ShorTrip study - Phase II study of Short-course radiotherapy followed by consolidation chemotherapy with the Triplet FOLFOXIRI as total neoadjuvant therapy for locally advanced rectal cancer.

Prior treatment

• Active uncontrolled infections or other clinically relevant concomitant illness contraindicating chemotherapy administration
• Previous pelvic radiation therapy
• Previous treatment with fluoropyrimidine and/or oxaliplatin and/or irinotecan
• Treatment with any investigational drug within 30 days prior to enrolment or 2 investigational agent half-lives (whichever is longer)
• Active uncontrolled infections or other clinically relevant concomitant illness contraindicating chemotherapy administration

Other illness

• Previous history of malignancy within the last 5 years will be excluded with the exception of localized basal and squamous cell carcinoma or cervical cancer in situ
• Active inflammatory bowel disease (i.e., patients requiring current medical interventions or who are symptomatic)
• Known hypersensitivity to fluorouracil, oxaliplatin or irinotecan
• Psychiatric or addictive disorders, or other conditions that, in the opinion of the investigator, would preclude study participation
• Clinically significant (e.g. active) cardiovascular disease for example cerebrovascular accidents (≤6 months), myocardial infarction (≤6 months), unstable angina, New York Heart Association (NYHA) grade II or greater congestive heart failure (CHF), serious cardiac arrhythmia requiring medication

Other

• Partial or total colectomy
• Pregnant or lactating women. Women of childbearing potential with either a positive or no pregnancy test at baseline. Sexually active males and females (of childbearing potential) unwilling to practice contraception during the study and until 180 days after the last trial treatment
• Withdrawal of the consent to take part to the study
• Patients with radiological evidence of distant metastases
• Symptomatic peripheral neuropathy > 2 grade NCIC-CTG criteria
• Patient with complete dihydropyrimidine dehydrogenase (DPYD) deficiency (homozygous of the following DPYD polymorphisms: c1679GG, c1905+1AA, c2846TT)

• Written informed consent to study procedures and to translational analyses;
• No history of invasive rectal malignancy, regardless of disease-free interval
• No other rectal cancers (i.e., sarcoma, lymphoma, carcinoid, squamous cell carcinoma, or cloacogenic carcinoma) or synchronous colon cancer
• No clear involvement of the pelvic side walls by imaging
• Life expectancy of at least 5 years (excluding diagnosis of cancer)
• Hematopoietic function: absolute neutrophil count ≥ 1,500/mm3; platelet count ≥100,000/mm3; haemoglobin level ≥ 9 g/dL
• Liver function: total bilirubin ≤ 1.5 times upper limit of normal (ULN); alkaline phosphatase ≤ 2 times ULN; AST ≤ 2 times ULN
• Renal function: creatinine clearance > 50 mL/min or serum creatinine 1.5 x UNL; no renal disease that would preclude study treatment or follow-up
• Women of childbearing potential must have a negative blood pregnancy test at the screening visit. For this trial, women of childbearing potential are defined as all women after puberty, unless they are postmenopausal for at least 12 months, are surgically sterile, or are sexually inactive. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient
• Subjects and their partners must be willing to avoid pregnancy during the trial. Male subjects with female partners of childbearing potential and female subjects of childbearing potential must, therefore, be willing to use adequate contraception. Contraception, starting during study screening visit throughout the study period up to 180 days after the last dose of chemotherapy
• Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject
• Age 18-70 years
• Will and ability to comply with the protocol
• Histologically proven diagnosis of rectal adenocarcinoma
• Patients with locally advanced rectal cancer defined by the presence of at least one of the following features: o cN2 (defined as at least 4 positive lymphnodes at pelvic MRI) o cT4 o tumor extending to within 1 mm of or beyond mesorectal fascia (i.e., circumferential radial margin threatened or involved) o cT3, N1
• Distal border of the tumour located between 5 and 12 cm from the anal verge (as measured by pelvic MRI)
• Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤1
• No evidence of metastatic disease by total body CT-scan
• Available tumour samples at baseline (archival biopsy)
• Tumour amenable to curative resection (including pelvic exenteration)