Efficacy and Safety of Everolimus in Combination Therapy, in Patients With HER2-overexpressing Metastatic Breast Cancer

A Phase Ib/II Study Investigating the Combination of Everolimus With Trastuzumab and Paclitaxel in Patients With HER2-overexpressing Metastatic Breast Cancer

Phase I: will look at different dose levels and regimens of everolimus combined with weekly trastuzumab and paclitaxel therapy in patients with HER-2 overexpressing metastatic breast cancer.

Phase II: will assess the efficacy and safety of the 10mg daily dose of everolimus combined with weekly trastuzumab and paclitaxel therapy in patients with HER-2 overexpressing metastatic breast cancer.

Study Overview

• Status: Completed
• Conditions: Metastatic Breast Cancer
• Intervention / Treatment: Drug: Everolimus; Drug: Trastuzumab; Drug: Paclitaxel

• Study Type: Interventional
• Enrollment (Actual): 88
• Phase: Phase 1

Contacts and Locations

Study Locations

• Belgium
  • Charleroi, Belgium, 6000
    • Novartis Investigative Site
  • Liege, Belgium, 4000
    • Novartis Investigative Site
  • Turnhout, Belgium, 2300
    • Novartis Investigative Site
• France
  • Paris, France, 75970
    • Novartis Investigative Site
  • Saint-Herblain Cédex, France, 44805
    • Novartis Investigative Site
  • Toulouse Cedex 9, France, 31059
    • Novartis Investigative Site
  • Villejuif Cedex, France, 94805
    • Novartis Investigative Site
• Netherlands
  • Maastricht, Netherlands, 6229 HX
    • Novartis Investigative Site
• Spain
  • Cataluna
    • Lleida, Cataluna, Spain, 25198
      • Novartis Investigative Site
• United States
  • California
    • *see Various Departments*, California, United States
      • Wilshire Oncology Medical Group La Verne
    • Fountain Valley, California, United States, 92708
      • Compassionate Cancer Care Medical Group Dept.ofCCCMG
    • Loma Linda, California, United States, 92354
      • Loma Linda University Dept.ofLomaLindaCancerCent(3)
    • Los Angeles, California, United States, 90095
      • University of California at Los Angeles Dept.of UCLA Dept.ofMed.
  • Florida
    • Davie, Florida, United States, 33328
      • Florida Cancer Research Institute
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University School of Medicine/Winship Cancer Institute Dept. of Hematology (2)
  • Illinois
    • Evanston, Illinois, United States, 60201
      • North Shore University Health System
  • Maryland
    • Salisbury, Maryland, United States, 21801
      • Peninsula Regional Medical Center Deptof Oncology and Hematology
  • Missouri
    • St. Louis, Missouri, United States, 63110
      • Washington University School Of Medicine-Siteman Cancer Ctr StudyCoordinator:CRAD001J2101
  • South Carolina
    • Greenville, South Carolina, United States, 29605
      • Cancer Centers of the Carolinas CC of C -Eastside
  • Texas
    • Dallas, Texas, United States, 78246
      • Sammons Cancer Center - Texas Oncology

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:

• Female or male patients ≥ 18 years old with WHO performance status ≤ 1
• HER-2 over-expressing metastatic breast cancer cells confirmed by histology
• Progressive disease on prior trastuzumab alone/or in combination with other anticancer agents, or relapsed any time after completion of this therapy (phase l)
• Patient resistance to trastuzumab and taxanes (Phase ll)
• Measurable disease according to RECIST (Phase ll)
• Patients neurologically stable with adequate bone marrow, liver and renal function

Exclusion Criteria:

• Patients receiving endocrine therapy for breast cancer ≤ 2 weeks prior to study treatment start
• Patients currently receiving chemotherapy, immunotherapy or radiotherapy or who have received these ≤ 4 weeks prior to study treatment start or patients who have received lapatinib ≤ 2 weeks prior to study treatment start
• Patients who have previously received mTOR inhibitors

Other protocol-defined inclusion/exclusion criteria may apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase I - RAD001 5mg + PT, daily; Daily dosing schedule of EPT = Paclitaxel & Trastuzumab verolimus 5mg plus Paclitaxel plus Trastuzumab.	Drug: Everolimus; Everolimus (RAD001) was supplied as tablets in 3 different dosage strengths, 2.5, 5, and 10 mg. The drug was packaged in blisters containing 10 tablets per blister. Blisters and packaging labels were compliant with local regulations and were printed in local language.; Other Names: RAD001; Drug: Trastuzumab; Commercially-available trastuzumab was used in this study. A 4 mg/kg loading dose was administered, intra-venous (IV), over 90 minutes on Day 1 (if patient was not already receiving trastuzumab); this was followed by weekly trastuzumab 2 mg/kg IV administered over 30 minutes. For patients who continued to receive trastuzumab and everolimus after completion/discontinuation of chemotherapy in the core treatment phase, trastuzumab may have been administered once every 3 weeks at a dose of 6 mg/kg. PT = Paclitaxel & Trastuzumab; Drug: Paclitaxel; Commercially-available paclitaxel was used in this study. Paclitaxel infusion was administered on Days 1, 8, and 15 of each 28-day cycle, after administration of trastuzumab. Paclitaxel (80 mg/m2) was administered as a 60-minute continuous IV infusion after standard premedication. Patients received paclitaxel for 6 cycles. At the investigator's discretion, treatment with paclitaxel could continue beyond 6 cycles.
Experimental: Phase I - RAD001 10mg + PT, daily; Daily dosing schedule of Everolimus 10mg plus Paclitaxel plus Trastuzumab. PT = Paclitaxel & Trastuzumab	Drug: Everolimus; Everolimus (RAD001) was supplied as tablets in 3 different dosage strengths, 2.5, 5, and 10 mg. The drug was packaged in blisters containing 10 tablets per blister. Blisters and packaging labels were compliant with local regulations and were printed in local language.; Other Names: RAD001; Drug: Trastuzumab; Commercially-available trastuzumab was used in this study. A 4 mg/kg loading dose was administered, intra-venous (IV), over 90 minutes on Day 1 (if patient was not already receiving trastuzumab); this was followed by weekly trastuzumab 2 mg/kg IV administered over 30 minutes. For patients who continued to receive trastuzumab and everolimus after completion/discontinuation of chemotherapy in the core treatment phase, trastuzumab may have been administered once every 3 weeks at a dose of 6 mg/kg. PT = Paclitaxel & Trastuzumab; Drug: Paclitaxel; Commercially-available paclitaxel was used in this study. Paclitaxel infusion was administered on Days 1, 8, and 15 of each 28-day cycle, after administration of trastuzumab. Paclitaxel (80 mg/m2) was administered as a 60-minute continuous IV infusion after standard premedication. Patients received paclitaxel for 6 cycles. At the investigator's discretion, treatment with paclitaxel could continue beyond 6 cycles.
Experimental: Phase I - RAD001 30mg + PT, weekly; Weekly dosing schedule of Everolimus 30mg plus Paclitaxel plus Trastuzumab. PT = Paclitaxel & Trastuzumab.	Drug: Everolimus; Everolimus (RAD001) was supplied as tablets in 3 different dosage strengths, 2.5, 5, and 10 mg. The drug was packaged in blisters containing 10 tablets per blister. Blisters and packaging labels were compliant with local regulations and were printed in local language.; Other Names: RAD001; Drug: Trastuzumab; Commercially-available trastuzumab was used in this study. A 4 mg/kg loading dose was administered, intra-venous (IV), over 90 minutes on Day 1 (if patient was not already receiving trastuzumab); this was followed by weekly trastuzumab 2 mg/kg IV administered over 30 minutes. For patients who continued to receive trastuzumab and everolimus after completion/discontinuation of chemotherapy in the core treatment phase, trastuzumab may have been administered once every 3 weeks at a dose of 6 mg/kg. PT = Paclitaxel & Trastuzumab; Drug: Paclitaxel; Commercially-available paclitaxel was used in this study. Paclitaxel infusion was administered on Days 1, 8, and 15 of each 28-day cycle, after administration of trastuzumab. Paclitaxel (80 mg/m2) was administered as a 60-minute continuous IV infusion after standard premedication. Patients received paclitaxel for 6 cycles. At the investigator's discretion, treatment with paclitaxel could continue beyond 6 cycles.
Experimental: Phase II - RAD001 10mg + PT, daily; Daily dosing schedule of Everolimus 10mg plus Paclitaxel plus Trastuzumab. PT = Paclitaxel & Trastuzumab	Drug: Everolimus; Everolimus (RAD001) was supplied as tablets in 3 different dosage strengths, 2.5, 5, and 10 mg. The drug was packaged in blisters containing 10 tablets per blister. Blisters and packaging labels were compliant with local regulations and were printed in local language.; Other Names: RAD001; Drug: Trastuzumab; Commercially-available trastuzumab was used in this study. A 4 mg/kg loading dose was administered, intra-venous (IV), over 90 minutes on Day 1 (if patient was not already receiving trastuzumab); this was followed by weekly trastuzumab 2 mg/kg IV administered over 30 minutes. For patients who continued to receive trastuzumab and everolimus after completion/discontinuation of chemotherapy in the core treatment phase, trastuzumab may have been administered once every 3 weeks at a dose of 6 mg/kg. PT = Paclitaxel & Trastuzumab; Drug: Paclitaxel; Commercially-available paclitaxel was used in this study. Paclitaxel infusion was administered on Days 1, 8, and 15 of each 28-day cycle, after administration of trastuzumab. Paclitaxel (80 mg/m2) was administered as a 60-minute continuous IV infusion after standard premedication. Patients received paclitaxel for 6 cycles. At the investigator's discretion, treatment with paclitaxel could continue beyond 6 cycles.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase II: Overall Response Rate	The primary objective of this phase II study was to evaluate the efficacy of the dose level/regimen of everolimus recommended from the Phase I with trastuzumab and paclitaxel (PT) therapy in patients with HER2-overexpressing metastatic breast cancer whose disease progressed on/after trastuzumab mono-and/or combination therapy based on the evaluation of objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST). Objective response rate (ORR) was defined as the proportion of patients with a best overall response (BOR) of complete response (CR) or partial response (PR). Only patients with measurable disease (the presence of at least one measurable lesion) at baseline were included in the study. CR = Disappearance of all target lesions; PR = At least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the baseline sum of the longest diameters.	every 8 - 9 weeks until disease progression or a new lesion is identified

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase I: Best Overall Response (BOR)	BOR was determined based on investigator assessment of overall lesion response using RECIST criteria guidelines. BOR = objective responses rate (ORR), disease control rate (DCR) or clinical benefit rate (CBR). ORR = (complete response (CR) or partial response(PR); DCR = (CR or PR or Stable disease (SD); CBR = (CR or PR or SD >= 24 weeks).CR = Disappearance of all target lesions; PR = At least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the baseline sum of the longest diameters; SD = Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for partial disease (PD). PD = At least a 20% increase in the sum of the longest diameter of all measured target lesions, taking as reference the smallest sum of longest diameter of all target lesions recorded at or after baseline.	every 8 - 9 weeks until disease progression or a new lesion is identified
Phase II: Progression Free Survival (PFS)	PFS is defined as the time from start of treatment to the date of first documented progression or death due to any cause. If a patient has not had an event, PFS will be censored at the date of last adequate tumor assessment.	every 8 - 9 weeks until disease progression or a new lesion is identified
Phase II: Overall Survival (OS)	Overall survival (OS) is defined as the time from start of treatment to the date of death due to any cause. If a patient is not known to have died, survival was censored at the last date of contact. OS was to be reported at extension and after 3-year follow-up. The Kaplan-Meier median was used to analyze the OS.	every 3 months until death

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

Helpful Links

• Breast Cancer
• Visit NovartisClinicalTrials.com: Pre-qualify for a trial, and view a list of trials and participating study centers.

Study record dates

Study Major Dates

• Study Start: July 1, 2007
• Primary Completion (Actual): March 1, 2014
• Study Completion (Actual): March 1, 2014

Study Registration Dates

• First Submitted: January 23, 2007
• First Submitted That Met QC Criteria: January 23, 2007
• First Posted (Estimate): January 24, 2007

Study Record Updates

• Last Update Posted (Estimate): December 28, 2015
• Last Update Submitted That Met QC Criteria: November 24, 2015
• Last Verified: November 1, 2015

More Information

Terms related to this study

• Keywords: paclitaxel; Breast cancer; Metastatic; trastuzumab; everolimus; HER-2; Cancer of the breast; Human mammary carcinoma
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Antineoplastic Agents, Immunological; Paclitaxel; Trastuzumab; Everolimus
• Other Study ID Numbers: CRAD001J2101; 2006-001596-37 (EudraCT Number)