Study of 2 Ribociclib Doses in Combination With Aromatase Inhibitors in Women With HR+, HER2- Advanced Breast Cancer

Breast Cancer Clinical Trial

— AMALEE  

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03822468
• Other study ID #: CLEE011A2207
• Secondary ID: 2018-004234-15
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: June 11, 2019
• Est. completion date: July 1, 2024

Study information

• Verified date: April 2024
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 376
• Est. completion date: July 1, 2024
• Est. primary completion date: June 11, 2021
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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 ß-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.

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms

Intervention

Drug:
• Ribociclib
Ribociclib (at a dosage of 400 mg or 600 mg) QD orally taken on days 1 to 21 of a 28-day cycle, followed by 7 days off ribociclib (days 22 to 28). Ribociclib is supplied as 200 mg tablets as individual patient supply packaged bottles.
• Anastrozole
Anastrozole 1 mg tablets for oral use QD continuously
• Letrozole
Letrozole 2.5 mg tablets for oral use QD continuously
• Goserelin
Goserelin 3.6 mg subcutaneously once every 4 weeks (pre-menopausal women only)

Locations

Country	Name	City	State
Argentina	Novartis Investigative Site	San Juan
Austria	Novartis Investigative Site	Innsbruck
Austria	Novartis Investigative Site	Linz
Austria	Novartis Investigative Site	Salzburg
Austria	Novartis Investigative Site	Vienna
Belgium	Novartis Investigative Site	Edegem	Antwerpen
Belgium	Novartis Investigative Site	Namur
Brazil	Novartis Investigative Site	Florianopolis	Santa Catarina
Brazil	Novartis Investigative Site	Goiania	GO
Brazil	Novartis Investigative Site	Natal	RN
Brazil	Novartis Investigative Site	Sao Jose do Rio Preto
Brazil	Novartis Investigative Site	Sao Paulo	SP
Brazil	Novartis Investigative Site	Sao Paulo	SP
Bulgaria	Novartis Investigative Site	Plovdiv
Bulgaria	Novartis Investigative Site	Sofia
Bulgaria	Novartis Investigative Site	Sofia
Canada	Novartis Investigative Site	Cambridge	Ontario
Colombia	Novartis Investigative Site	Bogota
Colombia	Novartis Investigative Site	Bogota
Colombia	Novartis Investigative Site	Ibague	Tolima
Colombia	Novartis Investigative Site	Monteria
Colombia	Novartis Investigative Site	Valledupar	Cesar
Costa Rica	Novartis Investigative Site	San Jose
Czechia	Novartis Investigative Site	Brno	Czech Republic
Czechia	Novartis Investigative Site	Praha 5
Finland	Novartis Investigative Site	Helsinki
Finland	Novartis Investigative Site	Tampere
France	Novartis Investigative Site	Besancon Cedex
France	Novartis Investigative Site	Caen
France	Novartis Investigative Site	Clermont Ferrand
France	Novartis Investigative Site	Lyon Cedex 08
France	Novartis Investigative Site	Marseille
France	Novartis Investigative Site	Montpellier
France	Novartis Investigative Site	Saint Herblain
France	Novartis Investigative Site	Strasbourg
France	Novartis Investigative Site	Valenciennes
Germany	Novartis Investigative Site	Augsburg
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Bonn
Germany	Novartis Investigative Site	Dresden
Germany	Novartis Investigative Site	Dresden
Germany	Novartis Investigative Site	Essen
Germany	Novartis Investigative Site	Langen	Hessen
Germany	Novartis Investigative Site	Tuebingen
Germany	Novartis Investigative Site	Weiden
Hungary	Novartis Investigative Site	Budapest
Hungary	Novartis Investigative Site	Debrecen
Hungary	Novartis Investigative Site	Szolnok
India	Novartis Investigative Site	Bhubaneshwar	Orissa
India	Novartis Investigative Site	Delhii
India	Novartis Investigative Site	Mumbai
India	Novartis Investigative Site	Nagpur	Maharashtra
India	Novartis Investigative Site	Raipur	Chhattisgarh
Jordan	Novartis Investigative Site	Amman
Lithuania	Novartis Investigative Site	Kaunas	LTU
Lithuania	Novartis Investigative Site	Vilnius
Peru	Novartis Investigative Site	San Borja	Lima
Peru	Novartis Investigative Site	San Isidro	Lima
Peru	Novartis Investigative Site	San Miguel	Lima
Peru	Novartis Investigative Site	Trujillo	La Libertad
Portugal	Novartis Investigative Site	Lisbon
Portugal	Novartis Investigative Site	Loures
Portugal	Novartis Investigative Site	Porto
Russian Federation	Novartis Investigative Site	Arkhangelsk
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	St Petersburg
Russian Federation	Novartis Investigative Site	St Petersburg
South Africa	Novartis Investigative Site	Cape Town
South Africa	Novartis Investigative Site	Johannesburg
South Africa	Novartis Investigative Site	Parktown
Sweden	Novartis Investigative Site	Stockholm
Sweden	Novartis Investigative Site	Stockholm
Sweden	Novartis Investigative Site	Uppsala
Thailand	Novartis Investigative Site	Bangkok
Thailand	Novartis Investigative Site	Chiang Mai
United States	New York Oncology Hematology SC	Albany	New York
United States	Weinberg Cancer Institute at Franklin Square Hospital	Baltimore	Maryland
United States	Montefiore Medical Center	Bronx	New York
United States	Marin Cancer Care	Greenbrae	California
United States	Comprehensive Cancer Centers of Nevada CCC of Nevada Henderson (4)	Henderson	Nevada
United States	Millennium Research Clin Develop .	Houston	Texas
United States	Nebraska Hematology-Oncology, P.C.	Lincoln	Nebraska
United States	Rocky Mountain Cancer Centers Rocky Mountain Cancer Ctr (50)	Longmont	Colorado
United States	Texas Oncology	McAllen	Texas
United States	Southern Cancer Center PC .	Mobile	Alabama
United States	Mount Sinai School of Medicine CFTY720D2306	New York	New York
United States	Nebraska Cancer Specialists Oncology Hematology West	Omaha	Nebraska
United States	Florida Retina Institute	Orlando	Florida
United States	Northwest Medical Specialties Dept.ofNW Med. Specialties	Tacoma	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Argentina,  Austria,  Belgium,  Brazil,  Bulgaria,  Canada,  Colombia,  Costa Rica,  Czechia,  Finland,  France,  Germany,  Hungary,  India,  Jordan,  Lithuania,  Peru,  Portugal,  Russian Federation,  South Africa,  Sweden,  Thailand, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Response Rate (ORR)	ORR defined as the percentage of participants with best overall response (BOR) of confirmed complete response (CR) or partial response (PR) assessed by local investigators according to RECIST 1.1.; CR: Disappearance of all lesions with lymph nodes measuring < 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.	Up to 23.8 months
Secondary	Change From Baseline in QTc (With Fridericia's Correction) at Cycle 1 Day 15 (at 2 Hours Post-dose)	Electrocardiogram (ECG) data was collected via 12-lead digital ECG machines. Change from baseline in the QT interval (a segment of the ECG that reflects the time it takes for the heart to repolarize after each heartbeat) was corrected for heart rate using Fridericia's formula (?QTcF).	Baseline and Cycle 1 Day 15 at 2 hours post-dose. Cycle = 28 days
Secondary	Progression-free Survival (PFS)	PFS was defined as the period starting from the date of randomization to the date of the first documented progression or death caused by any reason. PFS will be assessed via a local radiology assessment as well as BIRC according to RECIST 1.1.	Up to approximately 60 months
Secondary	Clinical Benefit Rate (CBR)	CBR is defined as the percentage of participants with a best overall response of complete response (CR), or partial response (PR), or an overall response of stable disease (SD), lasting for at least 24 weeks. CR, PR, and SD are defined as per local review as well as BIRC according to RECIST 1.1.; CR: Disappearance of all lesions with lymph nodes measuring < 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.; SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease.	Up to approximately 60 months
Secondary	Time to Response (TTR)	TTR defined as defined as the time from the date of randomization to the first documented response of either CR or PR. CR and PR are based on tumor response data as per local review and according to RECIST 1.1.; CR: Disappearance of all lesions with lymph nodes measuring < 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.	Up to approximately 60 months
Secondary	Duration of Response (DOR)	DOR defined as the time from the first documented response (CR or PR) to the first documented progression or death due to underlying cancer.; CR: Disappearance of all lesions with lymph nodes measuring < 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.	Up to approximately 60 months
Secondary	Pharmacokinetics (PK) of Ribociclib: Maximum Observed Plasma Concentration (Cmax)	PK parameters were calculated by non-compartmental analysis. Cmax is the maximum observed plasma drug concentration after single dose administration.	Cycle 1 Day 15 at pre-dose, and 2, 4, 6 and 24 hours post-dose. Cycle = 28 days
Secondary	PK of Ribociclib: Time to Reach Observed Maximum Concentration (Tmax)	PK parameters were calculated by non-compartmental analysis. Tmax is the time to reach maximum observed plasma concentration. Actual recorded sampling times were considered for the calculations.	Cycle 1 Day 15 at pre-dose, and 2, 4, 6 and 24 hours post-dose. Cycle = 28 days
Secondary	PK of Ribociclib: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours (AUC0-24)	PK parameters were calculated by non-compartmental analysis. AUC0-24 is the area under the plasma concentration-time curve from 0 to 24 hours	Cycle 1 Day 15 at pre-dose, and 2, 4, 6 and 24 hours post-dose. Cycle = 28 days