Study for Women and Men With Hormone-receptor Positive Locally Advanced or Metastatic Breast Cancer

Study Overview
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Brief Summary
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This was a national, multi-center, open-label, phase IIIb trial to determine the efficacy and safety of treatment with ribociclib (LEE011) plus letrozole in patients with HR+, HER2-negative advanced (recurrent or metastatic) breast cancer. Patients were treated with daily doses of 600 mg ribociclib (3-weeks-on/1-week-off schedule) in combination with 2.5 mg letrozole daily (continuous dosing). Dose adjustments (dose reduction or interruption) according to safety findings were allowed.

Detailed Description
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The main purpose of this study was to collect additional efficacy and safety data for the combination of ribociclib and letrozole in a patient population broader than the MONALEESA-2 study (NCT01958021 / CLEE011A2301), and to provide access to ribociclib to patients for which available treatment options are unsatisfactory treatment alternatives until the drug is approved for this indication. Furthermore, this trial aimed to collect data for the combination of ribociclib and letrozole in the context of current local routine therapy algorithms for the treatment of metastatic and advanced breast cancer. This multi-center, open-label, single-arm study aimed to evaluate the efficacy, safety, and quality of life for the combination of ribociclib and letrozole in a patient population than in the MONALEESA-2 study, i.e. in patients pretreated with one line of chemotherapy and/or a maximum of two lines of endocrine therapy as well as premenopausal patients, without limitations regarding the disease free interval after adjuvant therapy. For ethical reasons no endocrine comparator drugs were investigated in this study. The duration of study treatment of 80 weeks was adequate to determine the primary, secondary and exploratory study parameters. The sample size was suitable to estimate the clinical benefit rate (CBR) in this patient population with reasonable precision. Goserelin was used in premenopausal patients, since it was shown that ovarian suppression of estrogen release with luteinizing hormone-releasing hormone agonists (LHRHa) (such as goserelin) is effective in preventing relapse in premenopausal women with early stage ER+ breast cancer (Klijn et al. 2001). The efficacy and safety of ribociclib in combination with letrozole for the treatment of postmenopausal women with advanced or metastatic breast cancer vs. placebo (i.e., letrozole alone) was already demonstrated in the preceding, pivotal MONALESSA-2 study. Thus, for ethical reasons no endocrine comparator drugs were investigated in the present RIBECCA study. Generally, the single-arm, open-label design and the broadening of the study population (compared to the pivotal MONALESSA-2 study) in the RIBECCA study was deemed appropriate to further evaluate the efficacy and safety of ribociclib plus letrozole among breast cancer patients in a treatment setting closer to routine care. The duration of study treatment of up to 80 weeks was considered adequate to determine the primary, secondary and exploratory study parameters. Moreover, the sample size was suitable to estimate the CBR in this patient population with reasonable precision.

Official Title
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A National Phase IIIb, Multi-center, Open Label Study for Women and Men With Hormone-receptor Positive, HER-2 Negative Locally Advanced or Metastatic Breast Cancer Treated With Ribociclib (LEE011) in Combination With Letrozole

Conditions
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Advanced Metastatic Breast Cancer

Intervention / Treatment
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* Drug: ribociclib
* Drug: letrozole
* Drug: goserelin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient is an adult, ≥ 18 years old at the time of informed consent and has signed informed consent before any trial related activities and according to local guidelines Women and men with advanced (locoregionally recurrent or metastatic) breast cancer not amenable to curative therapy. Patient has a histologically and/or cytologically confirmed diagnosis of estrogen-receptor positive and/or progesterone receptor positive and HER2-negative breast cancer by local laboratory. Local pathology is sufficient for assessment. Patient must have either: Measurable disease, i.e., at least one measurable lesion as per RECIST 1.1 criteria ). Bone lesions: lytic or mixed (lytic + sclerotic) in the absence of measurable disease Non-measurable disease Patient has an Eastern Cooperative Oncology Group (ECOG) performance status ≤2 Exclusion Criteria Patient who received any CDK4/6 inhibitor or any mTOR inhibitor. Patient has a known hypersensitivity to any of the excipients of ribociclib or letrozole Patients with current inflammatory breast cancer. Patient has received > 1 chemotherapy for the treatment of advanced/metastatic breast cancer Patient has received > 2 endocrine therapies for the treatment of advanced/metastatic breast cancer Patient has central nervous system (CNS) involvement. If patient is fulfilling the following 3 criteria she/he is eligible for the trial. completed prior therapy (including radiation and/or surgery) for CNS metastases ≥ 28 days prior to the start of study and CNS tumor is clinically stable at the time of screening and Patient is not receiving steroids and enzyme inducing anti-epileptic medications for brain metastases Patient has active cardiac disease or a history of cardiac dysfunction

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ribociclib + letrozole cohort A<br>ribociclib + letrozole cohort A - postmenopausal women, or men; naïve. All patients received ribociclib 600mg p.o. daily + Letrozole 2.5 mg p.o. daily. | Drug: ribociclib<br>* All patients with oestrogen receptor positive advanced or metastatic breast cancer were treated with oral ribociclib at a dose of 600mg daily and oral letrozole 2.5mg daily. The study treatment for an individual patient began on Study Day 1 and continued until 80 weeks after the last patient enrolled the study or until disease progression, unacceptable toxicity, death or early discontinuation from the study for any other reason, whichever occured first.<br>* Other names: LEE011;Drug: letrozole<br>* All patients with oestrogen receptor positive advanced or metastatic breast cancer were treated with oral ribociclib at a dose of 600mg daily and oral letrozole 2.5mg daily. The study treatment for an individual patient began on Study Day 1 and continued until 80 weeks after the last patient enrolled the study or until disease progression, unacceptable toxicity, death or early discontinuation from the study for any other reason, whichever occured first.<br>Drug: goserelin<br>* Premenopausal patients additionally received goserelin 3.6mg as monthly implant<br>|
| Experimental: ribociclib + letrozole cohort B1<br>ribociclib + letrozole cohort B1 - premenopausal women or perimenopausal women; naïve All patients received ribociclib 600mg p.o. daily + Letrozole 2.5 mg p.o. daily. Premenopausal patients additionally received goserelin 3.6 mg i.m. monthly | Drug: ribociclib<br>* All patients with oestrogen receptor positive advanced or metastatic breast cancer were treated with oral ribociclib at a dose of 600mg daily and oral letrozole 2.5mg daily. The study treatment for an individual patient began on Study Day 1 and continued until 80 weeks after the last patient enrolled the study or until disease progression, unacceptable toxicity, death or early discontinuation from the study for any other reason, whichever occured first.<br>* Other names: LEE011;Drug: letrozole<br>* All patients with oestrogen receptor positive advanced or metastatic breast cancer were treated with oral ribociclib at a dose of 600mg daily and oral letrozole 2.5mg daily. The study treatment for an individual patient began on Study Day 1 and continued until 80 weeks after the last patient enrolled the study or until disease progression, unacceptable toxicity, death or early discontinuation from the study for any other reason, whichever occured first.<br>Drug: goserelin<br>* Premenopausal patients additionally received goserelin 3.6mg as monthly implant<br>|
| Experimental: ribociclib + letrozole cohort B2<br>ribociclib + letrozole cohort B2 - premenopausal women or perimenopausal women or postmenopausal women, or men; pre-treated. All patients received ribociclib 600mg p.o. daily + Letrozole 2.5 mg p.o. daily. Premenopausal patients additionally received goserelin 3.6 mg i.m. monthly | Drug: ribociclib<br>* All patients with oestrogen receptor positive advanced or metastatic breast cancer were treated with oral ribociclib at a dose of 600mg daily and oral letrozole 2.5mg daily. The study treatment for an individual patient began on Study Day 1 and continued until 80 weeks after the last patient enrolled the study or until disease progression, unacceptable toxicity, death or early discontinuation from the study for any other reason, whichever occured first.<br>* Other names: LEE011;Drug: letrozole<br>* All patients with oestrogen receptor positive advanced or metastatic breast cancer were treated with oral ribociclib at a dose of 600mg daily and oral letrozole 2.5mg daily. The study treatment for an individual patient began on Study Day 1 and continued until 80 weeks after the last patient enrolled the study or until disease progression, unacceptable toxicity, death or early discontinuation from the study for any other reason, whichever occured first.<br>Drug: goserelin<br>* Premenopausal patients additionally received goserelin 3.6mg as monthly implant<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Benefit Rate (CBR) in Women and Men With Hormone Receptor Positiv, HER-2 Negative Breast Cancer Treated With Ribocilib and Letrozole | Clinical Benefit Rate (CBR) after 24 weeks of treatment as defined by RECIST 1.1 as percentage of patients with Complete Response (CR), Partial response (PR) or Stable disease (SD) lasting 24 weeks or longer as well as patients with Non-complete response, nonprogressive disease (NCRNPD). | At 24 weeks after last patient enrolled in trial | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) for Different Populations - Kaplan-Meier Estimates (%, 95% CI) | PFS based on radiologic assessment by investigator using RECIST 1.1 criteria | At week 24 , week 48 and week 72 | 
| Progression Free Survival (PFS) for Different Populations - Median Time to Progression or Death With 95% CI [Months] | PFS based on radiologic assessment by investigator using RECIST 1.1 criteria | Up to approximately month 25 | 
| Overall Survival (OS) - Kaplan-Meier Estimates (%, 95% CI) | Overall survival (OS) defined as the time from date of start of treatment to date of death due to any cause. For the Kaplan-Meier estimates (%, 95% CI), the probability of survival at week 24, 48 and 72 is reported below. | At Week 24, Week 48 and Week 72 | 
| Overall Survival (OS) - Median Time to Progression or Death With 95% CI [Months] | Overall survival (OS) defined as the time from date of start of treatment to date of death due to any cause. | Up to approximatley 38 months | 
| Overall Survival (OS) - Number of Censored Participants and Number of Deaths | Overall survival (OS) defined as the time from date of start of treatment to date of death due to any cause. | Up to approximatley 38 months | 
| Overall Response Rate (ORR) - Kaplan-Meier Estimates (%, 95% CI) | Overall response rate (ORR) is the best overall response (BOR) of complete response (CR) or partial response (PR) as defined by RECIST 1.1. | At week 24 | 
| Change From Baseline at Week 24 of Patient Reported Quality of Life (QoL) Via EORTC QLQ-C30 | The QLQ-C30 is the core questionnaire of the EORTC QLQ, which has been developed for the assessment of the health-related QOL of cancer patients participating in international clinical trials. Using a linear transformation to standardize the raw scores, all scores finally range from 0 to 100, where a higher score represents a higher response level, e.g., a higher (better) level of functioning (applies to the first 6 items, items 1 to 6), but a higher (worse) level of symptoms (applies to the last 9 items, items 7 to 15). There is no aggregated total score, i.e., all scale scores were analyzed separately. | Change from Baseline to Week 24 | 
| Patient Reported Quality of Life (QoL) Via EORTC BR-23 - Change From Baseline at Week 24 (Cycle 7) | To evaluate health related quality of life (QoL) via EORTC BR-23. The scoring approach for the QLQ-BR23 is identical in principle to that for the function and symptom scales / single items of the QLQ-C30, i.e., all scores finally range from 0 to 100, where a higher score represents a higher response level, e.g., a higher (better) level of functioning, (applies to the first 4 items, items 1 to 4) but a higher (worse) level of symptoms (applies to the last 4 items, items 5 to 8). | Baseline and Week 24 (Cycle 7) | 
| Time to 10% Deterioration in EORTC Global Health Status | Time to 10% deterioration in the European Organisation for Research and Treatment of Cancer (EORTC) global health status | up to approximately 10 months | 
| Number of Participants With Treatment Emergent Adverse Events (TEAE) | Adverse Events (AEs) were separated into TEAEs (defined as AEs occurring/worsening from first study drug treatment until 30 days after the last study drug treatment) and AEs in the pre-/post-treatment period. | Up to Week 72 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ribociclib, LEE011, RIBECCA, breast cancer, breast carcinoma, HR-positive, HER2-negative, advanced breast cancer, Letrozole, CDK4/6, breast lump, HER2 positive, metastatic breast cancer, breast cancer positive for human epidermal growth factor receptor 2 (HER2) HER2 positive metastatic breast cancer, breast cancer progression, estrogen-receptor (ER) positive(+) breast cancer, Paget's disease