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 or Rectal Cancer, Phase III - Preventing Adenomas of the Colon with Eflornithine and Sulindac (PACES)
Elise D. Cook
The goal of this clinical research study is to learn if taking eflornithine and/or sulindac (possibly with a placebo) can help to prevent growths in the colon or rectum that may lead to colorectal cancer, as well as the growth of a new colorectal cancer, in patients who have already been treated for colon or rectal cancer (up to Stage III). Eflornithine blocks an enzyme in cells that is needed for cell growth and development. This may especially affect cells that grow and divide very quickly, like cancer cells. Sulindac is a type of drug called a non-steroidal anti-inflammatory drug (NSAID). Sulindac works by reducing the hormones that cause inflammation and pain in the body. A placebo is not a drug. It looks like the study 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.
Disease Group: Cancer Prevention,Colorectum
Treatment Agent: Eflornithine,Sulindac
Treatment Location: Both at MDACC & and Other Sites
Sponsor: Southwest Oncology Group
Primary Objective(s) To assess whether the combination of eflornithine and sulindac is 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 or rectal cancer. Secondary Objective(s) To assess whether the combination of eflornithine and sulindac (compared to corresponding placebos) has efficacy against colorectal lesions with respect to high-grade dysplasia, adenomas with villous features, adenomas 1 cm or greater, multiple adenomas, any adenomas = 0.3 cm, total advanced colorectal events, or total colorectal events. To assess quantitative and qualitative toxicities of patients when treated with the combination of eflornithine and sulindac compared to corresponding placebos. To evaluate a minimal set of tagging single nucleotide polymorphisms across multiple genes relevant to eflornithine and sulindac, in order to characterize associations with decreased adenoma/second primary colorectal (CRC) risk and adverse events. To evaluate biomarker responses of treatment effect using novel microfluidics- based digital droplet detection system. To explore the interaction of intervention arm and baseline statin use with respect to the 3-year event rate. To explore the interaction of the intervention arm and patient-reported meat consumption with respect to the 3-year event rate. To perform population pharmacokinetic (PK) analysis of eflornithine and sulindac in patients with previously treated Stage 0-III colon or rectal cancer. (Sites participating in PK sampling are listed on page 1a of the protocol).
IRB Review and Approval Date: 04/01/2013
Recruitment Status: Open
Projected Accrual: 480
1) Patients must be at least 18 years of age. Patients must have a
Zubrod Performance Status of 0-1 and must not be expecting to receive
radiation or additional chemotherapy. Patients must have the ability to
swallow oral medication.
2) Patients with history of segmental resections are eligible (i.e. right colectomy, extended right colectomy, transverse colectomy, left colectomy, extended left colectomy, sigmoid colectomy, low anterior resection, abdominoperineal resection). The definition of resection does not include endomucosal resection (EMR). Patients that have received total proctocolectomy are ineligible. For Tis (Stage 0) or pT1 patients only, resection may consist entirely of polypectomy (without completion of partial colectomy) if ALL of the following criteria are met: 1) Single specimen, completely removed. 2) Clear margins 3) None of the following must be present: 3a) Moderate or poor differentiation 3b) Lymphovascular invasion 3c) Perineural invasion
3) Patients with a history of Stage 0, I, II or III colon or rectal adenocarcinoma that has been treated per standard care with resection alone or in combination with radiation or chemotherapy. Adjuvant chemotherapy and RT treatment must have been completed at least 30 days prior to registration.
4) Patients must be registered between 180 days and 456 days (inclusive) of primary resection. Patients must show no evidence of disease (NED) based on post-operative colonoscopy (performed at least 180 days after the colon resection date or at least 120 days after the rectal resection date and prior to registration) and CT scans* of chest, abdomen and pelvis (performed at least 180 days after the colon resection date or at least 120 days after the rectal resection date and prior to registration). Patients with adenomas detected at the one-year postoperative colonoscopy are eligible if all adenomas have been completely removed. (*CT scan is for high risk patients, as per NCCN guidelines and at the discretion of the treating physician.) NOTE: MRI evaluation is an acceptable alternative to CT scans for eligibility purposes.
5) Patients must not have cardiovascular risk factors including unstable angina, history of documented myocardial infarction or cerebrovascular accident, coronary artery bypass surgery, or New York Heart Association Class III or IV heart failure. Patients must not have known uncontrolled hyperlipidemia (defined as LDL-C greater than or equal to 190 mg/dL or triglycerides greater than or equal to 500 mg/dL) within the last 3 years prior to registration or uncontrolled high blood pressure (systolic blood pressure > 150 mm Hg) within 28 days prior to registration. (A table of New York Heart Association Classifications is included in Appendix 18.6.).
6) Patients must not have a known history of familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer, or inflammatory bowel disease.
7) Patients must have a pure tone audiometry evaluation to document air conduction within 30 days prior to registration. Patients with hearing loss >40 dB in any of the five tested frequencies (250 Hz, 500 Hz, 1,000 Hz, 2,000 Hz, 4,000 Hz) are not eligible. Patients with active ear infections should be tested only after the acute phase of infection has resolved. For optimal results, it is recommended that testing be conducted by an audiologist, in a hearing test room, with insert earphones. Submit S0820 Audiometry Evaluation Form per Section 14.5.
8) Patients must not have known hypersensitivity to eflornithine or sulindac or the excipients byproducts. Patients must not have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs.
9) Patients must not have documented history of gastric/duodenal ulcer within the last 12 months. Patients with gastroesophageal reflux disease (GERD) are eligible, however, and these patients may receive over-the-counter histamine-2 (H2) antagonists, proton-pump inhibitors, or other prescription-based treatment for GERD.
10) Patients must not be receiving or plan to receive concomitant corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), nor anticoagulants on a regular or predictable intermittent basis. (NSAID use may not exceed 10 days per month.) Patients may receive daily aspirin for cardiovascular prophylaxis as long as ASA is less than or equal to 100 mg per day or less than or equal to two 325 mg tablets per week.
11) Patients must have adequate; blood counts as evidenced by the following results, total WBC great than or equal to 4.0 x 103/mcL, platelets great than or equal to 100,000/mcL and hemoglobin > 11.0 g/dL; liver function as evidenced by the following results: serum bilirubin less than or equal to 2.0 mg/dL and AST (SGOT) or ALT (SGPT) less than or equal to 2 x IULN (institutional upper limit of normal); kidney function as evidenced by serum creatinine less than or equal to 1.5 x IULN. All laboratory results obtained within 28 days prior to registration.
12) Women/men of reproductive potential must have agreed to use an effective contraceptive method. A women is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months. In addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevention pregnancy (or with a side-effect pregnancy intervention) defined as hysterectomy, bilateral oophorectomy or bilateral tubal ligation. However, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures.
13) Individuals may not currently be participating in any other clinical trial for the treatment or prevention of cancer unless they are no longer receiving the intervention and are in the follow-up phase only. Patients must also agree not to join such a trial while participating in this study.
14) Patients must be offered the option to participate in submission of specimens for banking for future translational medicine studies. Patients must also be offered the option to submit blood specimens for population pharmacokinetic analysis.
15) Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines.
16) Patients must be offered the option to participate in the Diet and Lifestyle Substudy (as described in protocol Section 15.2)
17) As a part of the OPEN registration process (see protocol section 13.4 for OPEN access instructions) the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system
18) Transanal excision is allowed for pT1 rectal cancer patients with well or moderately differentiated tumors if NCCN criteria (v.2.2017, 12/22/16) for transanal excision are met, as stipulated here: 1. <30% circumference of bowel, 2. <3cm in size, 3. Margin clear (>3mm), 4. Mobile, nonfixed, 5. Within 8cm of anal verge, 6. T1 only, 7. Endoscopically removed polyp with cancer, 8. No lymphovascular invasion or perineural invasion, 9. Well to moderately differentiated, 10. No evidence of lymphadenopathy on pretreatment imaging. Transanal endoscopic microsurgery (TEM) may be used when the lesion can be adequately identified in the rectum. TEM for more proximal lesions may be technically feasible.
1) Patients having planned radiation therapy or additional chemotherapy.
2) Patients with a known history of familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer, or inflammatory bowel disease.
3) Patients with greater than 40 dB of hearing loss in any of the 5 tested frequencies on prestudy audiogram
4) Patients with recurrent or metastatic disease.
5) Patients with a documented history of gastric/duodenal ulcer within last 12 months and/or current treatment or active symptoms of gastric/duodenal ulcer.
6) Patients must have no significant medical or psychiatric condition that would preclude study completion. Tests and exams for this determination should be completed within 28 days prior to registration.
7) No other prior malignancy except adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer for which the patient has been disease-free for > 5 years.
8) Women who are pregnant or nursing (due to the status of eflornithine and sulindac as pregnancy class C agents).
Information and next steps
Elise D. Cook
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