Neoadjuvant FOLFOX Therapy and Active Surveillance Without Use of Radiation in Locally Advanced Rectal Cancer

These patients will be evaluated for complete clinical response (cCR) after completing 10
cycles of FOLFOX (fluorouracil, leucovorin, oxaliplatin) chemotherapy, with interval analysis
after six cycles. Patients who have stable or progressive disease will be treated per
discretion of the treating physician following multidisciplinary discussion. Those determined
to have partial or complete response will complete full neoadjuvant treatment and undergo
close surveillance with watchful waiting for local recurrence without immediate surgery. The
primary endpoint of this study will be the rate of cCR, which is to include complete and near
complete clinical response, with secondary endpoints of disease free survival (DFS), overall
survival (OS), quality of life (QOL), as well as evaluation of safety and toxicity.

Inclusion Criteria:

1. Participants must be >18 years old at time of diagnosis

2. Histologically confirmed adenocarcinoma of the rectum from biopsy, defined as
adenocarcinoma <15 cm from the anal verge

3. Clinical staging including T3N0 tumors, or T1-3 with N1-2a disease

4. Patients with lower rectal cancer deemed by surgery to not be candidates for sphincter
sparing surgery are eligible to participate

5. There must be no evidence of metastatic disease any time prior to initiation of study

6. Rectal tumors must be determined as likely requiring total mesorectal excision (TME)

7. Participant must be treatment naïve for rectal cancer, with no prior radiation
chemotherapy, radiation, or surgery for specific rectal cancer

8. No history of prior pelvic radiation

9. No prior administration of platinum agents

10. No active infections requiring intravenous antibiotics

11. No additional active malignancy

12. No prior treatment of any malignancy within the past 3 years

13. Baseline lab work must meet the following parameters:

1. Absolute neutrophil count (ANC)>1500/mm3

2. Platelet count>100,000/mm3

3. Hemoglobin>8.0 g/dL

4. Total bilirubin and creatinine < 1.5x upper limit of normal (ULN)

5. AST and ALT < 3x ULN

14. Women of childbearing potential (WCBP) will be defined as those biologically capable
of becoming pregnant. WCBP must be negative for pregnancy testing (urine or blood) and
agree to use effective contraception. Viable contraception should be used after trial
screening, before initiation of chemotherapy, and throughout the duration of active
treatment in the study.

15. Participants must be read and explained the purposes of the study, and sign a
statement of informed consent prior to participation. Those who do not read or
understand English are eligible and may be consented according to institutional
federal regulations.

Exclusion Criteria:

1. Recurrent or refractory rectal adenocarcinoma

2. T1N0, T2N0, T4a, T4b, or N2b tumors

3. Any evidence of metastatic disease

4. Primary unresectable rectal cancer. A tumor will be considered unresectable when
invading adjacent organs such that an en bloc resection cannot achieve negative
margins

5. Patients with threatened margins, defined as tumor <1 mm from circumferential
resection margins or mesorectal fascia

6. Patients unable to undergo MRI imaging

7. Patient with a history of any arterial thrombotic event within the past 6 months. This
includes angina, myocardial infarction, transient ischemic attack, or cerebral
vascular accident.

8. Patients with history of venous thrombotic episodes such as deep vein thrombosis,
pulmonary embolus occurring more than 6 months prior to enrollment may be considered
for protocol participation, provided they are on stable doses of anticoagulant
therapy. Patients who are anticoagulated for atrial fibrillation or other conditions
may participate only if on stable doses of anticoagulant therapy.

9. Patients with cardiovascular, hepatic, or renal systemic diseases that would preclude
use of chemotherapy

10. Peripheral neuropathy>grade 1 by Common Terminology Criteria for Adverse Events, or
CTCAEa

11. The patient must not be on any clinical trials involving other experimental therapies
before or during study treatment

12. Women who are currently pregnant or breast-feeding

13. Men and women expecting to father/conceive children

14. Patients with any other concord medical or psychiatric condition which were deemed
inappropriate for entry into the study per the investigator.

15. History of other invasive malignancy within the past 3 years, except for adequately
treated non-melanoma skin cancer, ductal carcinoma in situ, bladder carcinoma in situ
or carcinoma in situ of the cervix.

aCTCAE version 5.0 from Department of Health and Human Services