Study of 2 Ribociclib Doses in Combination With Aromatase Inhibitors in Women With HR+, HER2- Advanced Breast Cancer (PMR)
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| ClinicalTrials.gov Identifier: NCT03822468 |
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Recruitment Status :
Recruiting
First Posted : January 30, 2019
Last Update Posted : December 19, 2020
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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).
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Breast Cancer | Drug: Ribociclib Drug: Letrozole or Anastrozole Drug: Goserelin | Phase 2 |
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 350 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| 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 |
| Actual Study Start Date : | June 11, 2019 |
| Estimated Primary Completion Date : | February 2, 2026 |
| Estimated Study Completion Date : | February 2, 2026 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: Ribociclib 400 mg
Ribociclib 400 mg QD 3 weeks on/1 week off + letrozole or anastrozole (+goserelin in premenopausal women)
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Drug: Ribociclib
Ribociclib will be supplied as 200 mg tablets as individual patient supply packaged bottles taken by mouth.
Other Name: LEE011 Drug: Letrozole or Anastrozole Letrozole 2.5 mg by mouth QD continuously or anastrozole 1 mg by mouth QD continuously (investigator choice) Drug: Goserelin Goserelin 3.6 mg subcutaneously once every 4 weeks (pre-menopausal women only) |
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Active Comparator: Ribociclib 600 mg
Ribociclib 600 mg QD 3 weeks on/1 week off + letrozole or anastrozole (+ goserelin in premenopausal women)
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Drug: Ribociclib
Ribociclib will be supplied as 200 mg tablets as individual patient supply packaged bottles taken by mouth.
Other Name: LEE011 Drug: Letrozole or Anastrozole Letrozole 2.5 mg by mouth QD continuously or anastrozole 1 mg by mouth QD continuously (investigator choice) Drug: Goserelin Goserelin 3.6 mg subcutaneously once every 4 weeks (pre-menopausal women only) |
- Overall Response Rate (ORR) [ Time Frame: At least 6 months ]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.
- Δ QTcF at Cycle 1 Day 15 (at 2h post-dose) (Key Secondary Endpoint) [ Time Frame: Cycle 1 Day 15 (2 hours post dose) ]To evaluate QTc (with Fridericia's correction) prolongation in the experimental arm
- Progression-free survival (PFS) [ Time Frame: Approximately 36 months ]PFS per RECIST 1.1
- Clinical benefit rate (CBR) [ Time Frame: Approximately 36 months ]CBR per RECIST 1.1
- Time to response (TTR) [ Time Frame: Approximately 36 months ]TTR per RECIST 1.1
- Duration of response (DOR) [ Time Frame: Approximately 36 months ]DOR per RECIST 1.1
- Pharmacokinetics (PK) of ribociclib: Cmax [ Time Frame: Cycle 1 Day 15 ]when given in combination with NSAI
- Pharmacokinetics (PK) of ribociclib: Tmax [ Time Frame: Cycle 1 Day 15 ]when given in combination with NSAI
- Pharmacokinetics (PK) of ribociclib: AUC0 - 24h [ Time Frame: Cycle 1 Day 15 ]when given in combination with NSAI
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | Female |
| Accepts Healthy Volunteers: | No |
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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03822468
| Contact: Novartis Pharmaceuticals | 1-888-669-6682 | novartis.email@novartis.com | |
| Contact: Novartis Pharmaceuticals | +41613241111 | novartis.email@novartis.com |
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| Study Director: | Novartis Pharmaceuticals | Novartis Pharmaceuticals |
| Responsible Party: | Novartis Pharmaceuticals |
| ClinicalTrials.gov Identifier: | NCT03822468 |
| Other Study ID Numbers: |
CLEE011A2207 2018-004234-15 ( EudraCT Number ) |
| First Posted: | January 30, 2019 Key Record Dates |
| Last Update Posted: | December 19, 2020 |
| Last Verified: | December 2020 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | Yes |
| Plan Description: | Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent expert panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data is currently available according to the process described on www.clinicalstudydatarequest.com. |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
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Breast Cancer HR-positive HER2-negative ER-positive advanced breast cancer |
ribociclib LEE011 premenopausal postmenopausal |
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Breast Neoplasms Neoplasms by Site Neoplasms Breast Diseases Skin Diseases Letrozole Anastrozole Goserelin Antineoplastic Agents |
Aromatase Inhibitors Steroid Synthesis Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Estrogen Antagonists Hormone Antagonists Hormones, Hormone Substitutes, and Hormone Antagonists Physiological Effects of Drugs Antineoplastic Agents, Hormonal |