Systemic Therapy in Combination With Stereotactic Radiotherapy in Patients With Metastatic Colorectal Cancer up to 10 Metastatic Sites (SIRIUS)

A Multicenter Phase II Randomized Trial to Evaluate Systemic Therapy Versus Systemic Therapy in Combination With Stereotactic Radiotherapy in Patients With Metastatic Colorectal Cancer

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Metastatic Colorectal Cancer; Oligometastatic Disease
• Intervention / Treatment: Drug: Maintenance therapy (CAP-B or 5-FU/LV plus bevacizumab.); Radiation: Stereotactic body radiation therapy (SBRT)

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.

• Study Type: Interventional
• Enrollment (Anticipated): 93
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Koen Zwart, Drs.; Phone Number: 088-7556084; Email: SIRIUS@umcutrecht.nl
• Study Contact Backup: Name: Guus Bol, Dr.; Email: G.M.Bol-2@umcutrecht.nl

Study Locations

• Netherlands
  • Utrecht, Netherlands, 3584CX
    • UMC Utrecht
    • Contact: Koen Zwart, Drs.; Phone Number: 088-7556084; Email: SIRIUS@umcutrecht.nl
  • Utrecht, Netherlands, 3543AZ
    • St. Antonius
    • Contact: Maartje Los, Dr.
  • Utrecht, Netherlands, 3582KE
    • Diakonessenhuis
    • Contact: Tanja Oostergo, Dr.
  • Utrecht
    • Amersfoort, Utrecht, Netherlands, 3813TZ
      • Meander Medical Centre
      • Contact: Hans-Martin Otten, Dr.

Participation Criteria

Eligibility Criteria

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

Description

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

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: Systemic maintenance therapy	Drug: Maintenance therapy (CAP-B or 5-FU/LV plus bevacizumab.); 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.
Experimental: Systemic maintenance therapy in combination with stereotactic body radiation therapy (SBRT)	Drug: Maintenance therapy (CAP-B or 5-FU/LV plus bevacizumab.); 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.; Radiation: Stereotactic body radiation therapy (SBRT); 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Through study completion, an average of 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Through study completion, an average of 24 months
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).	Through study completion, an average of 24 months
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)	Through study completion, an average of 24 months
Overall survival	Defined as time from randomization to death of any cause.	Up to 72 months
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.	Through study completion, an average of 24 months
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.	Through study completion, an average of 24 months
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).	Through study completion, an average of 24 months
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	Through study completion, an average of 24 months
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.	Through study completion, an average of 24 months
Tumor response	Based on radiographic imaging according to the RECIST 1.1 criteria.	Through study completion, an average of 24 months
Depth of response	Based on radiographic imaging	Through study completion, an average of 24 months

Collaborators and Investigators

• Sponsor: UMC Utrecht
• Investigators: Principal Investigator: Guus Bol, Dr., UMC Utrecht; Principal Investigator: Martijn Intven, Dr., UMC Utrecht; Principal Investigator: Miriam Koopman, Prof. Dr., UMC Utrecht

Study record dates

Study Major Dates

• Study Start (Anticipated): June 1, 2024
• Primary Completion (Anticipated): June 1, 2028
• Study Completion (Anticipated): June 1, 2028

Study Registration Dates

• First Submitted: April 5, 2022
• First Submitted That Met QC Criteria: May 10, 2022
• First Posted (Actual): May 17, 2022

Study Record Updates

• Last Update Posted (Estimate): May 11, 2023
• Last Update Submitted That Met QC Criteria: May 10, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: Metastatic colorectal cancer; Image guided radiation; MR guided therapy; Oligometastatic / polymetastatic cancer
• 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; Physiological Effects of Drugs; Antineoplastic Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Bevacizumab
• Other Study ID Numbers: NL76444.041.21

Drug and device information, study documents

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