Regorafenib Alone or in Combination With Hypofractionated/Low-dose Radiotherapy Plus Toripalimab for Metastatic Colorectal Cancer (SLOT)

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

The study compares the efficacy and safety of regorafenib alone or in combination with hypofractionated radiotherapy 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 54 patients will receive regorafenib monotherapy. Experimental arm: a total of 54 patients will first receive 1 cycle of regorafenib and toripalimab followed by hypofractionated/low-dose radiotherapy. Regorafenib and toripalimab will be continued after the completion of radiotherapy. The survival benefits, response rates, and adverse effects will be analyzed.

Study Overview

• Status: Recruiting
• Conditions: Microsatellite Stable Metastatic Colorectal Cancer
• Intervention / Treatment: Drug: Regorafenib; Drug: Regorafenib; Drug: Toripalimab; Radiation: Radiotherapy

Detailed Description

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 hypofractionated radiotherapy (5 fractions of 4-12Gy) and low-dose radiotherapy (5 fractions of 0.5-2Gy).

• Study Type: Interventional
• Enrollment (Estimated): 108
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Zhen Zhang, MD, PhD; Phone Number: 18801735029; Email: zhen_zhang@fudan.edu.cn

Study Locations

• China
  • Shanghai, China
    • Recruiting
    • Fudan University Shanghai Cancer Center
    • Contact: Zhen Zhang, MD, PhD; Phone Number: 18801735029; Email: zhen_zhang@fudan.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age ≥18 years old
2. An Eastern Cooperative Oncology Group (ECOG) performance status ≤1
3. Life expectancy of at least 3 months
4. Histopathological confirmed MSS/pMMR adenocarcinoma of the colon or rectum
5. At least one evaluable metastatic lesion for radiotherapy according to RECIST 1.1
6. Progressed on or after the standard first-and second-line therapies or stopped standard therapy because of unacceptable toxic effects
7. Previous radiotherapy completed at least 4 weeks before randomization
8. 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
9. Sign the informed consent and have good compliance

Exclusion Criteria:

1. History of previous treatment with regorafenib and ICIs such as anti-PD-1 or anti-PD-L1 mAbs
2. Current severe cardiovascular diseases such as unstable angina, congestive heart failure, or serious cardiac arrhythmia requiring medication
3. Acute cardiac infarction or cerebral ischemic stroke occurred within 6 months before recruitment
4. Active autoimmune diseases and immunodeficiencies, known history of organ transplantation, or systematic use of immunosuppressive agents
5. 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
6. Positive human immunodeficiency virus (HIV) infection, active syphilis infection, or active pulmonary tuberculosis infection
7. Severe infections requiring systemic antibiotics, antifungal or antiviral therapy
8. Uncontrollable pleural effusion, pericardial effusion, or ascites
9. 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.
10. Known history of severe neurological or mental illness such as schizophrenia, dementia, or epilepsy
11. Known history of allergy to any component involved in this study.
12. Pregnancy or breast-feeding women

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: monotherapy; a total of 54 patients will receive regorafenib monotherapy.	Drug: Regorafenib; Regorafenib 120 mg orally once daily on days 1-21 of each 28 days cycle.; Other Names: Stivarga; Drug: Regorafenib; Regorafenib 80mg orally once daily on days 1-21 of each 28 days cycle.
Experimental: combination therapies; a total of 54 patients will first receive 1 cycle of regorafenib and toripalimab followed by hypofractionated/low-dose radiotherapy. Regorafenib and toripalimab will be continued after the completion of radiotherapy.	Drug: Regorafenib; Regorafenib 120 mg orally once daily on days 1-21 of each 28 days cycle.; Other Names: Stivarga; Drug: Regorafenib; Regorafenib 80mg orally once daily on days 1-21 of each 28 days cycle.; Drug: Toripalimab; 240 mg intravenously every 3 weeks; Radiation: Radiotherapy; hypofractionated radiotherapy (5 fractions of 4-12Gy) and low-dose radiotherapy (5 fractions of 0.5-2Gy).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
OS	Defined as the time from initiation of treatment to death from any cause.	Up to 2 years

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
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
PFS	Defined as the time from initiation of treatment to PD or death from any cause.	Up to 2 years
ORR	The percentage of patients with objective response in all metastatic lesions.	Up to 1 year

Collaborators and Investigators

• Sponsor: Fudan University
• Investigators: Principal Investigator: Zhen Zhang, MD, PhD, Fudan University

Study record dates

Study Major Dates

• Study Start (Actual): April 25, 2023
• Primary Completion (Estimated): April 25, 2025
• Study Completion (Estimated): April 25, 2026

Study Registration Dates

• First Submitted: July 19, 2023
• First Submitted That Met QC Criteria: July 19, 2023
• First Posted (Actual): July 27, 2023

Study Record Updates

• Last Update Posted (Actual): September 24, 2024
• Last Update Submitted That Met QC Criteria: September 22, 2024
• Last Verified: September 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms
• Other Study ID Numbers: FDRT-2023-118-3237

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No