This prospective randomized, open-label, multicenter, phase II clinical trial investigates the safety and tolerability of standard neoadjuvant chemoradiotherapy (CRT) with sequential ipilimumab and nivolumab in rectal cancer.

Inclusion Criteria:

• 18 years of age and older
• All sexes
• Histologically confirmed carcinoma of the rectum
• Suitable for local therapy with curative intent
• Medical need for a standard neoadjuvant CRT
• Suitable to withstand a course of standard neoadjuvant CRT
• Written informed consent form (ICF) for participation in the study
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

Exclusion Criteria:

• Metastatic disease that is considered incurable by local therapies
• Previous surgery of the tumor other than biopsy
• Pregnancy, breastfeeding or expectancy to conceive
• Disagreement of participants with reproductive potential to use contraception throughout the study period and for up to 180 days after the last dose of study therapy
• Prior therapy with anti-CTLA-4, anti-PD-1, anti-PD-L1, anti-PD-L2 or any other agent directed against co-inhibitory T cell receptors or has previously participated in clinical studies with immunotherapy
• Any contraindication according to the official medical information of Ipilimumab or Nivolumab
• Live vaccine within 30 days prior to the first dose of study therapy
• Hepatitis B or C
• Human immunodeficiency virus (HIV)
• Immunodeficiency
• Allogeneic tissue or solid organ transplantation
• Autoimmune disease that has required systemic therapy in the past 2 years with modifying agents, steroids or immunosuppressive drugs
• Systemic steroids or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment
• Active non-infectious pneumonitis
• Active infection requiring systemic therapy
• Treatment with botanical preparations (i.e. herbal supplements or traditional Chinese medicines) intended for general health support or to treat the disease under study within 2 weeks prior to randomization/treatment
• Participants with serious or uncontrolled medical disorders
• Uncontrolled or significant cardiovascular disease (myocardial infarction, uncontrolled angina, any history of clinically significant arrhythmias, QTc prolongation in males > 450 ms and > 470 ms in females, participants with history of myocarditis)
• Allergies and adverse drug reaction (history of allergy or hypersensitivity to study drug components, contraindications to any of the study drugs of the chemotherapy regimen)
• Other exclusion criteria: Prisoners or participants who are involuntarily incarcerated, participants who are compulsorily detained for treatment of either a psychiatric or physical (i.e. infectious disease) illness
• White blood cells < 2000/μL (SI: < 2.00 × 109/L)
• Neutrophils < 1500/μL (SI: < 1.50 × 109/L)
• Platelets < 100 × 103/μL (SI: < 100 × 109/L) (transfusions not permitted within 72 h prior to qualifying laboratory value)
• Hemoglobin < 9.0 g/dl (SI: < 90 g/L) (transfusions not permitted within 72 h prior to qualifying laboratory value)
• Serum creatinine > 1.5 × upper limit of normal (ULN) or calculated creatinine clearance < 50 ml/min (using the Cockcroft-Gault formula)
• AST/ALT: > 3.0 × ULN
• Total bilirubin > 1.5 × ULN (except participants with Gilbert Syndrome who must have a total bilirubin level of < 3.0 × ULN)
• Troponin T (TnT) or I (TnI) > 2 × institutional ULN. TnT or TnI levels between > 1 to 2 × ULN will be permitted to participate in the study if a repeat assessment remains 2 × ULN and participant undergoes a cardiac evaluation. When repeat levels within 24 h are not available, a repeat test should be conducted as soon as possible.