Phase II Study of Neoadjuvant Regorafenib and Nivolumab with Short-Course Radiotherapy in Intermediate-Risk Stage II-III Rectal Cancer
- Trial ID
- 2024-516554-22-00
- Protocol
- IJB-REGINA-2020
- Sponsor
- Institut Jules Bordet
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this phase II trial is to demonstrate that administering a combination treatment of **nivolumab** and **regorafenib** before and after standard pre-operative short-course radiotherapy (SCRT) is associated with a promising complete response (CR) rate in subjects with locally-advanced stage II-III rectal cancer characterized by proficient mismatch repair (pMMR) and microsatellite stable (MSS) tumors. This is clinically relevant as achieving a higher CR rate could potentially improve patient outcomes and reduce the need for more invasive surgical interventions.
Secondary objectives include:
- Assessing the safety of the investigational treatment in terms of toxicity during and after completion of pre-operative therapy and intra-/post-operative complications.
- Evaluating the feasibility of combining regorafenib with nivolumab in the setting of locally-advanced rectal cancer, as demonstrated by subject compliance with the investigational strategy, SCRT, and surgery (if performed).
- Assessing other efficacy outcome measures, including R0 resection rate, pathological tumor regression grade, tumor downstaging/downsizing, disease-free survival, progression-free survival, and overall survival.
- Evaluating the immune activation induced by the investigational treatment as shown by the increase in inflammatory infiltrate in post-treatment tumor tissue samples.
Participants
The clinical trial involves participants diagnosed with **locally-advanced stage II-III rectal cancer**. The study population includes both male and female subjects aged 18 years and older. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial does not include a vulnerable population. Participants must have adequate renal, hepatic, and hematological function, and a life expectancy of at least three months. The selection criteria ensure that participants do not have distant metastases, as confirmed by baseline imaging. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet and physical activity are not specified in the trial data. The trial population was selected based on specific medical and physiological criteria, including the absence of psychological or geographical conditions that could impede compliance with the study protocol.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of a combination treatment involving **regorafenib** and **nivolumab** in patients with locally-advanced stage II-III rectal cancer. This is a phase II, randomized, double-blind, controlled trial. The primary objective is to assess the complete response rate in subjects with pMMR/MSS tumors. The trial is expected to run from January 1, 2021, to January 31, 2030, with participants involved for a maximum treatment period of 34 weeks for regorafenib and 5 weeks for nivolumab.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as adequate renal and hepatic function, absence of distant metastases, and a life expectancy of at least 3 months. Following successful screening, participants will be randomized to receive either the investigational treatment or a control. The treatment phase includes administration of regorafenib orally and nivolumab intravenously, alongside standard pre-operative short-course radiotherapy (SCRT).
Follow-up visits will be scheduled to monitor treatment compliance, assess toxicity, and evaluate the pathological tumor regression grade. The end-of-study visit will occur after the completion of the treatment regimen, where the primary and secondary endpoints, including the R0 resection rate and overall survival, will be assessed. Participants may be withdrawn from the study early due to adverse events, non-compliance, or at the discretion of the investigator if continued participation is deemed not in the participant's best interest.
Treatment
The clinical trial involves the administration of **Regorafenib**, an experimental medication provided in the form of a **tablet**. The active substance, regorafenib, is of chemical origin and is manufactured by Institut Jules Bordet. The medication is administered orally with a maximum daily dose of 60 mg and a total maximum dose of 2040 mg over a treatment period of 34 days. The dosing schedule is designed to ensure optimal therapeutic levels while monitoring participant compliance through regular assessments.
In addition to regorafenib, the trial includes the administration of **Nivolumab**, marketed under the name OPDIVO, which is provided as a **concentrate for solution for infusion**. This medication is produced by Bristol-Myers Squibb Pharma EEIG and contains the active substance nivolumab, a protein of other origin. The administration route is intravenous, with a maximum daily dose of 240 mg and a total maximum dose of 1200 mg over a treatment period of 5 days. The infusion schedule is carefully monitored to ensure adherence and to evaluate the pharmacokinetic profile of the drug in participants.
The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. The primary objective is to assess the efficacy of the combination treatment of nivolumab and regorafenib in achieving a complete response rate in subjects with intermediate-risk, stage II-III rectal cancer. Compliance with the dosing regimen is monitored through regular follow-ups and assessments to ensure the integrity of the trial data.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the **Complete Response (CR) rate**, which includes both pathological complete response (pCR) and clinical complete response (cCR) in subjects with pMMR/MSS tumors. Secondary endpoints for efficacy evaluation include the CR rate in the mMiITT population, which encompasses both pMMR/MSS and dMMR/MSI-H tumors, as well as other parameters such as toxicity, compliance to treatment, R0 resection rate, pathological tumor regression grade (pTRG), local recurrence rate, distant recurrence rate, event-free survival (EFS), overall survival (OS), and the increase of CD3 and CD8 T-cells infiltrate in post-treatment tumor tissue samples.
The measurement and collection of these efficacy parameters will be conducted at specified timepoints throughout the trial. The analysis will involve validated clinical and laboratory assessments to ensure accurate and reliable data. The trial aims to demonstrate that the combination treatment of nivolumab and regorafenib, administered before and after standard pre-operative short-course radiotherapy (SCRT), is associated with a promising CR rate in the target population. The trial is designed to provide comprehensive insights into the treatment's efficacy, contributing to the understanding of its potential benefits in intermediate-risk, stage II-III rectal cancer.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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
- treatment start) for women of childbearing potential 12) 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 7 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.
Exclusion Criteria
- Any prior or concurrent surgery, chemotherapy, radiotherapy, immunotherapy, biologic or hormonal therapy for rectal cancer. Concurrent use of hormones for noncancer-related conditions (i.e., insulin for diabetes and hormone replacement therapy) is acceptable.
- Any contraindication to pelvic irradiation as evaluated by the investigator
- Prior organ transplantation, including allogeneic stem cell transplantation
- Clinically significant acute or chronic infections including, among others: - known history of testing positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) - known history of testing positive for hepatitis B virus (HBV) surface antigen or anti-hepatitis C virus (HCV) antibody and confirmatory HCV ribonucleic acid (RNA) test
- Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent (subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible)
- Systemic corticosteroids administered as hormone replacement or as immunosuppressants at doses exceeding 10 mg/day of prednisone or equivalent. Other immunosuppressive medications including, but not limited to methotrexate, azathioprine, and TNF-α blockers. Use of immunosuppressive medications for the management of treatmentrelated AEs or in subjects with contrast allergies is acceptable. A temporary period of steroids is allowed for different indications, at the discretion of the investigator (i.e., chronic obstructive pulmonary disease, radiation, nausea, etc.). Administration of steroids through a route known to result in a minimal systemic exposure [topical, intranasal, intro-ocular, or inhalation] is acceptable
- Known severe hypersensitivity reactions to the investigational treatments, or any excipients or non-investigational medicinal products or concomitant medications
- Pregnant and/or lactating women
- Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke, myocardial infarction, unstable angina, congestive heart failure, uncontrolled arterial hypertension, or serious cardiac arrhythmia requiring medication
- Prior myocarditis
- Known history of immune colitis, immune pneumonitis, pulmonary fibrosis or other medical conditions (for example, inflammatory bowel disease, uncontrolled asthma), which, in the opinion of the Investigator, might impair the subject’s tolerance of trial treatment
- Vaccination within 28 days of the first dose of study treatment and while on trial (except for administration of inactivated vaccines)
- Other invasive malignancy within 2 years except for non-invasive malignancies such as cervical carcinoma in situ, non-melanomatous carcinoma of the skin or ductal carcinoma in situ of the breast that has/have been surgically cured. Anti-neoplastic treatment received in the past for malignancies cured 2 or more years before enrolment are permitted.
- Any investigational anti-cancer therapy other than the protocol specified therapies.
- therapies. 15) Strong inhibitors of CYP3A4 activity (e.g. clarithromycin, grapefruit juice, itraconazole, ketoconazole, posaconazole, telithromycin and voriconazole), strong UGT1A9 inhibitors (e.g. mefenamic acid, diflunisal, and niflumic acid), and strong inducers of CYP3A4 (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital and St. John’s wort) from 28 days before study enrolment up to the end of study treatment.
- Major surgery within 28 days of the first dose of study treatment
- Presence of gastrointestinal perforation or fistula
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 01 Jan 2021 | 90 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
OPDIVO 10 mg/mL concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 240 | 5 | PRD2941372 |
Regorafenib_IJB | Test | TABLET | ORAL USE | 60 | 34 | PRD11193464 |