Stereotactic Body Radiotherapy in Patients With Rare Oligometastatic Cancers (OligoRARE)

Study Overview
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Brief Summary
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This is a randomized open-label multicentre Phase III superiority study of the effect of adding SBRT to the standard of care treatment on overall survival in patients with rare oligometastatic cancers. Patients will be randomized in a 1:1 ratio between current standard of care treatment vs. standard of care treatment + SBRT to all sites of known metastatic disease. The primary objective of this trial is to assess if the addition of stereotactic body radiotherapy (SBRT) to standard of care treatment improves overall survival (OS) as compared to standard of care treatment alone in patients with rare oligometastatic cancers.

Official Title
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Stereotactic Body Radiotherapy in Addition to Standard of Care Treatment in Patients With Rare Oligometastatic Cancers (OligoRARE): a Randomized, Phase 3, Open-label Trial

Conditions
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Gynecologic Cancer, Skin Cancer, Head and Neck Cancer, Sarcoma, Renal Cancer, Bladder Cancer, Upper Urinary Tract Carcinoma, Pancreatic Cancer, Hepatobiliary Cancer, Gastric Cancer, Small Bowel Cancer, Esophageal Cancer, Melanoma, Colon Cancer, Oligometastasis

Intervention / Treatment
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* Radiation: Stereotactic body radiotherapy
* Radiation: Palliative RT


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed malignancy with metastatic disease detected on imaging. Biopsy of metastasis is preferred, but not required. Controlled primary tumour, defined as: at least 3 months since original tumour treated definitively, with no progression at primary site Total number of oligometastases of 1-5 including: Brain metastases amenable to radiosurgery or fractionated stereotactic radiotherapy patient who had neurosurgical resection before trial inclusion are allowed and resected brain metastases count to the total number of oligometastases All sites of disease can be safely treated based on the judgement of an experienced radiation oncologist ECOG score 0-2 Life expectancy > 6 months Age 18 or older Before patient randomization, written informed consent must be given according to ICH/GCP, and national/local regulations. Exclusion Criteria: Primary cancer of prostate, breast, lung or colorectal Serious medical comorbidities precluding radiotherapy: These include interstitial lung disease in patients requiring thoracic radiation, Crohn's disease in patients where the GI tract will receive radiotherapy, or ulcerative colitis where the bowel will receive radiotherapy and connective tissue disorders such as lupus or scleroderma. For patients with liver metastases, moderate/severe liver dysfunction (Child Pugh B or C) Substantial overlap with a previously treated radiation volume. Prior radiotherapy in general is allowed, as long as the composite plan meets dose constraints herein. For patients treated previously with radiation, biological effective dose calculations should be used to equate previous doses to the tolerance doses listed in the RTQA Guidelines. All such cases should be discussed with one of the study coordinators Brain metastases only, without extra-cerebral metastases Malignant pleural effusion, malignant ascites, meningeal carcinomatosis and peritoneal carcinomatosis Maximum size of 6 cm for lesions outside the brain, except: Bone metastases over 5 cm may be included, if in the opinion of the local radiation oncologist it can be treated safely (e.g. rib, scapula, pelvis) Clinical or radiologic evidence of symptomatic spinal cord compression. Patients can be eligible if surgical resection has been performed, but the surgical site counts toward the total of up to 3 metastases. Metastatic disease that invades any of the following: GI tract (including oesophagus, stomach, small or large bowel), mesenteric lymph nodes, or disseminated skin metastases and lymphangiosis Pregnant or breast feeding women Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before randomization in the trial

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm 1: Standard of Care + palliative RT<br>Radiotherapy for patients in the standard arm should follow the principles of palliative radiotherapy as per the individual institution, with the goal of alleviating symptoms or preventing imminent complications. Recommended dose fractionations in this arm will include 8 Gy in 1 fractions, 20 Gy in 5 fractions, and 30 Gy in 10 fractions. Patients in this arm should not receive stereotactic doses or radiotherapy boosts, unless there is a clearly known clinical benefit (e.g. stereotactic radiation to a new brain metastases when all disease is controlled on systemic therapy). Systemic therapy will be pre-specified based on the standard of care approach for that patient, and it may include cytotoxic, targeted, hormonal, or immunotherapy. | Radiation: Palliative RT<br>* Radiotherapy for patients in the standard arm should follow the principles of palliative radiotherapy as per the individual institution, with the goal of alleviating symptoms or preventing imminent complications. Recommended dose fractionations in this arm will include 8 Gy in 1 fractions, 20 Gy in 5 fractions, and 30 Gy in 10 fractions. Patients in this arm should not receive stereotactic doses or radiotherapy boosts, unless there is a clearly known clinical benefit (e.g. stereotactic radiation to a new brain metastases when all disease is controlled on systemic therapy).<br>|
| Experimental: Arm 2: Standard of Care + SBRT<br>The experimental arm consists of SBRT (and standard of care systemic therapy). Each lesion may be treated with 1, 3, or 5 SBRT fractions of 16-24 Gy, 24-33 Gy or 25-40 Gy, respectively, depending on the local practice and size & location of oligometastases. Three-fraction regimens will deliver a fraction every second day, and five-fraction regimens are delivered daily. All treatments must be completed within 2 weeks (10 working days) in order to avoid delays in starting systemic therapy. Patients treated with prior or concomitant systemic therapy are eligible for this study. Use of chemotherapy regimens, targeted therapy or immunotherapy containing potent enhancers of radiation damage (e.g. gemcitabine, doxorubicin) can be postponed or interrupted for a duration of one month after radiation. | Radiation: Stereotactic body radiotherapy<br>* Each lesion may be treated with 1, 3, or 5 SBRT fractions of 16-24 Gy, 24-33 Gy or 25-40 Gy, respectively, depending on the local practice and size & location of oligometastases. Three-fraction regimens will deliver a fraction every second day, and five-fraction regimens are delivered daily. All treatments must be completed within 2 weeks (10 working days) in order to avoid delays in starting systemic therapy.<br>* Other names: SBRT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | Overall survival is the time interval from the date of randomization to the date of death whatever the cause of death. Patients who are alive are censored at the last date known to be alive. | 7.5 years from first patient in | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival |  | 9 years from first patient in | 
| Disease-specific survival |  | 9 years from first patient in | 
| Time to disease progression | Disease-specific survival is the time interval from the date of randomization to the date of cancer-related death. | 9 years from first patient in | 
| Time to development of new metastatic lesions | Time to development of new metastatic lesions is the time interval from the date of randomization to the date of first occurrence of any of the following events: Development new metastatic lesions, Cancer-related death. | 9 years from first patient in | 
| Time to development of polymetastatic disease | Time to development of polymetastatic disease is the time interval from the date of randomization to the date of first occurrence of any of the following events: Presence of more than 5 metastases at a specific timepoint during follow-up, Development of metastases that preclude treatment with SBRT (e.g. due to large size or locating in previously irradiated region where re-irradiation is not possible), Cancer-related death. | 9 years from first patient in | 
| Adverse events graded according to the National Cancer Institute Common Terminology Criteria for adverse events (NCI-CTCAE) version 5.0 |  | 9 years from first patient in | 
| Health-related quality of life evaluated using self-administered EORTC QLQ-C30 questionnaires |  | 9 years from first patient in | 
| Health-related quality of life evaluated using self-administered EQ-5D-5L questionnaires |  | 9 years from first patient in | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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oligometastatic cancer, Stereotactic body radiotherapy, SBRT