Active Surveillance and Chemotherapy Before Surgery in Treating Participants With Stage II-III Rectal Cancer

PRIMARY OBJECTIVES:

I. To quantify the rates of organ preservation and tumor regrowth with non-operative
management of locally advanced rectal cancer in patients achieving a clinical complete
response (cCR).

SECONDARY OBJECTIVES:

I. To correlate clinical, radiographic, and pathologic findings after neoadjuvant therapy for
rectal cancer.

II. To determine the impact of active surveillance with deferral of surgery on oncologic
outcomes.

III. To assess decision quality for patients with rectal cancer facing multiple treatment
options.

IV. To explore the impact of patient-provider communication on patient decisions for surgical
versus nonsurgical treatment decision for rectal cancer.

V. To assess safety of deferral of surgery in distal rectal cancer patients with possibility
of cohort expansion to more proximal locally advanced rectal cancer patients.

CORRELATIVE OBJECTIVES:

I. Obtain tissue to monitor treatment response and any future biomarker analyses

OUTLINE: Participants are assigned to 1 of 2 groups.

GROUP I: Participants who have achieved clinical complete response undergo standard surgical
resection.

GROUP II: Participants who have achieved clinical complete response receive active
surveillance and consolidated chemotherapy for up to 4 months in the absence of disease
progression or unacceptable toxicity. Participants with incomplete response or regrowth of
tumor, undergo surgical resection as in Group I.

After the completion of study treatment, participants in Group I are followed up at 6 and 12
months, and then once a year for up to 3 years. Participants in Group II are followed up
every 3 months for 18 months, every 6 months for 2 years, and then every year for up to 3
years.

Inclusion Criteria:

- Histologically confirmed diagnosis of rectal adenocarcinoma

- Eligible for curative resection of rectal adenocarcinoma

- Rectal tumor location =< 12 cm from the anal verge as determined by endoscopy or
magnetic resonance imaging (MRI) (if endoscopy report is not available or deemed
inadequate my treating oncologist)

- Nodal involvement confined to the radiation field

- Radiologically measurable or clinically evaluable disease as defined in the protocol

- Eastern Cooperative Oncology Group (ECOG) performance status (PS): 0, 1 or 2

- Clinical Stage: Stage II and III. N2 disease is to be estimated as four or more lymph
nodes that are >= 10 mm. Clinical staging should be estimated based on the combination
of the following assessments: physical exam by the primary surgeon including digital
rectal exam (DRE), computed tomography (CT) or positron emission tomography (PET)/CT
scan of the chest/abdomen/pelvis and a pelvic MRI. If a pelvic MRI is performed, it is
acceptable to perform CT of the chest/abdomen, omitting CT imaging of the pelvis.
PET/CT is optional.

- No known contraindication to standard (fluoropyrimidine-based) pelvic chemoradiation
(e.g. dihydropyrimidine dehydrogenase [DPD] deficiency)

- Patient of child-bearing potential is willing to employ adequate contraception during
treatment and after treatment, as directed by treating clinical team

- Willing to provide written informed consent

- Willing to return to enrolling medical site for all study assessments

Exclusion Criteria:

- Diagnosis of inflammatory bowel disease (IBD)

- Diagnosis of MSI-H colorectal cancer at time of consent

- Recurrent rectal cancer

- Tumor is causing symptomatic bowel obstruction (patients who have diverting ostomy are
eligible)

- Any prior pelvic radiation

- Other invasive malignancy undergoing active treatment. Patients receiving prior
treatment that precludes standard chemoradiation or ability to receive
consolidation/adjuvant chemotherapy will be excluded from survival analyses

- Patients unwilling or unable to undergo pelvic MRI