Colon Carcinoma, Dysplasia in Crohn Disease, Low Grade Dysplasia in Ulcerative Colitis, Rectal Carcinoma
Conditions
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.
Detailed description
PRIMARY OBJECTIVES: I. 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: I. 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. III. To examine the effect of inositol on epithelial apoptosis (cleaved caspase-3) within dysplasia. IV. 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.
Interventions
DRUGInositol
Given PO
OTHERPlacebo
Given PO
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
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 details
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).
Participants by arm
| Arm | Count |
|---|---|
| Arm I (Inositol) 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 | 3 |
| Arm II (Placebo) 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 | 2 |
| Total | 5 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Treatment | Physician Decision | 1 | 1 |
Baseline characteristics
| Characteristic | Arm I (Inositol) | Arm II (Placebo) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 0 Participants | 3 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 2 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 2 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 2 Participants | 5 Participants |
| Region of Enrollment United States | 3 participants | 2 participants | 5 participants |
| Sex: Female, Male Female | 1 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Male | 2 Participants | 2 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 1 / 2 |
| serious Total, serious adverse events | 0 / 3 | 0 / 2 |
Outcome results
Primary
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.
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
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm I (Inositol) | 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 Cells/100 IEC | 2.5 Colonic Biopsies | Standard Deviation 2.5 |
| Arm I (Inositol) | 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. | Post Intervention Cells/100 IEC | 3.67 Colonic Biopsies | Standard Deviation 0.94 |
| Arm I (Inositol) | 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 Crypts w/2 cells | 7.75 Colonic Biopsies | Standard Deviation 7.85 |
| Arm I (Inositol) | 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. | Post Intervention Crypts w/ 2 cells | 8.67 Colonic Biopsies | Standard Deviation 2.49 |
| Arm I (Inositol) | 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 Crypts w/3 cells | 2 Colonic Biopsies | Standard Deviation 1.58 |
| Arm I (Inositol) | 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. | Post Intervention Crypts w/ 3 Cells | 2.67 Colonic Biopsies | Standard Deviation 1.25 |
| Arm I (Inositol) | 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 Crypts w/4 cells | 2 Colonic Biopsies | Standard Deviation 1.58 |
| Arm I (Inositol) | 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. | Post Intervention Crypts w/4 cells | 1.67 Colonic Biopsies | Standard Deviation 1.7 |
| Arm I (Inositol) | 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 Crypts w/>5 cells | 2.25 Colonic Biopsies | Standard Deviation 2.28 |
| Arm I (Inositol) | 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. | Post Intervention Crypts w/>5 cells | 0 Colonic Biopsies | Standard Deviation 0 |
| Arm I (Inositol) | 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 # HF Fields of View | 2.5 Colonic Biopsies | Standard Deviation 2.3 |
| Arm I (Inositol) | 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. | Post Intervention # HF Fields | 2 Colonic Biopsies | Standard Deviation 0.82 |
| Arm II (Placebo) | 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 # HF Fields of View | 0 Colonic Biopsies | Standard Deviation 0 |
| Arm II (Placebo) | 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 Cells/100 IEC | 0 Colonic Biopsies | Standard Deviation 0 |
| Arm II (Placebo) | 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 Crypts w/4 cells | 0 Colonic Biopsies | Standard Deviation 0 |
| Arm II (Placebo) | 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. | Post Intervention Cells/100 IEC | 0 Colonic Biopsies | — |
| Arm II (Placebo) | 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. | Post Intervention Crypts w/>5 cells | 0 Colonic Biopsies | Standard Deviation 0 |
| Arm II (Placebo) | 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 Crypts w/2 cells | 2.5 Colonic Biopsies | Standard Deviation 5 |
| Arm II (Placebo) | 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. | Post Intervention Crypts w/4 cells | 0 Colonic Biopsies | Standard Deviation 0 |
| Arm II (Placebo) | 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. | Post Intervention Crypts w/ 2 cells | 0 Colonic Biopsies | Standard Deviation 0 |
| Arm II (Placebo) | 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. | Post Intervention # HF Fields | 0 Colonic Biopsies | Standard Deviation 0 |
| Arm II (Placebo) | 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 Crypts w/3 cells | .5 Colonic Biopsies | Standard Deviation 0.5 |
| Arm II (Placebo) | 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 Crypts w/>5 cells | 0 Colonic Biopsies | Standard Deviation 0 |
| Arm II (Placebo) | 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. | Post Intervention Crypts w/ 3 Cells | 0 Colonic Biopsies | Standard Deviation 0 |