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

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2017 by Novartis
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT01872260
First received: May 30, 2013
Last updated: March 28, 2017
Last verified: March 2017
  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 225 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

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: No masking
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 ]
  • Safety and tolerability [ Time Frame: Average 18 months ]
    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:
  • 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 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

  • Plasma concentration-time profiles of LEE011, BYL719 and letrozole [ Time Frame: Average 24 months ]
    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 ]
    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 ]
    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 ]
    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.

  • Pharmacokinetics (PK) parameters, including but not limited to AUCtau, Cmin, Cmax, Tmax, accumulation ratio (Racc) [ Time Frame: Average 24 months ]
    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 ]
    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


Estimated Enrollment: 225
Actual Study Start Date: October 22, 2013
Estimated Study Completion Date: May 31, 2019
Estimated Primary Completion Date: May 31, 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: LEE011 + letrozole Arm 1
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) for Arms 1, 3. LEE011 28 days cycles (continuous) Arm 4.
Drug: Letrozole
Letrozole 2.5 mg/day
Experimental: BYL719 + letrozole Arm 2
BYL719 - daily (dose escalating) letrozole - 2.5 mg/day
Drug: Letrozole
Letrozole 2.5 mg/day
Drug: BYL719
BYL719 - 28 days cycle (continuous) for Arm 1; 3 and 4
Experimental: 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
Drug: LEE011
LEE011 - 28 day cycles (21 days followed by a 7 day break) for Arms 1, 3. LEE011 28 days cycles (continuous) Arm 4.
Drug: Letrozole
Letrozole 2.5 mg/day
Drug: BYL719
BYL719 - 28 days cycle (continuous) for Arm 1; 3 and 4
Experimental: LEE011+ BYL719+letrozole Arm 4
LEE011-daily (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) for Arms 1, 3. LEE011 28 days cycles (continuous) Arm 4.
Drug: Letrozole
Letrozole 2.5 mg/day
Drug: BYL719
BYL719 - 28 days cycle (continuous) for Arm 1; 3 and 4

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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
  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 +41613241111

  Show 30 Study Locations
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01872260     History of Changes
Other Study ID Numbers: CLEE011X2107
2013-001219-57 ( EudraCT Number )
Study First Received: May 30, 2013
Last Updated: March 28, 2017

Keywords provided by Novartis:
Hormone-receptor positive

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Letrozole
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

ClinicalTrials.gov processed this record on April 28, 2017