The Phoenix Trial: Phase II Trial of Cemiplimab for the Non-operative Management of Localized dMMR Colon Cancer

Inclusion Criteria:

Participants are eligible to be included in the study only if all of the following criteria apply:

• Age ≥18 years

• Histological confirmation of colon adenocarcinoma, as determined by pathology review (inferior colon margin defined as >10 cm from anal verge).

• Colon cancer that is deficient in mismatch repair (dMMR) or microsatelliteInstability high (MSI-H) as determined by one of three methods:

• Immunohistochemistry-determined dMMR by complete tumor nuclear loss of MLH1,PMS2, MSH2 or MSH6

• PCR-determined MSI at >30% of tested microsatellites

• Next-generation-determined MSI-H based upon instability at multiplemicrosatellites as determined by the specific next generation sequencing panel

• Localized colon cancer with (1) radiological staging of T3 or T4 or lymph nodepositive (stage II or III) OR (2) locally recurrent with luminal component OR (3)stage I with a surgical mortality defined as >5% by American College of Surgeons (ACS) National Surgery Quality Improvement Program

• Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.

• Primary tumor that is deemed to be accessible by endoscopic intervention andwillingness to undergo repeated endoscopic evaluations

• Measurable or non-measurable disease by cross-sectional imaging per RECIST v1.1criteria

• Laboratory values (obtained within 7 days prior to registration) meeting thefollowing criteria:

• Absolute neutrophil count (ANC) ≥1000/mme

• Platelet count >80,000/mm3

• Hemoglobin >8 g/dL

• Total bilirubin ≤1.5 x upper limit of normal (ULN) [for patients with Gilbertsdisease criteria is direct bilirubin ≤1.5 x ULN]

• Alanine aminotransferase (ALT) and aspartate transaminase (AST) ≤3 x ULN

• Creatinine <2.0 mg/dL

• Negative urine or serum pregnancy test done ≤7 days prior to registration (women ofchildbearing potential only). NOTE: If the urine test is positive or cannot beconfirmed as negative, a serum pregnancy test will be required.

• The effects of cemiplimab on the developing human fetus are unknown. For thisreason, women of childbearing potential and men must agree to use adequatecontraception (hormonal or barrier method of birth control; abstinence) prior tostudy entry and for the duration of study participation and 4 months after the lastdose of cemiplimab. (Refer to Pregnancy Assessment Policy MD Anderson InstitutionalPolicy # CLN1114). This includes all female patients, between the onset of menses (as early as 8 years of age) and 55 years unless the patient presents with anapplicable exclusionary factor which may be one of the following:

• Postmenopausal (no menses in greater than or equal to 12 consecutive months).

• History of hysterectomy or bilateral salpingo-oophorectomy.

• Ovarian failure (Follicle Stimulating Hormone and Estradiol in menopausalrange, who have received Whole Pelvic Radiation Therapy).

• History of bilateral tubal ligation or another surgical sterilizationprocedure.

• Approved methods of birth control are as detailed in Appendix 4.

• Men treated or enrolled on this protocol must also agree to use adequatecontraception prior to the study, for the duration of study participation, and 4months after completion of cemiplimab administration.

• Willingness to return to enrolling institution for follow-up.

• Willingness to provide mandatory blood specimens for correlative research (notapplicable to external sites: Cancer Network sites and LBJ Hospital)

• Ability to understand and the willingness to sign a written informed consentdocument.

• Willing and able to comply with clinical trial instructions and requirements.Individuals lacking the ability, based on reasonable medical judgment, to understandand appreciate the nature and consequences of participation in this study will notbe eligible for participation.

Exclusion Criteria:

Participants are excluded from the study if any of the following criteria apply:

• Failure to recover from acute, reversible effects of prior therapy regardless ofinterval since last treatment. EXCEPTION: Grade 1 or 2 peripheral (sensory)neuropathy or alopecia

• Comorbid systemic illnesses or other severe concurrent disease which, in thejudgment of the investigator, would make the patient inappropriate for entry intothis study or interfere significantly with the proper assessment of safety andtoxicity of the prescribed regimens; conditions including but not limited to:

• symptomatic congestive heart failure

• unstable angina pectoris

• cardiac arrhythmia

• ongoing or active infection

• psychiatric illness/social situations

• dyspnea at rest due to complications of advanced malignancy or other diseasethat requires continuous oxygen therapy

• any other conditions that would limit compliance with study requirements

• Immunocompromised patients and patients known to be HIV positive and currentlyreceiving antiretroviral therapy without undetectable viral load. NOTE: Patientsknown to be HIV positive, but without clinical evidence of an immunocompromisedstate, are eligible for this trial.

• Receiving any other investigational agent, chemotherapy or other targeted therapythat would be considered as a treatment for the colon cancer.

• Because this study involves an investigational agent whose genotoxic, mutagenic andteratogenic effect on the developing fetus and newborn are unknown, the followingare not eligible for participation in this trial:

• Pregnant persons

• Nursing persons

• Persons who are breastfeeding

• Persons of childbearing potential who are unwilling to employ adequatecontraception

• Persons expecting to conceive or father children within the projected durationof the study, starting with the screening visit through 120 days after the lastdose of trial treatment.

• Any of the following prior therapies, if applicable:

• Surgery ≤3 weeks prior to study treatment

• Chemotherapy ≤2 weeks prior to study treatment

• Radiation therapy ≤2 weeks prior to study treatment

• Patients who have received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PDL2 agent or with an agent directed to another stimulatory or co-inhibitory T-cellreceptor (e.g., CTLA-4, OX 40, CD137) for colon cancer

• Patients with a prior or concurrent malignancy whose natural history or treatmenthave the potential to interfere with the safety or efficacy assessment of theinvestigational regimen

• Patient has known metastatic sites of disease. Note: locoregional lymph nodes ortumor deposits are not considered metastatic disease. Also, locally recurrentdisease is allowed.

• Patient has active autoimmune disease that has required systemic treatment in thepast year (i.e. with use of disease modifying agents, corticosteroids orimmunosuppressive drugs). Replacement therapy (e.g.., thyroxine, insulin, orphysiologic corticosteroid replacement therapy for adrenal or pituitaryinsufficiency, etc.) is not considered a form of systemic treatment.

• Patient has a history of (non-infectious) pneumonitis that required steroids or hascurrent pneumonitis