Undersøgelse af LEE011, BYL719 og Letrozol i Advanced ER+ Breast Cancer
En fase Ib/II, multicenterundersøgelse af kombinationen af LEE011 og BYL719 med Letrozol hos voksne patienter med avanceret ER+ brystkræft
The purpose of this trial is to inform the future clinical development of the two investigational agents in ER+ breast cancer, LEE011 (CDK4/6 inhibitor) and BYL719 (PI3K-alpha inhibitor).
This is a multi-center, open-label Phase Ib study. The Phase Ib dose escalation will estimate the MTD and/or RP2D for three regimens: two double combinations, LEE011 with letrozole and BYL719 with letrozole, followed by triple combinations of LEE011 + BYL719 with letrozole (Arms 3 and 4).
The Phase Ib dose escalation part will be followed by Phase Ib dose expansions to further characterize the safety, tolerability, PK and preliminary clinical anti-tumor activity of the combinations. Optional crossover for patients who have progressed while on dose escalation or dose expansion with doublet treatment on Arms 1 or 2 to be treated with the triplet combination (Arm 3) after the determination of the RP2D for Arm 3; is no longer permitted after protocol amendment 6.
Approximately 270 adult women with ER+/HER2- locally advanced or metastatic breast cancer will be enrolled.
Studieoversigt
Status
Betingelser
Intervention / Behandling
Undersøgelsestype
Tilmelding (Faktiske)
Fase
- Fase 2
- Fase 1
Udvidet adgang
Kontakter og lokationer
Studiesteder
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New South Wales
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Westmead, New South Wales, Australien, 2145
- Novartis Investigative Site
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Victoria
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Parkville, Victoria, Australien, 3050
- Novartis Investigative Site
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Western Australia
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Nedlands, Western Australia, Australien, 6009
- Novartis Investigative Site
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Glasgow, Det Forenede Kongerige, G12 0YN
- Novartis Investigative Site
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Manchester, Det Forenede Kongerige, M20 2BX
- Novartis Investigative Site
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California
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San Diego, California, Forenede Stater, 92103
- Univ of California at San Diego Moores Cancer Ctr
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San Francisco, California, Forenede Stater, 94143
- UCSF Medical Center
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Florida
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Tampa, Florida, Forenede Stater, 33612
- H Lee Moffitt Cancer Center and Research Institute
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Massachusetts
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Boston, Massachusetts, Forenede Stater, 02114
- Massachusetts General Hospital
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Boston, Massachusetts, Forenede Stater, 02114
- Massachusetts General Hospital SC-5
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Tennessee
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Nashville, Tennessee, Forenede Stater, 37203
- Tennessee Oncology
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Nashville, Tennessee, Forenede Stater, 37232
- Vanderbilt University Medical Ctr
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Texas
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Amarillo, Texas, Forenede Stater, 79124
- Texas Oncology
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San Antonio, Texas, Forenede Stater, 78229
- Mays Cancer Ctr Uthsa Mdacc
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Washington
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Tacoma, Washington, Forenede Stater, 98405
- Northwest Medical Specialties
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Marseille, Frankrig, 13273
- Novartis Investigative Site
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Paris, Frankrig, 75475
- Novartis Investigative Site
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Saint-Herblain, Frankrig, 44805
- Novartis Investigative Site
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PI
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Pisa, PI, Italien, 56126
- Novartis Investigative Site
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Bellinzona, Schweiz, 6500
- Novartis Investigative Site
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Madrid, Spanien, 28050
- Novartis Investigative Site
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Madrid, Spanien, 28009
- Novartis Investigative Site
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Seville, Spanien, 41013
- Novartis Investigative Site
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Valencia, Spanien, 46010
- Novartis Investigative Site
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Seoul, Sydkorea, 03080
- Novartis Investigative Site
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Deltagelseskriterier
Berettigelseskriterier
Aldre berettiget til at studere
Tager imod sunde frivillige
Køn, der er berettiget til at studere
Beskrivelse
Inclusion Criteria:
- Postmenopausal, Estrogen-receptor positive and/or Progesterone-receptor positive breast cancer
- Phase Ib dose escalation only: Any number of prior lines of endocrine therapy is allowed with the exception of cytotoxic therapy which is limited to one prior line administered in the advanced (metastatic or locally advanced) setting.
- Phase Ib dose expansions Arms 1, 2 and 3
- No prior systemic treatment in the advanced (metastatic or locally advanced) setting with the exception of treatment with letrozole for a maximum of one month prior to starting study treatment.
- Patients who received (neo)adjuvant therapy for breast cancer are eligible. Prior therapy with letrozole or anastrozole in the (neo)adjuvant setting is permitted if the disease-free interval is greater than 12 months from the completion of treatment.
Exclusion Criteria:
- HER2-overexpression in the patient's tumor tissue
- Patients with active CNS or other brain metastases
- Major surgery within 2 weeks
- Acute or chronic pancreatitis
- Bilateral diffuse lymphangitic carcinomatosis
- Another malignancy within 3 years
- Receiving hormone replacement therapy that cannot be discontinued
- Impaired cardiac function
- Patients with clinically manifest diabetes mellitus (treated and/or clinical signs or with fasting glucose ≥ 126 mg/dL / 7.0 mmol/L or hemoglobin A1c >6.5%), history of gestational diabetes mellitus or documented steroid-induced diabetes mellitus.
- Other protocol-defined inclusion/exclusion criteria may apply
Studieplan
Hvordan er undersøgelsen tilrettelagt?
Design detaljer
- Primært formål: Behandling
- Tildeling: Randomiseret
- Interventionel model: Parallel tildeling
- Maskning: Ingen (Åben etiket)
Våben og indgreb
Deltagergruppe / Arm |
Intervention / Behandling |
|---|---|
|
Eksperimentel: LEE011 + letrozole Arm 1
LEE011 - 28 day cycles (21 days followed by a 7 day break - dose escalating), letrozole - 2.5 mg/day |
LEE011 - 28 day cycles (21 days followed by a 7 day break) for Arms 1, 3. LEE011 28 days cycles (continuous) Arm 4. Letrozole 2.5 mg/day |
|
Eksperimentel: BYL719 + letrozole Arm 2
BYL719 - daily (dose escalating) letrozole - 2.5 mg/day |
Letrozole 2.5 mg/day BYL719 - 28 days cycle (continuous) for Arm 2; 3 and 4 |
|
Eksperimentel: LEE011 + BYL719 + letrozole Arm 3
LEE011 - 28 day cycles (21 days followed by a 7 day break -dose escalating), BYL719 - daily (dose escalating), letrozole 2.5 mg/day |
LEE011 - 28 day cycles (21 days followed by a 7 day break) for Arms 1, 3. LEE011 28 days cycles (continuous) Arm 4. Letrozole 2.5 mg/day BYL719 - 28 days cycle (continuous) for Arm 2; 3 and 4 |
|
Eksperimentel: LEE011+ BYL719+letrozole Arm 4
LEE011-daily (dose escalating), BYL719 -daily (dose escalating), letrozole 2.5 mg/day |
LEE011 - 28 day cycles (21 days followed by a 7 day break) for Arms 1, 3. LEE011 28 days cycles (continuous) Arm 4. Letrozole 2.5 mg/day BYL719 - 28 days cycle (continuous) for Arm 2; 3 and 4 |
Hvad måler undersøgelsen?
Primære resultatmål
Resultatmål |
Foranstaltningsbeskrivelse |
Tidsramme |
|---|---|---|
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Forekomst af dosisbegrænsende toksicitet (DLT'er) - Kun fase lb
Tidsramme: 28 dage
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28 dage
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Safety and tolerability
Tidsramme: Average 18 months
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Adverse Events (AEs), serious AEs (SAEs), changes in hematology and chemistry values, vital signs, electrocardiograms (ECGs), dose interruptions, reductions and dose intensity. |
Average 18 months
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PK profiles of LEE011 and letrozole
Tidsramme: 18 months
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To characterize PK profiles of LEE011 and Letrozole. |
18 months
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Sekundære resultatmål
Resultatmål |
Foranstaltningsbeskrivelse |
Tidsramme |
|---|---|---|
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Safety and tolerability of LEE011 in combination with letrozole, BYL719 in combination with letrozole, and the triple combination of LEE011 +BYL719 with letrozole
Tidsramme: Average 24 months
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Safety and tolerability will be determined by type, frequency and severity of adverse events and laboratory abnormalities per Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 |
Average 24 months
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Plasma concentration-time profiles of LEE011, BYL719 and letrozole
Tidsramme: Average 24 months
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To characterize the PK profiles of LEE011, BYL719, and letrozole when used in combination as well as to evaluate any other clinically significant metabolites that may be identified. |
Average 24 months
|
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Overall Response Rate (ORR)
Tidsramme: Average 24 months
|
ORR is defined as the proportion of patients with a best overall response of complete response or partial response. |
Average 24 months
|
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Duration of Response (DOR)
Tidsramme: Average 24 months
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DOR 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. |
Average 24 months
|
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Progression Free Survival (PFS)
Tidsramme: Average 24 months
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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. |
Average 24 months
|
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Pharmacokinetics (PK) parameters, including but not limited to AUCtau, Cmin, Cmax, Tmax, accumulation ratio (Racc)
Tidsramme: Average 24 months
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To characterize the PK profiles of LEE011, BYL719, and letrozole when used in combination as well as to evaluate any other clinically significant metabolites that may be identified. |
Average 24 months
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Safety and tolerability of the triple combination of LEE011 +BYL719 with letrozole in patients previously treated with either doublet
Tidsramme: Average 24 months
|
Safety and tolerability will be determined by type, frequency and severity of adverse events and laboratory abnormalities per Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 |
Average 24 months
|
Samarbejdspartnere og efterforskere
Sponsor
Efterforskere
- Studieleder: Novartis Pharmaceuticals, Novartis Pharmaceuticals
Publikationer og nyttige links
Generelle publikationer
- Ji Y, Yartsev V, Quinlan M, Serra P, Wang Y, Chakraborty A, Miller M. Justifying Ribociclib Dose in Patients with Advanced Breast Cancer with Renal Impairment Based on PK, Safety, and Efficacy Data: An Innovative Approach Integrating Data from a Dedicated Renal Impairment Study and Oncology Clinical Trials. Clin Pharmacokinet. 2023 Mar;62(3):493-504. doi: 10.1007/s40262-022-01206-2. Epub 2023 Feb 17.
- Ji Y, Wang C, Combes FP, Ho YY, Fasching PA, Untch M, Zarate JP, Crown J. Quantitative Pharmacology Justifying Ribociclib Dose in Early Breast Cancer. Clin Pharmacokinet. 2026 Aug;65(8):1217-1228. doi: 10.1007/s40262-026-01643-3. Epub 2026 Jun 23.
Datoer for undersøgelser
Studer store datoer
Studiestart (Faktiske)
Primær færdiggørelse (Anslået)
Studieafslutning (Anslået)
Datoer for studieregistrering
Først indsendt
Først indsendt, der opfyldte QC-kriterier
Først opslået (Anslået)
Opdateringer af undersøgelsesjournaler
Sidste opdatering sendt (Faktiske)
Sidste opdatering indsendt, der opfyldte kvalitetskontrolkriterier
Sidst verificeret
Mere information
Begreber relateret til denne undersøgelse
Nøgleord
Yderligere relevante MeSH-vilkår
Andre undersøgelses-id-numre
- CLEE011X2107
- 2023-509511-84-00 (Registry Identifier: EU CT Number)
- 2023 (U.S. NIH-bevilling/kontrakt)
Plan for individuelle deltagerdata (IPD)
Planlægger du at dele individuelle deltagerdata (IPD)?
IPD-planbeskrivelse
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
Lægemiddel- og udstyrsoplysninger, undersøgelsesdokumenter
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