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S0820
A double blind placebo-controlled trial
of Eflornithine and Sulindac to prevent
recurrence of high risk adenomas and
second primary colorectal cancers in
patients with Stage 0-III Colon Cancer,
Phase III.
Study Coordinators
Jason A. Zell, D.O., M.P.H. (Medical Oncology)
UC Irvine Medical Center
Powel H. Brown, M.D., Ph.D. (Medical Oncology)
M.D. Anderson Cancer Center
Primary Objective
Assess whether eflornithine (+/- sulindac),
sulindac (+/- eflornithine) or the
combination are effective in reducing the
three-year event rate (high-risk adenomas
and second primary colorectal cancers) in
patients with previously treated Stage 0-III
colon cancer.
U.S. Cancer statistics, 2013
CA: A Cancer Journal for Clinicians
Volume 63, Issue 1, pages 11-30, 17 JAN 2013 DOI: 10.3322/caac.21166
http://onlinelibrary.wiley.com/doi/10.3322/caac.21166/full#fig1
Colorectal Cancer
• Primary Prevention: Screening
and early detection result in 5year survival rates of 90%
(colon) and 80% (rectum) for
localized disease
• Result: overall survival is 64%*
5-year Survival (%)
• The problem: 50-60% receive
proper screening, and 60%
present with advanced stage
disease
Survival
Estimates
Siegal, R, Ca-A Cancer Journal for
Clinicians 2013; 63 (1):11-30.
Second Primary Colorectal Cancers
among Stage I-III CRC cases
• Occur in ~1-4% of treated
CRC patients
• Among 69,809 colon
cancer cases in California
1990-2005, 40% increased
risk of 2nd primary CRC
among CRC cases
compared to the underlying
population at risk*
• Standardized Incidence Ratio
= 1.4 (95% CI 1.3-1.5)
* Raj, KP, et al. Risk of second primary colorectal cancer among colorectal cancer
cases: A population-based analysis. J Carcinogenesis 2011;10:6
Accrual Targets
Sex/Gender
Ethnic Category
Females
Males
Total
Hispanic or Latino
32
+
44
76
Not Hispanic or Latino
608
+
804
1,412
Ethnic Category: Total of all subjects
640
+
848
=
1,488
American Indian or Alaskan Native
9
+
13
=
22
Asian
19
+
26
=
45
Black or African American
51
+
68
=
119
Native Hawaiian or other Pacific Islander
9
+
13
=
22
White
552
+
728
=
1,280
Racial Category: Total of all subjects
640
+
848
=
1,488
Racial Category
S0820 Study Design:
(n=1340)
R
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S
T
E
R
S
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R
A
T
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F
Y*
R
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D
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Baseline data *Stratification
collection,
by stage
audiogram,
blood, CTscans, &
colonoscopy at
Year-1 post
resection
5-year
follow
-up
3-year study
intervention
eflornithine +
sulindac placebo
(n=335)
eflornithine placebo +
sulindac
(n=335)
eflornithine +
sulindac
(n=335)
eflornithine placebo +
sulindac placebo
(n=335)
Colonoscopy
Primary
endpoint =
3-year rate
of high risk
adenomas
or 2nd
primary
CRCs.
End-of-study
audiogram,
blood collection
Activated: March 1, 2013
F
O
L
L
O
W
U
P
Study Drug Information
 Eflornithine (DFMO) or Placebo, 250 mg,
2 tablets oral daily x 3 years
 Sulindac (NSAID) or Placebo, 150 mg,
1 tablet oral daily x 3 years
~1,488 volunteers assigned randomly to one of
four trial arms
take 2
take 1
Arm 1
placebo
placebo
Arm 2
eflornithine
placebo
Arm 3
placebo
sulindac
Arm 4
eflornithine
sulindac
Cardiovascular Risk
• Defined as a modified version of the criteria originally
proposed by Solomon et al
• Patients with baseline high cardiovascular risk scores are
not eligible for enrollment in S0820
• High cardiovascular risk = one of the following:
 diabetes mellitus
 prior history of cardiovascular disease
 or ≥ 2 of the risk factors used in isolation to define
moderate risk
• Patients may take daily aspirin for CV prophylaxis if ASA is
≤ 100 mg/day or ≤ two 325 mg tablets/week.
Eligibility
• Stage 0, I, II or III colon cancer treated per standard care with
resection alone or in combination with adjuvant
chemotherapy
• Adjuvant chemotherapy must have been completed at least
30 days prior to registration.
• Patients with rectosigmoid cancers are eligible only if their
treatment did NOT involve radiation therapy (i.e. neo-adjuvant
or adjuvant radiation) (mid-low rectal cancers are not eligible)
• Had a primary resection one year previously and had a oneyear post-op colonoscopy and CT scans of chest, abdomen and
pelvis showing no evidence of disease.
Eligibility (continued)
• Must be at least 18 years of age
• No history of familial adenomatous polyposis, hereditary
nonpolyposis colorectal cancer, or inflammatory bowel
disease
• Must have a pure tone audiometry evaluation to document
air conduction
• Not be expecting to receive radiation or additional
chemotherapy
• Not be receiving or plan to receive concomitant
corticosteroids NSAIDs, nor anticoagulants on a regular or
predictable intermittent basis
• Patients must have adequate blood counts
Patients will be randomized using a 2x2 factorial design
Follow-up
•
•
•
•
Year 1: H & P, CBC & chemistries every 3 months
Year 2 & 3: H & P, CBC & chemistries every 6 months
Colonoscopy & audiogram 3 years after randomization
Patients followed annually for 5 years (after completion of 3
years of intervention):
• H&P
• Weight and Performance Status
• Follow-up colonoscopy at 8 years post-registration per NCCN
guidelines
Adherence
•
•
•
•
Study drug adherence measured by returned tablet count
Unused medication returned to the clinic at each visit
Patients document study drug intake on an Intake Calendar
Individualized adherence strategies used if adherence
is ↓75%:
•
•
•
•
Communicate with patient to define barriers
Review patient’s routine for taking study drugs
Seek family assistance
Consider more frequent contact with patient using phone check-in
Primary Endpoint
• 3-year event rate after registration among Stage
0-III colon cancer patients
• Event = high risk adenoma or 2nd primary colorectal
cancer
• High risk adenoma = either advanced adenoma
(villous or tubulovillous histology, size ≥ 1 cm, or high
grade dysplasia) or multiple adenomas (3 or more each
> 0.3 cm)
Secondary Endpoints
•
•
•
•
•
•
•
•
•
Total advanced colorectal event rate
Recurrence
High-grade dysplasia
Adenomas with villous features
Adenomas ≥ 1 cm
Multiple adenomas
Adenoma
Total colorectal event rate
Time to first clinically apparent high-risk adenoma or 2nd
primary colorectal cancer
Optional for patients…….
• Submission of blood specimen for nutritional assays and
banking:
• including genotyping and biochemical assays
• fasting whole blood sample required after registration and prior
to beginning treatment
• Diet and Lifestyle Substudy:
• completion of Diet & Lifestyle Questionnaires after registration
Please help identify potential patients
History of stage 0, I, II or III colon cancer
Treated with resection alone or in combination with adjuvant
chemotherapy
NED at one year post-operative assessment
Timing:
 Patients must be registered between 274 and 465 days (inclusive) of primary
resection
 Colonoscopy and CT scans of chest, abdomen and pelvis NED performed at least
274 days after resection date and prior to registration
 Polyps detected at colonoscopy must be completely removed
 Adjuvant chemo completed ≥ 30 days prior to registration
 CT Scan is for high risk patients per NCCN guidelines & at discretion of
treating physician
S0820 Web Page
Recruitment Materials available:
• Printable Brochure
• Professional Slide Set
• Promotional Flyers
• Promotional Letter to Physicians
• Strategies
• Study Logo and Printing Instructions
Materials for the Investigators and Staff include:
• Thank You letter to Referring Physicians
• Webinar
• Adherence Strategies
• FAQs
• Pocket Protocol
Materials for the patient include:
• Thank You Letter from the PI for Enrolling
• List of Resources
S0820
Thank You