Totally Neoadjuvant FOLFOXIRI + Short-course Radiation + XELOX in Patients With Locally Advanced Rectal Cancer

Study Overview
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Brief Summary
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To evaluate the efficacy and safety of totally neoadjuvant FOLFOXIRI chemotherapy (irinotecan, oxaliplatin and fluorouracil) followed by short-course radiation therapy and XELOX chemotherapy in the patients with locally advanced rectal cancer.

Detailed Description
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Neoadjuvant chemoradiation therapy with double cytotoxic agents is the standard treatment for the patients with locally advanced rectal cancer. Conventional treatment reduced the local recurrence but did not prolong the long-term survival. Furthermore, the patients with pathological complete response (pCR) did not benefit from double cytotoxic chemotherapy. Therefore, we chose triple cytotoxic agents FOLFOXIRI as the neoadjuvant chemotherapy. We will evaluate the efficacy and safety of totally neoadjuvant FOLFOXIRI chemotherapy (irinotecan, oxaliplatin and fluorouracil) followed by short-course radiation and XELOX chemotherapy in the patients with locally advanced rectal cancer to achieve more pCR and longer survival. In this prospective study, 30 patients with locally advanced rectal cancer will be recruited. Firstly, 4 cycles of neoadjuvant FOLFOXIRI chemotherapy were administered. Subsequently, a short-course radiation therapy (5Gy*5) will be performed. After that, 4 cycles of XELOX chemotherapy will be administered followed by TME surgery. PET-CT examination will be performed before and after the 4 cycles of neoadjuvant FOLFOXIRI chemotherapy to assess the SUVmax changes. In addition, the dynamic changes of ctDNA in peripheral blood will be monitored at the PET-CT examination. In the course of treatment, safety evaluation will be carried out according to the standard of adverse reaction classification (CTCAE) 4.0.

Official Title
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Totally Neoadjuvant FOLFOXIRI Chemotherapy Followed by Short-course Radiation and XELOX Chemotherapy in Patients With Locally Advanced Rectal Cancer：an Open-label, Single-arm, Multicenter Phase II Study.

Conditions
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Rectal Neoplasms, Drug Therapy, Radiation

Intervention / Treatment
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* Drug: FOLFOXIRI
* Radiation: Short-Course Radiation Therapy(5Gy*5)
* Drug: XELOX


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age: 18-75 years old Primary and pathological diagnosis of rectal adenocarcinoma Radiographic evaluation of initial resectable rectal cancer T staging was determined by MRI as T3N+ or T4Nx Distal border of the tumor must be located < 12 cm from the anal verge ECOG status: 0～1 Adequate bone marrow, hepatic and renal function as assessed by the following laboratory requirements conducted within 7 days of starting study treatment: Neutrophil count≥1.5×10^9/L Platelet count≥90×10^9/L Hemoglobin≥90g/L Total bilirubin (TBI) ≤ 1.5 * ULN Alanine aminotransferase (ALT)≤2.5 * ULN Aspartate aminotransferase (AST)≤2.5 * ULN Alkaline phosphatase (ALP)≤2.5 * ULN - Signed informed consent; able to comply with study and/or follow- up procedures Exclusion Criteria: Previous treatment with oxaliplatin, irinotecan or fluorouracil Hypersensitivity to fluorouracil, oxaliplatin or irinotecan. Clear indication of involvement of the pelvic side walls by imaging With distant metastasis A history of malignant rectal cancer (i. e. sarcoma, lymphoma, carcinoid, squamous cell carcinoma) or synchronous colon cancer Cardiovascular disease that would preclude study treatment or follow-up; New York Heart Association class III or IV heart disease; active ischemic heart disease; myocardial infarction within the past 6 months; symptomatic arrhythmia uncontrolled hypertension. Unexplained syncope occurred within 3 months Digestive system diseases that would preclude study treatment or follow-up within the past 6 months Gastric ulcers or duodenal ulcers for the treatment of resistance; 3 or 4 grade gastrointestinal bleeding / bleeding; Gastrointestinal perforation / fistula; Abdominal abscess; Infectious or inflammatory bowel disease HIV infection and/or active hepatitis B virus infection Pregnant or lactating women. Fertile patients must use effective contraception Any serious acute or chronic disease that can not be involved in the study or to influence the interpretation of the results of the study Other intervention clinical trials were combined at the same time. Nerve or mental abnormality affecting cognitive ability Other malignancy except effectively treated squamous cell or basal cell skin cancer, Other situations that the researchers think should be excluded

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: FOLFOXIRI+short-course radiation+XELOX<br>Firstly, 4 cycles of neoadjuvant FOLFOXIRI chemotherapy were administered. Subsequently, a short-course radiation therapy (5Gy*5) will be performed. After that, 4 cycles of XELOX chemotherapy will be administered followed by surgery. | Drug: FOLFOXIRI<br>* IRINOTECAN 150 mg/m^2 IV over 1-h, day 1 + OXALIPLATIN 85 mg/m^2 IV over 2-h, day 1 + L-LEUCOVORIN 200 mg/m^2 IV over 2-h, day 1 + 5-FLUOROURACIL 2800 mg/m^2 IV 48-h continuous infusion, starting on day 1 administered every two weeks for 4 cycles (2 months).<br>* Other names: 5-Fluorouracil;Radiation: Short-Course Radiation Therapy(5Gy*5)<br>* Patients received a short-course radiation therapy(5Gy*5) after 4 cycles of FOLFOXIRI.<br>Drug: XELOX<br>* OXALIPLATIN 130 mg/m^2 IV over 2-h, day 1 Capecitabine 1000 mg/m^2 twice daily days 1-14 every 3 weeks for 4 cycles.<br>* Other names: Oxaliplatin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The ratio of tumor downstaging to stage 0 and stage I | Tumor downstaging from stage II or III to pathologic complete response (stage 0) and stage I | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor regression grade (TRG) | The level of tumor regression under pathological examination | 2 years | 
| Disease free survival | Estimated from the date of surgery to the date of recurrence. | 3 years | 
| Overall survival time | Estimated from the date of enrollment to death from any cause. | 3 years | 
| Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] | The grade of toxicity will be assessed using the NCI-CTCAE version 4.0. | 3 years | 
| ctDNA change | The relationship between ctDNA and survival will be evaluated. | 3 years | 
| SUVmax changes | Tumor metabolic response through FDG-PET examination before and after 4 cycles of neoadjuvant FOLFOXIRI chemotherapy | At the beginning of Cycle 1 and the end of Cycle 4 (each cycle is 14 days) | 
| Quality of life (QLQ C30) | Scores according to EORTC QLQ-C30 scoring manual | Every 2 weeks after the first treatment until 3 years |