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)

• ClinicalTrials.gov Identifier: NCT03439046
• Recruitment Status: Active, not recruiting
• First Posted: February 20, 2018
• Last Update Posted: May 6, 2023
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Study Description

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 287 participants
• Allocation: N/A
• Intervention Model: Sequential 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: January 31, 2024
• Estimated Study Completion Date: January 31, 2024

Arms and Interventions

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

Outcome Measures

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

Eligibility Criteria

• 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.

Contacts and Locations

Locations

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

Bologna, BO, Italy, 40138

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, 95123

Novartis Investigative Site

Catania, CT, Italy, 95124

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

Perugia, PG, Italy, 06129

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

Napoli, Italy, 80131

Novartis Investigative Site

Napoli, Italy, 80138

Sponsors and Collaborators

Novartis Pharmaceuticals

More Information

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03439046
• Other Study ID Numbers: CLEE011AIT01
• First Posted: February 20, 2018
• Last Update Posted: May 6, 2023
• Last Verified: May 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• 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:

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