Clinical trial NCT03822468: Study of 2 Ribociclib Doses in Combination With Aromatase Inhibitors in Women With HR+, HER2- Advanced Breast Cancer
Official title: A Phase II, Multicenter, Randomized, Open-label Study to Evaluate the Safety and Efficacy of 400 mg of Ribociclib in Combination With Non-steroidal Aromatase Inhibitors for the Treatment of Pre- and Postmenopausal Women With Hormone Receptor-positive, HER2-negative Advanced Breast Cancer Who Received no Prior Therapy for Advanced Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Breast Cancer
Keywords: Breast Cancer
HR-positive
HER2-negative
ER-positive
advanced breast cancer
ribociclib
LEE011
premenopausal
postmenopausal
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2019-01-30
Enrollment: 376
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: QT interval prolongation and neutropenia are considered to be important identified risks for ribociclib. The approved dosing regimen of ribociclib is 600 mg daily (QD) on a 3 weeks on/1 week off schedule. The purpose of the study is to explore whether a reduced dosing regimen of 400 mg ribociclib orally QD 3 weeks on/1 week off may decrease the risk of QTc prolongation without compromising the efficacy of ribociclib in combination with a non-steroidal aromatase inhibitor (NSAI) in pre- and postmenopausal women with hormone receptor-positive (HR-positive), HER2-negative advanced breast cancer (aBC) who have not received prior therapy for advanced disease.

Detailed description: This is a phase II, multicenter, randomized, open-label study to evaluate the safety and efficacy of a reduced ribociclib dose of 400 mg in combination with an NSAI (letrozole or anastrozole) for the treatment of pre- and postmenopausal women with HR-positive, HER2-negative aBC who have received no prior therapy for advanced disease.

Patients will be randomly assigned to one of the below treatment arms in a 1:1 ratio:

* Experimental arm - Ribociclib 400 mg QD 3 weeks on/1 week off + NSAI (+ goserelin in premenopausal women)
* Control arm - Ribociclib 600 mg QD 3 weeks on/1 week off + NSAI (+ goserelin in premenopausal women).

Participants will receive study treatment until disease progression (radiologically documented according to RECIST 1.1 criteria), unacceptable toxicity, death, or discontinuation from the study treatment for any other reason. Continuation of study treatment beyond initial disease progression (RECIST 1.1) will not be allowed.

For participants who discontinue treatment for reasons other than documented disease progression, death, lost to follow-up, or withdrawal of consent, tumor assessments must continue to be performed until disease progression, death, lost to follow-up, or withdrawal of consent (post-treatment efficacy follow-up).

Eligibility criteria: Key inclusion criteria:

* Patient has advanced (loco-regionally recurrent or metastatic) breast cancer not amenable to curative therapy.
* Patient has a histologically and/or cytologically confirmed diagnosis of ER-positive and/or PgR-positive breast cancer based on the most recently analyzed tissue sample, and all tested by local laboratory.
* Patient has HER2-negative breast cancer defined as a negative in situ hybridization test or an IHC status of 0, 1+ or 2+. If IHC is 2+, a negative in situ hybridization (FISH, CISH, or SISH) test is required by local laboratory testing and based on the most recently analyzed tissue sample.
* Patient must have measurable disease, i.e., at least one measurable lesion according to RECIST version 1.1. (a lesion in a previously irradiated site may only be counted as a target lesion if there is clear evidence of progression since the irradiation).
* Patient has an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
* Standard 12-lead ECG values defined as the mean of the triplicate ECGs and assessed by the central laboratory:

  * QTcF interval at screening \< 450 ms (QT interval using Fridericia's correction)
  * Mean resting heart rate 50 to 90 bpm (determined from the ECG)
* Women of childbearing potential (CBP), defined as all women physiologically capable of becoming pregnant, must have confirmed negative serum pregnancy test (for β-hCG) within 14 days prior to randomization.
* Women of CBP must be willing to use highly effective methods of contraception.

Key Exclusion Criteria:

* Patient with symptomatic visceral disease or any disease burden that makes the patient ineligible for endocrine therapy per the investigator's judgment.
* Patient who received any prior systemic anti-cancer therapy(including endocrine therapy, chemotherapy, prior CDK4/6 inhibitors) for aBC. Patients who received neo-/adjuvant therapy for breast cancer are eligible.
* Patient is concurrently using other anti-cancer therapy.
* Patient has had major surgery within 14 days prior to starting study drug or has not recovered from major toxicities.
* Patient has received extended-field radiotherapy ≤ 4 weeks or limited field radiotherapy ≤ 2 weeks prior to randomization, and has not recovered to grade 1 or better from related side effects of such therapy (with the exception of alopecia or other toxicities not considered a safety risk for the patient at investigator's discretion). Patients in whom ≥
* 25% of the bone marrow has been previously irradiated are also excluded.
* Patient has a concurrent malignancy or malignancy within 3 years of the randomization date, with the exception of adequately treated basal or squamous cell skin carcinoma, or curatively resected cervical carcinoma in situ.
* Patients with central nervous system (CNS) involvement unless they meet specific stability criteria.
* Patient has clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality.
* Patient is currently receiving or has received systemic corticosteroids ≤ 2 weeks prior to starting study drug, and has not fully recovered from side effects of such treatment.

Other protocol-defined Inclusion/Exclusion may apply.

Primary outcomes:
measure: Overall Response Rate (ORR)
timeFrame: Up to 23.8 months
Secondary outcomes:
measure: Change From Baseline in QTc (With Fridericia's Correction) at Cycle 1 Day 15 (at 2 Hours Post-dose)
timeFrame: Baseline and Cycle 1 Day 15 at 2 hours post-dose. Cycle = 28 days
measure: Progression-free Survival (PFS)
timeFrame: Up to approximately 60 months
measure: Clinical Benefit Rate (CBR)
timeFrame: Up to approximately 60 months
measure: Time to Response (TTR)
timeFrame: Up to approximately 60 months
measure: Duration of Response (DOR)
timeFrame: Up to approximately 60 months
measure: Pharmacokinetics (PK) of Ribociclib: Maximum Observed Plasma Concentration (Cmax)
timeFrame: Cycle 1 Day 15 at pre-dose, and 2, 4, 6 and 24 hours post-dose. Cycle = 28 days
measure: PK of Ribociclib: Time to Reach Observed Maximum Concentration (Tmax)
timeFrame: Cycle 1 Day 15 at pre-dose, and 2, 4, 6 and 24 hours post-dose. Cycle = 28 days
measure: PK of Ribociclib: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours (AUC0-24)
timeFrame: Cycle 1 Day 15 at pre-dose, and 2, 4, 6 and 24 hours post-dose. Cycle = 28 days
Other outcomes:
Locations:
city: Mobile
country: United States
facility: Southern Cancer Center PC
state: Alabama
city: Greenbrae
country: United States
facility: Marin Cancer Care
state: California
city: Longmont
country: United States
facility: Rocky Mountain Cancer Centers
state: Colorado
city: Orlando
country: United States
facility: Florida Retina Institute
state: Florida
city: Baltimore
country: United States
facility: Weinberg Cancer Institute at FSH
state: Maryland
city: Lincoln
country: United States
facility: Nebraska Hematology Oncology P C
state: Nebraska
city: Omaha
country: United States
facility: Nebraska Cancer Specialists
state: Nebraska
city: Henderson
country: United States
facility: Comprehensive Cancer Cntr Of Nevada
state: Nevada
city: Albany
country: United States
facility: New York Oncology Hematology
state: New York
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: New York
country: United States
facility: Mount Sinai School Of Medicine
state: New York
city: Houston
country: United States
facility: Millennium Research Clin Develop
state: Texas
city: McAllen
country: United States
facility: Texas Oncology
state: Texas
city: Tacoma
country: United States
facility: Northwest Medical Specialties
state: Washington
city: San Juan
country: Argentina
facility: Novartis Investigative Site
city: Innsbruck
country: Austria
facility: Novartis Investigative Site
state: Tyrol
city: Linz
country: Austria
facility: Novartis Investigative Site
city: Salzburg
country: Austria
facility: Novartis Investigative Site
city: Vienna
country: Austria
facility: Novartis Investigative Site
city: Edegem
country: Belgium
facility: Novartis Investigative Site
city: Namur
country: Belgium
facility: Novartis Investigative Site
city: Natal
country: Brazil
facility: Novartis Investigative Site
state: RN
city: Florianopolis
country: Brazil
facility: Novartis Investigative Site
state: Santa Catarina
city: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Goiania
country: Brazil
facility: Novartis Investigative Site
city: Sao Jose do Rio Preto
country: Brazil
facility: Novartis Investigative Site
city: Plovdiv
country: Bulgaria
facility: Novartis Investigative Site
city: Sofia
country: Bulgaria
facility: Novartis Investigative Site
city: Sofia
country: Bulgaria
facility: Novartis Investigative Site
city: Cambridge
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Valledupar
country: Colombia
facility: Novartis Investigative Site
state: Cesar
city: Ibague
country: Colombia
facility: Novartis Investigative Site
state: Tolima
city: Bogota
country: Colombia
facility: Novartis Investigative Site
city: Bogota
country: Colombia
facility: Novartis Investigative Site
city: Monteria
country: Colombia
facility: Novartis Investigative Site
city: San Jose
country: Costa Rica
facility: Novartis Investigative Site
city: Brno
country: Czechia
facility: Novartis Investigative Site
state: Czech Republic
city: Praha 5
country: Czechia
facility: Novartis Investigative Site
city: Helsinki
country: Finland
facility: Novartis Investigative Site
city: Tampere
country: Finland
facility: Novartis Investigative Site
city: Besancon Cedex
country: France
facility: Novartis Investigative Site
city: Caen
country: France
facility: Novartis Investigative Site
city: Clermont-Ferrand
country: France
facility: Novartis Investigative Site
city: Lyon 08
country: France
facility: Novartis Investigative Site
city: Marseille
country: France
facility: Novartis Investigative Site
city: Montpellier
country: France
facility: Novartis Investigative Site
city: Saint Herblain
country: France
facility: Novartis Investigative Site
city: Strasbourg
country: France
facility: Novartis Investigative Site
city: Valenciennes
country: France
facility: Novartis Investigative Site
city: Langen
country: Germany
facility: Novartis Investigative Site
state: Hessen
city: Augsburg
country: Germany
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Bonn
country: Germany
facility: Novartis Investigative Site
city: Dresden
country: Germany
facility: Novartis Investigative Site
city: Dresden
country: Germany
facility: Novartis Investigative Site
city: Essen
country: Germany
facility: Novartis Investigative Site
city: Tuebingen
country: Germany
facility: Novartis Investigative Site
city: Weiden
country: Germany
facility: Novartis Investigative Site
city: Budapest
country: Hungary
facility: Novartis Investigative Site
city: Debrecen
country: Hungary
facility: Novartis Investigative Site
city: Szolnok
country: Hungary
facility: Novartis Investigative Site
city: Raipur
country: India
facility: Novartis Investigative Site
state: Chhattisgarh
city: Nagpur
country: India
facility: Novartis Investigative Site
state: Maharashtra
city: Bhubaneshwar
country: India
facility: Novartis Investigative Site
state: Orissa
city: Delhii
country: India
facility: Novartis Investigative Site
city: Mumbai
country: India
facility: Novartis Investigative Site
city: Amman
country: Jordan
facility: Novartis Investigative Site
city: Kaunas
country: Lithuania
facility: Novartis Investigative Site
state: LTU
city: Vilnius
country: Lithuania
facility: Novartis Investigative Site
city: Trujillo
country: Peru
facility: Novartis Investigative Site
state: La Libertad
city: San Borja
country: Peru
facility: Novartis Investigative Site
state: Lima
city: San Isidro
country: Peru
facility: Novartis Investigative Site
state: Lima
city: San Miguel
country: Peru
facility: Novartis Investigative Site
state: Lima
city: Lisboa
country: Portugal
facility: Novartis Investigative Site
city: Loures
country: Portugal
facility: Novartis Investigative Site
city: Porto
country: Portugal
facility: Novartis Investigative Site
city: Arkhangelsk
country: Russian Federation
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: St Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Cape Town
country: South Africa
facility: Novartis Investigative Site
city: Johannesburg
country: South Africa
facility: Novartis Investigative Site
city: Parktown
country: South Africa
facility: Novartis Investigative Site
city: Stockholm
country: Sweden
facility: Novartis Investigative Site
city: Stockholm
country: Sweden
facility: Novartis Investigative Site
city: Uppsala
country: Sweden
facility: Novartis Investigative Site
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Chiang Mai
country: Thailand
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: