Study of Ribociclib With Everolimus + Exemestane in HR+ HER2- Locally Advanced/Metastatic Breast Cancer Post Progression on CDK 4/6 Inhibitor. (TRINITI-1)

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

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

Study Overview

• Status: Completed
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: Ribociclib; Drug: Everolimus; Drug: Exemestane

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.

• Study Type: Interventional
• Enrollment (Actual): 104
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Chandler, Arizona, United States, 85224
      • Ironwood Cancer and Research Centers Ironwood Cancer
  • Arkansas
    • Fayetteville, Arkansas, United States, 72703
      • Highlands Oncology Group
  • California
    • Los Angeles, California, United States, 90095
      • UCLA Department of Medicine UCLA Hematology/Oncology
    • San Francisco, California, United States, 94115
      • University of California San Francisco Comprehensive Cancer Center
    • Santa Maria, California, United States, 93454
      • Central Coast Medical Oncology Corporation Onc Dept
  • Connecticut
    • New Haven, Connecticut, United States, 06511
      • Yale University School Of Medicine Smilow Cancer Hospital
  • Florida
    • Davie, Florida, United States, 33328
      • Florida Cancer Research Institute Dept of Oncology
    • Fort Myers, Florida, United States, 33901
      • Florida Cancer Specialists FL Cancer Specialists
    • Orlando, Florida, United States, 32806
      • UF Health Cancer Center at Orlando Health UF Health (4)
    • Saint Petersburg, Florida, United States, 33705
      • Florida Cancer Specialists-North
  • Georgia
    • Atlanta, Georgia, United States
      • Atlanta Cancer Center
  • Kansas
    • Westwood, Kansas, United States, 66205
      • University of Kansas Cancer Center Univ of KS CC Medical Pavilion
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital Mass Gen Hos Cancer Center
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Health System
  • Missouri
    • Kansas City, Missouri, United States, 64111
      • St. Luke's Cancer Institute Regulatory
    • Kansas City, Missouri, United States, 64132
      • Research Medical Center HCA Midwest Division
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine Washington U School of Medicin
  • New Jersey
    • Livingston, New Jersey, United States, 07039
      • Saint Barnabas Medical Center
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Hershey Cancer Institute
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania Medical Center Abramson Cancer Ctr of the Uni
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Research Institute Sarah Cannon Research Insti
  • Texas
    • Houston, Texas, United States, 77024
      • Oncology Consultants Oncology Consultants
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center/University of Texas MDACC
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Huntsman Cancer Institute Huntsman Cancer Insti
  • Washington
    • Tacoma, Washington, United States, 98405
      • Northwest Medical Specialties Dept of Onc

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort A; 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	Drug: Ribociclib; supplied in 50 mg, 200 mg capsules/tablets taken orally and dosed daily for 28 day cycle; Drug: Everolimus; supplied in 2.5 mg tablets taken orally, daily for 28 day cycle; Drug: Exemestane; supplied in 25 mg tablets taken orally, daily for 28 day cycle
Experimental: Cohort B; Ribociclib (300 mg daily), everolimus (2.5 mg daily) and exemestane (25 mg daily) taken orally	Drug: Ribociclib; supplied in 50 mg, 200 mg capsules/tablets taken orally and dosed daily for 28 day cycle; Drug: Everolimus; supplied in 2.5 mg tablets taken orally, daily for 28 day cycle; Drug: Exemestane; supplied in 25 mg tablets taken orally, daily for 28 day cycle
Experimental: Cohort C; Ribociclib (200 mg daily), everolimus (5 mg daily) and exemestane (25 mg daily) taken orally	Drug: Ribociclib; supplied in 50 mg, 200 mg capsules/tablets taken orally and dosed daily for 28 day cycle; Drug: Everolimus; supplied in 2.5 mg tablets taken orally, daily for 28 day cycle; Drug: Exemestane; supplied in 25 mg tablets taken orally, daily for 28 day cycle
Experimental: Group 1; Ribociclib (300 mg daily), everolimus (2.5 mg daily) and exemestane (25 mg daily) taken orally	Drug: Ribociclib; supplied in 50 mg, 200 mg capsules/tablets taken orally and dosed daily for 28 day cycle; Drug: Everolimus; supplied in 2.5 mg tablets taken orally, daily for 28 day cycle; Drug: Exemestane; supplied in 25 mg tablets taken orally, daily for 28 day cycle
Experimental: Group 2; Ribociclib (200 mg daily), everolimus (5 mg daily) and exemestane (25 mg daily) taken orally	Drug: Ribociclib; supplied in 50 mg, 200 mg capsules/tablets taken orally and dosed daily for 28 day cycle; Drug: Everolimus; supplied in 2.5 mg tablets taken orally, daily for 28 day cycle; Drug: Exemestane; supplied in 25 mg tablets taken orally, daily for 28 day cycle

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
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
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
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
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
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

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): June 14, 2016
• Primary Completion (Actual): February 25, 2020
• Study Completion (Actual): February 25, 2020

Study Registration Dates

• First Submitted: April 4, 2016
• First Submitted That Met QC Criteria: April 4, 2016
• First Posted (Estimate): April 8, 2016

Study Record Updates

• Last Update Posted (Actual): May 5, 2021
• Last Update Submitted That Met QC Criteria: April 10, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Keywords: adult; Phase I; LEE011; everolimus; ribociclib; Phase II; Postmenopausal; Aromasin; CDK4/6; HER2-negative; Advanced breast cancer; CDK4; CDK6; CDK; exemestane; ER-positive; PR-positive; Afinitor; CDK4/6 inhibitor; HR-positive
• 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: CLEE011XUS29

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.

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