Safety Study of Adding Everolimus to Adjuvant Hormone Therapy in Women With High Risk of Relapse, ER+ and HER2- Primary Breast Cancer, Free of Disease After Receiving at Least One Year of Adjuvant Hormone Therapy

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2015 by UNICANCER
Ministry of Health, France
Information provided by (Responsible Party):
UNICANCER Identifier:
First received: December 6, 2012
Last updated: September 30, 2015
Last verified: September 2015

A significant number of patients relapse and eventually die, particularly if they were initially diagnosed with large nodes involvement and/or T3/4 diseases. When analyses focus on patients with ER+/Her2-negative breast cancer, with ≥4N+, 30% had relapsed at 5 years, emphasizing the need for new drugs in this setting (PACS01 data, UNICANCER internal data).

Strong evidence suggests that cross-talk between the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway and ER signaling is linked to hormone resistance in breast cancer patients.

In the present study, we plan to evaluate the benefit from adding everolimus to standard endocrine treatments after three years of treatment for patient ER+/HER2- at high risk of relapse due to high nodes involvement (≥4) and/or persistent node involvement after neo-adjuvant chemotherapy.

Genomic signatures have emerged during the last 10 years as a new and additive means to evaluate more precisely long term prognosis, and in some instances the amount of benefit from chemotherapy or endocrine therapy in the adjuvant setting. Therefore the UNIRAD study can be proposed to patients with 1-3 positive lymph nodes at primary surgery and a high risk of relapse with the EndoPredict test.

This study is a unique opportunity to prove the efficacy of everolimus in adjuvant setting. The study could be practice changing in case of positive results and could allow improving outcome of breast cancer patients presenting high risk of metastatic relapse.

Condition Intervention Phase
Primary Non-metastatic Breast Cancer
Who Remain Disease-free After Receiving at Least 1 Year of Adjuvant Hormone Therapy
Drug: Everolimus
Drug: Placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Randomized, Double Blind, Multicentric Phase III Trial Evaluating the Safety and Benefit of Adding Everolimus to Adjuvant Hormone Therapy in Women With High Risk of Relapse, ER+ and HER2- Primary Breast Cancer Who Remain Free of Disease After Receiving at Least 1 Year of Adjuvant Hormone Therapy

Resource links provided by NLM:

Further study details as provided by UNICANCER:

Primary Outcome Measures:
  • To evaluate the benefit from adding everolimus to standard endocrine treatments after two years of treatment on the disease-free survival (DFS) after randomization. [ Time Frame: 2 years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Assessment of impact of everolimus on the overall survival (OS), the Event Free Survival (EFS) and Distant Metastasis Free Survival (DMFS) [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  • Assessment of impact of everolimus on DFS and OS in ER+,PR+ and ER+/PR- subgroups [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  • Impact of everolimus on the incidence of secondary cancers [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  • Assessment of the safety profiles for everolimus and hormone therapy combination. [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
  • Biology: Predictive value of mTOR activation markers on DFS: IHC analysis of primary tumor for pS6K and p4EBP. [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  • quality of life sub-studies [ Time Frame: 2 years ] [ Designated as safety issue: No ]

Estimated Enrollment: 1984
Study Start Date: March 2013
Estimated Study Completion Date: January 2018
Estimated Primary Completion Date: January 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Everolimus
2 tablets/day (i.e.10mg/day )
Drug: Everolimus
(10mg/day, i.e. 2 tablets/day)
Other Name: Afinitor
Placebo Comparator: Placebo
2 tablets/day
Drug: Placebo


Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Female ≥ 18 years of age,
  2. Histologically proven invasive unilateral or bilateral breast cancer (regardless of the morphological subtype),
  3. Any T, M0
  4. Patient with high risk of relapse according to one of the conditions below:

    • at least 4 positive lymph nodes if the patient had primary surgery
    • or at least 1 positive lymph node if surgery was conducted after neo adjuvant chemotherapy or hormone therapy of at least 3 months duration
    • or 1-3 positive lymph nodes (pN1a, b, c) at primary surgery AND EPClin score ≥ 3.3 Note: Access to primary tumor for patients with 1-3 node positive is mandatory. Patient with EPClin score < 3.3 will not be randomized, but will be followed yearly during 10 years.
  5. ER+ and HER2 negative : Hormone receptor positive is defined as any staining on the primary tumor, HER2 negativity is defined as IHC 0-1+, or [IHC 2+ and FISH or CISH non-amplified]
  6. Primary tumor completely resected (deep margins and overlying skin involvement allowed if fully resected)
  7. Patients who have received at least 1 year but not more than 4 years of adjuvant hormone therapy. Hormone therapy could be either +/- LH-RH agonists, letrozole, anastrozole or exemestane.
  8. No clinically or radiologically detectable metastases at time of inclusion.
  9. WHO Performance status (ECOG) of 0 or 1.
  10. Adequate hematological function
  11. Adequate hepatic function: AST and ALT ≤ 2.5 ULN, alkaline phosphatases ≤ 2.5 ULN, total bilirubin ≤ 2 ULN.
  12. Adequate renal function: serum creatinine ≤ 1.5 ULN.
  13. Signed written informed consent.

Exclusion Criteria:

  1. Any local, or regional recurrence or metastatic disease.
  2. Any clinical or radiological suspicion of malignant or pre-malignant disease in the contralateral breast.
  3. Patients with pN1mi as sole nodal involvement
  4. Previous cancer (excepted basal cell carcinoma of the skin or in situ carcinoma of the cervix) in the preceding 5 years, including invasive contralateral breast cancer.
  5. Patient already included in another ongoing therapeutic trial involving an unlicensed drug for which follow-up is required.
  6. Patient who is pregnant or breast-feeding. Adequate birth control measures should be taken during the study treatment phase.
  7. Patient with significantly impaired lung function (e.g. Chronic Obstructive Pulmonary Disease, respiratory insufficiency, Interstitial Lung Disease)
  8. Positive serology for HIV infection or hepatitis C.
  9. Chronic carrier of HBV (positive Antigen HbsAg positive in the blood)
  10. Patient with chronic infection
  11. Uncontrolled diabetes defined as glycated haemoglobin , HbA1c>7%
  12. Uncontrolled hypercholesterolemia (cholesterol >300 mg/dl under adequate therapy).
  13. Known hypersensitivity to the active substance, to other rapamycin derivatives or to any of the excipients.
  14. Patient with other concurrent severe and/or uncontrolled medical disease or infection which could compromise participation in the study (e.g. patient who regularly require systemic steroids to control co-morbid disease).
  15. Patient with any psychological, familial, social or geographical condition which could potentially hamper compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT01805271

Contact: Cécile VISSAC-SABATIER, PhD +33 1 73 79 77 58

Centre Leon Berard Recruiting
Lyon, France
Principal Investigator: Thomas Bachelot         
Gustave Roussy Recruiting
Villejuif, France
Principal Investigator: Fabrice Andre         
Sponsors and Collaborators
Ministry of Health, France
Principal Investigator: Thomas Bachelot, MD, PhD Centre Leon Berard, Lyon, France
Principal Investigator: Fabrice Andre, MD, PhD Gustave Roussy, Villejuif, France
  More Information

No publications provided

Responsible Party: UNICANCER Identifier: NCT01805271     History of Changes
Other Study ID Numbers: UNIRAD, 2012-003187-44, UC-0140/1208
Study First Received: December 6, 2012
Last Updated: September 30, 2015
Health Authority: France: Agence Nationale de Sécurité du Médicament et des produits de santé

Keywords provided by UNICANCER:
ER-positive HER2-negative

Additional relevant MeSH terms:
Breast Neoplasms
Breast Diseases
Neoplasms by Site
Skin Diseases
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Antineoplastic Agents
Immunologic Factors
Immunosuppressive Agents
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses processed this record on November 25, 2015