Regorafenib Alone or in Combination With High/Low-dose Radiotherapy Plus Toripalimab for Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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The study compares the efficacy and safety of regorafenib alone or in combination with stereotactic ablative radiotherapy (SABR) and low-dose radiotherapy (LDRT) plus toripalimab in patients with microsatellite stable metastatic colorectal cancer (MSS mCRC). Patients are randomly assigned (1:1) into the control arm and the experimental arm. Control arm: a total of 45 patients will receive regorafenib monotherapy. Experimental arm: a total of 45 patients will first receive 1 cycle of regorafenib and toripalimab followed by SABR/LDRT radiotherapy. Regorafenib and toripalimab will be continued after the completion of radiotherapy. The objective response rate (ORR), survival benefits, and adverse effects will be analyzed.

Detailed Description
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Control arm: regorafenib 120 mg orally once daily on days 1-21 of each 28 days cycle. Experimental arm: regorafenib is administered 80 mg once daily on days 1-21 of each 28 days cycle with intravenous toripalimab 240 mg every 3 weeks. Radiotherapy regimes include 4-8 fractions of 8-12Gy via SABR and up to 1-10Gy at 0.5-2Gy/fraction via LDRT.

Official Title
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A Prospective, Randomized, Controlled Phase II Trial of Regorafenib Alone or in Combination With High/Low-dose Radiotherapy Plus Toripalimab as Third-line Treatment in Patients With Metastatic Colorectal Cancer

Conditions
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Microsatellite Stable Metastatic Colorectal Cancer

Intervention / Treatment
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* Drug: Regorafenib
* Drug: Toripalimab
* Radiation: High/low-dose radiotherapy
* Drug: Regorafenib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years old An Eastern Cooperative Oncology Group (ECOG) performance status ≤1 Life expectancy of at least 3 months Histopathological confirmed MSS/pMMR adenocarcinoma of the colon or rectum At least two evaluable metastatic lesions for SABR and LDRT according to RECIST 1.1 Progressed on or after the standard first-and second-line therapies or stopped standard therapy because of unacceptable toxic effects Previous radiotherapy completed at least 4 weeks before randomization Adequate bone-marrow, hepatic, and renal function: neutrophils ≥ 1.5 × 10^9/L, Hb ≥ 90 g/L, PLT ≥ 100 × 10^9/L, ALT/ AST≤2.5 ULN, Cr≤1 ULN Sign the informed consent and have good compliance Exclusion Criteria: History of previous treatment with regorafenib and ICIs such as anti-PD-1 or anti-PD-L1 mAbs Current severe cardiovascular diseases such as unstable angina, congestive heart failure, or serious cardiac arrhythmia requiring medication Acute cardiac infarction or cerebral ischemic stroke occurred within 6 months before recruitment Active autoimmune diseases and immunodeficiencies, known history of organ transplantation, or systematic use of immunosuppressive agents Active Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection: HBsAg positive or HBV DNA positive, anti-HCV antibody testing positive and confirmatory HCV RNA positive Positive human immunodeficiency virus (HIV) infection, active syphilis infection, or active pulmonary tuberculosis infection Severe infections requiring systemic antibiotics, antifungal or antiviral therapy Uncontrollable pleural effusion, pericardial effusion, or ascites Other malignancies within 5 years before recruitment, except for non-melanoma skin cancer, superficial bladder cancer, cervical carcinoma in situ, or breast cancer in situ that had been effectively treated. Known history of severe neurological or mental illness such as schizophrenia, dementia, or epilepsy Known history of allergy to any component involved in this study. Pregnancy or breast-feeding women

Ages Eligible for Study
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Minimum Age: 18 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 |
| --- | --- |
| Active Comparator: monotherapy<br>a total of 45 patients will receive regorafenib monotherapy. | Drug: Regorafenib<br>* Regorafenib 120 mg orally once daily on days 1-21 of each 28 days cycle.<br>* Other names: Stivarga;|
| Experimental: combination therapies<br>a total of 45 patients will first receive 1 cycle of regorafenib and toripalimab followed by SABR/LDRT radiotherapy. Regorafenib and toripalimab will be continued after the completion of radiotherapy. | Drug: Toripalimab<br>* 240 mg intravenously every 3 weeks<br>Radiation: High/low-dose radiotherapy<br>* 4-8 fractions of 8-12Gy via SABR and up to 1-10Gy at 0.5-2Gy/fraction via LDRT.<br>Drug: Regorafenib<br>* Regorafenib 80mg orally once daily on days 1-21 of each 28 days cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ORR | The percentage of patients with objective response in all metastatic lesions. Objective response is defined as complete response (CR) or partial response (PR) per response evaluation criteria (RECIST v1.1) and the immune-related response criteria (iRECIST) after treatment. | Up to 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| DCR | The percentage of patients with disease control in all metastatic lesions. Disease control is defined as CR, PR, or stable disease (SD) per RECIST v1.1 and iRECIST after treatment. | Up to 1 year | 
| DoR | Defined as the time between PR/CR and subsequent progression disease (PD) per RECIST v1.1 and iRECIST or death from any cause. | Up to 1 year | 
| PFS | Defined as the time from initiation of treatment to PD or death from any cause. | Up to 3 years | 
| OS | Defined as the time from initiation of treatment to death from any cause. | Up to 3 years | 
| Adverse events | The percentage of patients with treatment-related acute toxicities as assessed by NCI CTCAE v5.0, from treatment initiation until 90 days upon completion of immunotherapy. | Up to 1 year |