Cryoablation Combined with Sintilimab Plus Regorafenib in Previously Treated Colorectal Cancer Liver Metastasis

A Phase II Study of Cryoablation Combined with Sintilimab Plus Regorafenib in Previously Treated Colorectal Cancer Liver Metastasis (CASTLE-03)

The objective of this study is to evaluate the efficacy and safety of cryoablation combined with Sintilimab plus regorafenib for patients with colorectal cancer liver metastasis in the third-line setting.

Study Overview

• Status: Recruiting
• Conditions: Colorectal Cancer Metastatic; Liver Metastases
• Intervention / Treatment: Drug: Sintilimab; Drug: Regorafenib; Combination product: US/CT-guided Percutaneous Cryoablation

Detailed Description

Recent studies have suggested that local destruction of tumor tissue by cryoablation induced activation and maturation of dendritic cells and tumor-specific T cells by cross-presentation of tumor antigens. While pd-1 blocking antibody interferes with PD-1 mediated T-cell regulatory signaling. And combination of pd-1 blocking antibody plus regorafenib showed increased ORR in advanced colorectal cancer. Therefore, the objective of this study is to evaluate the efficacy and safety of cryoablation combined with Sintilimab plus regorafenib in previously treated colorectal cancer liver metastasis.

• Study Type: Interventional
• Enrollment (Estimated): 25
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Peng Wang, MD; Phone Number: 86-21-64175590; Email: peng_wang@fudan.edu.cn

Study Locations

• China
  • Shanghai
    • Shanghai, Shanghai, China, 200032
      • Recruiting
      • Fudan University Shanghai Cancer Center
      • Contact: Peng Wang, M.D.; Phone Number: 83630 862164175590; Email: peng_wang@fudan.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Written informed consent obtained.
• Age ≥ 18 years at time of study entry.
• Participants must have colorectal cancer liver metastasis.
• Participants must have failed at least two previous systemic chemotherapy regimens (containing fluorouracil, oxaliplatin, and irinotecan) in the liver metastatic setting.
• Participants who had received previous antiangiogenic or anti-epidermal growth factor receptor (EGFR) therapy were eligible.
• At least one measurable site of disease as defined by RECIST criteria with spiral CT scan or MRI.
• Performance status (PS) ≤ 2 (ECOG scale).
• Life expectancy of at least 12 weeks.
• Adequate blood count, liver-enzymes, and renal function: absolute neutrophil count ≥ 1,500/L, platelets ≥75 x103/L; Total bilirubin ≤ 3x upper normal limit; Aspartate Aminotransferase (SGOT), Alanine aminotransferase (SGPT) ≤ 5 x upper normal limit (ULN); International normalized ratio (INR) ≤1.25; Albumin ≥ 31 g/dL; Serum Creatinine ≤ 1.5 x institutional ULN or creatinine clearance (CrCl) ≥ 30 mL/min (if using the Cockcroft-Gault formula )
• Female patients with reproductive potential must have a negative urine or serum pregnancy test within 7 days prior to start of trial.
• Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment, adherence to contraceptive measures, scheduled visits and examinations including follow up.

Exclusion Criteria:

• History of cardiac disease, including clinically significant gastrointestinal bleeding within 4 weeks prior to start of study treatment
• Thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within the 6 months Prior to the first dose of study drug with the exception of thrombosis of a segmental portal vein.
• Prior treatment with cryoablation.
• Prior treatment with regorafenib.
• RFA and resection administered less then 4 weeks prior to study treatment start.
• Radiotherapy administered less then 4 weeks prior to study treatment start.
• Major surgery within 4 weeks of starting the study treatment OR subjects who have not recovered from effects of major surgery.
• Patients with second primary cancer, except adequately treated basal skin cancer or carcinoma in-situ of the cervix.
• Immunocompromised patients, e.g. patients who are known to be serologically positive for human immunodeficiency virus (HIV).
• Participation in another clinical study with an investigational product during the last 30 days before inclusion or 7 half-lifes of previously used trial medication, whichever is longer.

• Any condition or comorbidity that, in the opinion of the investigator, would interfere with evaluation of study Treatment or interpretation of patient safety or study results, including but not limited to:

  1. history of interstitial lung disease
  2. Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) coinfection (i.e double infection)
  3. known acute or chronic pancreatitis
  4. active tuberculosis
  5. any other active infection (viral, fungal or bacterial) requiring systemic therapy
  6. history of allogeneic tissue/solid organ transplant
  7. diagnosis of immunodeficiency or patient is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of nivolumab-monotherapy treatment.
  8. Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Exceptions: Subjects with vitiligo, hypothyroidism, diabetes mellitus type I or resolved childhood asthma/atopy are an exception to this rule. Subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Subjects with Hashimoto thyroiditis, hypothyroidism stable on hormone replacement or psoriasis not requiring treatment are not excluded from the study.
  9. Live vaccine within 30 days prior to the first dose of Sintilimab treatment or during study treatment.
  10. History or clinical evidence of Central Nervous System (CNS) metastases Exceptions are: Subjects who have completed local therapy and who meet both of the following criteria: I. are asymptomatic and II. have no requirement for steroids 6 weeks prior to start of Sintilimab treatment. Screening with CNS imaging (CT or MRI) is required only if clinically indicated or if the subject has a history of CNS
• Medication that is known to interfere with any of the agents applied in the trial.
• Any other efficacious cancer treatment except protocol specified treatment at study start.
• Patient has received any other investigational product within 28 days of study entry.
• Prior therapy with an anti-Programmed cell death protein 1 (anti-PD-1), anti-PD-L1, anti-Programmed cell death-ligand 2 (anti-PD-L2), anti-CD137 (4-1BB ligand, a member of the Tumor Necrosis Factor Receptor (TNFR) family), or anti-Cytotoxic T-lymphocyte-associated antigen-4 (anti-CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
• Female subjects who are pregnant, breast-feeding or male/female patients of reproductive potential who are not employing an effective method of birth control (failure rate of less than 1% per year). [Acceptable methods of contraception are: implants, injectable contraceptives, combined oral contraceptives, intrauterine pessars (only hormonal devices), sexual abstinence or vasectomy of the partner]. Women of childbearing potential must have a negative pregnancy test (serum β-HCG) at screening.
• Patient with any significant history of non-compliance to medical regimens or with inability to grant reliable informed consent.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Cryoablation in combination with Sintilimab plus regorafenib

Drug: Sintilimab; Sintilimab plus regorafenib will be initiated on day 14 after cryoablation. Sintilimab will be administered at 200 mg i.v. every 3 weeks.; Drug: Regorafenib; Regorafenib will be initiated on day 14 after cryoablation. Regorafenib 80 mg was given orally once daily on days 1-21 of a 28-day cycle until documented disease progression, development of unacceptable toxicity, participant request, or withdrawal of consent.; Combination product: US/CT-guided Percutaneous Cryoablation; Cryoablation will be performed with a two-cycle freeze-thaw phase protocol; US or non-contrast CT images will be obtained to visualize the evolving ablation zone

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR)	ORR according to RECIST 1.1	max 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
DoR	Duration of Response	max 24 months
PFS	Progression Free Survival	max 24 months
OS	Overall survival	max 42 months
DCR	Disease control rate	max 24 months
Adverse Events	Adverse event (AE), Treatment emergent adverse event(TEAE), Serious adverse event (SAE).	max 42 months

Collaborators and Investigators

• Sponsor: Fudan University
• Investigators: Principal Investigator: Peng Wang, MD, Fudan University

Study record dates

Study Major Dates

• Study Start (Actual): September 26, 2021
• Primary Completion (Estimated): September 25, 2026
• Study Completion (Estimated): September 25, 2026

Study Registration Dates

• First Submitted: September 16, 2021
• First Submitted That Met QC Criteria: September 16, 2021
• First Posted (Actual): September 27, 2021

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 25, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Site; Neoplasms; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Liver Diseases; Colonic Diseases; Neoplastic Processes; Colorectal Neoplasms; Neoplasm Metastasis; Liver Neoplasms
• Other Study ID Numbers: CASTLE-03

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No