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

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2014 by Novartis
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT01872260
First received: May 30, 2013
Last updated: September 18, 2014
Last verified: September 2014
  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/II study. The Phase Ib portion of the study is a dose escalation to estimate the MTD and/or RP2D for three regimens: two double combinations, LEE011 with letrozole and BYL719 with letrozole, followed by the triple combination of LEE011 + BYL719 with letrozole.

The Phase Ib will be followed by a randomized Phase II study to assess the preliminary anti-tumor activity of the two double combination regimens (LEE011+letrozole and BYL719+letrozole) versus the triple combination (LEE011+BYL719 with letrozole) and to further evaluate their safety in patients with ER+/HER2- locally advanced or metastatic breast cancer.

Approximately 300 adult women with ER+/HER2- locally advanced or metastatic breast cancer will be enrolled.


Condition Intervention Phase
Breast Cancer
Drug: LEE011
Drug: Letrozole
Drug: BYL719
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase Ib/II, Multicenter Study of the Combination of LEE011 and BYL719 With Letrozole in Adult Patients With Advanced ER+ Breast Cancer

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • Incidence of Dose limiting toxicities (DLTs) - Phase lb only [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
  • Progression free survival (PFS) - Phase ll only [ Time Frame: Average 17 months ] [ Designated as safety issue: No ]
    PFS as per RECIST v1.1 (by local investigator assessment)


Secondary Outcome Measures:
  • 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 ] [ Designated as safety issue: Yes ]
    Adverse Events (AEs), serious AEs (SAEs), changes in hematology and chemistry values, vital signs, electrocardiograms (ECGs), dose interruptions, reductions and dose intensity

  • Plasma concentration-time profiles of LEE011, BYL719 and letrozole [ Time Frame: Average 24 months ] [ Designated as safety issue: No ]
    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.

  • Overall Response Rate (ORR) [ Time Frame: Average 24 months ] [ Designated as safety issue: No ]
    ORR is defined as the proportion of patients with a best overall response of complete response or partial response.

  • Duration of Response (DOR) [ Time Frame: Average 24 months ] [ Designated as safety issue: No ]
    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.

  • Progression Free Survival (PFS) [ Time Frame: Average 24 months ] [ Designated as safety issue: No ]
    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.

  • Overall Survival (OS) - Phase ll only [ Time Frame: Average 24 months ] [ Designated as safety issue: No ]
    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.

  • Pharmacokinetics (PK) parameters, including but not limited to AUCtau, Cmin, Cmax, Tmax, accumulation ratio (Racc) [ Time Frame: Average 24 months ] [ Designated as safety issue: No ]
    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.

  • Safety and tolerability of the triple combination of LEE011 +BYL719 with letrozole in patients previously treated with either doublet [ Time Frame: Average 24 months ] [ Designated as safety issue: Yes ]
    Adverse Events (AEs), serious AEs (SAEs), changes in hematology and chemistry values, vital signs, electrocardiograms (ECGs), dose interruptions, reductions and dose intensity


Estimated Enrollment: 300
Study Start Date: October 2013
Estimated Study Completion Date: May 2017
Estimated Primary Completion Date: May 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: LEE011 + letrozole
LEE011 - 28 day cycles (21 days followed by a 7 day break - dose escalating), letrozole - 2.5 mg/day
Drug: LEE011
LEE011 - 28 day cycles (21 days followed by a 7 day break)
Drug: Letrozole
Letrozole 2.5 mg/day
Experimental: BYL719 + letrozole
BYL719 - daily (dose escalating), letrozole - 2.5 mg/day
Drug: Letrozole
Letrozole 2.5 mg/day
Drug: BYL719
Daily
Experimental: LEE011 + BYL719 + letrozole
LEE011 - 28 day cycles (21 days followed by a 7 day break -dose escalating), BYL719 - daily (dose escalating), letrozole 2.5 mg/day
Drug: LEE011
LEE011 - 28 day cycles (21 days followed by a 7 day break)
Drug: Letrozole
Letrozole 2.5 mg/day
Drug: BYL719
Daily

Detailed Description:

This study will investigate the combination of LEE011 (CDK4/6i) and BYL719 (PI3K-alpha-i) with letrozole in patients with ER+/HER2- breast cancer (BC). In Phase Ib there are three dose escalation cohorts that will enroll sequentially. Arm 1 is the escalation of the double combination LEE011 + letrozole; Arm 2 is the dose escalation of the double combination of BYL719 + letrozole. The two double combinations will be followed by Arm 3 the dose escalation of the triple combination of LEE011 + BYL719 with letrozole. The three dose escalation cohorts will enroll patients with ER+/HER2- BC with any number of prior lines of endocrine therapy with up to one prior cytotoxic regimen in the metastatic or locally advanced setting. Pre- and post-treatment tumor biopsies are required in the three dose escalation cohorts. Once the RP2D/MTD of each doublet and triplet regimen is identified, dose expansion cohorts of these three combinations will open and will enroll patients to confirm the doses selected in each combination; archival tumor tissue is required in these cohorts, although pre- and post-biopsies in these expansion cohorts are optional. In the Phase Ib and Phase II portion, patients must not have progressed within 12 months of completing (neo)adjuvant treatment with letrozole or anastrozole. Patients who have progressed while on the Phase Ib escalation or expansion doublet treatment may have the option to receive treatment with the triplet combination once the RP2D of the triplet is established.

Once the dose is identified for the triple combination, the randomized, three-arm Phase II portion of the study will commence enrollment. This part of the trial will enroll in the first line setting in patients with ER+/HER2- BC and will randomize patients in a 1:1:1 ratio to either double regimen (LEE011+letrozole or BYL719 +letrozole) or the triple combination of LEE011+BYL719 with letrozole.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Postmenopausal, Estrogen-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: 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.
  • Phase II: No prior systemic treatment in the advanced (metastatic or locally advanced) setting.
  • Phase Ib dose expansions and Phase II: 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
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01872260

Contacts
Contact: Novartis Pharmaceuticals 1-888-669-6682
Contact: Novartis Pharmaceuticals

  Show 40 Study Locations
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

No publications provided

Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT01872260     History of Changes
Other Study ID Numbers: CLEE011X2107
Study First Received: May 30, 2013
Last Updated: September 18, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Novartis:
estrogen-receptor positive

Additional relevant MeSH terms:
Breast Neoplasms
Breast Diseases
Neoplasms
Neoplasms by Site
Skin Diseases
Letrozole
Antineoplastic Agents
Aromatase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on October 22, 2014