Short Course Radiation Therapy and Combination Chemotherapy for the Treatment of Stage II-III Rectal Cancer

Study Overview
=================
Brief Summary
-----------------
This phase I trial investigates how well short-course radiation therapy followed by combination chemotherapy works in treating patients with stage II-III rectal cancer. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Chemotherapy drugs, such as leucovorin, fluorouracil, oxaliplatin, and capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving short-course radiation therapy and combination chemotherapy may reduce the need for surgery and therefore improve quality of life.

Detailed Description
-----------------
PRIMARY OBJECTIVE: I. Complete clinical response (cCR) rate of patients with clinical T3 and/or node-positive M0 rectal cancer being treated with short-course radiation therapy (SCRT) followed by 16 weeks of modified leucovorin, fluorouracil, and oxaliplatin (mFOLFOX)/capecitabine and oxaliplatin (CapeOX). SECONDARY OBJECTIVES: I. 1-year local recurrence free survival and 1-year progression free survival of the entire cohort, the cohort that initially undergoes non-operative management (NOM), and the cohort that initially undergoes total mesorectal excision (TME). II. Physician-reported acute and late >= grade 3 toxicity rates. III. 1-year post-treatment patient health-related quality of life and anorectal function as per Patient Reported Outcomes Measurement and Information System (PROMIS). IV. Explore how Signatera's residual disease test correlates with patient's cCR rates, local recurrence, progression-free, and overall survival rates. V. Explore radiomics features from longitudinal diffusion weighted magnetic resonance imaging (MRI) (diffusion weighted imaging [DWI]) data and build a predictive model for treatment effect (complete response) in rectal cancer patients undergoing SCRT. OUTLINE: Patients undergo SCRT in the form of intensity-modulated radiation therapy (IMRT) over 5 fractions daily for 5 consecutive days. Beginning 11-18 days after the last day of radiation therapy, patients receive either oxaliplatin intravenously (IV) and leucovorin IV on day 1 and fluorouracil IV on days 1-3 (mFOLFOX6) or oxaliplatin IV on day 1 and capecitabine orally (PO) twice daily (BID) on days 1-14 (CapeOX). Treatment with mFOLFOX6 repeats every 2 weeks for up to 8 cycles, and treatment with CapeOX repeats every 3 weeks for up to 6 cycles in the absence of disease progression or unacceptable toxicity. At 8-12 weeks after completion of all therapy, patients with residual tumor undergo TME. Patients with cCR undergo NOM. After completion of study treatment, patients who underwent NOM are followed up every 3 months for 2 years, then every 6 months for 3 years. TME patients are followed up every 3-6 months for 2 years, then every 6 months for 3 years.

Official Title
-----------------
Organ Preservation for Patients With Locally Advanced Rectal Adenocarcinoma: Evaluating the Efficacy of Short Course Radiation Therapy Followed by FOLFOX or CapeOX

Conditions
-----------------
Locally Advanced Rectal Carcinoma, Rectal Adenocarcinoma, Stage II Rectal Cancer AJCC v8, Stage IIA Rectal Cancer AJCC v8, Stage IIB Rectal Cancer AJCC v8, Stage IIC Rectal Cancer AJCC v8, Stage III Rectal Cancer AJCC v8, Stage IIIA Rectal Cancer AJCC v8, Stage IIIB Rectal Cancer AJCC v8, Stage IIIC Rectal Cancer AJCC v8

Intervention / Treatment
-----------------
* Drug: Capecitabine
* Drug: Fluorouracil
* Radiation: Intensity-Modulated Radiation Therapy
* Drug: Leucovorin
* Drug: Oxaliplatin
* Other: Quality-of-Life Assessment
* Behavioral: Surveillance
* Procedure: Total Mesorectal Excision


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically confirmed rectal adenocarcinoma Patients must have stage II (cT3, cN0) or stage III (cT1-3, cN1-3) tumor as staged by MRI No evidence of metastatic disease Resectable primary lesion Karnofsky performance status (KPS) >= 70 or Eastern Cooperative Oncology Group (ECOG) 0-2 Absolute neutrophil count (ANC) > 1.5 cell/mm^3 Hemoglobin (Hgb) > 8.0 gm/dL Platelets (PLT) > 150,000/mm^3 Total bilirubin < or equal to 1.5 x upper limit of normal Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < or equal to three times upper limit of normal If a woman is of childbearing potential, a negative serum pregnancy test must be documented prior to initiation of radiation therapy Exclusion Criteria: Active treatment of a separate malignancy Distant metastatic disease as assessed by staging positron emission tomography (PET)/computed tomography (CT) or CT of the chest and abdomen within 6 weeks of starting radiation therapy Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields Pregnant and/or breastfeeding Medical/psychological contraindication to MRI

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (IMRT, mFOLFOX6, CapeOX, TME)<br>Patients undergo SCRT in the form of IMRT over 5 fractions daily for 5 consecutive days. Beginning 11-18 days after the last day of radiation therapy, patients receive either oxaliplatin IV and leucovorin IV on day 1 and fluorouracil IV on days 1-3 (mFOLFOX6) or oxaliplatin IV on day 1 and capecitabine PO BID on days 1-14 (CapeOX). Treatment with mFOLFOX6 repeats every 2 weeks for up to 8 cycles, and treatment with CapeOX repeats every 3 weeks for up to 6 cycles in the absence of disease progression or unacceptable toxicity. At 8-12 weeks after completion of all therapy, patients with residual tumor undergo TME. Patients with cCR undergo NOM. | Drug: Capecitabine<br>* Given IV<br>* Other names: Xeloda;Drug: Fluorouracil<br>* Given IV<br>* Other names: Ro-2-9757;Radiation: Intensity-Modulated Radiation Therapy<br>* Undergo IMRT<br>* Other names: Radiation, Intensity-Modulated Radiotherapy;Drug: Leucovorin<br>* Given IV<br>* Other names: Folinic acid;Drug: Oxaliplatin<br>* Given IV<br>* Other names: SR-96669;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Behavioral: Surveillance<br>* Undergo NOM<br>* Other names: Epidemiology / Surveillance;Procedure: Total Mesorectal Excision<br>* Undergo TME<br>* Other names: TME;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete clinical response rate | Kaplan-Meier analysis will be carried out and used to estimate for the entire cohort as well the non-operational management (NOM) and total mesorectal excision (TME) cohorts separately. | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Local recurrence-free survival | Kaplan-Meier analysis will be carried out and used to estimate for the entire cohort as well the NOM and TME cohorts separately. | At 1 year | 
| Progression-free survival | Kaplan-Meier analysis will be carried out and used to estimate for the entire cohort as well the NOM and TME cohorts separately. | At 1 year | 
| Incidence of adverse events | Physician-reported acute and late >= grade 3 toxicity rates for the entire cohort will be graded according to Common Terminology Criteria for Adverse Events version 5.0. | Up to 5 years | 
| Health-related quality of life | Will be assessed by Patient Reported Outcomes Measurement and Information System and calculated and presented as a composite score. These scores will be calculated for the entire cohort as well as the NOM and TME cohorts separately. | At 1 year | 
| Anorectal function | Will be assessed by Patient Reported Outcomes Measurement and Information System and calculated and presented as a composite score. These scores will be calculated for the entire cohort as well as the NOM and TME cohorts separately. | At 1 year | 
| Signatera's residual disease test | Cox proportional hazards regression analysis will be used to assess the association of circulating tumor deoxyribonucleic acid with clinical response rates, local recurrent, progression-free, and overall survival rates. | Up to 5 years | 
| Prediction of complete clinical response rate status by radiomics | The relationship between complete clinical response as a binary variable and longitudinal radiomics features from a sequence of four diffusion weighted imaging data points will be assessed via a logistic regression model with a random effect term to account for within-subject correlation. | Up to 5 years |