Clinical trial NCT03096847: Study for Women and Men With Hormone-receptor Positive Locally Advanced or Metastatic Breast Cancer
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Advanced Metastatic Breast Cancer
Keywords: 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
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2017-03-30
Enrollment: 502
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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:

  1. Measurable disease, i.e., at least one measurable lesion as per RECIST 1.1 criteria ).
  2. Bone lesions: lytic or mixed (lytic + sclerotic) in the absence of measurable disease
  3. 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.

  1. completed prior therapy (including radiation and/or surgery) for CNS metastases ≥ 28 days prior to the start of study and
  2. CNS tumor is clinically stable at the time of screening and
  3. 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

Primary outcomes:
measure: Clinical Benefit Rate (CBR) in Women and Men With Hormone Receptor Positiv, HER-2 Negative Breast Cancer Treated With Ribocilib and Letrozole
timeFrame: At 24 weeks after last patient enrolled in trial
Secondary outcomes:
measure: Progression Free Survival (PFS) for Different Populations - Kaplan-Meier Estimates (%, 95% CI)
timeFrame: At week 24 , week 48 and week 72
measure: Progression Free Survival (PFS) for Different Populations - Median Time to Progression or Death With 95% CI [Months]
timeFrame: Up to approximately month 25
measure: Overall Survival (OS) - Kaplan-Meier Estimates (%, 95% CI)
timeFrame: At Week 24, Week 48 and Week 72
measure: Overall Survival (OS) - Median Time to Progression or Death With 95% CI [Months]
timeFrame: Up to approximatley 38 months
measure: Overall Survival (OS) - Number of Censored Participants and Number of Deaths
timeFrame: Up to approximatley 38 months
measure: Overall Response Rate (ORR) - Kaplan-Meier Estimates (%, 95% CI)
timeFrame: At week 24
measure: Change From Baseline at Week 24 of Patient Reported Quality of Life (QoL) Via EORTC QLQ-C30
timeFrame: Change from Baseline to Week 24
measure: Patient Reported Quality of Life (QoL) Via EORTC BR-23 - Change From Baseline at Week 24 (Cycle 7)
timeFrame: Baseline and Week 24 (Cycle 7)
measure: Time to 10% Deterioration in EORTC Global Health Status
timeFrame: up to approximately 10 months
measure: Number of Participants With Treatment Emergent Adverse Events (TEAE)
timeFrame: Up to Week 72
Other outcomes:
Locations:
city: Muenchen
country: Germany
facility: Novartis Investigative Site
state: Bayern
city: Langen
country: Germany
facility: Novartis Investigative Site
state: Hessen
city: Recklinghausen
country: Germany
facility: Novartis Investigative Site
state: North Rhine-westphalia
city: Luebeck
country: Germany
facility: Novartis Investigative Site
state: Schleswig-holstein
city: Aachen
country: Germany
facility: Novartis Investigative Site
city: Augsburg
country: Germany
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Bielefeld
country: Germany
facility: Novartis Investigative Site
city: Boeblingen
country: Germany
facility: Novartis Investigative Site
city: Bonn
country: Germany
facility: Novartis Investigative Site
city: Bottrop
country: Germany
facility: Novartis Investigative Site
city: Chemnitz
country: Germany
facility: Novartis Investigative Site
city: Dessau Rosslau
country: Germany
facility: Novartis Investigative Site
city: Dresden
country: Germany
facility: Novartis Investigative Site
city: Duesseldorf
country: Germany
facility: Novartis Investigative Site
city: Duesseldorf
country: Germany
facility: Novartis Investigative Site
city: Erlangen
country: Germany
facility: Novartis Investigative Site
city: Essen
country: Germany
facility: Novartis Investigative Site
city: Essen
country: Germany
facility: Novartis Investigative Site
city: Esslingen
country: Germany
facility: Novartis Investigative Site
city: Frankfurt
country: Germany
facility: Novartis Investigative Site
city: Frankfurt
country: Germany
facility: Novartis Investigative Site
city: Freiburg
country: Germany
facility: Novartis Investigative Site
city: Fuerstenwalde
country: Germany
facility: Novartis Investigative Site
city: Fuerth
country: Germany
facility: Novartis Investigative Site
city: Georgsmarienhuette
country: Germany
facility: Novartis Investigative Site
city: Goettingen
country: Germany
facility: Novartis Investigative Site
city: Goslar
country: Germany
facility: Novartis Investigative Site
city: Greifswald
country: Germany
facility: Novartis Investigative Site
city: Hamburg
country: Germany
facility: Novartis Investigative Site
city: Hamburg
country: Germany
facility: Novartis Investigative Site
city: Hamburg
country: Germany
facility: Novartis Investigative Site
city: Hannover
country: Germany
facility: Novartis Investigative Site
city: Hannover
country: Germany
facility: Novartis Investigative Site
city: Hannover
country: Germany
facility: Novartis Investigative Site
city: Heidelberg
country: Germany
facility: Novartis Investigative Site
city: Heidelberg
country: Germany
facility: Novartis Investigative Site
city: Hildesheim
country: Germany
facility: Novartis Investigative Site
city: Homburg
country: Germany
facility: Novartis Investigative Site
city: Jena
country: Germany
facility: Novartis Investigative Site
city: Kiel
country: Germany
facility: Novartis Investigative Site
city: Kiel
country: Germany
facility: Novartis Investigative Site
city: Koeln
country: Germany
facility: Novartis Investigative Site
city: Kulmbach
country: Germany
facility: Novartis Investigative Site
city: Landshut
country: Germany
facility: Novartis Investigative Site
city: Leer
country: Germany
facility: Novartis Investigative Site
city: Leipzig
country: Germany
facility: Novartis Investigative Site
city: Leipzig
country: Germany
facility: Novartis Investigative Site
city: Mannheim
country: Germany
facility: Novartis Investigative Site
city: Marburg
country: Germany
facility: Novartis Investigative Site
city: Minden
country: Germany
facility: Novartis Investigative Site
city: Moenchengladbach
country: Germany
facility: Novartis Investigative Site
city: Muenchen
country: Germany
facility: Novartis Investigative Site
city: Muenster
country: Germany
facility: Novartis Investigative Site
city: Muenster
country: Germany
facility: Novartis Investigative Site
city: Neuruppin
country: Germany
facility: Novartis Investigative Site
city: Nuernberg
country: Germany
facility: Novartis Investigative Site
city: Offenbach
country: Germany
facility: Novartis Investigative Site
city: Oldenburg
country: Germany
facility: Novartis Investigative Site
city: Passau
country: Germany
facility: Novartis Investigative Site
city: Potsdam
country: Germany
facility: Novartis Investigative Site
city: Ravensburg
country: Germany
facility: Novartis Investigative Site
city: Rotenburg
country: Germany
facility: Novartis Investigative Site
city: Saarbruecken
country: Germany
facility: Novartis Investigative Site
city: Schweinfurt
country: Germany
facility: Novartis Investigative Site
city: Stuttgart
country: Germany
facility: Novartis Investigative Site
city: Suhl
country: Germany
facility: Novartis Investigative Site
city: Torgau
country: Germany
facility: Novartis Investigative Site
city: Trier
country: Germany
facility: Novartis Investigative Site
city: Troisdorf
country: Germany
facility: Novartis Investigative Site
city: Tübingen
country: Germany
facility: Novartis Investigative Site
city: Ulm
country: Germany
facility: Novartis Investigative Site
city: Velbert
country: Germany
facility: Novartis Investigative Site
city: Voelklingen
country: Germany
facility: Novartis Investigative Site
city: Weinheim
country: Germany
facility: Novartis Investigative Site
city: Wetzlar
country: Germany
facility: Novartis Investigative Site
city: Wiesbaden
country: Germany
facility: Novartis Investigative Site
city: Wuerzburg
country: Germany
facility: Novartis Investigative Site
Study officials:
References:
citation: Peuker CA, Yaghobramzi S, Grunert C, Keilholz L, Gjerga E, Hennig S, Schaper S, Na IK, Keller U, Brucker S, Decker T, Fasching P, Fehm T, Janni W, Kummel S, Schneeweiss A, Schuler M, Luftner D, Busse A. Treatment with ribociclib shows favourable immunomodulatory effects in patients with hormone receptor-positive breast cancer-findings from the RIBECCA trial. Eur J Cancer. 2022 Feb;162:45-55. doi: 10.1016/j.ejca.2021.11.025. Epub 2021 Dec 23.