Total Neoadjuvant Therapy With mFOLFOX and Short-course Radiation in Resectable Rectal Cancer

Study Overview
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Brief Summary
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This is phase 2 trial of neoadjuvant therapy and short-course radiotherapy in resectable rectal cancer.

Detailed Description
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This trial involves 4 cycles of systemic chemotherapy followed by short-course RT with concurrent 5-FU neoadjuvant chemoradiotherapy (CRT) and subsequent consolidation with 4 cycles of systemic chemotherapy prior to surgery or, for those who achieve cCR, the option of non-operative active surveillance.Three-year disease free survival (DFS) defined as the percentage of patients alive without recurrence of disease at 3 years measured from the date of clinical complete response (cCR) or date of total mesorectal excision (TME) at surgery (whichever is earlier).

Official Title
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Phase 2 Study of Total Neoadjuvant mFOLFOX and Short-Course Radiotherapy in Resectable Rectal Cancer

Conditions
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Rectal Cancer

Intervention / Treatment
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* Drug: Chemotherapy
* Radiation: Radiation Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pathologic diagnosis of adenocarcinoma of the rectum (diagnosis by tissue biopsy) within 90 days prior to registration. At least a portion of the tumor must be located below the peritoneal reflection or begin within 12 cm of the anal verge on flexible endoscopy Clinically staged (AJCC 8th ed.) T3-4 N0 M0 or T any N1-2 M0 based upon the following minimum diagnostic workup: Colonoscopy within 90 days prior to registration Within 28 days prior to registration: History/physical examination Imaging to exclude distant metastases: either contrast-enhanced CT of the chest, abdomen, and pelvis or whole-body PET-CT Pelvic MRI (preferred) or transrectal ultrasound (TRUS) for T staging ECOG Performance Status ≤1 Age ≥ 18 years Adequate bone marrow function defined as follows: Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3 Platelets ≥ 100,000 cells/mm3 Hemoglobin ≥ 8.0 g/dL (Note: The use of transfusion or other intervention to achieve Hgb ≥8.0 g/dL is acceptable.) Adequate liver and renal function defined as follows: AST and alkaline phosphatase < 2.5 x upper limit of normal (ULN) Bilirubin ≤ 1.5 ULN Calculated creatinine clearance (CrCl) > 50 mL/min using Cockcroft-Gault formula as calculated by the standard Cockcroft-Gault equation using age, actual weight, creatinine, and gender Must be deemed a candidate for curative resection by the surgical oncologist who will be performing the operation Women of childbearing potential (WCBP) must have a negative serum pregnancy test performed within 7 days prior to the start of chemotherapy. WCBP and men must agree to use a medically accepted form of birth control during the treatment and for 3 months following completion of chemotherapy. Ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria: Prior RT that would result in overlap of RT fields with the planned study treatment Clinically significant cardiac disease, including major cardiac dysfunction, such as uncontrolled angina, clinical congestive heart failure with New York Heart Association (NYHA) class III or IV, ventricular arrhythmias requiring anti-arrhythmic therapy, recent (within the last 6 months) myocardial infarction, or unstable disease Serious (ie, ≥ grade 3) uncontrolled infection Within 30 days prior to registration, either of the following that would, in the opinion of the investigator, preclude study therapy: Chronic obstructive pulmonary disease exacerbation Respiratory illness requiring hospitalization Hepatic insufficiency resulting in clinical jaundice and/or known coagulation defects Major surgery within 28 days of study enrollment (other than diverting colostomy) History of inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis requiring significant intervention (eg, hospitalization, surgery, immunosuppressive medications that would, in the opinion of the investigator, preclude study therapy Prior known allergic reaction to 5-FU or oxaliplatin Known dipyrimidine dehydrogenase deficiency (DPD) Any evidence of distant metastases (M1) Pregnant or breast feeding Medical, psychological, or social condition that, in the opinion of the investigator, may increase the patient's risk or limit the patient's adherence with study requirements

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Concurrent Chemotherapy/ Radiation Therapy<br>5-Fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) four 14-day cycles will be given before CRT starts. Pelvic Intensity-modulated radiation therapy (IMRT): 25 Gy in 5 fractions over 5 days + Continuous infusion 5-fluorouracil (5-FU) for 4 days (96 hours) followed by four 14-day cycles of (mFOLFOX6) to be given after CRT ends. | Drug: Chemotherapy<br>* Neoadjuvant chemotherapy with 2 months of combination oxaliplatin and 5-Fluorouracil, leucovorin, and oxaliplatin (mFOLFOX)<br>Radiation: Radiation Therapy<br>* Pelvic Intensity-modulated radiation therapy (IMRT)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Three-year disease free survival (DFS) | The three-year disease free survival (DFS) defined as the number of patients alive without recurrence of disease at 3 years measured from the date of clinical complete response (cCR) or date of total mesorectal excision (TME) at surgery (whichever is earlier). | 3 years after end of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathologic complete response (pCR) rate | The number of patients that achieve pathologic complete response(pCR)(defined as negative surgical margins and no evidence of residual viable tumor) at time of total mesorectal excision (TME). | 3 Years after end of treatment | 
| Clinical complete response (cCR) following total neoadjuvant therapy (TNT) based on tumor response | Determine the cCR using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1), in patients evaluable for response | 3 Years after end of treatment | 
| The number of Adverse events (AEs) per participant | The number of Adverse events (AEs) per participant characterized and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI CTCAE v. 5.0) | 39 Months | 
| Progression (PFS) Rate | PFS defined as the time from initiation of chemotherapy until date of progression | 3 Years after end of treatment | 
| Overall Survival (OS) Rate | OS defined as the time from initiation of chemotherapy until death by any cause. | 3 Years after end of treatment | 
| Number of patients who do not require an ostomy at time of surgery | After neoadjuvant therapy is complete patients will undergo assessment of disease status prior to determination of whether they will proceed to surgical resection or active surveillance | 116 Days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rectal, Resectable