Clinical Trials /

Study of LEE011, BYL719 and Letrozole in Advanced ER+ Breast Cancer

NCT01872260

Description:

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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

    <li>Brief Title: Study of LEE011, BYL719 and Letrozole in Advanced ER+ Breast Cancerli><li>Official Title: A Phase Ib/II, Multicenter Study of the Combination of LEE011 and BYL719 With Letrozole in Adult Patients With Advanced ER+ Breast Cancerli>

Clinical Trial IDs

    <li>ORG STUDY ID: CLEE011X2107li><li>SECONDARY ID: 2013-001219-57li><li>NCT ID: NCT01872260li>

Conditions

    <li>Breast Cancerli>

Interventions

DrugSynonymsArms
LEE011LEE011 + letrozole Arm 1
LetrozoleLEE011 + letrozole Arm 1
BYL719BYL719 + letrozole Arm 2

Purpose

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 250 adult women with ER+/HER2- locally advanced or metastatic breast cancer will be enrolled.

Trial Arms

NameTypeDescriptionInterventions
LEE011 + letrozole Arm 1ExperimentalLEE011 - 28 day cycles (21 days followed by a 7 day break - dose escalating), letrozole - 2.5 mg/day
    <li>LEE011li><li>Letrozoleli>
BYL719 + letrozole Arm 2ExperimentalBYL719 - daily (dose escalating) letrozole - 2.5 mg/day
    <li>Letrozoleli><li>BYL719li>
LEE011 + BYL719 + letrozole Arm 3ExperimentalLEE011 - 28 day cycles (21 days followed by a 7 day break -dose escalating), BYL719 - daily (dose escalating), letrozole 2.5 mg/day
    <li>LEE011li><li>Letrozoleli><li>BYL719li>
LEE011+ BYL719+letrozole Arm 4ExperimentalLEE011-daily (dose escalating), BYL719 -daily (dose escalating), letrozole 2.5 mg/day
    <li>LEE011li><li>Letrozoleli><li>BYL719li>

Eligibility Criteria

        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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of Dose limiting toxicities (DLTs) - Phase lb only
Time Frame:28 days
Safety Issue:
Description:Adverse Events (AEs), serious AEs (SAEs), changes in hematology and chemistry values, vital signs, electrocardiograms (ECGs), dose interruptions, reductions and dose intensity.

Secondary Outcome Measures

Measure:Safety and tolerability of LEE011 in combination with letrozole, BYL719 in combination with letrozole, and the triple combination of LEE011 +BYL719 with letrozole
Time Frame:Average 24 months
Safety Issue:
Description: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
Measure:Plasma concentration-time profiles of LEE011, BYL719 and letrozole
Time Frame:Average 24 months
Safety Issue:
Description: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.
Measure:Overall Response Rate (ORR)
Time Frame:Average 24 months
Safety Issue:
Description:ORR is defined as the proportion of patients with a best overall response of complete response or partial response.
Measure:Duration of Response (DOR)
Time Frame:Average 24 months
Safety Issue:
Description: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.
Measure:Progression Free Survival (PFS)
Time Frame:Average 24 months
Safety Issue:
Description: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.
Measure:Pharmacokinetics (PK) parameters, including but not limited to AUCtau, Cmin, Cmax, Tmax, accumulation ratio (Racc)
Time Frame:Average 24 months
Safety Issue:
Description: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.
Measure:Safety and tolerability of the triple combination of LEE011 +BYL719 with letrozole in patients previously treated with either doublet
Time Frame:Average 24 months
Safety Issue:
Description: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

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Novartis Pharmaceuticals

Trial Keywords

    <li>Hormone-receptor positiveli>

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