. In addition to reducing patients’ 
quality of life, mucositis may act as a dose-limiting adverse event in chemotherapy 
and/or radiation therapy and thus, it requires attention and treatment in the 
oncologic setting[3].  
 
The cause of oral mucositis induced by cancer treatment is believed to be due to 
the over-production of free radicals induced by the chemo- or radiotherapy, which 
damages cell DNA and further activates pro-inflammatory transcriptional factors 
such as NF-κB. Activation of NF-κB up-regulates inflammatory cytokines. The 
major inflammatory cytokines involved are IL-6, TNF-α and IL-1β[4, 5]. 
 
Typically, patients undergoing chemotherapy for cancer begin to show symptoms 
of oral mucositis about four to five days after starting treatment. Symptoms are at 
their peak at around the tenth day, after which they slowly improve over the 
following few weeks. Patients undergoing radiotherapy generally develop 
symptoms at the end of the second week of treatment. The symptoms can last 
from six to eight weeks.  
 
 
Although many prophylactic and supportive treatment options exist, including 
cryotherapy, palifermin, amifostine, intravenous glutamine, honey, topical oral 
antimicrobials[6]  and Lactobacillus lozenges[7], there is little consensus for a 
stand-out treatment for breakthrough mucositis. Hundreds of institution-specific 
oral rinses known as “magic “ or “miracle” mouthwashes, that contain some 
combination of anticholinergic (i.e. diphenhydramine), anesthetic (i.e. viscous 
lidocaine), antacid (i.e. Maalox), coating agent (Sucralfate), anti-inflammatory 
(glucocorticoids), 
antifungal 
(Nystatin) 
and/or 
antibiotic 
(tetracycline 
or 
erythromycin) ingredients, are often used as first-line treatment[8] for breakthrough 
mucositis. One major issue regarding “magic” mouthwash formulations is a 
variance of institutional and literature standardization which inhibits the ability to 
accurately determine its overall efficacy in the treatment of chemotherapy and 
radiation-induced mucositis[9]. One controlled study to evaluate the efficacy of 
magic mouthwash showed no difference in efficacy among the common 
formulation and other treatment agents such as chlorhexidine and a simple 
saline/baking soda solution[10]. In addition, all these “magic mouthwashes” are 
formulated to provide symptomatic relief of the pain or to create a protective 
barrier to prevent and reduce the severity of oral mucositis caused by 
chemotherapy and /or radiation. However, these mouthwashes are generally not 
designed to target the inflammatory response associated with chemotherapy and 
/or radiation which cause the mucositis. 
 
Curcumin (extracted from turmeric) is an herbal supplement that has an extensive 


Page 5 of 23 
 
history of use in India and Asia for its potent anti-inflammatory action and lately is 
being investigated for use in treatments of rheumatoid arthritis, various cancers, 
and Alzheimer’s disease[11]. Curcumin has been shown to prevent chemotherapy- 
and radiotherapy-induced mucositis in animal models[12]. Two recent studies 
provide a basis for our current investigation. In the first study, Luer et al. 
demonstrated that curcumin reduced oropharyngeal bacterial load and prevented 
inflammation in cultured epithelial cells[13]. In a small pilot study of juvenile 
patients with chemotherapy-induced mucositis, topical curcumin was found to be 
safe and well-tolerated[14].  Curcumin’s anti-inflammatory and antibacterial action 
make it a viable and compelling option for chemotherapy-induced mucositis.  
 
2.  Objectives/Endpoints 
 
The primary objective of this Phase I/II study is to determine the maximum 
tolerated dose (MTD) of oral curcumin in patients who have chemotherapy-
induced mucositis. The secondary objectives of this study are to determine 
whether oral curcumin: 
• 
Decreases an objective measurement of oral mucositis 
• 
Decreases the pain associated with oral mucositis 
• 
Decreases the duration of mucositis 
• 
Has an acceptable safety profile.  
3.  Study Design 
 
This is a phase I/II study involving 2 parts: a dose escalation part and an 
expansion at the maximum tolerated dose.  
 
In the first part, there will be 3 subjects at each dose level of curcumin (see table 
below). The doses will be taken 3 times each day for 14 days. Each dose will be 
taken as a mouth rinse containing curcumin and water, 3 times each day for 14 
days. The mouth rinse will be used for 30 seconds and then swallowed. Subjects 
will be evaluated for dose-limiting toxicity (DLT, defined in section 6.1). The 
maximum tolerated dose (MTD, defined in section 2) will be determined. Subjects 
may participate in the study at a higher dose level, after they have completed the 
study at the current dose level and if they are eligible. 
 
# Subjects 
Curcumin/dose 
(gram) 
Curcumin/day 
(gram) 
3 
0.33 
1 
3 
1.0 
3 
3 
2.0 
6 
3 
3.0 
9 
 
In the second part of the study, there will be 23 subjects enrolled to an 
experimental (curcumin) arm and 23 subjects enrolled to a control (standard of 
care) arm. Subjects will be randomized to take a mouth rinse with or without the 
MTD of curcumin, 3 times each day for 14 days. The rinses will be swallowed. 
Subjects will be evaluated for response and toxicity. Subjects in the first part of the 
study may participate in the second part of the study, if they are eligible. 
 
In both parts of the study, if the mucositis score ≤ Grade 2 but is unresolved after 
14 days of taking the study mouth rinse (curcumin or control), then the subject will 


Page 6 of 23 
 
continue to receive the study mouth rinse until the mucositis is resolved (Grade 0).  
 
This study will involve 12 subjects in the first part, plus an additional 3 subjects if a 
dose-limiting toxicity occurs (see section 2) and 46 subjects in the second part for 
a total of 61 subjects. This study is expected to take 2 years to complete 
enrollment, treatment and follow-up (6 months for the first part and 18 months for 
the second part). 
 
4.  Subject Selection 
 
Potential subjects will be identified and recruited from within the practice 
population of the investigators (including via referrals to the investigators from 
other physicians). Patients' medical charts may be reviewed to identify potential 
subjects and to help determine eligibility; a 502-A form is being submitted to allow 
this preparatory to research activity. 
 
4.1 Inclusion Criteria 
 
• 
   ≥ grade 2 oral mucositis related to chemotherapy for cancer 
• 
Ability to understand and the willingness to review and sign a written 
informed consent document. 
• 
≥ 18 years of age  
• 
Willingness to use adequate contraception prior to study entry, for 
the duration of study participation and for 30 days after the last dose 
for women of child-bearing potential and men 
 
4.2 Exclusion Criteria 
 
• 
Current use of therapeutic doses of anticoagulants such as warfarin 
or antiplatelet agents (prophylactic doses and agents are acceptable) 
• 
Biliary tract obstruction or cholelithiasis 
• 
History of gastric or duodenal ulcers or hyperacidity syndromes 
• 
AST or ALT > 2 x ULN 
• 
Total bilirubin ≥ 2 x ULN 
• 
INR > 1.5 
• 
Previous stem cell transplant (allogeneic or autologous) 
• 
Preexisting oral disease, such as active oral infection, trauma to the 
oral mucosa or oral ulceration prior to chemotherapy 
• 
Known allergy/hypersensitivity to curcumin, yellow food colorings, or 
other members of the Zingiberaceae (ginger) family 
• 
Pregnant or breastfeeding 
 
Potential subjects are identified by medical record review. Eligible subjects are 
asked to give their written consent to participate in this study. The tests required to 
screen subjects for this study include a pregnancy test, INR and CMP.  
5.  Study Procedures and Schedule 
 
The study mouth rinse will be initiated when subjects have > grade 2 mucositis, 
which could be at any point during their chemotherapy cycle. Subjects who 
develop > grade 2 mucositis will receive appropriate adjustments in their 
chemotherapy dose to reduce toxicity with subsequent cycles. 


Page 7 of 23 
 
 
In the first part, there will be 3 subjects at each dose level of curcumin.  Each dose 
will be given as a mouth rinse containing curcumin and water.  
In the second part, subjects will be randomized to take a mouth rinse with the MTD 
of curcumin or a standard mouth rinse, 3 times each day for 14 days. The 
curcumin mouth rinse will be designated “study mouth rinse” to differentiate it from 
the standard mouth rinse. 
All subjects will be instructed to rinse their mouths with the study or standard 
mouth rinse 3 times each day for 14 days. Subjects will be instructed to use the 
study or standard mouth rinse for 30 seconds and then swallow the rinse. Subjects 
will be instructed not to eat within one hour after using the study or standard mouth 
rinse. Subjects will be instructed to use a saline mouth rinse after eating any food 
to keep their mouth clean. A daily log (Appendix A) will be available for each 
subject and will include a checklist that will simplify the rinsing schedule as well as 
an area for the subject (or family member) to document mouth rinse 
administration. No other adjunctive topical treatment will be used during the study. 
Subject adherence to the treatment schedule will be assessed through subject 
reports, by review of the daily log (Appendix A) and by review of returned 
medications collected during the site visits.  
 
5.1 Study Visits 
 
All procedures and assessments are conducted for research purposes. 
 
5.1.1 Visit 1 (Screening) 
Subjects will be asked to sign a consent form. An oral exam will be conducted 
to ensure good oral hygiene. A blood or urine sample will be collected for 
pregnancy testing, if applicable. A blood sample will be collected to assess liver 
function (CMP) and clotting function (PT and INR).  A mucositis assessment 
(CTAE version 4.0 and WHO Oral Toxicity Scale) will be conducted and 
documented by a health provider (Appendix B). This visit will take 
approximately one hour. 
 
5.1.2 Visit 2 


Page 8 of 23 
 
5.1.3 THIS VISIT MUST OCCUR WITHIN 48 HOURS AFTER THE 
SCREENING VISIT. IF VISIT 2 OCCURS ON A DIFFERENT DAY 
THAN VISIT 1, ANOTHER MUCOSITIS ASSESSMENT (CTAE 
VERSION 4.0 AND WHO ORAL TOXICITY SCALE) WILL BE 
CONDUCTED AND DOCUMENTED BY A HEALTH PROVIDER 
(APPENDIX B) AND WILL BE CONSIDERED THE BASELINE 
ASSESSMENT. THE PROVIDER WILL ALSO ASK THE SUBJECT TO 
COMPLETE A SUBJECT SELF-ASSESSMENT (APPENDIX C). 
SUFFICIENT MOUTH RINSE WILL BE GIVEN TO THE SUBJECT 
FOR THE FIRST WEEK OF THE STUDY. THE DAILY LOG 
(APPENDIX A) AND THE PATIENT SELF-ASSESSMENT TOOL 
(APPENDIX C) WILL BE GIVEN TO THE SUBJECT. THE SUBJECT 
WILL BE ASKED TO COMPLETE THE LOG EVERY DAY UNTIL 
VISIT 3. THE SUBJECT WILL BE ASKED TO COMPLETE THE SELF-
ASSESSMENT TOOL ON DAY 3 OR 4 AFTER THE FIRST DAY OF 
TAKING THE MOUTH RINSE. A BLOOD AND SALIVA SAMPLE 
WILL BE OBTAINED FOR RESEARCH PURPOSES (SECTION 10). 
THIS VISIT WILL TAKE APPROXIMATELY 30 MINUTES.Phone call 1 
On day 3 or 4 after the first day of taking the mouth rinse for the study, the 
subject will be called by a study staff member, who will review and follow up on 
any side-effects that the subject is experiencing and answer any questions 
about the study or study mouth rinse. The staff member will remind the subject 
to complete a subject self-assessment tool (Appendix C) and the daily log 
(Appendix A) and bring them to the next visit. The phone call will take about 15 
minutes. 
 
5.1.4 Visit 3 
This visit will occur 7 days (+/- 1 day) after Visit 2. A mucositis assessment 
(CTAE version 4.0 and WHO Oral Toxicity Scale) will be conducted and 
documented by a health provider (Appendix B), who will also review and follow 
up on any side-effects that the subject is experiencing and check the daily log 
(Appendix A) to ensure that the subject is complying with the study. Sufficient 
mouth rinse will be given to the subject for the second week of the study. A 
blood sample will be obtained to assess liver function (CMP) and clotting 
function (PT and INR). A blood and saliva sample will be obtained for research 
purposes (section 10). This visit will take approximately 30 minutes. 
 
5.1.5 Phone call 2 
On day 10 or 11 after the first day of taking the mouth rinse for the study, the 
subject will be called by a study staff member, who will review and follow up on 
any side-effects that the subject is experiencing and answer any questions 
about the study or study mouth rinse. The staff member will remind the subject 
to complete a subject self-assessment tool (Appendix C) and the daily log  
(Appendix A) and bring them to the next visit. The phone call will take about 15 
minutes. 
 
5.1.6 Visit 4 


Page 9 of 23 
 
This visit will occur 7 days (+/- 1 day) after Visit 3. A mucositis assessment 
(CTAE version 4.0 and WHO Oral Toxicity Scale) will be conducted and 
documented by a health provider (Appendix B), who will review and follow up 
on any side-effects that the subject is experiencing and obtain the daily log 
(Appendix A) from the subject. A blood sample will be obtained to assess liver 
function (CMP) and clotting function (PT and INR). A blood and saliva sample 
will be obtained for research purposes (section 10). If the mucositis score ≤ 
Grade 2 but is unresolved, then the subject will continue to receive the study 
mouth rinse (curcumin or standard mouth rinse) until the mucositis is resolved 
(Grade 0). Sufficient mouth rinse will be given to the subject for the subsequent 
week of the study. This visit will take approximately 30 minutes. 
 
5.1.7 Phone call 3 
On day 17 or 18 after the first day of taking the mouth rinse for the study, the 
subject will be called by a study staff member, who will review and follow up on 
any side-effects that the subject is experiencing and answer any questions 
about the study or study mouth rinse. The staff member will remind the subject 
to complete a subject self-assessment tool (Appendix C) and the daily log  
(Appendix A) (only if they are still on study mouth rinse) and bring them to the 
next visit. The phone call will take about 15 minutes. 
 
5.1.8 Visit 5 
This visit will occur 7 days (+/- 1 day) after Visit 4. A mucositis assessment 
(CTAE version 4.0 and WHO Oral Toxicity Scale) will be conducted and 
documented by a health provider (Appendix B), who will review and follow up 
on any side-effects that the subject is experiencing and obtain the daily log  
(Appendix A) from the subject (if the subject is still on study mouth rinse). A 
blood sample will be obtained to assess liver function (CMP) and clotting 
function (PT and INR). A blood and saliva sample will be obtained for research 
purposes (section 10). If the mucositis score ≤ Grade 2 but is unresolved, then 
the subject will continue to receive the study treatment (curcumin or standard 
mouth rinse) until the mucositis is resolved (Grade 0). Sufficient mouth rinse 
will be given to the subject for the subsequent week of the study. This visit will 
take approximately 30 minutes. 
 
5.1.9 Weekly phone calls to subjects receiving study mouth rinse (curcumin or 
standard mouth rinse) 
Between each visit, each subject will be called by a study staff member, who 
will review and follow up on any side-effects that the subject is experiencing 
and answer any questions about the study or study mouth rinse. The staff 
member will remind the subject to complete a subject self-assessment tool 
(Appendix C) and the daily log (Appendix A) and bring them to the next visit. 
The phone call will take about 15 minutes. 
 
5.1.10  Weekly visits for subjects receiving study mouth rinse (curcumin or 
standard mouth rinse) 


Page 10 of 23 
 
A mucositis assessment (CTAE version 4.0 and WHO Oral Toxicity Scale) will 
be conducted and documented by a health provider (Appendix B), who will 
review and follow up on any side-effects that the subject is experiencing and 
obtain the daily log  (Appendix A) from the subject. A blood sample will be 
obtained to assess liver function (CMP) and clotting function (PT and INR). A 
blood and saliva sample will be obtained for research purposes (section 10). If 
the mucositis score ≤ Grade 2 but is unresolved, then the subject will continue 
to receive the study mouth rinse (curcumin or standard mouth rinse) until the 
mucositis is resolved (Grade 0). Sufficient mouth rinse will be given to the 
subject for the subsequent week of the study. This visit will take approximately 
30 minutes. 
 


Page 11 of 23 
 
5.2 Study Calendar 
 
 
Week 1 
Week 2 
Week 3 
Week 4- mucosits resolution 
 
Study Procedure 
Visit 1 
(Screening
) 
Visit 2: 
Phone 
call 1: 
Visit 3: 
Phone call 
2: 
Visit 4: 
Phone call 
3: 
Visit: 
Phone calls 
Final visit 
 
day -1 
day 0 
day 3 
day 7  
day 10 
day 14 
day 17 
For phase II: weekly cycle 
repeated until mucositis is 
resolved (and no AEs) 
day 21, or 7 days after 
visit when  
mucositis was 
resolved 
activity window 
 
At or w/in 
48hr of 
Visit 1 
+ 1 day  
+/- 1 day 
+ 1 day 
 +/- 1 day 
+ 1 day 
+/- 1 day 
+ 1 day 
+/- 1 day 
Sign Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Oral exam for hygiene 
X 
 
 
 
 
 
 
 
 
 
Pregnancy test 
X1 
 
 
 
 
 
 
 
 
 
Provider mucositis 
assessment2 
X 
X3 
 
X 
 
X 
 
Xa 
 
X 
Provider supplies study 
mouth rinse  
 
X 
 
X 
 
Xa 
 
Xa 
 
X 
Provider supplies study 
journal, self-assessment 
 
X 
 
X 
 
Xa 
 
Xa 
 
X 
Provider collects journal 
and self-assessments 
 
 
 
X 
 
X 
 
Xa 
 
X 
Remind subject to complete 
self-assessment  
 
X  
X 
 
X 
 
X 
 
Xa 
 
Blood collection for liver 
function (CMP) 4 
X 
 
 
X 
 
X 
 
Xa 
 
X 
Blood collection for clotting 
(PT and INR) 4 
X 
 
 
X 
 
X 
 
Xa 
 
X 
Research blood collection 5 
 
X 
 
X 
 
X 
 
Xa 
 
 
Research saliva collection 5 
 
X 
 
X 
 
X 
 
Xa 
 
 
Collect AEs 
 
 
X 
X 
X 
X 
X 
Xa 
Xa 
X 
Review of concomitant 
medications 
X 
X 
 
X 
 
X 
 
Xa 
 
X 
1 Blood or urine pregnancy test, if not already done as part of standard of care 
2 Includes CTAE version 4.0 and WHO oral Toxicity scale. 
3 Mucositis assessment at Visit 2, only if a different day than Visit 1 (does not need to be repeated is Visit 1 and 2 are done on the same day) 
4 Does not need to be repeated if already done for standard of care. 
5 6 ml of peripheral blood into a non-anti-coagulated tube, 2 ml salvia into a sterile tube; processed and stored as described in the operations manual.   
a Only if subject is still taking study mouth rinse based on improvement of mucositis at each visit, beginning at visit 4. 


Page 12 of 23 
 
5.3 Preparation of Standard Mouth Rinse  
The standard mouth rinse will be prepared by the pharmacy and provided in 200 
mL bottles and will utilize measured dosing cup for accurate dosing. The 
standard mouth rinse contains 40% Benadryl, 40% Maalox, and 20% of 2% 
Viscous Lidocaine.  Subjects will use 15 ml each of the 3 times they rinse their 
mouths each day. 
 
5.4 Preparation of Study Mouth Rinse (Curcumin) 
 
The appropriate daily dose of study drug (powder) will be dispensed by the 
pharmacy in a plastic amber vial. Subjects will receive 8 vials (1 week supply +1 
in case of spilled/lost dose) of curcumin powder and vials of sterile water to 
prepare their study mouth rinse at home.  The volume of water dispensed in each 
vial will vary based on the dose of curcumin the subject is assigned to.  
Regardless of dose, all prepared curcumin solutions will total 45 ml in volume.  
These vials will be stored at room temperature. Subjects will be instructed to add 
a vial of sterile water to each vial of curcumin powder on each day. Subjects will 
shake the vial to disperse the curcumin powder and then use a third of the 
volume (15 mLs) three times a day.  Subjects will be provided a plastic dosing 
cup to help measure out 15 mLs. Subjects will store the curcumin suspended in 
water at room temperature until it is used up.  Subjects will obtain a second one 
week supply of study mouth rinse, prior to preparation of day 7 (+/- 1 day) dosing 
in order to ensure no break in treatment.  
 
 
5.5 Study Drug (Curcumin) Dose 
 
The recommended oral dose of curcumin is 1-3 gram/day for healthy adults. 
Previous studies in adults with gastrointestinal disorders ranged from 72 mg/day 
to 2 g/day and the dose duration lasted from 1 to 6 months (IND Table 2). The 
dosing regimen for topical use of curcumin in a recent study in adolescents and 
young adults with oral mucositis[14] was 165 mg twice per day for 2 weeks (330 
mg/day).  
 
To determine MTD in this study, the first dose level will be the dose used in the 
aforementioned study[14], multiplied by 3 (adult dose is 3 times the pediatric 
dose), which is 1 gram/day. The subsequent dose levels will be 3 grams/day, 6 
grams/day and 9 grams/day. The duration of patient exposure to the drug will be 
3 times a day for 30 seconds of topical exposure each time before swallowing, 
for 14 days.  
 
5.6 Determination of MTD 
 
The MTD will be determined as follows: If a DLT occurs in any one of the 3 
patients at a specific dose level, an additional 3 patients must be treated at that 
dose level to achieve statistical validity of the MTD. If 2 of the 6 patients (17%) at 
a dose level develop a DLT, the previous dose level will be used as the MTD. If 
no DLT is observed, then the MTD will be the highest dose. To ensure safety of 
subjects at each dose level, all assessments will be completed at Visit 5 for 
subjects at a dose level before another subject is given study drug at the 


Page 13 of 23 
 
subsequent dose level. 
6.  Expected Adverse Events 
 
Toxicities will be graded by health care providers using the Common 
Terminology Criteria for Adverse Events (CTCAE) Version 4.0 weekly after 
initiation of study mouth rinse until mucositis is resolved (Grade 0) (see Provider 
Assessment in calendar, section 5.2). Toxicities will be assessed by subject self-
evaluation during study mouth rinse administration between clinic visits (see 
Subject Assessment in calendar, section 5.2).  
 
Very few studies have reported any severe or serious side effects from curcumin 
and most studies have involved oral administration of curcumin. No major toxicity 
has been found in studies where curcumin is used short-term. Increased 
bleeding may occur due to inhibition of platelet aggregation (very rare). Possible 
other side effects associated with curcumin include: vomiting, nausea, rash and 
GI distress. In a study of subjects with colon cancer, oral curcumin at doses 
ranging from 0.45 to 3.6 gram/day for 1 to 4 months was associated with nausea 
and diarrhea and caused an increase in serum alkaline phosphatase and lactate 
dehydrogenase[15]. In one study of patients with advanced pancreatic cancer, 5 
of the 17 patients receiving oral curcumin (8 gram/day) in combination with 
gemcitabine reported intractable abdominal pain after a few days to 2 weeks of 
curcumin intake[16]. In a recent study of topical curcumin for mucositis in 
juveniles and children[14], there were no oral adverse events documented and 
no systemic adverse events that possibly could be related to the use of the 
curcumin mouthwash. 
 
Patients will receive full supportive care as appropriate. The rationale for 
treatment, dosage and the date of treatment will be recorded in the medical 
record. 
 
6.1 Dose-limiting Toxicity 
 
DLT resulting from any treatment component of the study will be defined in the 
list below. There will be no dose reductions in response to DLT. 
• Any grade 2 or greater allergic response 
• Any grade 3 or greater toxicity 
 
6.2 Criteria for Subject Removal 
 
A subject will be removed from the study for the following reasons: 
• Dose limiting toxicity. 
• No improvement in mucositis after 14 days of taking the study mouth 
rinse.   
• Patient decision to withdraw consent or discontinue the study. 
• Deemed by the physician to be the best medical interest of the patient. 
• At the discretion of the investigator, patients who are non-compliant. 


Page 14 of 23 
 
 
6.3 Criteria for Study Discontinuation 
 
If 2 patients develop a DLT at dose 1, then the trial will be closed due to 
unacceptable toxicity.  If any patient has Grade V toxicity, then, the trial will be 
placed on immediate hold until the protocol investigators, the sponsor of the IND, 
the IRB and the FDA have been notified and a determination has been made as 
to the re-opening of this trial. 
 
If < 5 of the first 10 subjects in the curcumin arm of the second part of the study 
have Grade 0 mucositis (CTAE version 4.0 and WHO Oral Toxicity Scale) at Visit 
4, then the study will be discontinued due to lack of activity. 
 
6.4 Criteria for Dose Reduction 
 
Subjects taking the curcumin-containing mouth rinse that experience intolerable 
or prolonged (>14 days) grade 2 toxicity will receive the next lowest dose from 
the dose escalation part of the study. 
 
6.5 Serious Adverse Events (SAEs)  
 
SAEs are defined as: 
• Death 
• Life-threatening events 
• Inpatient hospitalization 
• Persistent or significant disability/incapacity 
• Congenital anomaly or birth defects 
SAEs will be reported as described in the Regulatory/Reporting Requirements 
section. 
 
7.  Benefits 
Turmeric has been reported to be a potent anti-inflammatory and antioxidant 
which may be of value in treating oral mucositis. In Ayurvedic (traditional Indian) 
medicine, curcumin has been used for centuries as a tonic for gastrointestinal 
complaints. It has also been used topically in various skin diseases. Thus its 
safety profile in human is well documented. The antioxidant activity of turmeric 
can act as free radical scavengers as well as inhibitors of leukotrienes and 
prostaglandin synthesis. The anti-inflammatory activity has been claimed to be 
comparable to NSAIDs (such as indomethacin), producing significant 
improvement in clinical trials involving individuals with other disease such as 
rheumatoid arthritis. Thus our patients who suffer from cancer-treatment 
associate oral mucositis may benefit from curcumin as the above indicated 
positive effects of curcumin. Our study may offer important data for using 
curcumin as a new treatment for cancer patients who develop cancer treatment 
induced mucositis.   
8.  Sample Size  


Page 15 of 23 
 
This study will involve 12 subjects in the first part, plus an additional 3 subjects if 
a dose-limiting toxicity occurs (see section 2). This sample size is similar to other 
phase I dose escalation studies and will result in a determination of maximum-
tolerated dose. The first objective for the second part (n=46) is to determine 
whether curcumin decreases an objective measurement of oral mucositis. 
Mucositis assessment will be conducted by the provider using the WHO scale 
and CTCAE scale. The scales are continuous between 0 and 4. Analysis of 
variance will be used to compare the two groups of subjects (standard mouth 
rinse versus study mouth rinse) separately for each time period (baseline and 
each week after study mouth rinse initiation). In a one-way ANOVA study, 
sample sizes of 23, and 23 are obtained from the 2 groups whose means are to 
be compared. The total sample of 46 subjects achieves 91% power to detect 
differences among the means versus the alternative of equal means using an F 
test with a 0.05 significance level. The size of the variation in the means is 
represented by their standard deviation which is 0.50. The common standard 
deviation within a group is assumed to be 1.00. 
 
9.  Measurement of Effect  
Differences between the two mouth rinse groups will be studied with the chi-
square test for categoric factors and the analysis of variance F-test for 
continuous variables with a 0.05 significance level. 
 
9.1 Determination of objective measurement of oral mucositis 
 
The objective measurements of oral mucositis will be obtained by a health 
provider’s assessment of mucositis. Providers will be uninvolved, trained 
oncology clinic staff (not affiliated with the study) to reduce bias. Providers will 
use the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 
and World Health Organization’s (WHO’s) Oral Toxicity Scale (OTS). They will be 
instructed to circle where on the scale they would assess the subject’s mucositis 
level. A baseline evaluation will occur prior to study mouth rinse administration, 
and then each week after study mouth rinse initiation. The Health Care Provider 
Assessment Tool is attached as Appendix B. 
 
9.2 Determination of subjective measurement of oral mucositis 
 
The subjective measurement of oral mucositis will be obtained through patient 
self-assessment of mucositis using the Common Terminology Criteria for 
Adverse Events (CTCAE) Version 4.0 pain scales in person at visit 1 and  
between each site visit. Subjects will be instructed to say where on the scale they 
would assess their mucositis level and providers will complete the form. The 
Subject Self-Assessment Tool is attached as Appendix C.  
 
9.3 Determination of pain associated with oral mucositis 
 
This subjective measurement will be obtained through patient self-assessment of 
pain scales in person at the baseline visit and independently between each site 
visit. Subjects will be instructed to say where on the scale they would assess 
their pain level and providers will complete the form. The Subject Self-
Assessment Tool is attached as Appendix C. 


Page 16 of 23 
 
 
9.4 Determination of the duration of mucositis  
 
The healing time will be calculated using the health provider’s assessment of 
mucositis (CTCAE and WHO scales) by determining the number of days 
between study mouth rinse initiation and the day on which grade 0 is achieved. 
 
9.5 Determination of toxicity profile  
 
Toxicities will be graded by health care providers using the Common 
Terminology Criteria for Adverse Events (CTCAE) Version 4.0. A baseline 
evaluation will occur prior to study mouth rinse administration, and then weekly 
during study mouth rinse administration. Data will be recorded and entered into a 
database. 
 
9.6 Criteria to be Evaluable for Efficacy and Safety 
 
A subject is evaluable for efficacy (reduction in mucositis) if at least 70% of the 
study mouth rinse doses were taken as documented on the daily log (Appendix 
A). Differences between groups in terms of response rate will be evaluated by 
ANOVA (section 8).  
 
A subject is evaluable for safety (toxicity) if a minimum of one dose of the study 
mouth rinse was taken.  
 
10.  Correlative Studies (Laboratory Studies) 
 
10.1 Sample collection 
 
• Serum: A sample (6 ml) of peripheral blood will be obtained by venipuncture 
into a non-anti-coagulated tube at each visit during administration of study 
mouth rinse. The sample will be kept at room temperature for 1 h and then 
centrifuged at 300 g for 10 minutes at 4°C, and the serum fraction will be 
divided into four aliquots that will be stored at -70°C until processed.  
• Saliva: A sample (2 ml) of non-stimulated saliva will be collected into a sterile 
tube at each visit during administration of study mouth rinse and then taken 
into the laboratory on ice. The sample will be centrifuged at 300 g for 15 
minutes at 4°C. The supernatant will be divided into 2 aliquots that will be 
stored at -70°C until processed. 
 
10.2 Evaluation of Proinflammatory Cytokines 
 
NF-κB is among the most important and thoroughly studied transcription factors 
with regard to the development of mucositis. It is an important regulator of 
proinflammatory cytokines, such as TNF-α, IL-1β, and IL-6. These proteins are 
effective mediators of injury, and the increase in the levels in tissue and 
peripheral blood correlates well with non-haematological toxicities induced by 
chemotherapy[17]. Levels of proinflammatory cytokines such as TNF-α, IL-1β, 
and IL-6 will be evaluated in serum and/or saliva samples using a Becton 


Page 17 of 23 
 
Dickinson Cytometric Bead Array (CBA) flow cytometric assay. This testing is 
required for participation in the study. 
 
10.3 Future Research and Sample Disposition 
 
Serum and saliva samples will be stored at -70°C in the Immunology Research 
Laboratory on the Aurora St. Luke’s Medical Center campus. Samples will be 
coded. All patient identifiers will be removed. A key for the code will be stored in 
the office of the study staff. Only study staff will have access to the code. 
Samples that are left-over after the proinflammatory cytokine analysis will be 
stored at -70°C for future research on chemotherapy-induced mucositis. Subjects 
will be asked to complete a separate consent form for this future research. 
Samples will be stored until they are used up. If other researchers use the 
samples on an IRB-approved study, they will not be given any information that 
will link subject identifiers to the sample. If subjects do not consent to this future 
research, their leftover samples will be discarded following institutional 
procedures. 
 
11.  Data Collection  
 
Data collected will include: patient demographic data, cancer treatment 
information (chemotherapy regimen, date started chemo), the name of the 
referring oncologist, dental work within the past six months and/or pre-existing 
mouth issues,  medications within 30 days of screening, grade of oral mucositis 
prior to study and during the whole course of the study, pain scale, duration of 
mucositis, duration of neutropenia, the need and length of hospitalization, use 
and dosage of pain medicine, need for total potential nutrition, blood culture 
positive infection, other mucositis related complications and cytokine levels in 
blood and saliva.  
 
If data from this study is published or otherwise shared with outside institutions, 
all identifying information will be removed and the data will be coded. The local 
study staff will have access to the code. There will be no differences in data 
collection between the different sites at Aurora Health Care that may eventually 
participate in this study. 
 
12.  Monitoring Plan 
 
Careful evaluation to ascertain the toxicity and efficacy of topical curcumin on 
mucositis will be performed by the Principal Investigator and the research team. 
For all patients, the Principal Investigator will review all serious adverse events 
and will monitor the data and toxicities to identify trends weekly during the study.  
The Principal Investigator will be responsible for revising the protocol as needed 
to maintain safety.  The IRB will review submitted adverse events to also 
evaluate trends and will require a follow up plan from the Principal Investigator 
whenever a trend is identified.  Independent quality, compliance and safety 
monitoring of the study will occur at least once each year that the study is 
enrolling subjects and may include a review of protocol compliance, informed 


Page 18 of 23 
 
consent documentation, data collection accuracy, adverse event reporting, 
patient safety and outcomes analysis.  
 
13.  Reporting Requirements 
 
• Subject data accrued on this study will be reported in accordance with 
21CFR 312.32. 
• This study will utilize the CTCAE Version 4.0 for Adverse Event (AE) 
Reporting. The CTCAE v4.0 can be downloaded from the CTEP home 
page (http://ctep.info.nih.gov).  
• The Principal Investigator will notify the IRB, and the FDA and other 
regulatory agencies of all serious adverse events as required by law or 
regulation.  
• Reporting requirements to the Aurora IRB is described in IRB SOP 
RR:403 Ongoing Oversight of Approved Research and Reporting of 
Problems/Events. 
• Reporting requirements to the FDA is described in the “Guidance for 
Industry and Investigators Safety Reporting Requirements for INDs 
and BA/BE Studies” December 2012: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryI
nformation/Guidances/UCM227351.pdf. 
• All participating investigators will be notified of IND Safety Reports by 
email. 
 
13.1 Reporting Requirements for SAEs  (21 CFR Part 312) 
 
NOTE: Investigators MUST immediately report to the Principal Investigator ANY 
Serious Adverse Events, whether or not they are considered related to the 
investigational agent(s)/intervention (21 CFR 312.64). 
 
An adverse event is considered SERIOUS if it results in ANY of the following 
outcomes: 
• Death 
• A life-threatening adverse event 
• An adverse event that results in inpatient hospitalization or prolongation of 
existing hospitalization for > 24 hours 
• A persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions 
• Congenital anomaly/birth defect. 
• Important Medical Events (IME) that may not result in death, be life-
threatening, or require hospitalization may be considered serious when, 
based upon 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 (FDA, 21 CFR 312.32; ICH E2A and ICH 
E6). 
 
The reporting timeframes for SAE are listed in the table below. 
 


Page 19 of 23 
 
Hospitalization 
Grade 1 
Grade 2 
Grade 3 
Grade 4 and 
5 
Resulting in 
Hospitalization 
> 24 hours 
10 Calendar Days* 
24 Hour;  5 
Calendar 
Days** 
Resulting in  
Hospitalization 
< 24 hours 
Not Required 
10 Calendar 
Days 
SAE reporting timelines are defined as: 
* “10 Calendar Days” – A complete SAE report on the SAE must be submitted 
within 10 calendar days of learning of the AE.  
** “24 Hour; 5 Calendar Days” – The AE must initially be reported within 24 hours 
of learning of the AE, followed by a complete SAE report within 5 calendar days 
of the initial 24 hour report. 
 
14.  Regulatory Requirements 
 
14.1 Informed Consent 
 
Before a subject’s participation in the clinical study, the investigator is 
responsible for obtaining written informed consent from the subject or legally 
acceptable representative after adequate explanation of the aims, methods, 
anticipated benefits, and potential hazards of the study and before any protocol-
specific screening procedures or any investigational products are administered. A 
legally acceptable representative is an individual or other body authorized under 
applicable law to consent, on behalf of a prospective subject, to the subject’s 
participation in the clinical study. 
 
The investigator is also responsible for asking the subject if the subject agrees to 
have their primary care physician informed of the subject’s participation in the 
clinical study. If the subject agrees to such notification, the investigator shall 
inform the subject’s primary care physician of the subject’s participation in the 
clinical study.  
 
The acquisition of informed consent and the subject’s agreement or refusal of 
his/her notification of the primary care physician will be documented in the 
subject’s medical records, and the informed consent form will be signed and 
personally dated by the subject or a legally acceptable representative and by the 
person who conducted the informed consent discussion. The original signed 
informed consent form will be retained in accordance with institutional policy, and 
a copy of the signed consent form will be provided to the subject or legally 
acceptable representative. 
 


Page 20 of 23 
 
If a potential subject is illiterate or visually impaired and does not have a legally 
acceptable representative, the investigator will provide an impartial witness to 
read the informed consent form to the subject and must allow for questions. 
Thereafter, both the subject and the witness will sign the informed consent form 
to attest that informed consent was freely given and understood. 
 
14.2 Institutional Review Board 
 
A copy of the protocol, proposed informed consent form, other written subject 
information, and any proposed advertising material will be submitted to the IRB 
for written approval.  
 
The investigator will submit and, where necessary, obtain approval from the IRB 
for all subsequent protocol amendments and changes to the informed consent 
document. The investigator will notify the IRB of deviations from the protocol or 
serious adverse events occurring at the site and other adverse event reports in 
accordance with IRB SOP RR:403 Ongoing Oversight of Approved Research 
and Reporting of Problems/Events. 
 
The investigator is responsible for obtaining annual IRB approval/renewal 
throughout the duration of the study.  
 
14.3 Subject Confidentiality 
 
The investigator will ensure that the subject’s confidentiality is maintained: 
• On case report forms and other documents that are submitted, 
subjects will be identified by a subject identification number only. 
• On Serious Adverse Event forms submitted, subjects will be identified 
by their initials and a subject identification number only. 
• Documents that are not for submission (eg, signed informed consent 
forms) will be kept in strict confidence by the investigator. 
 
In compliance with Federal regulations/ICH GCP Guidelines, it is required that 
the investigator and institution permit authorized representatives of the company, 
of the regulatory agency(s), and the IRB direct access to review the subject’s 
original medical records for verification of study-related procedures and data. 
Direct access includes examining, analyzing, verifying, and reproducing any 
records and reports that are important to the evaluation of the study. The 
investigator is obligated to inform and obtain the consent of the subject to permit 
named representatives to have access to her study-related records, including 
personal information, without violating the confidentiality of the subject. 


Page 21 of 23 
 
 
 
15.  Experience of the Investigators 
 
Principal Investigator: (Biosketch is attached as Appendix D):  
Dhimant Patel MD 
Aurora BayCare Medical Center 
2845 Greenbrier Rd. 
Green Bay, WI 54311 
 
Sub-Investigators:  
Nancy Davis, MD 
Umang Gautam, MD 
Ubaid Nawaz, MD 
Jessica Lawton, PharmD, BCOP 
Aurora BayCare Medical Center 
2845 Greenbrier Rd. 
Green Bay, WI 54311 
 
Nina Garlie, PhD 
John Richards, PhD 
Aurora St. Luke’s Medical Center 
2900 West Oklahoma Avenue 
Milwaukee, WI 53213 
 
Research Facility: 
  Aurora BayCare Medical Center 
  2845 Greenbrier Rd. 
  Green Bay, WI 54311 
 
Institutional Review Board: 
  Aurora IRB 
  945 North 12th Street 
  P.O. Box 342 W310 
  Milwaukee, WI 53201-0342 


Page 22 of 23 
 
16.  References 
1. 
Elting LS, C.C., Chambers M, Cantor SB, Manzullo E, Rubenstein EB, 
The burdens of cancer therapy. Clinical and economic outcomes of 
chemotherapy-induced mucositis. . Cancer Oct 2003. 98(7): p. 1531-39. 
2. 
Vera-Llonch M, O.G., Ford CM, Lu J, Sonis S. , Oral mucositis and 
outcomes of allogeneic hematopoietic stem-cell transplantation in patients 
with hematologic malignancies. Support Care Cancer, 2007. 15(5): p. 491-
496. 
3. 
RS, N., B. JFB, and T. JA., Oral toxicity associated with chemotherapy. Up 
To Date, 2012. 
4. 
R. M. Logan, R.J.G., J. M. Bowen, A. M. Stringer, S. T. Sonis, and D. M. 
K. Keefe, “Characterisation of mucosal changes in the alimentary tract 
following administration of irinotecan: implications for the pathobiology of 
mucositis,” Cancer Chemotherapy and Pharmacology, 2008. 62(1): p. 33-
41. 
5. 
Firestein, P.P.T.a.G.S., “NF-κB: a key role in inflammatory diseases,” 
Journal of Clinical Investigation, 2001. 107(1): p. 7-11. 
6. 
Worthington, H.V., et al., Interventions for preventing oral mucositis for 
patients with cancer receiving treatment. . Cochrane Database Syst Rev, 
2011. 4: p. CD000978. 
7. 
Sharma, A., et al., Lactobacillus brevis CD2 lozenges reduce radiation- 
and chemotherapy-induced mucositis in patients with head and neck 
cancer: a randomized double-blind placebo-controlled study. Eur J 
Cancer, 2012. 48(6): p. 875-81. 
8. 
Wan-Chih, T., Magic Mouthwash. Pharmacist's Letter, 2009. 25. 
9. 
Chan, A.a.R.J.I., Survey of topical oral solutions for the treatment of 
chemo-induced oral mucositis. . J Oncol Pharm Pract, 2005. 11(4): p. 139-
43. 
10. 
Dodd, M.J., et al., Randomized clinical trial of the effectiveness of 3 
commonly used mouthwashes to treat chemotherapy-induced mucositis. 
Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology, 2000. 
90(1): p. 39-47. 
11. 
Hsu, C.H.a.A.L.C., Clinical studies with curcumin. Advances in 
Experimental Medicine and Biology, 2007. 595: p. 471-80. 
12. 
Rezvani, M.a.G.A.R., Modification of radiation-induced acute oral 
mucositis in the rat. Int J Radiat Biol, 2004. 80(2): p. 177-82. 


Page 23 of 23 
 
13. 
Luer, S., et al, Topical curcumin can inhibit deleterious effects of upper 
respiratory tract bacteria on human oropharyngeal cells in vitro: potential 
role for patients with cancer therapy induced mucositis. Support Care 
Cancer, 2011. 19(6): p. 799-806. 
14. 
Elad, S., et al., Topical Curcumin for the Prevention of Oral Mucositis in 
Pediatric Patients: Case Series. Alternative Therapies, 2013. 19(3): p. 21-
24. 
15. 
Sharma R, E.S., Platton S, et al., Phase I Clinical Trial of Oral Curcumin : 
Biomarkers of Systemic Activity and Compliance Clin Cancer Res 2004. 
10: p. 6847-54. 
16. 
Epelbaum R, S.M., Vizel B, Badmaev V, Bar-Sela G., Curcumin and 
gemcitabine in patients with advanced pancreatic cancer. Nutr Cancer, 
2010. 62(8): p. 1137-41. 
17. 
Morales-Rojas, T.e.a., Proinflammatory cytokines during the initial phase 
of oral mucositis in patients with acute lymphoblastic leukaemia. 
International Journal of Paediatric Dentistry 2012. 22: p. 191-196.