Multicenter Phase II Study of Transanal TME (taTME)

The management of rectal cancer is multidisciplinary and outcomes are dependent on accurate
preoperative staging, performance of a curative resection, and the selective use of
neoadjuvant and adjuvant therapy to improve long-term oncologic outcomes. Despite the
increasing use of laparoscopic and robotic approaches, radical rectal cancer resection is
associated with relatively high rates of conversion to open surgery, variable rates of TME
specimen completeness, and morbidity rates that are equivalent to that of open TME with
respect to infectious and wound-related complications, as well as defecatory, sexual and
urinary dysfunction,.

Transanal TME (taTME) with laparoscopic assistance was developed in an effort to facilitate
completion of TME using a primarily transanal endoscopic approach. Based on the preliminary
results from several published single-center case series and the first international taTME
registry, in carefully selected patients with resectable rectal cancer, taTME with
laparoscopic assistance is associated with perioperative outcomes and short-term oncologic
outcomes that are equivalent to tht of standard TME.

This study is the first phase II multicenter trial of taTME conducted in the United States to
evaluate the efficacy and safety of taTME with laparoscopic or robotic assistance relative to
standard LAR. A total of 100 subjects with resectable rectal cancer located up to 10 cm from
the anal verge will be enrolled across 10 US study sites. It is anticipated that this larger,
phase II multicenter study will validate the safety and efficacy of taTME with respect to
perioperative outcomes, short and long-term oncologic outcomes and functional results.

Study procedure:

Study procedures will consist in 1-team (sequential) or 2-team (combined) LAR with transanal
TME using laparoscopic or robotic abdominal assistance. Laparoscopic or robotic abdominal
access will be obtained followed by inferior mesenteric vessels transection, mobilization or
the proximal colon and splenic flexure takedown if indicated. Transanal TME is performed
either at the same time or following the above steps. Intersphincteric resection (ISR) may be
included for very low tumors. Following pursestring closure of the rectum below the tumor,
transanal endoscopic TME dissection will proceed circumferentially until the peritoneal
cavity is entered anteriorly. Following complete mobilization of the rectosigmoid, the
specimen is extracted transanally or transabdominally followed by colorectal or coloanal
anastomosis, with or without a diverting loop ileostomy. Operative details will be recorded
in case report forms (CRF's).

TME pathology assessment:

Resected specimens will be processed and analyzed by the participating institution's
Pathology Department according to standard TME protocol. De-identified photographs of all
fresh TME specimens will be independently reviewed by a Pathology Review Committee blinded to
the source of the specimen.

Postoperative care and follow-up:

Subjects will be managed according to standard postoperative protocols. Postoperative visits
and oncology follow-up visits will occur as per standard practice and oncologic outcomes. All
adverse events occurring during the study period will be graded using the Clavien-Dindo
system. Postoperative functional questionnaires will be obtained 6-8 months and 12-14 months
postoperatively in non-diverted subjects. In diverted subjects, functional questionnaires
will be collected 3-4 months and 9-10 months following ileostomy closure (or 12-18 months
following the study procedure).

Inclusion Criteria:

- New diagnosis of histologically confirmed adenocarcinoma of the rectum

- Age ≥18

- Clinical stage cT1 (high-risk), T2, or T3, cN0, N1, N2 on staging pelvic MRI

- Negative predicted CRM on staging pelvic MRI

- No evidence of metastasis on CT scans of the chest, abdomen and pelvis

- Rectal cancer located within 10 cm from the anal verge based on proctoscopy and
digital rectal examination (DRE)

- Complete preoperative colonoscopy demonstrating no synchronous colon cancer

- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 60%)

- Eligible to undergo laparoscopic or robotic LAR with or without a temporary diverting
stoma, based on multidisciplinary tumor board consensus

- Able to understand and willing to sign a written informed consent form

Exclusion Criteria:

- cT4 on staging pelvic MRI

- >12 weeks delay between completion of neoadjuvant CRT and planned study procedure

- Severely symptomatic rectal tumors

- Tumors invading into the internal anal sphincter muscle based on DRE and pelvic MRI

- Fecal incontinence at baseline

- Prior history of rectal resection

- Prior history of colorectal cancer

- History of inflammatory bowel disease

- Uncontrolled concurrent illness

- Pregnancy

- Subjects who cannot read or understand English