A Comparative Study of Pravastatin vs Placebo as Primary Prevention of Severe Subcutaneous Breast Fibrosis in Hyper-radiosensitive Identified Patients With Breast Cancer (PRAVAPREV-01)

• ClinicalTrials.gov Identifier: NCT04385433
• Recruitment Status: Recruiting
• First Posted: May 13, 2020
• Last Update Posted: January 11, 2022
• Sponsor: Institut du Cancer de Montpellier - Val d'Aurelle
• Information provided by (Responsible Party): Institut du Cancer de Montpellier - Val d'Aurelle

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Breast Cancer	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)	Phase 3

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).

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 400 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: December 4, 2020
• Estimated Primary Completion Date: December 31, 2022
• Estimated Study Completion Date: December 1, 2032

Arms and Interventions

Arm	Intervention/treatment
Experimental: EXPERIMENTAL GROUP; RADIOTHERAPY + PRAVASTATIN	Drug: EXPERIMENTAL ARM; 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).; Other Name: 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); Radiotherapy will last 5 weeks during treatment by Pravastatine or Placebo
Placebo Comparator: CONTROL GROUP; RADIOTHERAPY + PLACEBO	Other: CONTROL GROUP; 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).; Other Name: 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); Radiotherapy will last 5 weeks during treatment by Pravastatine or Placebo

Outcome Measures

Primary Outcome Measures :

1. 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 [ Time Frame: From randomization to 24 months ]
   2-year breast fibrosis-free survival (BF-FS) rate

Secondary Outcome Measures :

1. Impact of this personalized radiotherapy on Acute toxicities [ Time Frame: from randomization to 3 months ]
   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.
2. Impact of this personalized radiotherapy on late toxicities [ Time Frame: from randomization to 3 years ]
   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.
3. Adverse events due to Pravastatine [ Time Frame: from randomization to 2 years ]
   rate of myalgia and arthralgia
4. Local recurrence [ Time Frame: at 1, 2, 3, 5 and 10 years ]
   Local recurrence rate
5. Relapse free survival (RFS) [ Time Frame: at 1, 2, 3, 5 and 10 years ]
   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.
6. Breast fibrosis-free survival (BF-FS) [ Time Frame: at 6 months, at 1 and 3 years ]
   BF-FS rates
7. Breast fibrosis-relapse-free survival (BF-RFS) [ Time Frame: at 1, 2, 3 and 5 years ]
   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.
8. Specific quality of life measure for breast cancer patient [ Time Frame: at baseline, 5 weeks after RT and 6, 12, 18, 24 and 36 months , at 4 and 5 years ]
   EORTC QLQ-C30 questionnaires : minimum value = 1 (no effect) maximum value = 4 (bad effect)
9. Specific quality of life measure for breast cancer patient [ Time Frame: at baseline, 5 weeks after RT and 6, 12, 18, 24 and 36 months , at 4 and 5 years ]
   QLQ-BR23 questionnaires:minimum value = 1 (no effect) maximum value = 4 (bad effect)
10. the Cosmetic affect [ Time Frame: at baseline, at 12 months and at 2 years of pravastatin/Placebo treatment ]
    rate of the acute and rate of later side effects with photographics
11. feasibility of a new production technique for NovaGray RILA Breast® test [ Time Frame: at baseline ]
    test score sensitivity
12. Stability of the test [ Time Frame: at 12 months ]
    The radiation-induced lymphocyte apoptosis (RILA) assay is the leading candidate as a biological predictor of radiotherapy toxicity

Eligibility Criteria

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

Criteria

Inclusion Criteria:

1. Women ≥ 18 years old (no age limit)
2. Conservative breast cancer surgery
3. High risk level of breast fibrosis identified by the centralized NovaGray RILA Breast® test
4. Invasive carcinoma : pT1-T2; pN0 (negative sentinel nodes or axillary nodes dissection) and/or Ductal in situ carcinoma
5. Negative surgical margins
6. Indication of whole breast irradiation only (with or without boost to tumor bed according to physician discretion)
7. Only 3D-conformal RT will be allowed
8. 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).
9. 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).
10. Must be geographically accessible for follow-up
11. Written and dated informed consent
12. Affiliated to the French national social security system

Exclusion Criteria:

1. Current treatment by : statin, fibrate, ciclosporin, systemic fusidic acid, long-term treatment by corticoids
2. History of muscular dystrophy diseases or chronic and/or hereditary muscular diseases
3. Patients with distant metastases
4. Indications of node irradiation (axillar or supraclavicular or mammary chain)
5. T3-4 or N1-3 breast cancer
6. Patients who underwent radical mastectomy
7. Neoadjuvant systemic therapy (chemotherapy, hormonotherapy, targeted therapies)
8. 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
9. Patients with other non-malignant systemic diseases (cardiovascular, renal, hepatic, lung embolism, infection etc.) which would disrupt extended follow-up
10. Untreated hypothyroidism
11. Known positive test for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAG) or hepatitis C virus (HCV) antibody
12. Pregnant or breastfeeding women
13. women of childbearing potential who are unwilling to employ adequate contraception, from the beginning of the study to 4 weeks after last treatment dose
14. Known hypersensitivity to pravastatine, or any constituent of the product.
15. Patient with alcohol misuse.
16. Legal incapacity or physical, psychological or mental status interfering with the patient's ability to sign the informed consent or to terminate the study.

Contacts and Locations

Contacts

Contact: BOURGIER MD CELINE; 0467613102; celine.bourgier@icm.unicancer.fr

Locations

France

Centre Azuréen de Cancérologie; Recruiting

Mougins, Alpes-Maritimes, France, 06250

Contact: Eric Teissier, MD

Principal Investigator: Eric Teissier, MD

Clinique Sainte-Anne; Recruiting

Strasbourg, Bas-Rhin, France, 67000

Contact: Steve Heymann, MD

Principal Investigator: Steve Heymann, MD

Centre Hospitalier de Brive; Recruiting

Brive, Corrèze, France, 19100

Contact: Christel Breton-Callu, MD

Principal Investigator: Christel Breton-Callu, MD

Centre Georges-François Leclerc; Recruiting

Dijon, Côte d'Or, France, 21079

Contact: Karine Peigneaux, MD

Principal Investigator: Karine Peigneaux, MD

Icm Val D'Aurelle; Recruiting

Montpellier, Herault, France, 34298

Contact: BLEUSE JEAN-PIERRE

Contact 0467613102 jean-pierre.bleuse@icm.unicancer.fr

Centre Hospitalier Universitaire Lyon Sud; Recruiting

Lyon, France, 69000

Contact: IONELA DR CARAIVAN

Monaco

Centre Hospitalier Princesse Grace; Recruiting

Monaco, Monaco, 98000

Contact: Aurélie Ginot, MD

Principal Investigator: Aurélie Ginot, MD

Sponsors and Collaborators

Institut du Cancer de Montpellier - Val d'Aurelle

Investigators

• Study Chair: Céline Bourgier, MD; ICM Co. Ltd.

More Information

• Responsible Party: Institut du Cancer de Montpellier - Val d'Aurelle
• ClinicalTrials.gov Identifier: NCT04385433
• Other Study ID Numbers: PROICM 2019-11 PRA
• First Posted: May 13, 2020
• Last Update Posted: January 11, 2022
• Last Verified: January 2022

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

Keywords provided by Institut du Cancer de Montpellier - Val d'Aurelle:

radiotherapy

Additional relevant MeSH terms:

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Pravastatin; Anticholesteremic Agents; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Enzyme Inhibitors