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The purpose of this trial is to explore the clinical utility of the three investigational agents in HR+, HER2- breast cancer. LEE011 (CDK4/6 inhibitor), BKM120 (PI3K-pan class I-inhibitor) and BYL719 (PI3K-alpha specific class I inhibitor) in combination with fulvestrant.
This is a multi-center, open-label Phase Ib/II study. The Phase Ib portion of the study is a dose escalation to estimate the MTD and/or RP2D for three regimens: LEE011 with fulvestrant; LEE011 and BKM120 with fulvestrant; LEE011and BYL719 with fulvestrant.
The Phase II portion of the study was planned to be a randomized study to assess the anti-tumor activity as well as safety and tolerability of LEE011 with fulvestrant to LEE011 and BKM120 with fulvestrant, and LEE011 and BYL719 with fulvestrant in patients with ER+/HER2- locally advanced or metastatic breast cancer.
Approximately 216 adult women with ER+/HER2- locally advanced or metastatic breast cancer were planned to be enrolled.
On 31-May-2016 Novartis's made the decision decision to not open the Phase II portion of the study, for business reasons. Sufficient data had already been collected and no additional data for the triplet combinations was needed. As a result, the Phase II portion of the trial was not opened.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| LEE011 + BKM120 + fulvestrant | Experimental | LEE011 - 28 day cycles (21 days followed by a 7 day break - dose escalating) BKM120 - daily (dose escalating) fulvestrant - i.m. - 500 mg given on day 1 and day 15 of Cycle 1, then on Day 1 of each subsequent cycle. |
|
| LEE011 + BYL719 + fulvestrant | Experimental | LEE011 - 28 day cycles (21 days followed by a 7 day break - dose escalating) BYL719 - daily (dose escalating) fulvestrant - i.m. - 500 mg given on day 1 and day 15 of Cycle 1, then on Day 1 of each subsequent cycle. |
|
| LEE011 + fulvestrant | Experimental | LEE011 - 28 day cycles (3 weeks on, 1 week off) or (continuous daily dosing - dose escalating) fulvestrant - 500 mg i.m. given on Day 1 and Day 15 of Cycle 1, then on Day 1 of each subsequent cycle. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| LEE011 | Drug | LEE011: supplied as capsules of dosage strength of 50 mg or 200 mg. The capsules will be differentiated through different sizes |
|
| Measure | Description | Time Frame |
|---|---|---|
| Incidence of Dose limiting toxicities (DLTs) - Phase lb only | Dose limiting toxicities | 28 days |
| Progression free survival (PFS) - Phase ll only | Progression Free Survival per RECIST v 1.1 by local investigator assessment | 36 months |
| Measure | Description | Time Frame |
|---|---|---|
| Safety and Tolerability of the combinations of LEE011 with fulvestrant, LEE011 + BKM120 with fulvestrant and LEE011 + BYL719 with fulvestrant | Adverse Events (AEs), serious AEs (SAEs), changes in hematology and chemistry values, vital signs, electrocardiograms (ECGs), dose interruptions, reductions and dose intensity | 36 months |
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Inclusion Criteria:
Exclusion Criteria:
Other protocol-defined inclusion/exclusion criteria may apply
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| Name | Affiliation | Role |
|---|---|---|
| Novartis Pharmaceuticals | Novartis Pharmaceuticals | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Alabama at Birmingham/ Kirklin Clinic Dept Onc | Birmingham | Alabama | 35294-0006 | United States | ||
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 32887722 | Derived | Tolaney SM, Im YH, Calvo E, Lu YS, Hamilton E, Forero-Torres A, Bachelot T, Maur M, Fasolo A, Tiedt R, Nardi L, Stammberger U, Abdelhady AM, Ruan S, Lee SC. Phase Ib Study of Ribociclib plus Fulvestrant and Ribociclib plus Fulvestrant plus PI3K Inhibitor (Alpelisib or Buparlisib) for HR+ Advanced Breast Cancer. Clin Cancer Res. 2021 Jan 15;27(2):418-428. doi: 10.1158/1078-0432.CCR-20-0645. Epub 2020 Sep 4. |
| Label | URL |
|---|---|
| link to Novartis Clinical Trial result Database | View source |
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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 review 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 availability is according to the criteria and process described on www.clinicalstudydatarequest.com
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| ID | Term |
|---|---|
| D001943 | Breast Neoplasms |
| ID | Term |
|---|---|
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D001941 | Breast Diseases |
| D012871 | Skin Diseases |
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| ID | Term |
|---|---|
| C000589651 | ribociclib |
| C585539 | Alpelisib |
| D000077267 | Fulvestrant |
| C571178 | NVP-BKM120 |
| ID | Term |
|---|---|
| D004958 | Estradiol |
| D004963 | Estrenes |
| D004962 | Estranes |
| D013256 | Steroids |
| D000072473 |
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| BYL719 | Drug | BYL719: supplied as tablets of dosage strength of 10 mg, 50 mg or 200 mg. Tablets will be differentiated through different sizes and/or colors. |
|
| fulvestrant | Drug | Fulvestrant will be supplied according to local practice and regulation. Fulvestrant is a commercially available product, comes in 500 mg dose and is an injection for intramuscular (i.m.) administration. |
|
| BKM120 | Drug | BKM120: supplied as 10 mg or 50 mg capsules. The capsules will be differentiated through different sizes. |
|
| Plasma concentration-time profiles of LEE011, BKM120, BYL719 and fulvestrant. |
To characterize the PK profiles of LEE011, BKM120, BYL719, and fulvestrant when used in combination as well as to evaluate any other clinically significant metabolites that may be identified. PK parameters for LEE011, BKM120 and BYL719, including but not limited to Cmax, Cmin, Tmax, AUCtau, accumulation ratio (Racc),and Ctrough values for fulvestrant. |
| 36 months |
| Overall Response Rate (ORR) | ORR is defined as the proportion of patients with a best overall response of complete response or partial response. | 36 months |
| Duration of Response (DOR) | Duration of Response is calculated as the time from the date of first documented response (complete response (CR) or partial response (PR)) to the first documented date of progression or death due to underlying cancer. | 36 months |
| Progression Free Survival (PFS) (phase l only) | PFS is the time from date of randomization/start of treatment to the date of event defined as the first documented progression or death due to any cause. | 36 months |
| Overall Survival (OS) - Phase II only | OS is defined as the time from date of randomization/start of treatment to date of death due to any cause. If a patient is not known to have died, survival will be censored at the date of last known date patient alive. | 36 months |
| Dana Farber Cancer Institute Onc. Dept. |
| Boston |
| Massachusetts |
| 02215 |
| United States |
| Sarah Cannon Research Institute Onc Dept | Nashville | Tennessee | 37203 | United States |
| Novartis Investigative Site | Lyon | 69373 | France |
| Novartis Investigative Site | Milan | MI | 20132 | Italy |
| Novartis Investigative Site | Modena | MO | 41124 | Italy |
| Novartis Investigative Site | Singapore | 119228 | Singapore |
| Novartis Investigative Site | Seoul | Korea | 06351 | South Korea |
| Novartis Investigative Site | Madrid | 28050 | Spain |
| Novartis Investigative Site | Taipei | Taiwan ROC | 10041 | Taiwan |
| Novartis Investigative Site | Leicester | LE1 5WW | United Kingdom |
| D017437 |
| Skin and Connective Tissue Diseases |
| Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
| D045166 | Estradiol Congeners |
| D012739 | Gonadal Steroid Hormones |
| D042341 | Gonadal Hormones |
| D006728 | Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |