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Study of the Molecular Features of Postmenopausal Women With HR+ HER2-negative aBC on First-line Treatment With Ribociclib and Letrozole and, in Patients With a PIK3CA Mutation, on Second-line Treatment With Alpelisib Plus Fulvestrant (BioItaLEE)

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ClinicalTrials.gov Identifier: NCT03439046
Recruitment Status : Active, not recruiting
First Posted : February 20, 2018
Last Update Posted : August 7, 2019
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Brief Summary:
The purpose of this clinical trial is to study of the molecular features of postmenopausal women with hormone receptor-positive (HR+) HER2-negative advanced breast cancer on first-line treatment with ribociclib and letrozole and, in patients with a PIK3CA mutation, on second-line treatment with alpelisib plus fulvestrant

Condition or disease Intervention/treatment Phase
Breast Cancer Drug: Ribociclib Drug: Letrozole Drug: Alpelisib Drug: Fulvestrant Phase 3

Detailed Description:

The main purpose of this local, multicenter study is to investigate genetic and gene expression alterations in tumor prior to and following progression on ribociclib, during core phase and then prior to and following progression on alpelisib and thus identify patterns of mutations, how they evolve, and their association with CDK4/6 inhibition and outcomes such as sustained response or early progression. The study also aims to evaluate pharmacogenomics and its association with adverse events (frequency and severity), drug-drug interactions and clinical outcomes.

Finally, the study will also generate additional long-term safety and efficacy data in this specific Italian population.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 287 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase IIIb, Open-label, Local, Multicenter Study of the Molecular Features of Postmenopausal Women With Hormone Receptor-positive (HR+) HER2-negative Advanced Breast Cancer on First-line Treatment With Ribociclib Plus Letrozole and, in Patients With a PIK3CA Mutation, on Second-line Treatment With Alpelisib Plus Fulvestrant (BioItaLEE)
Actual Study Start Date : February 2, 2018
Estimated Primary Completion Date : December 28, 2020
Estimated Study Completion Date : November 30, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: ribociclib+letrozole
Ribociclib oral (3weeks on/1week off) in combination with oral once daily letrozole: 600mg tablets ribociclib QD + 2.5 mg tablets letrozole QD
Drug: Ribociclib
Ribociclib oral (3weeks on/1week off) in combination with oral once daily letrozole: 600mg tablets ribociclib QD + 2.5 mg tablets letrozole QD
Other Name: LEE011

Drug: Letrozole
Ribociclib oral (3weeks on/1week off) in combination with oral once daily letrozole: 600mg tablets ribociclib QD + 2.5 mg tablets letrozole QD

Experimental: alpelisib+fulvestrant
Alpelisib 300 mg oral daily on a continuous dosing schedule in combination with fulvestrant 500 mg intramuscular on Days 1 and 15 of Cycle 1, and on Day 1 of each cycle thereafter in a 28 days cycle
Drug: Alpelisib
Alpelisib 300 mg oral daily on a continuous dosing schedule in combination with fulvestrant 500 mg intramuscular on Days 1 and 15 of Cycle 1, and on Day 1 of each cycle thereafter in a 28 days cycle
Other Name: BYL719

Drug: Fulvestrant
Alpelisib 300 mg oral daily on a continuous dosing schedule in combination with fulvestrant 500 mg intramuscular on Days 1 and 15 of Cycle 1, and on Day 1 of each cycle thereafter in a 28 days cycle




Primary Outcome Measures :
  1. Change from baseline ctDNA alterations to progression disease during Core and Extension Phase [ Time Frame: Up to approximately 36 months starting from Baseline of the core phase and Up to approximately 9 months starting from Baseline of the extension phase ]
    The percentage of patients with ctDNA alterations (i.e. such as but not limited to Rb, ESR1, cyclin D1, CDKN2A, PIK3CA, p53 and PTEN) will be provided over time to characterize the biological evolution of the disease in each patient. The association of these alterations with clinical outcomes will also be provided.


Secondary Outcome Measures :
  1. Change from baseline serum TK1 concentrations to progression disease during core phase [ Time Frame: Up to approximately 36 months starting from Baseline of the core phase ]
    Descriptive statistics of serum TK1 concentrations will be provided over time. The association/correlation of serum TK1 concentrations with clinical outcomes will also be provided.

  2. The percentage of patients with ctDNA alterations will be provided over time in the subsets during Core and Extension Phase [ Time Frame: Up to approximately 36 months starting from Baseline of the core phase and Up to approximately 9 months starting from Baseline of the extension phase ]
    The percentage of patients with ctDNA alterations will be provided over time in the subsets of long responder patients and those with early progression

  3. Change from baseline tumor mutational burden (TMB) to progression disease during Core and Extension Phase [ Time Frame: Up to approximately 36 months starting from Baseline of the core phase and Up to approximately 9 months starting from Baseline of the extension phase ]
    Descriptive statistics of tumor mutational burden (TMB), defined as a quantitative measure of the total number of ctDNA mutations per coding area of tumor genome, will be provided over time, according to the scheduled sample collections. The association of TMB values with clinical outcomes will also be provided.

  4. The percentage of patients with mutations as assessed at baseline of the Core and Extension phase across different patient profiles [ Time Frame: Screening Core Phase and Screening Extension Phase ]
    The percentage of patients with mutations as assessed at baseline by means of ctDNA sample, and tissue biopsy will be compared between the following patient profiles defined according to disease history (i.e. newly diagnosed vs. recurrent disease).

  5. The percentage of patients with alterations detected through liquid biopsy vs. tissue biopsy during Core and Extension Phase [ Time Frame: Up to approximately 36 months starting from Baseline of the core phase and Up to approximately 9 months starting from Baseline of the extension phase ]
    The percentage of patients with alterations detected at baseline and at disease progression will be compared between the two different procedures of detection (i.e. detection through liquid biopsy vs. tissue biopsy).

  6. Change from baseline tumor microenvironment parameters to progression disease during Core and Extension Phase [ Time Frame: Up to approximately 36 months starting from Baseline of the core phase and Up to approximately 9 months starting from Baseline of the extension phase ]
    Descriptive statistics of tumor microenvironment parameters on tumor biopsy will be provided at baseline and upon disease progression. The association of these tumor micro-environment parameters with clinical outcomes will also be provided.

  7. Time-to-Progression (TTP) during Core and Extension Phase [ Time Frame: Up to approximately 36 months starting from Baseline of the core phase and Up to approximately 9 months starting from Baseline of the extension phase ]
    Time to progression (TTP) is defined as time from date of start of treatment to the date of event defined as the first documented progression or death due to underlying cancer.

  8. The number of patients with adverse events as a measure of safety and tolerability during Core and Extension Phase [ Time Frame: Up to approximately 36 months starting from Baseline of the core phase and Up to approximately 9 months starting from Baseline of the extension phase ]
    Fequency and severity of AEs and SAEs

  9. The percentage of patients with best overall response rate CR or PR during Core and Extension Phase [ Time Frame: Up to approximately 36 months starting from Baseline of the core phase and Up to approximately 9 months starting from Baseline of the extension phase ]
    Overall response rate (ORR) is defined as the percentage of patients, with measurable disease, that showed best overall response of complete response (CR) or partial response (PR) according to RECIST 1.1.

  10. The percentage of patients with clinical benefit during Core and Extension Phase [ Time Frame: Up to approximately 36 months starting from Baseline of the core phase and Up to approximately 9 months starting from Baseline of the extension phase ]
    Clinical benefit rate (CBR) is defined as the percentage of patients with a best overall response of complete response (CR), or partial response (PR) or an overall lesion response of stable disease (SD), lasting as per local review, for a duration of at least 24 weeks. CR, PR and SD are defined according to RECIST 1.1.

  11. The percentage of participants with adverse events as a measure of safety and tolerability during Core and Extension Phase [ Time Frame: Up to approximately 36 months starting from Baseline of the core phase and Up to approximately 9 months starting from Baseline of the extension phase ]
    Frequency and severity of AEs and SAEs



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Gender Based Eligibility:   Yes
Accepts Healthy Volunteers:   No
Criteria

CORE PHASE Inclusion Criteria:

  • Patient has an advanced (locoregionally recurrent or metastatic) breast cancer in first line treatment (treatment naïve for the advanced setting).
  • Patient is in post-menopause, defined by one of the following:
  • Prior bilateral oophorectomy
  • Age ≥60
  • Age <60 and amenorrhea for 12 or more months (in the absence of chemotherapy, tamoxifen, toremifen, or ovarian suppression) and FSH and estradiol in the postmenopausal range per local normal range
  • Patient has a histologically and/or cytologically confirmed diagnosis of estrogenreceptor positive and/or progesterone receptor positive breast cancer by local laboratory.
  • Patient has an 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.
  • Patient is willing to undergo blood and tumor sample collection for the biological assessments/objectives as scheduled in the protocol.

CORE PHASE Exclusion Criteria:

  • Patient who received prior treatment with any CDK4/6 inhibitor.
  • Patient who received any prior systemic hormonal therapy or chemotherapy for advanced breast cancer.

Note:

Patients who received neo/adjuvant therapy for breast cancer are eligible. If the prior neo/adjuvant therapy included letrozole or anastrozole, the disease-free interval must be greater than 12 months from the completion of treatment until study entry.

• Patients who received ≤ 28 days of letrozole or anastrozole for advanced disease prior to inclusion in this trial are eligible.

- Patient is currently using other anti-cancer therapy. Other protocol-defined inclusion/exclusion criteria may apply.

EXTENSION PHASE Inclusion criteria:

  • Patient has been discontinued (any reason allowed) from treatment with ribociclib + letrozole in the core phase and is deemed suitable for treatment with alpelisib + fulvestrant in second line. Ribociclib + letrozole must be the last treatment regimen before alpelisib + fulvestrant.
  • Patient has PIK3CA mutation as determined in tumor tissue and/or plasma by a Novartis designated laboratory. Results of tissue samples obtained during the core phase (screening or EOT) are acceptable

EXTENSION PHASE Exclusion criteria:

  • Patient has received prior treatment with any PI3K inhibitors.
  • Patient is concurrently using other anti-cancer therapy. Ribociclib and letrozole used in the core phase must be discontinued at least 7 days prior to day one of the extension study treatment.

All drugs with overlapping toxicities must be discontinued within 7 days and AE resolved to NCI CTCAE v4.03 Grade ≤1 prior to study treatment. Exception to this criterion: patients with any grade of alopecia are allowed to enter the study.


Information from the National Library of Medicine

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): NCT03439046


Locations
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Italy
Novartis Investigative Site
Casale Monferrato, AL, Italy, 15033
Novartis Investigative Site
Bari, BA, Italy, 70124
Novartis Investigative Site
Bergamo, BG, Italy, 24127
Novartis Investigative Site
Benevento, BN, Italy, 82100
Novartis Investigative Site
Brindisi, BR, Italy, 72100
Novartis Investigative Site
Brescia, BS, Italy, 25123
Novartis Investigative Site
Cremona, CR, Italy, 26100
Novartis Investigative Site
Catania, CT, Italy, 95124
Novartis Investigative Site
Catania, CT, Italy, 95125
Novartis Investigative Site
Cona, FE, Italy, 44100
Novartis Investigative Site
San Giovanni Rotondo, FG, Italy, 71013
Novartis Investigative Site
Genova, GE, Italy, 16132
Novartis Investigative Site
Livorno, LI, Italy, 57124
Novartis Investigative Site
Monza, MB, Italy, 20900
Novartis Investigative Site
Macerata, MC, Italy, 62100
Novartis Investigative Site
Messina, ME, Italy, 98158
Novartis Investigative Site
Milano, MI, Italy, 20132
Novartis Investigative Site
Milano, MI, Italy, 20133
Novartis Investigative Site
Milano, MI, Italy, 20141
Novartis Investigative Site
Rozzano, MI, Italy, 20089
Novartis Investigative Site
Nuoro, NU, Italy, 08100
Novartis Investigative Site
Palermo, PA, Italy, 90127
Novartis Investigative Site
Palermo, PA, Italy, 90146
Novartis Investigative Site
Padova, PD, Italy, 35100
Novartis Investigative Site
Pisa, PI, Italy, 56126
Novartis Investigative Site
Aviano, PN, Italy, 33081
Novartis Investigative Site
Prato, PO, Italy, 59100
Novartis Investigative Site
Fano, PU, Italy, 61032
Novartis Investigative Site
Faenza, RA, Italy, 48018
Novartis Investigative Site
Roma, RM, Italy, 00128
Novartis Investigative Site
Roma, RM, Italy, 00168
Novartis Investigative Site
Roma, RM, Italy, 00189
Novartis Investigative Site
Salerno, SA, Italy, 84131
Novartis Investigative Site
Candiolo, TO, Italy, 10060
Novartis Investigative Site
Torino, TO, Italy, 10128
Novartis Investigative Site
Udine, UD, Italy, 33100
Novartis Investigative Site
Negrar, VR, Italy, 37024
Novartis Investigative Site
Bologna, Italy, 40138
Novartis Investigative Site
Napoli, Italy, 80131
Novartis Investigative Site
Napoli, Italy, 80138
Novartis Investigative Site
Perugia, Italy, 06129
Sponsors and Collaborators
Novartis Pharmaceuticals

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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT03439046     History of Changes
Other Study ID Numbers: CLEE011AIT01
First Posted: February 20, 2018    Key Record Dates
Last Update Posted: August 7, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
HR-positive HER2-negative
advanced breast cancer
LEE011
ribociclib
letrozole
CDK
CDK4
CDK6
CDK4/6
Phase IIIb
ER-positive
PR-positive
postmenopausal
biomarker
ctDNA
liquid biopsy
PIK3CA
alpelisib
fulvestrant
BYL719
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Letrozole
Fulvestrant
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
Estrogen Receptor Antagonists