Neoadjuvant Chemotherapy Combined with Magnetic Resonance Image Guided Pelvic Adaptive Radiation Therapy for the Treatment of Locally Advanced Rectal Cancer, SMART TNT Study

PRIMARY OBJECTIVES:

I. To prove the feasibility and the safety of dose escalated magnetic resonance imaging (MRI)-guided (g) pelvic adaptive radiation therapy (ART) after total neoadjuvant chemotherapy (TNT) to offer a conservative approach to patients diagnosed with locally advanced rectal carcinoma (LARC).

SECONDARY OBJECTIVES:

I. To document the rate of acute and long term gastrointestinal (GI), genitourinary (GU), bone marrow (BM) toxicity and sexual dysfunction associated with this treatment approach.

II. To document the disease control (defined as local control, distant metastasis, disease specific and overall survival at two years) associated with the proposed treatment regimen.

III. To correlate radiogenomics findings and clinical response.

IV. To document the sensitivity and specificity of multiparametric (mp) MRI to measure tumor response during treatment of patients with LARC.

V. To document the quality of life (QOL) at baseline (before treatment), post chemotherapy, post radiation therapy (RT), at 12 weeks, six and twelve months post-treatment and compare with historical data.

VI. To monitor the presence of circulating tumor deoxyribonucleic acid (ctDNA) at baseline, after six weeks of chemotherapy, post chemotherapy, post radiation, 12 weeks post chemoradiation and every 6 months post treatment for two years to determine if there is any correlation between the presence/level of ctDNA and disease control (both local control and rate of distant metastasis).

VII. To document if there is any genetic signature or other pathologic features predictive of chemo-radiation response.

OUTLINE: This is a dose escalation study of the MRI-g ART boost. Patients are assigned to 1 of 3 groups.

GROUP 1: Patients receive fluorouracil intravenously (IV) over 46 hours on days 1 and 2 of each cycle and leucovorin IV over 2 hours and oxaliplatin IV over 2 hours on day 1 of each cycle. Cycles repeat every 14 days for 4-6 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo MRI-g pelvic intensity-modulated radiation therapy (IMRT) given once per day Monday through Friday for a total of 25 treatments with capecitabine orally (PO) twice per day (BID) throughout MRI IMRT. Patients then undergo MRI-g ART boost given once per day Monday through Friday for a total of 4 treatments. Patients who do not have a complete clinical response undergo surgery as per standard of care. Patients undergo a colonoscopy during screening, computed tomography (CT) scan and mpMRI throughout the study and endoscopy on study. Patients may also undergo a biopsy during screening and follow-up and blood sample collection throughout the trial.

GROUP 2: Patients receive oxaliplatin IV over 2 hours on day 1 of each cycle and capecitabine PO BID on days 1-14 of each cycle. Cycles repeat every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo MRI-g pelvic IMRT given once per day Monday through Friday for a total of 25 treatments with capecitabine PO BID throughout MRI IMRT. Patients then undergo MRI-g ART boost given once per day Monday through Friday for a total of 4 treatments. Patients who do not have a complete clinical response undergo surgery as per standard of care. Patients undergo a colonoscopy during screening, CT scan and mpMRI throughout the study and endoscopy on study. Patients may also undergo a biopsy during screening and follow-up and blood sample collection throughout the trial.

GROUP 3: Patients receive fluorouracil IV over 46 hours on days 1 and 2 of each cycle and leucovorin IV over 2 hours, irinotecan IV over 90 minutes and oxaliplatin IV over 2 hours on day 1 of each cycle. Cycles repeat every 14 days for 4-6 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo MRI-g pelvic IMRT given once per day Monday through Friday for a total of 25 treatments with capecitabine PO BID throughout MRI IMRT. Patients then undergo MRI-g ART boost given once per day Monday through Friday for a total of 4 treatments. Patients who do not have a complete clinical response undergo surgery as per standard of care. Patients undergo a colonoscopy during screening, CT scan and mpMRI throughout the study and endoscopy on study. Patients may also undergo a biopsy during screening and follow-up and blood sample collection throughout the trial.

After completion of study treatment, patients are followed up every 3 months for up to 2 years.