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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Ribociclib
* Drug: Everolimus
* Drug: Exemestane


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CDK, HR-positive, HER2-negative, Advanced breast cancer, LEE011, ribociclib, everolimus, Afinitor, exemestane, Aromasin, CDK4, CDK6, CDK4/6, CDK4/6 inhibitor, Phase I, Phase II, ER-positive, PR-positive, Postmenopausal, adult