Organ Preservation Program Using Short-Course Radiation & FOLFOXIRI in Rectal Cancer

Study Overview
=================
Brief Summary
-----------------
The purpose of the research is to evaluate whether both chemotherapy and radiotherapy can lead to higher rates of clinical complete response leading to organ preservation in human subjects with cancer. The objective is to learn if this treatment approach may safely be used as an alternative to the standard treatment for rectal cancer and to know the quality-of-life in these patients.

Detailed Description
-----------------
Primary Objective: To assess clinical complete response of an organ preservation approach using short course radiation followed by intensified chemotherapy. Secondary Objective: To assess safety in all enrolled patients, local regrowth rate and other cancer specific outcomes (metastasis-free survival, colostomy-free survival and overall survival), longitudinal health-related quality of life of this organ preservation approach

Official Title
-----------------
Phase II Trial of Organ Preservation Program Using Short-Course Radiation and FOLFOXIRI for Rectal Cancer (SHORT-FOX)

Conditions
-----------------
Rectal Cancer

Intervention / Treatment
-----------------
* Drug: FOLFOXIRI
* Drug: FOLFOX regimen
* Drug: XELOX
* Radiation: IMRT


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 1. Pathologically (histologically or cytologically) proven diagnosis of adenocarcinoma of rectum requiring total mesorectal excision as deemed by multidisciplinary evaluation 2.At least 18 years of age 3.For women of childbearing potential or who are not postmenopausal (see Appendix B for Definition of Menopausal Status), a negative urine or serum pregnancy test must be done. Also, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) for the duration of study participation and for up to 4 weeks following the study. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. 4.ECOG 0, 1, or 2 5.Ability to understand and the willingness to personally sign the written IRB approved informed consent document. 6.Patients must have acceptable organ and marrow function as defined below: Absolute neutrophil count (ANC) >1,500/uL Hg > 8.0 g/dL; if blood transfusion is performed for achieving adequate hemoglobin level, the level should stay above goal for at least 1 week after transfusion Platelets >100,000/uL Total bilirubin <1.5X normal institutional limits aspartate aminotransferase (AST) (SGOT) / alanine aminotransferase (ALT)(SGPT) < 3X upper limit of normal Creatinine <1.5X upper limit of normal or creatinine clearance (CrCL)>50 by Cockcroft-Gault 7 Clinical stage >T2N0 or low T2N0 rectal cancer (AJCC, 8th ed.) including no metastases based on the following diagnostic workup: General history and physical examination with DRE (if deemed appropriate by treating physician) within 45 days prior to enrollment Sigmoidoscopy within 90 days prior to enrollment The following imaging studies are required within 45 days prior to enrollment: CT chest/abdomen/pelvis MRI Pelvis Exclusion Criteria: 1.Prior pelvic RT or chemotherapy for rectal cancer. 2.Upper T2N0 rectal cancers eligible for sphincter-preservation surgery 3.Use of other investigational agents. 4.Ongoing or active infections requiring systemic antibiotic treatment or uncontrolled intercurrent illness including but not limited to symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. 5.Any concurrent malignancy other than non-melanoma skin cancer or carcinoma in situ of the cervix. Patients with any previous malignancy without evidence of disease for >3 years will be allowed to enter the trial. 6.Known hypersensitivity to 5-FU compounds. 7.Pregnant and breastfeeding women are excluded. Women of child-bearing potential who are unwilling or unable to use an acceptable method of birth control to avoid pregnancy for the entire study period and for up to 4 weeks after the study are excluded. (This applies to women who have experienced menarche and have not undergone successful surgical sterilization or are not postmenopausal). Because patients with immune deficiency are at increased risk of lethal infections when treated with marrow-suppressive therapy, known HIV-positive patients with detectable viral loads and/or receiving combination anti-retroviral therapy are excluded from the study. - 8.Primary unresectable rectal cancer (tumor invading adjacent organs and en bloc resection will not achieve negative margins).

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: Radiation/FOLFOXIRI<br>Treatment will comprise 6 daily fractions of radiotherapy at 5 Gy per fraction followed by 4 months of FOLFOXIRI. Patients who have performance status or conditions that may preclude use of FOLFOXIRI may be treated with FOLFOX or XELOX. Those who achieve a clinical complete response will be considered for organ preservation approach. All other patients will receive standard of care total mesorectal excision (TME). | Drug: FOLFOXIRI<br>* Chemotherapy regimen of Oxaliplatin 85mg/m2 , Leucovorin 400 mg/m2 , Irinotecan 165mg/m2 , 5-Fluorouracil<br>Drug: FOLFOX regimen<br>* Chemotherapy regimen of Oxaliplatin 85mg/m2, Leucovorin 400 mg/m2, 5-Fluorouracil 2400mg/m2<br>Drug: XELOX<br>* Chemotherapy regimen of Oxaliplatin 130 mg/m2, Capecitabine 1000mg/m2<br>Radiation: IMRT<br>* Radiotherapy (5 Gy x 5 fractions) with an additional boost fraction (5 Gy x 1 fraction) delivered sequentially<br>* Other names: Intensity-modulated radiotherapy (IMRT);|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical complete response (cCR) | Proportion of patients who achieve a clinical complete response following therapy, expressed as a number and proportion without dispersion. | 8 (+/-4 ) weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measure Toxicity | Toxicity defined as non-hematologic grade 4 adverse events using CTCAE v5 or higher toxicity at least possibly related to treatment, and assessed up to 3 months after completion of radiotherapy (RT) and chemotherapy, expressed as a number and proportion without dispersion | 3 months | 
| Local regrowth rate | Local regrowth is defined as the presence of adenocarcinoma within the rectal wall or within the mesorectum confirmed by pathology, expressed as a percentage with its 95% confidence interval. | 2 year | 
| Disease free survival (DFS) | DFS defined as the time from the start date of RT to the date of the first documented progression or death due to any cause assessed up to 2 years after completion of chemotherapy. Patients will be censored at the last date of follow-up if lost to follow-up prior to two years, expressed as a median with interquartile range. | 2 years | 
| Colostomy-free survival | Colostomy-free survival defined as the time from the start date of RT to the date of colostomy or death due to any cause assessed up to 2 years after completion of chemotherapy, expressed as a median with interquartile range. Patients will be censored at the last date of follow-up if lost to follow-up prior to two years. | 2 years | 
| Overall Survival (OS) | OS defined as death from any cause from start date of RT until death, study completion, or loss to follow-up, whichever occurs first. This will be reported as median survival time with interquartile range. | 84 months |