A Phase II Trial of Neoadjuvant Regorafenib in Combination with Nivolumab and Short-course Radiotherapy in Stage II-III Rectal Cancer
This is a multicenter, single-arm, phase II study of nivolumab in combination with regorafenib in subjects with locally-advanced rectal cancer who are eligible for a curative treatment including pre-operative SCRT and TME(or watch \& wait approach). The study is based on the Simon's two-stage design and a maximum of 60 subjects will be enrolled. In addition to the standard efficacy interim analysis according to the statistical design, a safety interim analysis will be performed on the first 6 subjects who have completed the study treatment to ensure safe continuation of the study investigation. Eligible subjects will be treated according to the following sequential treatment plan: * Induction treatment: This consists of treatment with nivolumab (240 mg intravenously, on day 1 and 15) and regorafenib (60 mg/day orally, from day 1 to 14) * Standard SCRT: This consists of 25 Gy delivered in 5 fractions (from day 22 to 26) * Consolidation treatment: This consists of treatment with nivolumab (240 mg intravenously, on day 29, 43 and 57) and regorafenib (60 mg/day orally, from day 29 to 49) * Surgery: Surgical resection will be performed according to the principles of TME (between day 74 and 87, i.e., between 7 to 8 weeks after completion of SCRT). As an alternative to surgery, subjects who achieve cCR can be offered a watch \& wait approach. * Adjuvant chemotherapy: Administration of adjuvant chemotherapy will be left to the discretion of the treating physician The study also includes translational procedures (i.e. collection of tumour biopsies, blood samples and stool samples at pre-specified time points) for exploratory molecular and immune contexture analyses. These are mandatory for all study subjects.
• Female or Male
• Age ≥ 18 years old
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
• Histologically or cytologically verified adenocarcinoma of the rectum
• Tumour with distal border below the peritoneal reflection and within 15 cm from the anal verge
• Stage cT3/T4a and Nany or cT1-2 and N+ as documented by baseline pelvic MRI
• Absence of distant metastases as shown by baseline computed tomography (CT) of the thorax-abdomen or CT scan of the thorax and MRI of the abdomen
• Adequate haematological function as defined by absolute neutrophil count (ANC) ≥1.5 × 109/L, platelet count ≥100 × 109/L, and haemoglobin ≥9 g/dL
• Adequate hepatic function as defined by a total bilirubin level ≤1.5 × the upper limit of normal (ULN) range (excluding subjects with known Gilbert's syndrome) and alanine aminotransferase (ALT) levels ≤2.5 × ULN
⁃ Adequate renal function as defined by an estimated creatinine clearance ≥30 mL/min according to the Cockcroft-Gault or Wright formula
⁃ Negative serum pregnancy test at screening (up to 7 days before treatment start) for women of childbearing potential
⁃ Women of childbearing potential must agree to use of one highly effective method of contraception prior study entry, during the course of the study and at least 5 months after the last administration of study treatment.
⁃ Men with childbearing potential partner must agree to use condom during the course of this study and for at least 5 months after the last administration of the study treatment.
⁃ Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
⁃ Absence of clinical conditions that, in the opinion of the investigator, would contraindicate neoadjuvant therapy and/or surgery
⁃ Life expectancy of at least 3 months
⁃ Completion of all necessary screening procedures within 28 days prior to enrolment.
⁃ Signed Informed Consent form (ICF) obtained prior to any study related procedure.