Cryoablation Combined With Sintilimab Plus Regorafenib In Previously Treated Colorectal Cancer Liver Metastasis
Primary Purpose
Liver Metastases, Colorectal Cancer Metastatic
Status
Recruiting
Phase
Phase 2
Locations
China
Study Type
Interventional
Intervention
Sintilimab
Regorafenib
US/CT-guided Percutaneous Cryoablation
Sponsored by
About this trial
This is an interventional treatment trial for Liver Metastases
Eligibility Criteria
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:
- history of interstitial lung disease
- Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) coinfection (i.e double infection)
- known acute or chronic pancreatitis
- active tuberculosis
- any other active infection (viral, fungal or bacterial) requiring systemic therapy
- history of allogeneic tissue/solid organ transplant
- 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.
- 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.
- Live vaccine within 30 days prior to the first dose of Sintilimab treatment or during study treatment.
- 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.
Sites / Locations
- Fudan University Shanghai Cancer CenterRecruiting
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Cryoablation in combination with Sintilimab plus regorafenib
Arm Description
Outcomes
Primary Outcome Measures
Objective Response Rate (ORR)
ORR according to RECIST 1.1
Secondary Outcome Measures
DoR
Duration of Response
PFS
Progression Free Survival
OS
Overall survival
DCR
Disease control rate
Adverse Events
Adverse event (AE), Treatment emergent adverse event(TEAE), Serious adverse event (SAE).
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT05057052
Brief Title
Cryoablation Combined With Sintilimab Plus Regorafenib In Previously Treated Colorectal Cancer Liver Metastasis
Official Title
A Phase II Study of Cryoablation Combined With Sintilimab Plus Regorafenib in Previously Treated Colorectal Cancer Liver Metastasis (CASTLE-03)
Study Type
Interventional
2. Study Status
Record Verification Date
November 2022
Overall Recruitment Status
Recruiting
Study Start Date
September 26, 2021 (Actual)
Primary Completion Date
September 25, 2023 (Anticipated)
Study Completion Date
September 25, 2024 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Fudan University
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
5. Study Description
Brief Summary
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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Liver Metastases, Colorectal Cancer Metastatic
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
25 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Cryoablation in combination with Sintilimab plus regorafenib
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
Sintilimab
Intervention Description
Sintilimab plus regorafenib will be initiated on day 14 after cryoablation. Sintilimab will be administered at 200 mg i.v. every 3 weeks.
Intervention Type
Drug
Intervention Name(s)
Regorafenib
Intervention Description
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.
Intervention Type
Combination Product
Intervention Name(s)
US/CT-guided Percutaneous Cryoablation
Intervention Description
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
Primary Outcome Measure Information:
Title
Objective Response Rate (ORR)
Description
ORR according to RECIST 1.1
Time Frame
max 24 months
Secondary Outcome Measure Information:
Title
DoR
Description
Duration of Response
Time Frame
max 24 months
Title
PFS
Description
Progression Free Survival
Time Frame
max 24 months
Title
OS
Description
Overall survival
Time Frame
max 42 months
Title
DCR
Description
Disease control rate
Time Frame
max 24 months
Title
Adverse Events
Description
Adverse event (AE), Treatment emergent adverse event(TEAE), Serious adverse event (SAE).
Time Frame
max 42 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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:
history of interstitial lung disease
Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) coinfection (i.e double infection)
known acute or chronic pancreatitis
active tuberculosis
any other active infection (viral, fungal or bacterial) requiring systemic therapy
history of allogeneic tissue/solid organ transplant
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.
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.
Live vaccine within 30 days prior to the first dose of Sintilimab treatment or during study treatment.
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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Peng Wang, MD
Phone
86-21-64175590
Email
peng_wang@fudan.edu.cn
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Peng Wang, MD
Organizational Affiliation
Fudan University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Fudan University Shanghai Cancer Center
City
Shanghai
State/Province
Shanghai
ZIP/Postal Code
200032
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Peng Wang, M.D.
Phone
862164175590
Ext
83630
Email
peng_wang@fudan.edu.cn
12. IPD Sharing Statement
Learn more about this trial
Cryoablation Combined With Sintilimab Plus Regorafenib In Previously Treated Colorectal Cancer Liver Metastasis
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