The Combination of Immunotherapy and Stereotactic Ablative Radiotherapy in MSS Oligometastatic Colorectal Cancer
Primary Purpose
Colorectal Cancer
Status
Unknown status
Phase
Phase 2
Locations
China
Study Type
Interventional
Intervention
Stereotactic Ablative Radiotherapy (SABR)
Sintilimab
Sponsored by
About this trial
This is an interventional treatment trial for Colorectal Cancer
Eligibility Criteria
Inclusion Criteria:
- Aged 18-70 years old, regardless of gender
- Fully informed and willing to provide written informed consent for the trial
- ECOG performance status 0-1
- Has an investigator determined life expectancy of at least 6 months
- Histologically confirmed colorectal adenocarcinoma, with MSS or pMMR status
- Has 2-5 measurable metastatic lesions detected on imaging, with none of them indicated for surgery; or the participant refuses to receive surgery. Biopsy of metastasis is preferred, but not required
- Has undergone at least one dose of first-line systemic chemotherapy, except for any type of immunotherapy
- Multiple sites of lesions can be safely treated by SABR, and at least one lesion spared from irradiation, so as for assessment. The maximum diameter of each lesion for irradiation is no more than 5cm.
- Demonstrate adequate organ function
- Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up
Exclusion Criteria:
- Pregnant or lactating women
- Serious medical comorbidities precluding radiotherapy
- Prior radiotherapy to a site requiring treatment
- Malignant pleural effusion
- Inability to treat all sites of active disease
- Has clinical or radiologic evidence of spinal cord compression or tumor within 3mm of spinal cord on MRI.
- Dominant brain metastasis requiring surgical decompression
- Has prior treatment with cancer immunotherapy including, but not limited to immune checkpoint inhibitors.
- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy at a dose of >10 mg Prednisone daily or equivalent at time of trial treatment.
- Has a known history of active Bacillus Tuberculosis
- Has active autoimmune disease that has required systemic treatment in the past 2 years
- Hypersensitivity to PD-1 inhibitor or any of its excipients.
- Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study day 1 or who has not recovered from adverse events due to a previously administered agent.
Sites / Locations
- Fudan University Shanghai Cancer CenterRecruiting
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Treatment Arm
Arm Description
A total of 60 MSS oligometastatic colorectal cancer patients will receive multisite SABR followed by Sintilimab within one week from completion. The dosing will continue for up to two years until disease progression, unacceptable toxicity or patient withdrawal.
Outcomes
Primary Outcome Measures
Objective Response Rate
The percentage of patients with objective response in the non-irradiated 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.
Secondary Outcome Measures
Disease Control Rate
The percentage of patients with disease control in the non-irradiated metastatic lesions. Disease control is defined as CR, PR, or stable disease (SD) per RECIST v1.1 and iRECIST after treatment.
Duration of Response
Defined as the time between PR/CR and subsequent progression disease (PD) per RECIST v1.1 and iRECIST or death from any cause.
Progression-Free Survival
Defined as the time from initiation of treatment to PD or death from any cause.
Overall Survival
Defined as the time from initiation of treatment to death from any cause.
Acute Toxicity
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.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT04535024
Brief Title
The Combination of Immunotherapy and Stereotactic Ablative Radiotherapy in MSS Oligometastatic Colorectal Cancer
Official Title
Phase II Trial of Multisite Stereotactic Ablative Radiotherapy (SABR) Combined With Sintilimab for Microsatellite Stable (MSS) Oligometastatic Colorectal Cancer
Study Type
Interventional
2. Study Status
Record Verification Date
May 2021
Overall Recruitment Status
Unknown status
Study Start Date
March 4, 2021 (Actual)
Primary Completion Date
June 2022 (Anticipated)
Study Completion Date
December 2022 (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
This is a prospective, single-center, single-arm phase II clinical trial. This study aims to evaluate the safety and tolerability of stereotactic ablative radiotherapy (SABR) in combination with Sintilimab, and to examine the impact of the combination therapy on tumor control, long-term survival and quality of life in patients with microsatellite stable (MSS) oligometastatic colorectal cancer.
A total of 60 MSS oligometastatic colorectal cancer patients will be recruited and receive multisite SABR followed by immunotherapy of Sintilimab within one week from completion. Sintilimab will be given at a fixed dose of 200mg (100mg if weight < 50 kg) via intravenous infusion on the first day of each cycle, repeated every three weeks. The dosing will continue for up to two years until disease progression, unacceptable toxicity or patient withdrawal. The tumor regression, disease control, adverse events and long-term survival will be analyzed.
Detailed Description
Immune-checkpoint inhibitor (ICI) has led to a paradigm shift in the treatment of patients with metastatic cancer, as proved by improved survival and durable responses in a group of these patients. However, the response rates to ICI when given alone are limited. In gastrointestinal cancer, patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumors shown a response rate of approximately 40% to ICI, while patients with microsatellite stable (MSS) or mismatch repair-proficient (pMMR) tumors respond poorly to ICI. Such observations have spurred efforts to expand the benefit of immunotherapy, especially in these immune "non-sensitive" tumors, by combining ICI with treatments that induce T-cell associated immune response such stereotactic ablative radiotherapy (SABR).
High-dose ablative radiation was showed to facilitate immunotherapy through promote the activation of innate and adaptive immune responses against tumors in preclinical model and early phase clinical trials. However, a large portion of trials which were launched to test the efficacy of radiotherapy and immunotherapy produced suboptimal results. One important reason could be that majority of these trails were designed with single lesion irradiation, which is insufficient to unveil enough tumor antigens and/or to break the barrier of immunosuppressive tumor microenvironment (TME).
The investigators hypothesized that irradiation to multiple or all sites of diseases is more likely to produce an optimized regimen with ICI by broadly stimulate anti-tumor immunity and reduce tumor burden. Therefore, this study plans to administrate SABR to as many metastatic lesions as possible, in combination with ICI (Sintilimab) in patients with MSS oligometastatic colorectal cancers, to assess safety and tolerability of the regimen, and evaluate its early efficacy as well.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Colorectal Cancer
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
60 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Treatment Arm
Arm Type
Experimental
Arm Description
A total of 60 MSS oligometastatic colorectal cancer patients will receive multisite SABR followed by Sintilimab within one week from completion.
The dosing will continue for up to two years until disease progression, unacceptable toxicity or patient withdrawal.
Intervention Type
Radiation
Intervention Name(s)
Stereotactic Ablative Radiotherapy (SABR)
Intervention Description
We plan to irradiate as many metastatic lesions as possible, in the precondition that normal tissues can tolerate.
Target dose will be adjusted depending on site of the lesion and organs at risk (BED > 100Gy).
Treatment schedule is once per day and five days per week. Sequence of irradiation for multiple metastases is at the discretion of the investigators based on their experience.
Intervention Type
Drug
Intervention Name(s)
Sintilimab
Intervention Description
Starts within one week upon SABR completion: 200mg, d1, q3w; Continued until disease progression, unacceptable toxicity or patient withdrawal.
Primary Outcome Measure Information:
Title
Objective Response Rate
Description
The percentage of patients with objective response in the non-irradiated 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.
Time Frame
Up to 2 years
Secondary Outcome Measure Information:
Title
Disease Control Rate
Description
The percentage of patients with disease control in the non-irradiated metastatic lesions. Disease control is defined as CR, PR, or stable disease (SD) per RECIST v1.1 and iRECIST after treatment.
Time Frame
Up to 2 years
Title
Duration of Response
Description
Defined as the time between PR/CR and subsequent progression disease (PD) per RECIST v1.1 and iRECIST or death from any cause.
Time Frame
Up to 2 years
Title
Progression-Free Survival
Description
Defined as the time from initiation of treatment to PD or death from any cause.
Time Frame
Up to 3 years
Title
Overall Survival
Description
Defined as the time from initiation of treatment to death from any cause.
Time Frame
Up to 3 years
Title
Acute Toxicity
Description
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.
Time Frame
Up to 2 years
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Aged 18-70 years old, regardless of gender
Fully informed and willing to provide written informed consent for the trial
ECOG performance status 0-1
Has an investigator determined life expectancy of at least 6 months
Histologically confirmed colorectal adenocarcinoma, with MSS or pMMR status
Has 2-5 measurable metastatic lesions detected on imaging, with none of them indicated for surgery; or the participant refuses to receive surgery. Biopsy of metastasis is preferred, but not required
Has undergone at least one dose of first-line systemic chemotherapy, except for any type of immunotherapy
Multiple sites of lesions can be safely treated by SABR, and at least one lesion spared from irradiation, so as for assessment. The maximum diameter of each lesion for irradiation is no more than 5cm.
Demonstrate adequate organ function
Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up
Exclusion Criteria:
Pregnant or lactating women
Serious medical comorbidities precluding radiotherapy
Prior radiotherapy to a site requiring treatment
Malignant pleural effusion
Inability to treat all sites of active disease
Has clinical or radiologic evidence of spinal cord compression or tumor within 3mm of spinal cord on MRI.
Dominant brain metastasis requiring surgical decompression
Has prior treatment with cancer immunotherapy including, but not limited to immune checkpoint inhibitors.
Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy at a dose of >10 mg Prednisone daily or equivalent at time of trial treatment.
Has a known history of active Bacillus Tuberculosis
Has active autoimmune disease that has required systemic treatment in the past 2 years
Hypersensitivity to PD-1 inhibitor or any of its excipients.
Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study day 1 or who has not recovered from adverse events due to a previously administered agent.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Zhen Zhang, MD, PhD
Phone
18801735029
Email
zhen_zhang@fudan.edu.cn
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Zhen Zhang, MD, PhD
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
Zhen Zhang, MD, PhD
Phone
18801735029
Email
zhen_zhang@fudan.edu.cn
12. IPD Sharing Statement
Learn more about this trial
The Combination of Immunotherapy and Stereotactic Ablative Radiotherapy in MSS Oligometastatic Colorectal Cancer
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