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

Tracking Information
First Submitted Date ICMJE	January 23, 2007
First Posted Date ICMJE	January 24, 2007
Results First Submitted Date	March 20, 2015
Results First Posted Date	March 31, 2015
Last Update Posted Date	December 28, 2015
Study Start Date ICMJE	July 2007
Actual Primary Completion Date	March 2014 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: April 2, 2015)	Phase II: Overall Response Rate [ Time Frame: every 8 - 9 weeks until disease progression or a new lesion is identified ]; 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.
Original Primary Outcome Measures ICMJE; (submitted: January 23, 2007)	To establish the feasible dose levels/regimens based on end-of-cycle-1 dose limiting toxicity
Change History	Complete list of historical versions of study NCT00426556 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: April 2, 2015)	Phase I: Best Overall Response (BOR) [ Time Frame: every 8 - 9 weeks until disease progression or a new lesion is identified ]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.; Phase II: Progression Free Survival (PFS) [ Time Frame: every 8 - 9 weeks until disease progression or a new lesion is identified ]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.; Phase II: Overall Survival (OS) [ Time Frame: every 3 months until death ]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.
Original Secondary Outcome Measures ICMJE; (submitted: January 23, 2007)	To assess the ability to deliver the trastuzumab and paclitaxel therapy; To assess everolimus, trastuzumab and paclitaxel blood levels in this combination; To evaluate the overall tumor response
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	Efficacy and Safety of Everolimus in Combination Therapy, in Patients With HER2-overexpressing Metastatic Breast Cancer
Official Title ICMJE	A Phase Ib/II Study Investigating the Combination of Everolimus With Trastuzumab and Paclitaxel in Patients With HER2-overexpressing Metastatic Breast Cancer
Brief Summary	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.
Detailed Description	Not Provided
Study Type ICMJE	Interventional
Study Phase	Phase 1
Study Design ICMJE	Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition ICMJE	Metastatic Breast Cancer
Intervention ICMJE	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 Name: 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.
Study Arms	Experimental: Phase I - RAD001 5mg + PT, daily Daily dosing schedule of EPT = Paclitaxel & Trastuzumab verolimus 5mg plus Paclitaxel plus Trastuzumab. Interventions: Drug: Everolimus Drug: Trastuzumab Drug: Paclitaxel; Experimental: Phase I - RAD001 10mg + PT, daily Daily dosing schedule of Everolimus 10mg plus Paclitaxel plus Trastuzumab. PT = Paclitaxel & Trastuzumab Interventions: Drug: Everolimus Drug: Trastuzumab Drug: Paclitaxel; Experimental: Phase I - RAD001 30mg + PT, weekly Weekly dosing schedule of Everolimus 30mg plus Paclitaxel plus Trastuzumab. PT = Paclitaxel & Trastuzumab. Interventions: Drug: Everolimus Drug: Trastuzumab Drug: Paclitaxel; Experimental: Phase II - RAD001 10mg + PT, daily Daily dosing schedule of Everolimus 10mg plus Paclitaxel plus Trastuzumab. PT = Paclitaxel & Trastuzumab Interventions: Drug: Everolimus Drug: Trastuzumab Drug: Paclitaxel
Publications *	Not Provided
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Completed
Actual Enrollment ICMJE; (submitted: June 13, 2014)	88
Original Enrollment ICMJE; (submitted: January 23, 2007)	60
Actual Study Completion Date	March 2014
Actual Primary Completion Date	March 2014 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	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
Sex/Gender	Sexes Eligible for Study: Female
Ages	18 Years and older (Adult, Older Adult)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries ICMJE	Belgium, France, Netherlands, Spain, United States
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT00426556
Other Study ID Numbers ICMJE	CRAD001J2101; 2006-001596-37 ( EudraCT Number )
Has Data Monitoring Committee	Not Provided
U.S. FDA-regulated Product	Not Provided
IPD Sharing Statement	Not Provided
Responsible Party	Novartis ( Novartis Pharmaceuticals )
Study Sponsor ICMJE	Novartis Pharmaceuticals
Collaborators ICMJE	Not Provided
Investigators ICMJE	Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
PRS Account	Novartis
Verification Date	November 2015
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP