Study of Ribociclib With Everolimus + Exemestane in HR+ HER2- Locally Advanced/Metastatic Breast Cancer Post Progression on CDK 4/6 Inhibitor.

Breast Cancer Clinical Trial

— TRINITI-1  

Official title:

A Phase I/II, Single Arm, Open-label Study of Ribociclib in Combination With Everolimus + Exemestane in the Treatment of Men and Postmenopausal Women With HR+, HER2- Locally Advanced or Metastatic Breast Cancer Following Progression on a CDK 4/6 Inhibitor

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02732119
• Other study ID #: CLEE011XUS29
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: June 14, 2016
• Est. completion date: February 25, 2020

Study information

• Verified date: April 2021
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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 information / eligibility

• Status: Completed
• Enrollment: 104
• Est. completion date: February 25, 2020
• Est. primary completion date: February 25, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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.

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms

Intervention

Drug:
• Ribociclib
supplied in 50 mg, 200 mg capsules/tablets taken orally and dosed daily for 28 day cycle
• Everolimus
supplied in 2.5 mg tablets taken orally, daily for 28 day cycle
• Exemestane
supplied in 25 mg tablets taken orally, daily for 28 day cycle

Locations

Country	Name	City	State
United States	Atlanta Cancer Center	Atlanta	Georgia
United States	Massachusetts General Hospital Mass Gen Hos Cancer Center	Boston	Massachusetts
United States	Ironwood Cancer and Research Centers Ironwood Cancer	Chandler	Arizona
United States	Florida Cancer Research Institute Dept of Oncology	Davie	Florida
United States	Henry Ford Health System	Detroit	Michigan
United States	Highlands Oncology Group	Fayetteville	Arkansas
United States	Florida Cancer Specialists FL Cancer Specialists	Fort Myers	Florida
United States	Penn State Hershey Cancer Institute	Hershey	Pennsylvania
United States	MD Anderson Cancer Center/University of Texas MDACC	Houston	Texas
United States	Oncology Consultants Oncology Consultants	Houston	Texas
United States	Research Medical Center HCA Midwest Division	Kansas City	Missouri
United States	St. Luke's Cancer Institute Regulatory	Kansas City	Missouri
United States	Saint Barnabas Medical Center	Livingston	New Jersey
United States	UCLA Department of Medicine UCLA Hematology/Oncology	Los Angeles	California
United States	Sarah Cannon Research Institute Sarah Cannon Research Insti	Nashville	Tennessee
United States	Yale University School of Medicine Smilow Cancer Hospital	New Haven	Connecticut
United States	UF Health Cancer Center at Orlando Health UF Health (4)	Orlando	Florida
United States	University of Pennsylvania Medical Center Abramson Cancer Ctr of the Uni	Philadelphia	Pennsylvania
United States	Washington University School of Medicine Washington U School of Medicin	Saint Louis	Missouri
United States	Florida Cancer Specialists-North	Saint Petersburg	Florida
United States	Huntsman Cancer Institute Huntsman Cancer Insti	Salt Lake City	Utah
United States	University of California San Francisco Comprehensive Cancer Center	San Francisco	California
United States	Central Coast Medical Oncology Corporation Onc Dept	Santa Maria	California
United States	Northwest Medical Specialties Dept of Onc	Tacoma	Washington
United States	University of Kansas Cancer Center Univ of KS CC Medical Pavilion	Westwood	Kansas

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Participants With Dose Limiting Toxicities by Preferred Term in Cycle 1 (28 Days) - in Phase I	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.	Baseline up to 28 days
Primary	Clinical Benefit Rate as Per Central Review by Group- Phase II	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%.	From baseline up to 24 weeks
Primary	Best Overall Responses (BOR) Summary Table as Per Central Review by Group - Phase II	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.	Baseline up to 24 weeks and at 24 weeks
Secondary	Everolimus Pharmacokinetic Plasma Concentrations by Cohort - Phase I	Plasma concentrations; below limit of quantitation values set to zero	Cycle 1,2: Day 1 and 15 - pre-dose, 2 and 4 hour post dose, Cycle 3 , Day 1 - pre-dose
Secondary	Best Overall Responses (BOR) Summary Table as Per Central Review by Cohort - Phase I	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)	From baseline up to 24 weeks
Secondary	Clinical Benefit Rate as Per Central Review by Dose Cohort - Phase I	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.	Baseline up to 24 weeks and at week 24
Secondary	Summary of Progression-free Survival (PFS) (Months), as Per Central Review by Group - Phase II	Progression is defined as <= 12 weeks after randomization/ start of treatment (and not qualifying for CR, PR or SD).	Baseline up to approximately 32 months
Secondary	Overall Survival (OS) by Group - Phase II	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.	Baseline up to approximately 32 months
Secondary	Duration of Overall Response (DOR) by Group - Phase II	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.	Baseline up to approximately 16 months
Secondary	Time to Definitive Deterioration of ECOG Performance Status in One Category of the Score by Group - Phase II	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.	Baseline up to approximately 8 months
Secondary	Everolimus Pharmacokinetic Plasma Concentrations - Phase II	Plasma concentrations; below limit of quantitation values set to zero	Cycle 1,2: Day 1 and 15 - pre-dose, 2 and 4 hour post dose, Cycle 3 , Day 1 - pre-dose