Neoadjuvant Chemoradiotherapy With Sequential Ipilimumab and Nivolumab in Rectal Cancer

Study Overview
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Brief Summary
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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.

Official Title
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Neoadjuvant CHemoradiotherapy With Sequential Ipilimumab and NivOlumab in RECtal Cancer (CHINOREC): a Prospective Randomized, Open-label, Multicenter, Phase II Clinical Trial

Conditions
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Rectal Cancer

Intervention / Treatment
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* Radiation: Chemoradiotherapy
* Drug: Ipilimumab
* Drug: Nivolumab


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Neoadjuvant Chemoradiotherapy<br>Neoadjuvant Chemoradiotherapy (50 Gy in 2 Gy fractions + Capecitabine 1650 mg/m2/d over 25 working days) | Radiation: Chemoradiotherapy<br>* Capecitabine tablet with fractionated radiotherapy<br>* Other names: Chemoradiation;|
| Experimental: Neoadjuvant Chemoradiotherapy, Ipilimumab, Nivolumab<br>Neoadjuvant Chemoradiotherapy (50 Gy in 2 Gy fractions + Capecitabine 1650 mg/m2/d over 25 working days) with sequential Ipilimumab (1 mg/kg IV on day 7) and Nivolumab (3 mg/kg IV on day 14, 28 and 42) | Radiation: Chemoradiotherapy<br>* Capecitabine tablet with fractionated radiotherapy<br>* Other names: Chemoradiation;Drug: Ipilimumab<br>* Infusion<br>* Other names: Yervoy®;Drug: Nivolumab<br>* Infusion<br>* Other names: Opdivo®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment-emergent adverse events (safety and tolerability) | Incidence of treatment-emergent adverse events will be assessed according to the latest Clavien- Dindo Classification of surgical complications and Common Terminology Criteria of Adverse Events (CTCAE). | 20 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Radiographic therapy response between pre-and post-neoadjuvant treatment | Radiographic therapy response will be determined by magnetic resonance imaging-assessed tumor regression grade (mrTRG) | 20 weeks | 
| Pathologic therapy response to neoadjuvant treatment | Pathological therapy response will be determined according to the latest American Joint Committee on Cancer/International Union Against Cancer-Tumor Node Metastasis (AJCC/UICC-TNM) staging and tumor regression grade (TRG). | 20 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ipilimumab, Nivolumab, Chemoradiotherapy, Rectal cancer