Evaluation of Circulating Tumor DNA for Predicting the Likelihood of Organ Preservation or Pathologic Complete Response after Neoadjuvant Therapy for Patients with Rectal Cancer

PRIMARY OBJECTIVE:

I. To compare rates of successful non-operative management (NOM) or pathologic complete response (pCR) at one year in patients who test positive for ctDNA 8 weeks following total neoadjuvant therapy (TNT) and those who test negative with the C2i assay.

SECONDARY OBJECTIVES:

I. To determine local recurrence rates up to 5 years in patients who have achieved a complete clinical response (cCR) or near complete clinical response (nCR), after rectal cancer treatment by ctDNA status with the C2i assay at study entry, post-TNT restaging, or at 3, 6, 9, 12, 15, 18, 21, or 24 months follow-up.

II. To describe quality of life based on validated surveys at study entry, post-TNT restaging, 6 months, 12 months and 24 months by clinical response status after TNT for rectal cancer.

III. To determine disease-free survival (DFS) and overall survival (OS) by ctDNA status at study entry, post-TNT restaging, or at 3, 6, 9, 12, 15, 18, 21, or 24 months follow-up.

EXPLORATORY OBJECTIVES:

I. To describe the rate of clinical complete response or near complete clinical response and ctDNA positivity rate on the C2i assay 8 weeks following neoadjuvant therapy.

II. To investigate clonal evolution in patients who proceed to total mesorectal excision (TME), either following neoadjuvant therapy or at the time of later recurrence, using the C2i assay with blood samples collected prior to

biopsy and surgery and tissue samples from the baseline biopsy and later surgery.

III. To determine overall rate of recurrence by KRAS/NRAS/HRAS/BRAF/TP53 status and possibly other genes through tumor genomic profiling.

IV. To compare ctDNA trends with CEA trends at baseline, post-TNT restaging, and at 3, 6, 12, 15, 18, 21, or 24 month follow up.

V. To determine overall rate of 30 day surgical complications from proctectomy (i.e. 30 day hospital readmission, unplanned reoperation, superficial surgical site infection, and organ / space infection) and rate of temporary ostomy non-reversal.

OUTLINE: This is an observational study.

Participants undergo biopsy and tumor tissue sample collection, complete questionnaires, undergo collection of blood samples, and have medical records reviewed on study. Participants also undergo digital rectal exam (DRE), magnetic resonance imaging (MRI) or endoscopic ultrasound (EUS), sigmoidoscopy, computerized tomography (CT), and colonoscopy per SOC on study.

Participants are followed up to 5 years.