Clinical Trials /

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

NCT03822468

Description:

QT interval prolongation and neutropenia are considered to be important identified risks for ribociclib (Kisqali® Prescribing Information, Investigator Brochure). 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 an NSAI in pre- and postmenopausal women with HR-positive, HER2-negative aBC who have received no prior therapy for advanced disease. The risks of other AEs of special interest, such as neutropenia and hepatobiliary toxicity will be evaluated in this study as well. Approximately 350 patients will be randomly assigned to one of the below treatment arms in a 1:1 ratio: Experimental arm (Arm 1) - Ribociclib 400 mg QD 3 weeks on/1 week off + NSAI (+ goserelin in premenopausal women): 175 patients Control arm (Arm 2) - Ribociclib 600 mg QD 3 weeks on/1 week off + NSAI (+ goserelin in premenopausal women): 175 patients Randomization will be stratified by the presence of lung and/or liver metastases (yes versus no).

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: 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

Clinical Trial IDs

  • ORG STUDY ID: CLEE011A2207
  • SECONDARY ID: 2018-004234-15
  • NCT ID: NCT03822468

Conditions

  • Breast Cancer

Interventions

DrugSynonymsArms
RibociclibLEE011Ribociclib 400 mg
Letrozole or AnastrozoleRibociclib 400 mg
GoserelinRibociclib 400 mg

Purpose

QT interval prolongation and neutropenia are considered to be important identified risks for ribociclib (Kisqali® Prescribing Information, Investigator Brochure). 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 an NSAI in pre- and postmenopausal women with HR-positive, HER2-negative aBC who have received no prior therapy for advanced disease. The risks of other AEs of special interest, such as neutropenia and hepatobiliary toxicity will be evaluated in this study as well. Approximately 350 patients will be randomly assigned to one of the below treatment arms in a 1:1 ratio: Experimental arm (Arm 1) - Ribociclib 400 mg QD 3 weeks on/1 week off + NSAI (+ goserelin in premenopausal women): 175 patients Control arm (Arm 2) - Ribociclib 600 mg QD 3 weeks on/1 week off + NSAI (+ goserelin in premenopausal women): 175 patients Randomization will be stratified by the presence of lung and/or liver metastases (yes versus no).

Trial Arms

NameTypeDescriptionInterventions
Ribociclib 400 mgExperimentalRibociclib 400 mg QD 3 weeks on/1 week off + letrozole or anastrozole (+goserelin in premenopausal women)
  • Ribociclib
  • Letrozole or Anastrozole
  • Goserelin
Ribociclib 600 mgActive ComparatorRibociclib 600 mg QD 3 weeks on/1 week off + letrozole or anastrozole (+ goserelin in premenopausal women)
  • Ribociclib
  • Letrozole or Anastrozole
  • Goserelin

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:

          -  QTc interval at screening < 450 ms (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).

        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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall Response Rate (ORR)
Time Frame:At least 6 months
Safety Issue:
Description:ORR is based on local tumor assessments (RECIST version 1.1) for all patients that have been treated for at least 6 months or have discontinued the study treatment.

Secondary Outcome Measures

Measure:Δ QTcF at Cycle 1 Day 15 (at 2h post-dose) (Key Secondary Endpoint)
Time Frame:Cycle 1 Day 15 (2 hours post dose)
Safety Issue:
Description:To evaluate QTc (with Fridericia's correction) prolongation in the experimental arm
Measure:Progression-free survival (PFS)
Time Frame:Approximately 36 months
Safety Issue:
Description:PFS per RECIST 1.1
Measure:Clinical benefit rate (CBR)
Time Frame:Approximately 36 months
Safety Issue:
Description:CBR per RECIST 1.1
Measure:Time to response (TTR)
Time Frame:Approximately 36 months
Safety Issue:
Description:TTR per RECIST 1.1
Measure:Duration of response (DOR)
Time Frame:Approximately 36 months
Safety Issue:
Description:DOR per RECIST 1.1
Measure:Pharmacokinetics (PK) of ribociclib: Cmax
Time Frame:Cycle 1 Day 15
Safety Issue:
Description:when given in combination with NSAI
Measure:Pharmacokinetics (PK) of ribociclib: Tmax
Time Frame:Cycle 1 Day 15
Safety Issue:
Description:when given in combination with NSAI
Measure:Pharmacokinetics (PK) of ribociclib: AUC0 - 24h
Time Frame:Cycle 1 Day 15
Safety Issue:
Description:when given in combination with NSAI

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Novartis Pharmaceuticals

Trial Keywords

  • Breast Cancer; HR-positive; HER2-negative; ER-positive; advanced breast cancer; ribociclib; LEE011; premenopausal; postmenopausal

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