Study of Ribociclib With Everolimus + Exemestane in HR+ HER2- Locally Advanced/Metastatic Breast Cancer Post Progression on CDK 4/6 Inhibitor.
- Conditions
- Breast Cancer
- Interventions
- Registration Number
- NCT02732119
- Lead Sponsor
- Novartis Pharmaceuticals
- Brief Summary
The purpose of this study is determine if the triplet combination of ribociclib, everolimus and exemastane is safe and effective in the treatment of locally advanced/metastatic breast cancer following treatment with a CDK 4/6 inhibitor
- Detailed Description
This trial had two phases. The purpose of Phase I dose escalation and dose de-escalation was to determine the maximum tolerated doses (MTDs) and/or identify the recommended Phase II dose (RP2D) of the combination treatment of ribociclib+ everolimus + exemestane. The dosing was continuous in adult men and postmenopausal women with HR+ HER2-negative advanced breast cancer which was resistant to the non-steroidal aromatase inhibitors, fulvestrant or tamoxifen.
The purpose of the phase II portion of this trial was to evaluate the anti-tumor activity of exemestane, everolimus and ribociclib combination therapy following progression on a CDK 4/6 inhibitor.
The planned duration of the study was 30 months.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 104
- Adult men and women
- Patient has a confirmed diagnosis of estrogen-receptor positive and/or progesterone receptor positive breast cancer by local laboratory and has HER2-negative breast cancer
- Patient must have either measurable disease by RECIST 1.1 or bone lesions in absence of measurable disease.
- ECOG Performance Status 0 - 1
- Disease refractory to either, AI, tamoxifen or fulvestrant
- Previously treated on any CDK 4/6 inhibitor.
- Patient has adequate bone marrow and organ function.
- Patient with symptomatic visceral disease or any disease burden that makes the patient ineligible for endocrine therapy per the investigator's best judgment.
- Patient has received more than one line of chemotherapy for advanced disease.
- Previous treatment with mTOR inhibitors, or exemestane for advanced disease.
- Progressed on more than one CDK 4/6 inhibitor
- Patient with CNS involvement unless they are at least 4 weeks from prior therapy completion.
- Clinically significant, uncontrolled heart disease and/or recent cardiac events.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Cohort C Exemestane Ribociclib (200 mg daily), everolimus (5 mg daily) and exemestane (25 mg daily) taken orally Cohort A Ribociclib Ribociclib (250 mg daily), everolimus (2.5 mg daily) and exemestane (25 mg daily) taken orally for 28 days. If no DLTs occurred, progressed to Cohort B Cohort C Ribociclib Ribociclib (200 mg daily), everolimus (5 mg daily) and exemestane (25 mg daily) taken orally Cohort C Everolimus Ribociclib (200 mg daily), everolimus (5 mg daily) and exemestane (25 mg daily) taken orally Group 2 Everolimus Ribociclib (200 mg daily), everolimus (5 mg daily) and exemestane (25 mg daily) taken orally Group 2 Exemestane Ribociclib (200 mg daily), everolimus (5 mg daily) and exemestane (25 mg daily) taken orally Cohort A Everolimus Ribociclib (250 mg daily), everolimus (2.5 mg daily) and exemestane (25 mg daily) taken orally for 28 days. If no DLTs occurred, progressed to Cohort B Cohort A Exemestane Ribociclib (250 mg daily), everolimus (2.5 mg daily) and exemestane (25 mg daily) taken orally for 28 days. If no DLTs occurred, progressed to Cohort B Cohort B Ribociclib Ribociclib (300 mg daily), everolimus (2.5 mg daily) and exemestane (25 mg daily) taken orally Cohort B Everolimus Ribociclib (300 mg daily), everolimus (2.5 mg daily) and exemestane (25 mg daily) taken orally Cohort B Exemestane Ribociclib (300 mg daily), everolimus (2.5 mg daily) and exemestane (25 mg daily) taken orally Group 1 Ribociclib Ribociclib (300 mg daily), everolimus (2.5 mg daily) and exemestane (25 mg daily) taken orally Group 1 Everolimus Ribociclib (300 mg daily), everolimus (2.5 mg daily) and exemestane (25 mg daily) taken orally Group 2 Ribociclib Ribociclib (200 mg daily), everolimus (5 mg daily) and exemestane (25 mg daily) taken orally Group 1 Exemestane Ribociclib (300 mg daily), everolimus (2.5 mg daily) and exemestane (25 mg daily) taken orally
- Primary Outcome Measures
Name Time Method Participants With Dose Limiting Toxicities by Preferred Term in Cycle 1 (28 Days) - in Phase I Baseline up to 28 days A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value assessed as having a reasonably possible relationship to the study medication(s) and is unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurs within the first 28 days of treatment (cycle 1) and meets any of the criteria defined in the protocol. National Cancer Institute Common Terminology Criteria for Adverse events (NCI CTCAE) version 4.03 will be used for all grading.
Clinical Benefit Rate as Per Central Review by Group- Phase II From baseline up to 24 weeks Clinical Benefit Rate (CBR) is defined as the percentage of participants with a complete response (CR) or partial response (PR) or with stable disease (SD) as per Response Evaluation Criteria in Solid Tumors (RECIST) V1.1 or Non-Complete Response or Non-Progressive Disease (NCRNPD) during first 24 weeks of first dose. CR=disappearance of all non-nodal target lesions, PR=at least a 30% decrease in the sum of diameter of all target lesions, SD=neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease (PD), PD=at least a 20% increase in the sum of diameter of all target lesions.
The hypothesis was to be rejected if the lower limit of the 95% Confidence Interval for Clinical Benefit Rate (CBR) was greater than 10%.Best Overall Responses (BOR) Summary Table as Per Central Review by Group - Phase II Baseline up to 24 weeks and at 24 weeks Complete response (CR) or partial response (PR), or stable disease (SD) at 24 weeks as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or Non-CR Non-PD (NCRNPD) at Week 24.
- Secondary Outcome Measures
Name Time Method Clinical Benefit Rate as Per Central Review by Dose Cohort - Phase I Baseline up to 24 weeks and at week 24 Clinical Benefit Rate (CBR) is defined as the percentage of patients with a complete response (CR) or partial response (PR) or with stable disease (SD) at 24 weeks as per Response Evaluation Criteria in Solid Tumors (RECIST) V1.1 or Non-Complete Response Non-Progressive Disease (NCRNPD) up to Week 24 and at Week 24.
Summary of Progression-free Survival (PFS) (Months), as Per Central Review by Group - Phase II Baseline up to approximately 32 months Progression is defined as \<= 12 weeks after randomization/ start of treatment (and not qualifying for CR, PR or SD).
Overall Survival (OS) by Group - Phase II Baseline up to approximately 32 months Overall survival is the time from date of first treatment to the date of death due to any cause. If a patient is not known to have died, survival will be censored at the last date of contact.
Duration of Overall Response (DOR) by Group - Phase II Baseline up to approximately 16 months Patients whose best response is complete response (CR) or partial response (PR). The start date is the date of first documented response (CR or PR) and the end date is the date of first documented progression or death due to underlying cancer.
Time to Definitive Deterioration of ECOG Performance Status in One Category of the Score by Group - Phase II Baseline up to approximately 8 months Time to definitive deterioration of ECOG performance status in one category of score is defined as the time from the date of randomization to the date of event, which is defined as at least one score lower than the baseline.
Everolimus Pharmacokinetic Plasma Concentrations - Phase II Cycle 1,2: Day 1 and 15 - pre-dose, 2 and 4 hour post dose, Cycle 3 , Day 1 - pre-dose Plasma concentrations; below limit of quantitation values set to zero
Everolimus Pharmacokinetic Plasma Concentrations by Cohort - Phase I Cycle 1,2: Day 1 and 15 - pre-dose, 2 and 4 hour post dose, Cycle 3 , Day 1 - pre-dose Plasma concentrations; below limit of quantitation values set to zero
Best Overall Responses (BOR) Summary Table as Per Central Review by Cohort - Phase I From baseline up to 24 weeks Complete response (CR) or partial response (PR), or stable disease (SD)as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or Non-CR Non-PD (NCRNPD)
Trial Locations
- Locations (25)
Florida Cancer Specialists FL Cancer Specialists
🇺🇸Fort Myers, Florida, United States
St. Luke's Cancer Institute Regulatory
🇺🇸Kansas City, Missouri, United States
Research Medical Center HCA Midwest Division
🇺🇸Kansas City, Missouri, United States
Florida Cancer Research Institute Dept of Oncology
🇺🇸Davie, Florida, United States
Yale University School of Medicine Smilow Cancer Hospital
🇺🇸New Haven, Connecticut, United States
Highlands Oncology Group
🇺🇸Fayetteville, Arkansas, United States
Washington University School of Medicine Washington U School of Medicin
🇺🇸Saint Louis, Missouri, United States
UF Health Cancer Center at Orlando Health UF Health (4)
🇺🇸Orlando, Florida, United States
University of Kansas Cancer Center Univ of KS CC Medical Pavilion
🇺🇸Westwood, Kansas, United States
Penn State Hershey Cancer Institute
🇺🇸Hershey, Pennsylvania, United States
Northwest Medical Specialties Dept of Onc
🇺🇸Tacoma, Washington, United States
Central Coast Medical Oncology Corporation Onc Dept
🇺🇸Santa Maria, California, United States
Saint Barnabas Medical Center
🇺🇸Livingston, New Jersey, United States
Florida Cancer Specialists-North
🇺🇸Saint Petersburg, Florida, United States
UCLA Department of Medicine UCLA Hematology/Oncology
🇺🇸Los Angeles, California, United States
University of California San Francisco Comprehensive Cancer Center
🇺🇸San Francisco, California, United States
Atlanta Cancer Center
🇺🇸Atlanta, Georgia, United States
Massachusetts General Hospital Mass Gen Hos Cancer Center
🇺🇸Boston, Massachusetts, United States
Henry Ford Health System
🇺🇸Detroit, Michigan, United States
University of Pennsylvania Medical Center Abramson Cancer Ctr of the Uni
🇺🇸Philadelphia, Pennsylvania, United States
Sarah Cannon Research Institute Sarah Cannon Research Insti
🇺🇸Nashville, Tennessee, United States
MD Anderson Cancer Center/University of Texas MDACC
🇺🇸Houston, Texas, United States
Huntsman Cancer Institute Huntsman Cancer Insti
🇺🇸Salt Lake City, Utah, United States
Ironwood Cancer and Research Centers Ironwood Cancer
🇺🇸Chandler, Arizona, United States
Oncology Consultants Oncology Consultants
🇺🇸Houston, Texas, United States