Study in Post-menopausal Women With Hormone Receptor Positive, HER2-negative Advanced Breast Cancer (EVEREXES)

A Phase IIIb, Multi-center, Open-label Study of RAD001 in Combination With EXemestane in Post-menopausal Women With EStrogen Receptor Positive, Human Epidermal Growth Factor Receptor 2 Negative Locally Advanced or Metastatic Breast Cancer

This international, multi-center, open-label, single-arm study evaluated the safety and tolerability profile of everolimus in post-menopausal women with HR positive, HER2 negative locally advanced or metastatic breast cancer after documented recurrence or progression following a non-steroidal aromatase inhibitors (NSAI) therapy in Novartis Oncology emergent growth market (EGM) countries.Data was presented by Asian countries vs Non-Asian countries to confirm no difference in safety and efficacy. Summary statistics were presented.

Study Overview

• Status: Completed
• Conditions: Post Menopausal Breast Cancer
• Intervention / Treatment: Drug: everolimus; Drug: exemestane

• Study Type: Interventional
• Enrollment (Actual): 235
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Australian Capital Territory
    • Garran, Australian Capital Territory, Australia, 2605
      • Novartis Investigative Site
  • New South Wales
    • Caringbah, New South Wales, Australia, 2229
      • Novartis Investigative Site
    • Liverpool, New South Wales, Australia, 2170
      • Novartis Investigative Site
  • Victoria
    • Box Hill, Victoria, Australia, 3128
      • Novartis Investigative Site
    • Heidelberg, Victoria, Australia, 3084
      • Novartis Investigative Site
    • Ringwood East, Victoria, Australia, 3135
      • Novartis Investigative Site
    • St Albans, Victoria, Australia, 3021
      • Novartis Investigative Site
• India
  • Gujarat
    • Karamsad, Gujarat, India, 388325
      • Novartis Investigative Site
  • Maharashtra
    • Nashik, Maharashtra, India, 422 004
      • Novartis Investigative Site
    • Pune, Maharashtra, India, 411013
      • Novartis Investigative Site
  • Orissa
    • Cuttack, Orissa, India, 753 007
      • Novartis Investigative Site
• Indonesia
  • Bandung, Indonesia, 40161
    • Novartis Investigative Site
  • Jakarta, Indonesia, 11420
    • Novartis Investigative Site
  • Jogyakarta, Indonesia, 55284
    • Novartis Investigative Site
  • Semarang, Indonesia, 50212
    • Novartis Investigative Site
• Jordan
  • Amman, Jordan, 11941
    • Novartis Investigative Site
• Korea, Republic of
  • Busan, Korea, Republic of, 602739
    • Novartis Investigative Site
  • Jeollanam-do, Korea, Republic of, 519763
    • Novartis Investigative Site
  • Seoul, Korea, Republic of, 03080
    • Novartis Investigative Site
  • Seoul, Korea, Republic of, 06351
    • Novartis Investigative Site
  • Seoul, Korea, Republic of, 03722
    • Novartis Investigative Site
  • Seoul, Korea, Republic of, 02841
    • Novartis Investigative Site
  • Seoul, Korea, Republic of, 06273
    • Novartis Investigative Site
  • Seoul, Korea, Republic of, 01812
    • Novartis Investigative Site
  • Taegu, Korea, Republic of, 41944
    • Novartis Investigative Site
  • Gyeonggi-do
    • Suwon, Gyeonggi-do, Korea, Republic of, 443380
      • Novartis Investigative Site
  • Korea
    • Gyeonggi do, Korea, Korea, Republic of, 10408
      • Novartis Investigative Site
    • Seoul, Korea, Korea, Republic of, 05505
      • Novartis Investigative Site
  • Seocho Gu
    • Seoul, Seocho Gu, Korea, Republic of, 06591
      • Novartis Investigative Site
• Malaysia
  • MYS
    • Kuala Lumpur, MYS, Malaysia, 56000
      • Novartis Investigative Site
  • Sabah
    • Kota Kinabalu, Sabah, Malaysia, 88586
      • Novartis Investigative Site
  • Wilayah Persekutuan
    • Kuala Lumpur, Wilayah Persekutuan, Malaysia, 50586
      • Novartis Investigative Site
• Morocco
  • Casablanca, Morocco
    • Novartis Investigative Site
  • Rabat, Morocco, 6527
    • Novartis Investigative Site
• South Africa
  • Western Cape, South Africa, 7925
    • Novartis Investigative Site
  • Western Cape
    • Cape Town, Western Cape, South Africa, 7925
      • Novartis Investigative Site
    • George, Western Cape, South Africa, 6530
      • Novartis Investigative Site
• Taiwan
  • Changhua, Taiwan, 50006
    • Novartis Investigative Site
  • Kaohsiung City, Taiwan, 83301
    • Novartis Investigative Site
  • Kaoshiung, Taiwan, 80756
    • Novartis Investigative Site
  • Taipei, Taiwan, 10048
    • Novartis Investigative Site
  • Taipei, Taiwan, 10449
    • Novartis Investigative Site
  • TWN
    • New Taipei City, TWN, Taiwan, 23561
      • Novartis Investigative Site
• Thailand
  • Bangkok, Thailand, 10400
    • Novartis Investigative Site
  • Bangkok, Thailand, 10300
    • Novartis Investigative Site
  • Chiang Mai, Thailand, 50200
    • Novartis Investigative Site
• Tunisia
  • Ariana, Tunisia, 2080
    • Novartis Investigative Site
• Turkey
  • Ankara, Turkey, 06100
    • Novartis Investigative Site
  • Ankara, Turkey, 06500
    • Novartis Investigative Site
  • Ankara, Turkey, 06460
    • Novartis Investigative Site
  • Gaziantep, Turkey, 27310
    • Novartis Investigative Site
  • Izmir, Turkey, 35040
    • Novartis Investigative Site
  • Kartal, Turkey, 34890
    • Novartis Investigative Site
  • Pendik / Istanbul, Turkey, 34899
    • Novartis Investigative Site
• Vietnam
  • Ho Chi Minh, Vietnam, 700000
    • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Postmenopausal women with metastatic, recurrent or locally advanced breast cancer not amenable to curative treatment by surgery or radiotherapy.
• Histological or cytological confirmation of hormone-receptor positive (HR+) breast cancer.
• Disease refractory to non-steroidal aromatase inhibitors, defined as:
• Recurrence while on, or within 12 months (365 days) of completion of adjuvant therapy with letrozole or anastrozole, or
• Progression while on, or within one month (30 days) of completion of letrozole or anastrozole treatment for locally advanced or metastatic breast cancer (ABC).
• Radiological or objective evidence of recurrence or progression on or after the last systemic therapy prior to enrolment.
• Patients must have had:

• At least one lesion that could have been accurately measured in at least one dimension

  • 20 mm with conventional imaging techniques or ≥ 10 mm with spiral CT or MRI, or
• Bone lesions: lytic or mixed (lytic + blastic) in the absence of measurable disease as defined above.
• Adequate bone marrow, coagulation, liver and renal function.
• ECOG performance status ≤ 2.

Exclusion Criteria:

• Patients overexpressing HER2 by local laboratory testing (IHC 3+ staining or in situ hybridization positive). Patients with IHC 2+ must have a negative in situ hybridization test.
• Patients with only non-measurable lesions other than bone metastasis (e.g. pleural effusion, ascites).
• Patients with more than one prior chemotherapy line for ABC. A chemotherapy line is an anticancer regimen(s) that contained at least 1 cytotoxic chemotherapy agent, given for a minimum of 21 days.
• Previous treatment with mTOR inhibitors.
• Known hypersensitivity to mTOR inhibitors, e.g. Sirolimus (rapamycin).
• Patients with a known history of HIV seropositivity. Screening for HIV infection at baseline was not required.
• Patient who were being treated with drugs recognized as being strong inhibitors or inducers of the isoenzyme CYP3A
• History of brain or other CNS metastases, including leptomeningeal metastasis.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: everolimus + exemestane; Everolimus (10 mg) and exemestane (25 mg) tablets taken orally in combination once daily	Drug: everolimus; one 10 mg tablet or two 5 mg tablets of everolimus were administered orally once daily on a continuous dosing schedule starting on Day 1; Other Names: RAD001; Drug: exemestane; 25 mg tablet was administered orally once daily on a continuous dosing schedule starting on Day 1

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Summary of Number of Participants With Treatment Emergent Adverse Events (TEAE) - All Grades	Adverse events (AEs), serious adverse events (SAEs), changes from baseline in vital signs and laboratory results (hematology, blood chemistry, lipid profile) qualifying and reported as AEs. Although a patient might had two or more adverse events the patient is only counted once in a category. The same patient might appear in different categories. AESI: Adverse events of special interest.	Baseline up to approximately 43 weeks for Asian countires and 32 weeks for Non-Asian countries including a 30 day post treatment follow up period

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Response Rates (Best Overall and Overall)	The best overall response for each patient is determined from the sequence of investigator overall lesion responses according to RECIST 1.1: Complete Response (CR)=disappearance of target lesions, Partial Response (PR) was >=30% decrease in sum of diameter of lesions, Progressive Disease (PD) was >=20% decrease in sum of diameter of lesions, Stable Disease (SD) does not qualify for PR, CR or PD, Unknown=not documented or assessed. To be assigned a best overall response of CR at least two determinations of CR at least 4 weeks apart before progression are required. To be assigned a best overall response of PR at least two determinations of PR or better at least 4 weeks apart before progression (and not qualifying for a CR) are required. The Overall response rate (ORR) is the percentage of patients with a best overall response of confirmed complete (CR) or partial (PR) response. The 95% confidence intervals (CI) were computed using the Clopper-Pearson method	Baseline up to approximately 43 weeks for Asian countires and 32 weeks for Non-Asian countries
Percentage of Participants Clinical Benefit Rate	Clinical benefit rate: Patients with best overall response rate of CR (any duration), PR (any duration) and SD with duration of 24 weeks or longer according to RECIST 1.1 criteria: Complete Response (CR)=disappearance of target lesions, Partial Response (PR) was >=30% decrease in sum of diameter of lesions, Progressive Disease (PD) was >=20% decrease in sum of diameter of lesions, Stable Disease (SD) does not qualify for PR, CR or PD, Unknown=not documented or assessed. Best overall response of CR = at least two determinations of CR at least 4 weeks apart before progression are required. Best overall response of PR = at least two determinations of PR or better at least 4 weeks apart before progression (and not qualifying for a CR) are required. The Overall response rate (ORR) is the percentage of patients with a best overall response of confirmed complete (CR) or partial (PR) response. The 95% confidence intervals (CI) were computed using the Clopper-Pearson method.	Baseline up to approximately 43 weeks for Asian countires and 32 weeks for Non-Asian countries
Progression Free Survival (PFS)	PFS is time from date of start of treatment to date of disease progression or death due to any cause, whichever occurs first. b Percentiles with 95% CIs are calculated from PROC LIFETEST output using method of Brookmeyer and Crowley (1982)	Baseline up to approximately 43 weeks for Asian countires and 40 weeks for Non-Asian countries
Percent of Participants Event-free Probability Estimates of Deterioration of Eastern Cooperative Oncology Group (ECOG) Performance Status	Time to deterioration of ECOG performance status, from baseline will be assessed using the ECOG Performance Status Scale (Oken, 1982). Time to deterioration is the time from date of start of treatment to the date of the event defined as deterioration. Deterioration is defined as an increase in performance status from 0 to 2 or greater, an increase in performance status from 1-2 to 3 or greater, or death due to any cause. Event-free probability estimate is the estimated probability that a patient will remain event-free up to the specified time point. Event-free probability estimates were are obtained from the Kaplan-Meier survival estimates.	Baseline up to approximately 50 weeks

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): March 29, 2013
• Primary Completion (Actual): January 29, 2019
• Study Completion (Actual): January 29, 2019

Study Registration Dates

• First Submitted: June 1, 2017
• First Submitted That Met QC Criteria: June 1, 2017
• First Posted (Actual): June 5, 2017

Study Record Updates

• Last Update Posted (Actual): April 7, 2020
• Last Update Submitted That Met QC Criteria: April 6, 2020
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Keywords: adult; everolimus; advanced breast cancer; estrogen receptor positive; metastatic breast cancer; endocrine therapy; exemestane; mTor inhibitor; post menopausal; CRAD001; human epidermal growth factor
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormone Antagonists; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Estrogen Antagonists; Everolimus; Exemestane
• Other Study ID Numbers: CRAD001JIC06

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No