Back to resultsSystemic Therapy in Combination With Stereotactic Radiotherapy in Patients With Metastatic Colorectal Cancer up to 10 Metastatic Sites (SIRIUS)
Primary Purpose
Metastatic Colorectal Cancer, Oligometastatic Disease
Status
Not yet recruiting
Phase
Phase 2
Locations
Netherlands
Study Type
Interventional
Intervention
Stereotactic body radiation therapy (SBRT)
Maintenance therapy (CAP-B or 5-FU/LV plus bevacizumab.)
Sponsored by
About this trial
This is an interventional treatment trial for Metastatic Colorectal Cancer focused on measuring Metastatic colorectal cancer, Image guided radiation, MR guided therapy, Oligometastatic / polymetastatic cancer
Eligibility Criteria
Inclusion Criteria:
- Registered in the prospective Dutch colorectal cancer cohort (PLCRC)
- Intention at start of palliative systemic therapy to receive six maximum tolerated dose (MTD) cycles of CAPOX-B or eight MTD cycles of FOLFOX-B or FOLFOXIRI-B.
- Ten or less metastases as determined by the university medical center Utrecht (UMCU) central review
- Stable disease or partial response after initial chemotherapy according to RECIST 1.1 criteria.
- Expected adequacy of follow-up
- World Health organization (WHO) performance status 0-1
- Life expectancy >12 weeks
- Adequate organ functions at start of initial therapy, as determined by normal bone marrow function (Hb≥6.0 mmol/L, absolute neutrophil count ≥1.5 x 10^9/L, platelets ≥100 x 10^9/L), renal function (serum creatinine ≤ 1.5x upper limit of normal (ULN) and creatinine clearance, Cockcroft formula, ≥30 ml/min) and liver function (serum bilirubin ≤ 2 x ULN, serum transaminases ≤ 3 x ULN without presence of liver metastases or ≤ 5x ULN with presence of liver metastases)
- Written informed consent (SIRIUS)
Exclusion Criteria:
- Less than three cycles of CAPOX-B or four cycles of FOLFOX-B or FOLFOXIRI-B (dose reductions allowed).
- More than six cycles of CAPOX-B or eight cycles of FOLFOX-B of FOLFOXIRI-B.
- Possible treatment with curative intent according to local tumor board
- Substantial overlap with a previously treated radiation volume. Previous radiotherapy is allowed as long as the composite plan meets dose constraints herein.
- Not amenable for radiotherapy (e.g. peritonitis carcinomatosa)
- Previous systemic treatment for metastatic disease; prior adjuvant treatment for stage II/III colorectal cancer when given >6 months before the start of initial systemic treatment is allowed.
- Serious comorbidity or any other condition preventing the safe administration of treatment (including both systemic treatment and radiation)
- Pregnant or lactating women
- Other malignancy interfering with prognosis
- Any concomitant experimental treatment.
- Contra-indication MR-LINAC (pacemaker or implantable cardioverter-defibrillator)
- Microsatellite instability or deficient mismatch repair tumor
Sites / Locations
- Meander Medical Centre
- St. Antonius
- Diakonessenhuis
- UMC Utrecht
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Experimental
Arm Label
Systemic maintenance therapy
Systemic maintenance therapy in combination with stereotactic body radiation therapy (SBRT)
Arm Description
Outcomes
Primary Outcome Measures
Progression-free survival
Defined as time from randomization to progression of disease or death, whichever occurs first. Progression of disease is based on tumor response as observed on radiographic imaging according to the RECIST 1.1 criteria.
Secondary Outcome Measures
Accrual rate as assessed by the number of patients included in the study compared to the expected accrual rate.
We expect to include 93 patients in 24 months. The expected accrual rate in this study is, therefore, around 4 patients per month. Information for the accrual rate is used from the total accrual rate, the accrual rate in each study center and screening failures.
Treatment success rate
Dose intensity of SBRT based on the number of patients that receive more than 90% of the planned dose on all lesions in 95% of the planned target volume (PTV).
Number of participants with treatment-related adverse events as assessed by CTCAE v5.0
This will be based on the number of patients with SBRT related toxicity, defined as newly developed grade 2 toxicity of specific interest and grade 3-4 toxicity since randomization according to the Common Terminology Criteria for Adverse Events (CTCAE v5.0)
Overall survival
Defined as time from randomization to death of any cause.
Comparing changes on health-related quality of life based on summary score of Quality of Life Questionnaire-Core30 (QLQ-C30) from baseline and 3-monthly timepoints.
EORTC QLQ-C30 is a 30-item questionnaire to assess the overall quality of life in cancer patients. Most questions used 4-point scale (1 'Not at All' to 4 'Very Much'); 2 questions used 7-point scale (1 'Very Poor' to 7 'Excellent'). Scores are averaged, and transformed to 0-100 scale; higher score is better level of functioning.
Comparing changes on health-related quality of life based on summary score of Quality of Life Questionnaire-Core29 (QLQ-C29) from baseline and 3-monthly timepoints.
EORTC QLQ-C30 is a 29-item questionnaire to assess the overall quality of life in cancer patients. All questions used 4-point scale (1 'Not at All' to 4 'Very Much'). Scores are averaged, and transformed to 0-100 scale; higher score is better level of functioning.
Comparing changes from health-related quality of life based on summary score of Multidimensional Fatigue Inventory (MFI-20) from baseline and 3-monthly timepoints.
MFI is a validated 20-item, self-reported instrument designed to measure fatigue in the following dimensions: general fatigue, physical fatigue, mental fatigue, reduced motivation, and reduced activity. The respondent is asked to mark an 'X' in 1 of 5 boxes arranged linearly where 1 is 'Yes, that is true' and 5 is 'No, that is not true.' Each subscale consists of 4 items, 2 indicative for fatigue and 2 contraindicative. For the indicative questions, a high score indicates a high fatigue level and low scores indicate a low fatigue levels. Conversely, for the contraindicative questions a high score indicates a low fatigue level and a low score indicates a high fatigue level. Overall, respondents are rated on a scale of 0 (no fatigue) to 7 (high fatigue).
Pattern of reccurence according to RECIST 1.1: New metastatic lesions, progression of existing lesions or a combination.
New metastatic lesions, progression of existing lesions or a combination of both new metastatic lesions and progression of existing lesions based on radiographic imaging according to RECIST 1.1
Time to treatment failure
Defined as the time of randomization to failure of treatment. If radiologically visible metastatic lesions before systemic therapy are no longer visible at randomization (vanishing lesions) and recurrence of vanishing lesions occurs in patients in the experimental arm without progression of other lesions, this is not yet determined as failure of treatment; additional local therapy is highly encouraged on these lesions (to the discretion of the local investigator). When progression of existing lesions or new lesions occur, it will be determined as failure of treatment.
Tumor response
Based on radiographic imaging according to the RECIST 1.1 criteria.
Depth of response
Based on radiographic imaging
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT05375708
Brief Title
Systemic Therapy in Combination With Stereotactic Radiotherapy in Patients With Metastatic Colorectal Cancer up to 10 Metastatic Sites
Acronym
SIRIUS
Official Title
A Multicenter Phase II Randomized Trial to Evaluate Systemic Therapy Versus Systemic Therapy in Combination With Stereotactic Radiotherapy in Patients With Metastatic Colorectal Cancer
Study Type
Interventional
2. Study Status
Record Verification Date
May 2023
Overall Recruitment Status
Not yet recruiting
Study Start Date
June 1, 2024 (Anticipated)
Primary Completion Date
June 1, 2028 (Anticipated)
Study Completion Date
June 1, 2028 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
UMC Utrecht
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
A small number of colorectal cancer patients with limited oligometastases may be candidates for local treatment of metastases (e.g., resection, ablation). However, it is unclear if patients with more extensive metastatic disease benefit from local therapies to control visible metastasis.
The purpose of this study is to assess the impact of stereotactic body radiation therapy (SBRT) in combination with systemic therapy compared to systemic therapy alone on safety and efficacy in patients with metastatic colorectal cancer (mCRC) and ≤10 metastases.
Detailed Description
The addition of stereotactic body radiation therapy (SBRT) to metastases in a limited unresectable metastatic setting might improve progression-free survival (PFS). The success of the addition of local treatments in mCRC patients depends largely on: control of microscopic disease, diagnostic accuracy of macroscopic disease and effective treatment of all detected metastases with limited additional toxicity to surrounding tissues. Until shortly, the use of SBRT was possible to a limited number of locations due to target movement or toxicity to surrounding radiosensitive structures. With the introduction of MRI-guided radiotherapy these limitations have been largely reduced due to the possibility to make a daily new treatment plan based on MRI-visualized anatomy. This allows the use of smaller margins for uncertainty with less healthy tissues in the radiation field. Thereby, a broader application of SBRT to add local control to metastases became possible.
This study is an open-label, multicenter, randomized phase II screening trial assessing the impact of SBRT in combination with systemic therapy compared to systemic therapy alone on safety and efficacy in patients with mCRC and ≤10 metastases with no option of local treatment with curative intent and with stable disease or partial response after treatment of CAPOX-B, FOLFOX-B or FOLFOXIRI-B.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Metastatic Colorectal Cancer, Oligometastatic Disease
Keywords
Metastatic colorectal cancer, Image guided radiation, MR guided therapy, Oligometastatic / polymetastatic cancer
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
93 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Systemic maintenance therapy
Arm Type
Active Comparator
Arm Title
Systemic maintenance therapy in combination with stereotactic body radiation therapy (SBRT)
Arm Type
Experimental
Intervention Type
Radiation
Intervention Name(s)
Stereotactic body radiation therapy (SBRT)
Intervention Description
Patients will receive a single fraction of 15 Gy to each of the macroscopic tumor sites including the primary tumor if still in situ. All lesions are treated. The treatment will be delivered in an image-guided way, either on a conventional linear accelerator (LINAC) or a MR-LINAC, whichever has the best targeting according to the treating radiation oncologist.
Intervention Type
Drug
Intervention Name(s)
Maintenance therapy (CAP-B or 5-FU/LV plus bevacizumab.)
Intervention Description
CAP + bevacizumab (following CAPOX-B) Bevacizumab 7.5mg/kg i.v. on day 1 and 1250 mg/m2 of capecitabine, orally twice daily on days 1-14 if age is <70 years and 1000 mg/m2 of capecitabine, orally twice daily on days 1-14 if age is higher than 70 years. CAP + bevacizumab is repeated every three weeks.
5-FU/LV + bevacizumab (following FOLFOX-B) Bevacizumab 5.0mg/kg i.v. together with leucovorin 400 mg/m2 i.v. bolus 5FU 400 mg/m2 all on day 1. Followed by continuous infusion of 5-fluorouracil 2400 mg/m2 in 46 hours. 5-FU + bevacizumab is repeated every two weeks.
5-FU/LV + bevacizumab (following FOLFOXIRI-B) Bevacizumab 5.0mg/kg i.v. together with leucovorin 400 mg/m2 i.v. all on day 1. Followed by continuous infusion of 5-fluorouracil 3200 mg/m2 in 46 hours. 5-FU + bevacizumab is repeated every two weeks.
When S1 is used a replacement for fluoropyrimidine therapy it is administered in a dose of 30mg/m2 twice daily on days 1-14. S1 is repeated every three weeks.
Primary Outcome Measure Information:
Title
Progression-free survival
Description
Defined as time from randomization to progression of disease or death, whichever occurs first. Progression of disease is based on tumor response as observed on radiographic imaging according to the RECIST 1.1 criteria.
Time Frame
Through study completion, an average of 24 months
Secondary Outcome Measure Information:
Title
Accrual rate as assessed by the number of patients included in the study compared to the expected accrual rate.
Description
We expect to include 93 patients in 24 months. The expected accrual rate in this study is, therefore, around 4 patients per month. Information for the accrual rate is used from the total accrual rate, the accrual rate in each study center and screening failures.
Time Frame
Through study completion, an average of 24 months
Title
Treatment success rate
Description
Dose intensity of SBRT based on the number of patients that receive more than 90% of the planned dose on all lesions in 95% of the planned target volume (PTV).
Time Frame
Through study completion, an average of 24 months
Title
Number of participants with treatment-related adverse events as assessed by CTCAE v5.0
Description
This will be based on the number of patients with SBRT related toxicity, defined as newly developed grade 2 toxicity of specific interest and grade 3-4 toxicity since randomization according to the Common Terminology Criteria for Adverse Events (CTCAE v5.0)
Time Frame
Through study completion, an average of 24 months
Title
Overall survival
Description
Defined as time from randomization to death of any cause.
Time Frame
Up to 72 months
Title
Comparing changes on health-related quality of life based on summary score of Quality of Life Questionnaire-Core30 (QLQ-C30) from baseline and 3-monthly timepoints.
Description
EORTC QLQ-C30 is a 30-item questionnaire to assess the overall quality of life in cancer patients. Most questions used 4-point scale (1 'Not at All' to 4 'Very Much'); 2 questions used 7-point scale (1 'Very Poor' to 7 'Excellent'). Scores are averaged, and transformed to 0-100 scale; higher score is better level of functioning.
Time Frame
Through study completion, an average of 24 months
Title
Comparing changes on health-related quality of life based on summary score of Quality of Life Questionnaire-Core29 (QLQ-C29) from baseline and 3-monthly timepoints.
Description
EORTC QLQ-C30 is a 29-item questionnaire to assess the overall quality of life in cancer patients. All questions used 4-point scale (1 'Not at All' to 4 'Very Much'). Scores are averaged, and transformed to 0-100 scale; higher score is better level of functioning.
Time Frame
Through study completion, an average of 24 months
Title
Comparing changes from health-related quality of life based on summary score of Multidimensional Fatigue Inventory (MFI-20) from baseline and 3-monthly timepoints.
Description
MFI is a validated 20-item, self-reported instrument designed to measure fatigue in the following dimensions: general fatigue, physical fatigue, mental fatigue, reduced motivation, and reduced activity. The respondent is asked to mark an 'X' in 1 of 5 boxes arranged linearly where 1 is 'Yes, that is true' and 5 is 'No, that is not true.' Each subscale consists of 4 items, 2 indicative for fatigue and 2 contraindicative. For the indicative questions, a high score indicates a high fatigue level and low scores indicate a low fatigue levels. Conversely, for the contraindicative questions a high score indicates a low fatigue level and a low score indicates a high fatigue level. Overall, respondents are rated on a scale of 0 (no fatigue) to 7 (high fatigue).
Time Frame
Through study completion, an average of 24 months
Title
Pattern of reccurence according to RECIST 1.1: New metastatic lesions, progression of existing lesions or a combination.
Description
New metastatic lesions, progression of existing lesions or a combination of both new metastatic lesions and progression of existing lesions based on radiographic imaging according to RECIST 1.1
Time Frame
Through study completion, an average of 24 months
Title
Time to treatment failure
Description
Defined as the time of randomization to failure of treatment. If radiologically visible metastatic lesions before systemic therapy are no longer visible at randomization (vanishing lesions) and recurrence of vanishing lesions occurs in patients in the experimental arm without progression of other lesions, this is not yet determined as failure of treatment; additional local therapy is highly encouraged on these lesions (to the discretion of the local investigator). When progression of existing lesions or new lesions occur, it will be determined as failure of treatment.
Time Frame
Through study completion, an average of 24 months
Title
Tumor response
Description
Based on radiographic imaging according to the RECIST 1.1 criteria.
Time Frame
Through study completion, an average of 24 months
Title
Depth of response
Description
Based on radiographic imaging
Time Frame
Through study completion, an average of 24 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Registered in the prospective Dutch colorectal cancer cohort (PLCRC)
Intention at start of palliative systemic therapy to receive six maximum tolerated dose (MTD) cycles of CAPOX-B or eight MTD cycles of FOLFOX-B or FOLFOXIRI-B.
Ten or less metastases as determined by the university medical center Utrecht (UMCU) central review
Stable disease or partial response after initial chemotherapy according to RECIST 1.1 criteria.
Expected adequacy of follow-up
World Health organization (WHO) performance status 0-1
Life expectancy >12 weeks
Adequate organ functions at start of initial therapy, as determined by normal bone marrow function (Hb≥6.0 mmol/L, absolute neutrophil count ≥1.5 x 10^9/L, platelets ≥100 x 10^9/L), renal function (serum creatinine ≤ 1.5x upper limit of normal (ULN) and creatinine clearance, Cockcroft formula, ≥30 ml/min) and liver function (serum bilirubin ≤ 2 x ULN, serum transaminases ≤ 3 x ULN without presence of liver metastases or ≤ 5x ULN with presence of liver metastases)
Written informed consent (SIRIUS)
Exclusion Criteria:
Less than three cycles of CAPOX-B or four cycles of FOLFOX-B or FOLFOXIRI-B (dose reductions allowed).
More than six cycles of CAPOX-B or eight cycles of FOLFOX-B of FOLFOXIRI-B.
Possible treatment with curative intent according to local tumor board
Substantial overlap with a previously treated radiation volume. Previous radiotherapy is allowed as long as the composite plan meets dose constraints herein.
Not amenable for radiotherapy (e.g. peritonitis carcinomatosa)
Previous systemic treatment for metastatic disease; prior adjuvant treatment for stage II/III colorectal cancer when given >6 months before the start of initial systemic treatment is allowed.
Serious comorbidity or any other condition preventing the safe administration of treatment (including both systemic treatment and radiation)
Pregnant or lactating women
Other malignancy interfering with prognosis
Any concomitant experimental treatment.
Contra-indication MR-LINAC (pacemaker or implantable cardioverter-defibrillator)
Microsatellite instability or deficient mismatch repair tumor
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Koen Zwart, Drs.
Phone
088-7556084
Email
SIRIUS@Umcutrecht.nl
First Name & Middle Initial & Last Name or Official Title & Degree
Guus Bol, Dr.
Email
G.M.Bol-2@umcutrecht.nl
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Guus Bol, Dr.
Organizational Affiliation
UMC Utrecht
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Martijn Intven, Dr.
Organizational Affiliation
UMC Utrecht
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Miriam Koopman, Prof. Dr.
Organizational Affiliation
UMC Utrecht
Official's Role
Principal Investigator
Facility Information:
Facility Name
Meander Medical Centre
City
Amersfoort
State/Province
Utrecht
ZIP/Postal Code
3813TZ
Country
Netherlands
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Hans-Martin Otten, Dr.
Facility Name
St. Antonius
City
Utrecht
ZIP/Postal Code
3543AZ
Country
Netherlands
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Maartje Los, Dr.
Facility Name
Diakonessenhuis
City
Utrecht
ZIP/Postal Code
3582KE
Country
Netherlands
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Tanja Oostergo, Dr.
Facility Name
UMC Utrecht
City
Utrecht
ZIP/Postal Code
3584CX
Country
Netherlands
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Koen Zwart, Drs.
Phone
088-7556084
Email
SIRIUS@umcutrecht.nl
12. IPD Sharing Statement
Learn more about this trial
Systemic Therapy in Combination With Stereotactic Radiotherapy in Patients With Metastatic Colorectal Cancer up to 10 Metastatic Sites
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