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

• ClinicalTrials.gov Identifier: NCT05375708
• Recruitment Status: Not yet recruiting
• First Posted: May 17, 2022
• Last Update Posted: May 11, 2023
• Sponsor: UMC Utrecht
• Information provided by (Responsible Party): Guus Bol, UMC Utrecht

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.

Condition or disease	Intervention/treatment	Phase
Metastatic Colorectal Cancer; Oligometastatic Disease	Radiation: Stereotactic body radiation therapy (SBRT); Drug: Maintenance therapy (CAP-B or 5-FU/LV plus bevacizumab.)	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 93 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Estimated Study Start Date: June 1, 2024
• Estimated Primary Completion Date: June 1, 2028
• Estimated Study Completion Date: June 1, 2028

Arms and Interventions

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)	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.; 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.

Outcome Measures

Primary Outcome Measures :

1. Progression-free survival [ Time Frame: Through study completion, an average of 24 months ]
   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 :

1. Accrual rate as assessed by the number of patients included in the study compared to the expected accrual rate. [ Time Frame: Through study completion, an average of 24 months ]
   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.
2. Treatment success rate [ Time Frame: Through study completion, an average of 24 months ]
   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).
3. Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 [ Time Frame: Through study completion, an average of 24 months ]
   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)
4. Overall survival [ Time Frame: Up to 72 months ]
   Defined as time from randomization to death of any cause.
5. 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. [ Time Frame: Through study completion, an average of 24 months ]
   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.
6. 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. [ Time Frame: Through study completion, an average of 24 months ]
   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.
7. Comparing changes from health-related quality of life based on summary score of Multidimensional Fatigue Inventory (MFI-20) from baseline and 3-monthly timepoints. [ Time Frame: Through study completion, an average of 24 months ]
   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).
8. Pattern of reccurence according to RECIST 1.1: New metastatic lesions, progression of existing lesions or a combination. [ Time Frame: Through study completion, an average of 24 months ]
   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
9. Time to treatment failure [ Time Frame: Through study completion, an average of 24 months ]
   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.
10. Tumor response [ Time Frame: Through study completion, an average of 24 months ]
    Based on radiographic imaging according to the RECIST 1.1 criteria.
11. Depth of response [ Time Frame: Through study completion, an average of 24 months ]
    Based on radiographic imaging

Eligibility Criteria

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

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

Contacts and Locations

Contacts

Contact: Koen Zwart, Drs.; 088-7556084; SIRIUS@Umcutrecht.nl

Contact: Guus Bol, Dr.; G.M.Bol-2@umcutrecht.nl

Locations

Netherlands

Meander Medical Centre

Amersfoort, Utrecht, Netherlands, 3813TZ

Contact: Hans-Martin Otten, Dr.

St. Antonius

Utrecht, Netherlands, 3543AZ

Contact: Maartje Los, Dr.

Diakonessenhuis

Utrecht, Netherlands, 3582KE

Contact: Tanja Oostergo, Dr.

UMC Utrecht

Utrecht, Netherlands, 3584CX

Contact: Koen Zwart, Drs. 088-7556084 SIRIUS@umcutrecht.nl

Sponsors and Collaborators

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

More Information

• Responsible Party: Guus Bol, Principal investigator, UMC Utrecht
• ClinicalTrials.gov Identifier: NCT05375708
• Other Study ID Numbers: NL76444.041.21
• First Posted: May 17, 2022
• Last Update Posted: May 11, 2023
• Last Verified: May 2023

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Guus Bol, UMC Utrecht:

Metastatic colorectal cancer; Image guided radiation; MR guided therapy; Oligometastatic / polymetastatic cancer

Additional relevant MeSH terms:

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Bevacizumab; Antineoplastic Agents, Immunological; Antineoplastic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Physiological Effects of Drugs; Growth Inhibitors