Inositol in Preventing Colorectal Cancer in Patients With Colitis-Associated Dysplasia

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Terminated
• CT.gov ID: NCT01111292
• Collaborator: (none)
• Enrollment: 5
• Locations: 3
• Arms: 2
• Duration (Months): 47
• Patients Per Site: 1.7
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This pilot, randomized phase I/II trial studies how well inositol works in preventing colorectal cancer in patients with abnormal cells (dysplasia) associated with inflammation of the colon (colitis). Patients with colitis-associated dysplasia may have an increased risk of developing colorectal cancer. Inositol is a vitamin-like substance that may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Condition or Disease	Intervention/Treatment	Phase
Colon Carcinoma; Dysplasia in Crohn Disease; Low Grade Dysplasia in Ulcerative Colitis; Rectal Carcinoma	Drug: Inositol; Other: Placebo	Phase 1/Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To evaluate the effect of myo-inositol (inositol), administered for 3 months, on phospho (P)-beta (B)-catenin staining in areas of low-grade dysplasia or in areas of prior low grade dysplasia in subjects with known colitis-induced low grade dysplasia at baseline.

SECONDARY OBJECTIVES:

1. To examine the effect of myo-inositol on regression of dysplasia. II. To examine the effect of inositol on p53 and Ki67 staining within remaining dysplasia.

2. To examine the effect of inositol on epithelial apoptosis (cleaved caspase-3) within dysplasia.

3. To examine the effect of inositol on reductions in mucosal messenger ribonucleic acid (mRNA) levels of monocyte chemotactic protein 1 (MCP1), inducible nitric oxide synthase (iNOS), and cyclooxygenase (Cox)-2.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Beginning within 14 days after colonoscopy, patients receive inositol orally (PO) once daily (QD) on days 1-14 and twice daily (BID) on days 15-90.

ARM II: Beginning within 14 days after colonoscopy, patients receive placebo PO QD on days 1-14 and BID on days 15-90.

After completion of treatment, patients undergo biopsy and colonoscopy with or without mucosal resection.

After completion of study treatment, patients are followed up at 2 weeks.

Study Design

• Study Type: Interventional
• Actual Enrollment: 5 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Prevention
• Official Title: Myo-Inositol Chemoprevention in Colitis-Associated Dysplasia
• Study Start Date: Oct 1, 2010
• Actual Primary Completion Date: Sep 1, 2014
• Actual Study Completion Date: Sep 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I (inositol) Beginning within 14 days after colonoscopy, patients receive inositol PO QD on days 1-14 and BID on days 15-90.	Drug: Inositol; Given PO; Other Names: myo-Inositol
Placebo Comparator: Arm II (placebo) Beginning within 14 days after colonoscopy, patients receive placebo PO QD on days 1-14 and BID on days 15-90.	Other: Placebo; Given PO; Other Names: PLCB

Outcome Measures

Primary Outcome Measures

1. The Effect of Myo-inositol (Inositol) on P-β-catenin Staining in Areas of Low Grade Dysplasia in Subjects With Known Colitis-induced Low Grade Dysplasia. [Baseline to 90 days]

   The primary objective of this study will be to evaluate the effect of myo-inositol (inositol), administered for three months, on P-β-catenin staining in areas of low grade dysplasia or in areas of prior low grade dysplasia in subjects with known colitis-induced low grade dysplasia at baseline.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Participants must have ulcerative colitis or Crohn's disease with low grade dysplasia or polyploid dysplasia or have a history of dysplasia and increased positive beta-catenin levels confirmed by a consensus of the study pathologists (2 of 2, or 2 of 3)

• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

• Absolute neutrophil count (ANC) > 1,500/uL

• Platelets > 100,000/uL

• Total bilirubin within normal institutional limits

• Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT]/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT] =< 1.5 times upper limit of normal

• Creatinine within normal institutional limits

• International normalized ratio (INR) < 1.5

• Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) from the time of baseline pregnancy test, throughout the duration of the study, and for 1 month following cessation of study drug; females must begin adequate contraception immediately following screening pregnancy test; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately; if she is pregnant, she will be immediately withdrawn from the study and followed until the birth of the child

• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

• Subjects with life-threatening medical conditions that would preclude study treatment intervention and colonoscopy

• Participants may not be receiving any other investigational agents

• History of allergic reactions to rice or compounds of similar chemical or biologic composition to myo-inositol (i.e., urticaria, dermatologic reaction)

• Use of medications known to elevate serum blood glucose; participants on steroids are still eligible, as they will be monitored weekly for fasting blood glucose

• Participants with dysplasia-associated lesion or mass (DALM), high-grade dysplasia or invasive colonic carcinoma are excluded

• Uncontrolled intercurrent illness including, but not limited to

• Ongoing or active infection

• Symptomatic congestive heart failure

• Unstable angina pectoris

• Cardiac arrhythmia

• Chronic renal failure

• Chronic renal insufficiency

• Psychiatric illness or social situations that would limit compliance with study requirements

• Prior treatment with myo-inositol

• History of systemic chemotherapy within 18 months of screening

• Subjects taking valproic acid and/or lithium

• Diabetes mellitus

• History of total proctocolectomy

• Concomitant primary sclerosing cholangitis (PSC)

• Pregnant or lactating subjects are excluded

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Northwestern University	Chicago	Illinois	United States	60611
2	University of Chicago Comprehensive Cancer Center	Chicago	Illinois	United States	60637
3	Mount Sinai Medical Center	New York	New York	United States	10029

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Seema Khan, Northwestern University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT01111292
• Other Study ID Numbers: NCI-2011-01434; NCI-2011-01434; CDR0000671302; NCI09-13-02; NWU09-13-02; P30CA060553; N01CN35157
• First Posted: Apr 27, 2010
• Last Update Posted: Jul 12, 2016
• Last Verified: Jun 1, 2016

• Additional relevant MeSH terms: Carcinoma; Crohn Disease; Colitis; Hyperplasia; Inositol

Study Results

Participant Flow

Recruitment Details	A total of 73 patients were screened for study eligibility. Of those, 68 patients were ineligible (no biopsies were taken from 5 patients and 63 did not have a diagnosis of dysplasia at the initial visit).
Pre-assignment Detail	Serum myo-inositol levels were measured from 13 patients who were screened for study eligibility, and those levels (23.28+/-6.46 μM) were consistent with previously published data (Chiu et al, Dolhofer et al, Lewin et al).

Arm/Group Title	Arm I (Inositol)	Arm II (Placebo)
Arm/Group Description	Beginning within 14 days after colonoscopy, patients receive inositol PO QD on days 1-14 and BID on days 15-90. Inositol: Given PO Laboratory Biomarker Analysis: Correlative studies	Beginning within 14 days after colonoscopy, patients receive placebo PO QD on days 1-14 and BID on days 15-90. Placebo: Given PO Laboratory Biomarker Analysis: Correlative studies
Period Title: Randomization
STARTED	3	2
COMPLETED	3	2
NOT COMPLETED	0	0
Period Title: Randomization
STARTED	3	2
COMPLETED	2	1
NOT COMPLETED	1	1
Period Title: Randomization
STARTED	2	1
COMPLETED	2	1
NOT COMPLETED	0	0
Period Title: Randomization
STARTED	2	1
COMPLETED	2	1
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Arm I (Inositol)	Arm II (Placebo)	Total
Arm/Group Description	Beginning within 14 days after colonoscopy, patients receive inositol PO QD on days 1-14 and BID on days 15-90. Inositol: Given PO Laboratory Biomarker Analysis: Correlative studies	Beginning within 14 days after colonoscopy, patients receive placebo PO QD on days 1-14 and BID on days 15-90. Placebo: Given PO Laboratory Biomarker Analysis: Correlative studies	Total of all reporting groups
Overall Participants	3	2	5
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	0 0%	2 100%	2 40%
>=65 years	3 100%	0 0%	3 60%
Sex: Female, Male (Count of Participants)
Female	1 33.3%	0 0%	1 20%
Male	2 66.7%	2 100%	4 80%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	3 100%	2 100%	5 100%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	3 100%	2 100%	5 100%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	3 100%	2 100%	5 100%

Outcome Measures

1. Primary Outcome

Title	The Effect of Myo-inositol (Inositol) on P-β-catenin Staining in Areas of Low Grade Dysplasia in Subjects With Known Colitis-induced Low Grade Dysplasia.
Description	The primary objective of this study will be to evaluate the effect of myo-inositol (inositol), administered for three months, on P-β-catenin staining in areas of low grade dysplasia or in areas of prior low grade dysplasia in subjects with known colitis-induced low grade dysplasia at baseline.
Time Frame	Baseline to 90 days

Outcome Measure Data

Analysis Population Description

pβ-cat-positive cell counts in pre- and post-study biopsies with dysplasia or adenoma. Counts are broken down as the number of crypts with 3, 4, or 5 pβ-cat positive cells. High frequency (HF) fields of view are those containing at least 2 crypts with three or more pβ-cat positive cells per crypt (at 20X). I

Arm/Group Title	Arm I (Inositol)	Arm II (Placebo)
Arm/Group Description	Beginning within 14 days after colonoscopy, patients receive inositol PO QD on days 1-14 and BID on days 15-90. Inositol: Given PO Laboratory Biomarker Analysis: Correlative studies	Beginning within 14 days after colonoscopy, patients receive placebo PO QD on days 1-14 and BID on days 15-90. Placebo: Given PO Laboratory Biomarker Analysis: Correlative studies
Measure Participants	2	1
Baseline Cells/100 IEC	2.5 (2.5)	0 (0)
Post Intervention Cells/100 IEC	3.67 (.94)	0
Baseline Crypts w/2 cells	7.75 (7.85)	2.5 (5)
Post Intervention Crypts w/ 2 cells	8.67 (2.49)	0 (0)
Baseline Crypts w/3 cells	2 (1.58)	.5 (.5)
Post Intervention Crypts w/ 3 Cells	2.67 (1.25)	0 (0)
Baseline Crypts w/4 cells	2 (1.58)	0 (0)
Post Intervention Crypts w/4 cells	1.67 (1.7)	0 (0)
Baseline Crypts w/>5 cells	2.25 (2.28)	0 (0)
Post Intervention Crypts w/>5 cells	0 (0)	0 (0)
Baseline # HF Fields of View	2.5 (2.3)	0 (0)
Post Intervention # HF Fields	2 (.82)	0 (0)

Adverse Events

Arm/Group Title	Arm I (Inositol)		Arm II (Placebo)
Arm/Group Description	Beginning within 14 days after colonoscopy, patients receive inositol PO QD on days 1-14 and BID on days 15-90. Inositol: Given PO Laboratory Biomarker Analysis: Correlative studies		Beginning within 14 days after colonoscopy, patients receive placebo PO QD on days 1-14 and BID on days 15-90. Placebo: Given PO Laboratory Biomarker Analysis: Correlative studies
All Cause Mortality
	Arm I (Inositol)		Arm II (Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Arm I (Inositol)		Arm II (Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		0/2 (0%)
Other (Not Including Serious) Adverse Events
	Arm I (Inositol)		Arm II (Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100%)		1/2 (50%)
Gastrointestinal disorders
Gastrointestinal disorder: Stomach Pain	1/3 (33.3%)	2	0/2 (0%)	0
Gastrointestinal Disorder: Diarrhea	1/3 (33.3%)	20	1/2 (50%)	3
Gastrointestinal disorder: Amal Henorrhage: Blood in sttol	0/3 (0%)	0	1/2 (50%)	3
Gastrointestinal disorders - other	0/3 (0%)	0	1/2 (50%)	1
Gastrointestinal disorder: Abdominal pain	1/3 (33.3%)	1	0/2 (0%)	0
Gastrointestinal disorder: Flatulence	1/3 (33.3%)	1	0/2 (0%)	0
Gastrointestinal disprder: Hemorroids	1/3 (33.3%)	1	0/2 (0%)	0
Investigations
Gastrointestinal Disorder: High Bilirubin	1/3 (33.3%)	1	0/2 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.