A Comparative Study of Pravastatin vs Placebo as Primary Prevention of Severe Subcutaneous Breast Fibrosis in Hyper-radiosensitive Identified Patients With Breast Cancer

Study Overview
=================
Brief Summary
-----------------
-Interventional trials aim at preventing severe RIF occurrence in BC patients selected by individual radiosensitivity: PRAVAPREV-01 will be the first interventional double blind trial that will offer a personalised strategy to breast cancer patients who will be treated with adjuvant RT after breast conserving surgery: By assessing individual risk of severe RIF development By offering a statin targeted therapy to the high-risk patients identified.

Detailed Description
-----------------
According to VICAN5 report, near 50% of survivorship breast cancer (BC) patients suffered impairment of their QoL 2 and 5 years after BC diagnosis compared to overall population. In France, adjuvant radiotherapy (RT) is performed to 88.5% of BC patients. Severe toxicities after adjuvant RT such as radio-induced fibrosis (RIF) in BC patients can have a negative impact on quality of life and a marked effect on subsequent psychological outcomes. However, current practice standards commonly prescribe RT irrespective of the individual radiosensitivity risk. This study propose to identify BC at high RIF risk and to prevent severe RIF occurrence in this selected BC population by the use of anti-fibrotic agent (pravastatin). How to identify the risk of individual radiosensitivity? Since 1995 a rapid (72 h) radiosensitivity assay based on flow cytometric assessment of radiation-induced CD8 T-lymphocyte apoptosis (RILA) has been developed. A lot of laboratory observed a significant relationship between RILA and toxicities occurrence, in particular in a prospective multicenter French study (NCT00893035, Azria et al, EBioMedicine 2015). Data from this study have validated the use of the NovaGray RILA Breast® test in clinical routine and enabled its CE-mark obtention in 2016. How to prevent severe RIF occurrence? Few phase II clinical trials have assessed anti-fibrotic properties of some drugs in a preventive setting (pentoxyfilline/vitamine E, ambroxol, ACE inhibitors, amifostine) and showed controversial results regarding efficacy and/ or tolerance. To date, no large phase III clinical trial confirmed these therapeutic strategies in the prevention of severe breast RIF occurrence. Since 2000, Rho/ROCK pathway inhibition habe been showed, in particular by Pravastatin, was able to prevent and cure severe RIF in different preclinical RIF models. Based on those results, a phase II clinical trial PRAVACUR (NCT01268202) has been conducted,assessing efficacy of 12-months daily pravastatin delivered in patients with established RIF after head and neck radiotherapy. The use of Pravastatin significantly reduced RIF grade in 51% of patients (clinical assessment at 12-months) without any rebound effect after pravastatin completion (Bourgier IJROBP 2019). This hypothesis is therefore that pravastatin given in a preventive approach will significantly decrease severe breast fibrosis occurrence in a highly selected breast cancer population treated by adjuvant breast RT and considered at high risk of RIF (tailored by the NovaGray RILA Breast® test).

Official Title
-----------------
A Comparative Study of Pravastatin vs Placebo as Primary Prevention of Severe Subcutaneous Breast Fibrosis in Hyper-radiosensitive Identified Patients With Breast Cancer

Conditions
-----------------
Breast Cancer

Intervention / Treatment
-----------------
* Drug: EXPERIMENTAL ARM
* Other: CONTROL GROUP
* Radiation: Standard adjuvant whole breast radiotherapy (50Gy/ 25 fractions to whole breast) followed or not by a boost to tumor bed (16Gy/ 8 fractions)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Women ≥ 18 years old (no age limit) Conservative breast cancer surgery High risk level of breast fibrosis identified by the centralized NovaGray RILA Breast® test Invasive carcinoma : pT1-T2; pN0 (negative sentinel nodes or axillary nodes dissection) and/or Ductal in situ carcinoma Negative surgical margins Indication of whole breast irradiation only (with or without boost to tumor bed according to physician discretion) Only 3D-conformal RT will be allowed Blood sample allowing pravastatin use : serum creatinine ≤ 130 µmol/l; ASAT and ALAT≤ 2N; total bilirubin ≤ 1.5N; CK MM levels < 3 x ULN for women ≥ 70 years (at least 15 days before randomization). Negative pregnancy test in women of childbearing potential (β-HCG dosage ≤ 7 days prior to randomization), an adequate contraception should be used from the beginning of the study to 4 weeks after last treatment dose. The women not of reproductive potential are female patients who are postmenopausal (with a minimum of one year without menstruation and without alternative medical cause) or permanently sterilized: e.g., tubal occlusion, hysterectomy, bilateral salpingectomy). Must be geographically accessible for follow-up Written and dated informed consent Affiliated to the French national social security system Exclusion Criteria: Current treatment by : statin, fibrate, ciclosporin, systemic fusidic acid, long-term treatment by corticoids History of muscular dystrophy diseases or chronic and/or hereditary muscular diseases Patients with distant metastases Indications of node irradiation (axillar or supraclavicular or mammary chain) T3-4 or N1-3 breast cancer Patients who underwent radical mastectomy Neoadjuvant systemic therapy (chemotherapy, hormonotherapy, targeted therapies) Patients with previous or concomitant other (not breast cancer) malignancy within the past 5 years EXCEPT adequately treated basal or squamous cell carcinoma of the skin or in situ carcinoma of the cervix. Patients who have had a previous other malignancy must have been disease free for at least five years Patients with other non-malignant systemic diseases (cardiovascular, renal, hepatic, lung embolism, infection etc.) which would disrupt extended follow-up Untreated hypothyroidism Known positive test for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAG) or hepatitis C virus (HCV) antibody Pregnant or breastfeeding women women of childbearing potential who are unwilling to employ adequate contraception, from the beginning of the study to 4 weeks after last treatment dose Known hypersensitivity to pravastatine, or any constituent of the product. Patient with alcohol misuse. Legal incapacity or physical, psychological or mental status interfering with the patient's ability to sign the informed consent or to terminate the study.

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

Sexes Eligible for Study
-----------------
Female

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

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

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: EXPERIMENTAL GROUP<br>RADIOTHERAPY + PRAVASTATIN | Drug: EXPERIMENTAL ARM<br>* Patients in the experimental arm will receive: Daily pravastatin (40mg/d) during 12 months (pravastatin initiation: first day of radiotherapy). Standard adjuvant whole breast radiotherapy (50Gy/ 25 fractions to whole breast) followed or not by a boost to tumor bed (16Gy/ 8 fractions).<br>* Other names: pravastatin group;Radiation: Standard adjuvant whole breast radiotherapy (50Gy/ 25 fractions to whole breast) followed or not by a boost to tumor bed (16Gy/ 8 fractions)<br>* Radiotherapy will last 5 weeks during treatment by Pravastatine or Placebo<br>|
| Placebo Comparator: CONTROL GROUP<br>RADIOTHERAPY + PLACEBO | Other: CONTROL GROUP<br>* Patients in the standard arm will receive: Daily placebo during 12 months (placebo initiation: first day of radiotherapy) Standard adjuvant whole breast radiotherapy (50Gy/ 25 fractions to whole breast) followed or not by a boost to tumor bed (16Gy/ 8 fractions).<br>* Other names: placebo group;Radiation: Standard adjuvant whole breast radiotherapy (50Gy/ 25 fractions to whole breast) followed or not by a boost to tumor bed (16Gy/ 8 fractions)<br>* Radiotherapy will last 5 weeks during treatment by Pravastatine or Placebo<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Impact of Pravastatin on the occurrence of grade ≥2 breast fibrosis in a selected breast cancer patient population considered at high risk of severe breast fibrosis occurrence | 2-year breast fibrosis-free survival (BF-FS) rate | From randomization to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Impact of this personalized radiotherapy on Acute toxicities | Incidence of acute effects assessed and graded according to the NCI-CTCAE v5.0 scale; the most severe grade observed during the period per patient will be reported. | from randomization to 3 months | 
| Impact of this personalized radiotherapy on late toxicities | late side effects assessed and graded according to the NCI-CTCAE v5.0 scale; the most severe grade observed during the period per patient will be reported. | from randomization to 3 years | 
| Adverse events due to Pravastatine | rate of myalgia and arthralgia | from randomization to 2 years | 
| Local recurrence | Local recurrence rate | at 1, 2, 3, 5 and 10 years | 
| Relapse free survival (RFS) | Relapse-free survival (RFS) rates with RFS defined as the time from the date of randomization to the date of the first relapse (including local relapse, or distant metastasis or death (all causes), whichever occurs first. | at 1, 2, 3, 5 and 10 years | 
| Breast fibrosis-free survival (BF-FS) | BF-FS rates | at 6 months, at 1 and 3 years | 
| Breast fibrosis-relapse-free survival (BF-RFS) | BF-RFS rates with BF-RFS defined as the time from the date of randomization to the date of the first relapse (including local relapse, or distant metastasis or death (all causes) or the first documented grade ≥2 breast fibrosis whichever occurs first. | at 1, 2, 3 and 5 years | 
| Specific quality of life measure for breast cancer patient | EORTC QLQ-C30 questionnaires : minimum value = 1 (no effect) maximum value = 4 (bad effect) | at baseline, 5 weeks after RT and 6, 12, 18, 24 and 36 months , at 4 and 5 years | 
| Specific quality of life measure for breast cancer patient | QLQ-BR23 questionnaires:minimum value = 1 (no effect) maximum value = 4 (bad effect) | at baseline, 5 weeks after RT and 6, 12, 18, 24 and 36 months , at 4 and 5 years | 
| the Cosmetic affect | rate of the acute and rate of later side effects with photographics | at baseline, at 12 months and at 2 years of pravastatin/Placebo treatment | 
| feasibility of a new production technique for NovaGray RILA Breast® test | test score sensitivity | at baseline | 
| Stability of the test | The radiation-induced lymphocyte apoptosis (RILA) assay is the leading candidate as a biological predictor of radiotherapy toxicity | at 12 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
radiotherapy