S-Adenosylmethionine (SAMe) for Chemoprevention of Colorectal Adenomas

This is a single-institution phase I clinical trial designed to evaluate the safety of using an oral nutritional supplement known as S-Adenosylmethionine (SAMe) as an experimental intervention to prevent the formation of precancerous polyps that can eventually develop into colorectal cancer. Survivors of stage I-II colorectal cancer after curative-intent surgery when postoperative or adjuvant chemotherapy is not indicated will be the target population for this study given that they are at increased risk of developing polyps, also known as adenomas, as well as colorectal cancer. This study is aiming to investigate whether SAMe could represent a new colorectal cancer chemoprevention strategy, which is the use of medications, supplements, or other agents to reduce the risk of cancer or prevent cancer altogether.

Potential participants will be identified by the study team anytime from the period of initial diagnosis of colorectal cancer who are candidates for surgery up to the point of curative surgery. A goal n=18 participants will be enrolled to receive up to 12 months of oral SAMe as chemoprevention. A pre-intervention (baseline) stool sample and colon biopsy by a low-risk procedure called flexible sigmoidoscopy will be obtained. The study intervention (SAMe) will start within 30 days ±7 days of the baseline biopsy. Upon completion of up to 12 months of intervention, a postoperative surveillance colonoscopy (routinely performed within 1 year of curative surgery for stage I-II colorectal cancer) with repeat colon biopsy and a repeat stool sample within 7 days ±4 days of the last dose of study intervention will be obtained. The postoperative colonoscopy will be performed as standard of care, meaning that this procedure will have been routinely performed regardless of this clinical trial, where removal of all polyps as per standard of care will be performed. The pre- and post-SAMe stool samples collected will be used to investigate the effects of SAMe on gut bacteria and stool metabolites. The pre- and post-SAMe colon biopsies will be performed in the region of the colon known as the distal colon and tissue biopsies will undergo testing to evaluate the effects of SAMe on various proteins that are involved in the process by which adenomas and cancer arise from the normal colon.

The primary objective of this trial will be to identify the highest dose of SAMe that is safe to use in patients (known as the recommended phase II dose or RP2D). This portion of the trial, known as the dose-finding phase, will occur during the first 4 weeks of SAMe administration and will take place across 3 different doses of SAMe (1600 mg/daily, 2000 mg/daily, and 2400 mg/daily). The usual dose of SAMe is typically up to 1600 mg/day as a dietary supplement, while doses up to 2400 mg/day have been investigated in certain patients with liver disease, providing rationale for our proposed dose levels. This study hypothesizes that SAMe is safe and tolerable with preliminary efficacy in reducing rates of adenoma formation in subjects with stage I-II colorectal cancer who are undergoing surveillance. Secondary objectives include to determine the frequency of colorectal adenomas detected on the postoperative surveillance colonoscopy, the change in tissue proteins involved in the process by which adenomas and cancer arise from the normal colon measured before and after SAMe intervention, and the change in gut bacteria and stool metabolites before and after SAMe intervention.

This study plans to enroll a goal n=18 subjects to this phase I dose-finding trial. Stage I-III colorectal cancer comprises nearly 70% of all colorectal cancer cases in Europe and the U.S., where surgery is curative. However, patients having undergone curative surgery for stage I-III colorectal cancer are at increased risk for developing adenomas and recurrent cancer. Here, surveillance colonoscopy detects adenomas in up to 72% of colorectal cancer survivors by 5 years after surgery. In stage I-II colorectal cancer, our target population, adenomas (≤6 months after surgery) were found in 38.1% of patients postoperatively, while adenomas (\>6 months after surgery) were found in 20% of patients postoperatively. Of those with adenomas detected \>6 months after surgery, 47% were identified on colonoscopies within the first year after surgery. The team conducting this study therefore believe that patients with stage I-II colorectal cancer having undergone curative surgery who are at increased risk of developing adenomas post-surgery represent an ideal population for chemoprevention. There will otherwise be no exclusion of patients on the basis of age, sex, geographical location, health status, or race to the extent that they meet the eligibility criteria.

This study will be conducted at a single institution, Cedars-Sinai Medical Center (CSMC). The total study duration will be 2 years. Patients will be actively participating in the study and consuming oral daily SAMe for a duration of up to 12 months. This study will administer SAMe at an oral daily dose of 1600-2400 mg daily divided into 400 mg tablets in the morning before breakfast and in the evening before dinner to constitute the total daily dose. There will only be one intervention group and therefore there will be no placebo or randomization in this study. No special methods are needed in the delivery of the experimental intervention. The study was designed with the input of the biostatistician such that the RP2D and safety of SAMe could be determined using the fewest participants needed.

• Rate of Adenomas [Time frame: Post treatment, roughly 1 year]
• Safety by Adverse Events [Time frame: Post treatment, roughly 1 year]