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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)

Primary Purpose

Breast Cancer

Status

Terminated

Phase

Phase 3

Locations

International

Study Type

Interventional

Intervention

EXPERIMENTAL ARM

CONTROL GROUP

Standard adjuvant whole breast radiotherapy (50Gy/ 25 fractions to whole breast) followed or not by a boost to tumor bed (16Gy/ 8 fractions)

About this trial

This is an interventional treatment trial for Breast Cancer focused on measuring radiotherapy

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleDoes not accept healthy volunteers

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.

Sites / Locations

Centre Azuréen de Cancérologie
Clinique Sainte-Anne
Centre Hospitalier de Brive
Centre Georges-François Leclerc
Icm Val D'Aurelle
Centre Hospitalier Universitaire Lyon Sud
Centre Hospitalier Princesse Grace

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

EXPERIMENTAL GROUP

CONTROL GROUP

Arm Description

RADIOTHERAPY + PRAVASTATIN

RADIOTHERAPY + PLACEBO

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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.

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.

Adverse events due to Pravastatine

rate of myalgia and arthralgia

Local recurrence

Local recurrence rate

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.

Breast fibrosis-free survival (BF-FS)

BF-FS rates

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.

Specific quality of life measure for breast cancer patient

EORTC QLQ-C30 questionnaires : minimum value = 1 (no effect) maximum value = 4 (bad effect)

Specific quality of life measure for breast cancer patient

QLQ-BR23 questionnaires:minimum value = 1 (no effect) maximum value = 4 (bad effect)

the Cosmetic affect

rate of the acute and rate of later side effects with photographics

feasibility of a new production technique for NovaGray RILA Breast® test

test score sensitivity

Stability of the test

The radiation-induced lymphocyte apoptosis (RILA) assay is the leading candidate as a biological predictor of radiotherapy toxicity

Full Information

NCT ID

NCT04385433

First Posted

April 23, 2020

Last Updated

August 22, 2023

Sponsor

Institut du Cancer de Montpellier - Val d'Aurelle

1. Study Identification

Unique Protocol Identification Number

NCT04385433

Brief Title

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

Acronym

PRAVAPREV-01

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

Study Type

Interventional

2. Study Status

Record Verification Date

May 2023

Overall Recruitment Status

Terminated

Why Stopped

Not enough patients enrolled

Study Start Date

December 4, 2020 (Actual)

Primary Completion Date

April 27, 2023 (Actual)

Study Completion Date

April 27, 2023 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Institut du Cancer de Montpellier - Val d'Aurelle

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. 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.

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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Breast Cancer

Keywords

radiotherapy

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

ParticipantInvestigator

Allocation

Randomized

Enrollment

15 (Actual)

8. Arms, Groups, and Interventions

Arm Title

EXPERIMENTAL GROUP

Arm Type

Experimental

Arm Description

RADIOTHERAPY + PRAVASTATIN

Arm Title

CONTROL GROUP

Arm Type

Placebo Comparator

Arm Description

RADIOTHERAPY + PLACEBO

Intervention Type

Drug

Intervention Name(s)

EXPERIMENTAL ARM

Other Intervention Name(s)

pravastatin group

Intervention Description

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).

Intervention Type

Other

Intervention Name(s)

CONTROL GROUP

Other Intervention Name(s)

placebo group

Intervention Description

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).

Intervention Type

Radiation

Intervention Name(s)

Standard adjuvant whole breast radiotherapy (50Gy/ 25 fractions to whole breast) followed or not by a boost to tumor bed (16Gy/ 8 fractions)

Intervention Description

Radiotherapy will last 5 weeks during treatment by Pravastatine or Placebo

Primary Outcome Measure Information:

Title

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

Description

2-year breast fibrosis-free survival (BF-FS) rate

Time Frame

From randomization to 24 months

Secondary Outcome Measure Information:

Title

Impact of this personalized radiotherapy on Acute toxicities

Description

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.

Time Frame

from randomization to 3 months

Title

Impact of this personalized radiotherapy on late toxicities

Description

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.

Time Frame

from randomization to 3 years

Title

Adverse events due to Pravastatine

Description

rate of myalgia and arthralgia

Time Frame

from randomization to 2 years

Title

Local recurrence

Description

Local recurrence rate

Time Frame

at 1, 2, 3, 5 and 10 years

Title

Relapse free survival (RFS)

Description

Time Frame

at 1, 2, 3, 5 and 10 years

Title

Breast fibrosis-free survival (BF-FS)

Description

BF-FS rates

Time Frame

at 6 months, at 1 and 3 years

Title

Breast fibrosis-relapse-free survival (BF-RFS)

Description

Time Frame

at 1, 2, 3 and 5 years

Title

Specific quality of life measure for breast cancer patient

Description

EORTC QLQ-C30 questionnaires : minimum value = 1 (no effect) maximum value = 4 (bad effect)

Time Frame

at baseline, 5 weeks after RT and 6, 12, 18, 24 and 36 months , at 4 and 5 years

Title

Specific quality of life measure for breast cancer patient

Description

QLQ-BR23 questionnaires:minimum value = 1 (no effect) maximum value = 4 (bad effect)

Time Frame

at baseline, 5 weeks after RT and 6, 12, 18, 24 and 36 months , at 4 and 5 years

Title

the Cosmetic affect

Description

rate of the acute and rate of later side effects with photographics

Time Frame

at baseline, at 12 months and at 2 years of pravastatin/Placebo treatment

Title

feasibility of a new production technique for NovaGray RILA Breast® test

Description

test score sensitivity

Time Frame

at baseline

Title

Stability of the test

Description

The radiation-induced lymphocyte apoptosis (RILA) assay is the leading candidate as a biological predictor of radiotherapy toxicity

Time Frame

at 12 months

10. Eligibility

Sex

Female

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Céline Bourgier, MD

Organizational Affiliation

ICM Co. Ltd.

Official's Role

Study Chair

Facility Information:

Facility Name

Centre Azuréen de Cancérologie

City

Mougins

State/Province

Alpes-Maritimes

ZIP/Postal Code

06250

Country

France

Facility Name

Clinique Sainte-Anne

City

Strasbourg

State/Province

Bas-Rhin

ZIP/Postal Code

67000

Country

France

Facility Name

Centre Hospitalier de Brive

City

Brive

State/Province

Corrèze

ZIP/Postal Code

19100

Country

France

Facility Name

Centre Georges-François Leclerc

City

Dijon

State/Province

Côte d'Or

ZIP/Postal Code

21079

Country

France

Facility Name

Icm Val D'Aurelle

City

Montpellier

State/Province

Herault

ZIP/Postal Code

34298

Country

France

Facility Name

Centre Hospitalier Universitaire Lyon Sud

City

Lyon

ZIP/Postal Code

69000

Country

France

Facility Name

Centre Hospitalier Princesse Grace

City

Monaco

ZIP/Postal Code

98000

Country

Monaco

12. IPD Sharing Statement

Learn more about this trial

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

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