Stereotactic Ablative Radiotherapy for OligoMetastatic Breast Cancer

Study Overview
=================
Brief Summary
-----------------
TAORMINA is an international, multicentre, randomised phase 3 trial for patients with oligometastatic breast cancer (OMBC) that will be allocated to combined stereotactic ablative radiotherapy (SABR) + systemic therapy (investigational arm) versus systemic therapy alone (control arm) as 1st line therapy.

Detailed Description
-----------------
TAORMINA is an international, multicentre, randomised phase 3 trial for patients with oligometastatic breast cancer (OMBC) that will be allocated to combined stereotactic ablative radiotherapy (SABR) + systemic therapy (investigational arm) versus systemic therapy alone (control arm) as 1st line therapy. Patients with 1-5 metastases in 1-2 organs (confirmed by PET-CT) with any breast cancer subtype can be enrolled. All metastases must be available for SABR. The primary aim is to investigate if the addition of SABR to the oligometastatic sites in addition to the standard first-line treatment can improve progression-free survival (PFS). Secondary aims are to compare overall survival (OS), response rate and time to development of new lesions, acute and late toxicity. quality of life, time to start of chemotherapy (luminal patients). Exploratory analyses: Circulating tumour DNA as an early sign of disease progression. Immun panel for determination of the effect of SABR on patients´ immune response. To investigate the survival for each BC subtype (Luminal, HER2+ and TNBC). To investigate survival in patients with de novo OMBC and recurrent OMBC respectively. Stratifications are based on subtype (luminal, HER2-positive vs TNBC) and type of OMBC (de novo vs. recurrent) without formal sample size calculation for the stratification factor (exploratory analysis). Patients with de novo metastatic OMBC that is planned for neoadjuvant treatment are recommended to complete treatment followed by standard surgery and radiotherapy or SABR towards the primary tumour lesion(s).

Official Title
-----------------
Treatment of Oligometastatic Breast Cancer - a Randomised Phase 3 Trial Comparing Stereotactic Ablative Radiotherapy and Systemic Treatment With Systemic Treatment Alone as 1st Line Treatment

Conditions
-----------------
Breast Cancer Stage IV, Oligometastatic Disease

Intervention / Treatment
-----------------
* Radiation: SABR


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically or cytological confirmed recurrent OMBC. Age ≥18 years old. OMBC defined as 1-5 metastases in a maximum of two organs confirmed by PET-CT. Patients already on 1st line systemic treatment can be enrolled if repeated tumour evaluations show stable disease. Patients with de novo stage IV OMBC must have a controlled primary tumour regardless of primary surgery or primary systemic treatment. Patients with local recurrence and OMBC must have a controlled local recurrence. ECOG/WHO 0-2. Life expectancy > 6 months. Known ER, PgR and HER2 status of either primary tumour or metastasis (preferred). If measurable lesions, each ≤ 5 cm. Symptomatic bone metastases are allowed if ablative therapy can be delivered (femoral metastasis not allowed). Adequate organ function for the planned treatment according to local guide-lines. For patients with liver metastasis: No cirrhosis or hepatitis Hepatic function: Total bilirubin level < 3.0 x institutional ULN ALT, AST, GGT, and alkaline phosphatase levels < 3.0 x institutional ULN Albumin > 2.5 mg/dL Metastasis not adjutant to stomach or small bowel. For patients with abdominal metastases: adequate renal function with a calculated creatinine clearance of > 60mL/min. Toxicities from previous adjuvant therapies (excluding alopecia) must have recovered to grade 1 (defined by CTCAE 5.0). Stable grade 2 peripheral neuropathy are considered individually by the investigator. Negative pregnancy test within 14 days prior to start of treatment*. If childbearing potential, willing to use an effective form of contraception*. No other malignancy during the last 5 years except for radically treated basal or squamous cell carcinoma of the skin or CIS of the cervix. Signed informed consent and willingness to follow the trial procedures. Exclusion Criteria: > 1 line of systemic treatment for OMBC due to previous progressing disease (previous treatment of isolated local recurrences with a 2nd adjuvant treatment not included). Oligometastases in brain. Malignant pleural effusion or ascites. Metastasis growth that involves > 3 vertebra and adjacent spinal cord, spine instability or neurological deficit resulting from compression, 25% spinal canal compromise or progressive neurological deficit. Unable to undergo imaging by either CT scan or MRI. Evidence of any other medical conditions (such as psychiatric illness, infectious diseases, neurological conditions, physical examination or laboratory findings) that may interfere with the planned treatment or affect patient compliance. Pregnancy or breast-feeding. Concurrent malignancy requiring therapy (excluding non-invasive carcinoma or carcinoma in situ).

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomisation 2:1 (systemic treatment + SABR vs systemic treatment)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental SABR arm<br>Standard first line systemic therapy + SABR. | Radiation: SABR<br>* Stereotactic Ablative Radiotherapy is delivered to all metastatic lesions.<br>|
| No Intervention: Control systemic therapy arm<br>Standard first line systemic therapy. | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) | Time from the date of randomisation to the date of disease-progression at any site or death from any cause. | 3 years after the last patient inclusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | Time from the date of randomisation to the date of death from any cause. | 3 years after the last patient inclusion | 
| Local Control Rate (LCR) | Time from the date of randomisation to the date of progress in previously treated metastases | 3 years after the last patient inclusion | 
| Safety analysis - acute toxicity | Reported according to CTCAE v.5.0 | From the first dose of SABR to 3 months after the last dose of SABR | 
| Safety analysis - late toxicity | Reported according to CTCAE v.5.0 | From the first dose of SABR to 3 years after the last dose of SABR | 
| Health-related quality of life Cancer-30 | European Organisation for Research and Treatment of Cancer-Quality of Life Questionnaires Cancer-30 (EORTC-QLQ C30) | At base-line and after 3, 6, 9, 12, 18, 24 and 36 months after registration. | 
| Health-related quality of life Breast-23 | European Organisation for Research and Treatment of Cancer-Quality of Life Questionnaire Breast-23 (EORTC-QLQ B23) | At base-line and after 3, 6, 9, 12, 18, 24 and 36 months after registration. |