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Phase Ib Trial of LEE011 With Everolimus (RAD001) and Exemestane in the Treatment of Hormone Receptor Positive HER2 Negative Advanced Breast Cancer

This study is currently recruiting participants. (see Contacts and Locations)
Verified November 2016 by Novartis
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT01857193
First received: May 16, 2013
Last updated: November 11, 2016
Last verified: November 2016
  Purpose

Dose Escalation part of the study: To estimate the MTD(s) and/ or RP2D of LEE011 in combination with everolimus + exemestane, and LEE011 in combination with exemestane, and to characterize the safety and tolerability of the combinations of everolimus + exemestane + LEE011 and LEE011 + exemestane in patients with ER+ HER2- advanced breast cancer

Dose Expansion part of the study: To characterize the safety and tolerability of the triplet combination of LEE011 + everolimus + exemestane in patients naïve or refractory to CDK4/6 inhibitor based therapy, and the safety and tolerability of the doublet combination of LEE011 + exemestane in patients refractory to CDK4/6 inhibitor based therapy (except patients treated with prior LEE011 are not allowed in Group 3).


Condition Intervention Phase
Breast Cancer
Drug: LEE011
Drug: Exemestane
Drug: Everolimus
Phase 1

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 Trial of LEE011 in Combination With Everolimus (RAD001) and Exemestane in the Treatment of Postmenopausal Women With Hormone Receptor Positive, HER2 Negative Locally Advanced or Metastatic Breast Cancer

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • Incidence of dose limiting toxicity (DLT)- Phase Ib [ Time Frame: Day 1- Day 28 of Cycle 1 (28 day cycle) ] [ Designated as safety issue: Yes ]
    DLT is defined as treatment-related toxicity (classified according Common Toxicity Criteria for Adverse Events (CTCAE) Version 4) occurring during the first 28 treatment days and meeting specific protocol-predefined criteria. The information will be integrated in a Bayesian logistic regression model with overdose control to estimate the maximum tolerated dose (MTD).

  • Safety and tolerability during the dose expansion part of the study [ Time Frame: Approximately 26 months after FPFV ] [ Designated as safety issue: No ]
    As measured by the incidence and severity of adverse events and serious adverse events, clinical laboratory values, vital signs, ECGs, dose interruptions, dose reductions and dose intensity


Secondary Outcome Measures:
  • Incidence of adverse drug reactions [ Time Frame: Every cycle (1 cycle = 28 days) until study evlauation completion visit ] [ Designated as safety issue: Yes ]
    Incidence of adverse events (based on CTCAE Version 4) summarized by system organ class and/or preferred term, severity and relation to study treatment.

  • Incidence of serious adverse events [ Time Frame: every cycle (1cycle = 28 days) until study evaluation completion ] [ Designated as safety issue: Yes ]
    based on CTCAE Version 4- summarized by system organ class and/or preferred term, severity and relation to study treatment.

  • Plasma concentration-time profiles - Phase Ib [ Time Frame: 6 cycles of treatment (28-day cycles) ] [ Designated as safety issue: No ]
    Plasma PK parameters of LEE011 and everolimus and exemestane when given with food and fasted. Phase 1b: Cycle 1/Days 1, 2, 8, 15, 16, 21; Cycles 2, 3, 4, 5, and 6 on Day 1 of each cycle (if applicable).

  • Overall Response Rate (ORR)- Phase Ib [ Time Frame: Approximately 26 months after FPFV ] [ 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) - Phase Ib [ Time Frame: Approximately 26 months after FPFV ] [ 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: Approximately 26 months after FPFV ] [ Designated as safety issue: No ]
    PFS is defined as 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. If a patient has not had an event, progression-free survival is censored at the date of last adequate tumor assessment.

  • Plasma concentration-time profiles: AUCtau - Phase Ib [ Time Frame: 6 Cycles of treatment (28 day cycles) ] [ Designated as safety issue: No ]
    Plasma PK parameters of LEE011 and everolimus and exemestane when given with food and fasted. Phase 1b: Cycle 1/Days 1, 2, 8, 15, 16, 21; Cycles 2, 3, 4, 5, and 6 on Day 1 of each cycle (if applicable).

  • Plasma concentration-time profiles - Cmin Phase Ib [ Time Frame: 6 Cycles of treatment (28 day cycles) ] [ Designated as safety issue: No ]
    Plasma PK parameters of LEE011 and everolimus and exemestane when given with food and fasted. Phase 1b: Cycle 1/Days 1, 2, 8, 15, 16, 21; Cycles 2, 3, 4, 5, and 6 on Day 1 of each cycle (if applicable).

  • Plasma concentration-time profiles - Cmax Phase Ib [ Time Frame: 6 Cycles of treatment (28 day cycles) ] [ Designated as safety issue: No ]
    Plasma PK parameters of LEE011 and everolimus and exemestane when given with food and fasted. Phase 1b: Cycle 1/Days 1, 2, 8, 15, 16, 21; Cycles 2, 3, 4, 5, and 6 on Day 1 of each cycle (if applicable).

  • Plasma concentration-time profiles - Tmax Phase Ib [ Time Frame: 6 Cycles of treatment (28 day cycles) ] [ Designated as safety issue: No ]
    Plasma PK parameters of LEE011 and everolimus and exemestane when given with food and fasted. Phase 1b: Cycle 1/Days 1, 2, 8, 15, 16, 21; Cycles 2, 3, 4, 5, and 6 on Day 1 of each cycle (if applicable).

  • Plasma concentration-time profiles - Racc Phase Ib [ Time Frame: 6 Cycles of treatment (28 day cycles) ] [ Designated as safety issue: No ]
    Plasma PK parameters of LEE011 and everolimus and exemestane when given with food and fasted. Phase 1b: Cycle 1/Days 1, 2, 8, 15, 16, 21; Cycles 2, 3, 4, 5, and 6 on Day 1 of each cycle (if applicable).

  • Disease Control Rate (DCR) - Phase Ib [ Time Frame: Approximately 26 months after FPFV ] [ Designated as safety issue: No ]
    DCR is the proportion of patients with a best overall response of CR or PR or SD.


Estimated Enrollment: 142
Study Start Date: September 2013
Estimated Study Completion Date: January 2018
Estimated Primary Completion Date: January 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: L-R-E arm
LEE011 + everolimus + exemestane triple combination
Drug: LEE011
LEE011 is taken orally once per day for 21 days of each 28 day cycle. LEE011 comes in 50 mg and 200 mg capsules.
Drug: Exemestane
Exemestane is taken orally once per day. Exemestane comes in 25 mg tablets.
Drug: Everolimus
Everolimus is taken orally once per day. Everolimus comes in 1 mg, 2.5 mg, 5mg, and 7.5 mg tablets
Experimental: L-E arm
LEE011 + exemestane double combination
Drug: LEE011
LEE011 is taken orally once per day for 21 days of each 28 day cycle. LEE011 comes in 50 mg and 200 mg capsules.
Drug: Exemestane
Exemestane is taken orally once per day. Exemestane comes in 25 mg tablets.

Detailed Description:

The primary purpose of the phase Ib part of this study is to determine the maximum tolerated dose(s) (MTD(s)) and/or recommended phase II dose (RP2D) of LEE011 + everolimus + exemestane in patients with ER+ Her2- advanced breast cancer. This part of the study will also assess safety, tolerability, and PK of the LEE011 + exemestane, LEE011 + everolimus + exemestane combinations.

The Dose Expansion part of the study will evaluate the triple combination of LEE011 + everolimus + exemestane and the double combination of LEE011 + exemestane for safety and tolerability.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Adult women (≥ 18 years of age) with metastatic or locally advanced breast cancer
  • Histological or cytological confirmation of ER+ and/or PR+ breast cancer
  • A representative tumor specimen must be available for molecular testing.
  • Postmenopausal women. Postmenopausal status is defined either by:
  • Age ≥ 18 with prior bilateral oophorectomy
  • Age ≥ 60 years
  • Age <60 years with amenorrhea for at least 12 months and both follicle-stimulating hormone (FSH) and estradiol levels are in postmenopausal range (according to the local laboratory)
  • Recurrence while on, or within 12 months of end of adjuvant treatment with letrozole or anastrozole, or
  • Progression while on, or within one month of end of letrozole or anastrozole treatment for locally advanced or metastatic breast cancer.
  • Patients must have:

    • Measurable disease*: At least one lesion that can be accurately measured in at least one dimension ≥ 20 mm with conventional imaging techniques or ≥ 10 mm with spiral CT or MRI or
    • Bone lesions: lytic or mixed (lytic + sclerotic) in the absence of measurable disease as defined above.
  • ECOG Performance Status 0-1.
  • Fasting serum cholesterol ≤ 300 mg/dl or 7.75 mmol/L and fasting triglycerides ≤ 2.5 × ULN. In case one or both of these thresholds are exceeded, the patient can only be included after initiation of statin therapy and when the above mentioned values have been achieved
  • Standard 12-lead ECG values defined as the mean of the triplicate ECGs and assessed by the central laboratory.

    • QTcF interval at screening < 450 msec (using Fridericia's correction).
    • Resting heart rate 50-90 bpm

Exclusion Criteria:

  • HER2-overexpressing patients by local laboratory testing (IHC 3+ staining or in situ hybridization positive).
  • Patients who received more than one chemotherapy line for advanced breast cancer.
  • Previous treatment with exemestane or mTOR inhibitors* (Note:

Patients with disease refractory to prior LEE011 are excluded for dose expansion Group 3 only).

  • History of brain or other CNS metastases.
  • Clinically significant, uncontrolled heart disease and/or recent cardiac repolarization abnormality including any of the following:
  • History of myocardial infarction (MI), angina pectoris, symptomatic pericarditis, or coronary artery bypass graft (CABG) within 6 months prior to study entry
  • Documented cardiomyopathy
  • Left ventricular ejection fraction (LVEF) < 50% as determined by Multiple Gated acquisition scan (MUGA) or echocardiogram (ECHO)
  • Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome, and etc.
  • Clinically significant cardiac arrhythmias, complete left bundle branch block, high-grade AV block
  • Systolic Blood Pressure (SBP) >160 or <90 mmHg
  • Patients who are currently receiving treatment with agents that are known to cause QTc prolongation in humans (Refer to Appendix 3)
  • Patients who are currently receiving treatment (within 7 days prior to starting study treatment) with strong and moderate inhibitors or inducers of CYP3A4/5, substrates of CYP3A4/5 with a narrow therapeutic index or Herbal preparations/medications (Refer to Section 6.4 and Appendix 3)

Inclusion Criteria Exceptions for Phase Ib Dose Expansion patients:

Dose Expansion part of the study has 3 groups, following are the Inclusion Criteria exceptions for these 3 groups

  1. Group 1 - Patients must not have received prior treatment with any CDK4/6 inhibitors
  2. Group 2 - Patients must have disease progression while on or within one month after CDK4/6 inhibitor based therapy
  3. Group 3 - Patients must have disease progression while on or within one month after CDK4/6 inhibitor based therapy (except those patients who received prior LEE011 based therapy).

Other protocol-defined Inclusion/Exclusion 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: NCT01857193

Contacts
Contact: Novartis Pharmaceuticals 1-888-669-6682
Contact: Novartis Pharmaceuticals +41613241111

Locations
United States, Arkansas
Highlands Oncology Group Dept of Highlands Oncology Grp Recruiting
Fayetteville, Arkansas, United States, 72703
Contact: Amanda Nickel    +1 479 872 8130    anickel@hogonc.com   
Principal Investigator: Joseph Thaddeus Beck         
United States, Florida
Sylvester Comprehensive Cancer Center Main Center Recruiting
Miami, Florida, United States, 33136
Contact: Kristen Englund    305-243-9899    k.englund@med.miami.edu   
Principal Investigator: Aruna Mani         
United States, Illinois
Oncology Specialists, SC Dept.of Oncology Specialists Recruiting
Park Ridge, Illinois, United States, 60068-0736
Contact: Milenna Undda    847-410-0660    mundda@oncmed.net   
Principal Investigator: Sigrun Hallmeyer         
United States, Massachusetts
Massachusetts General Hospital Onc Dept Recruiting
Boston, Massachusetts, United States, 02114
Contact: Kathleen E. Harrington    617-643-2208    eharrington@mgh.harvard.edu   
Principal Investigator: Aditya Bardia         
United States, Michigan
Karmanos Cancer Institute Dept of Onc Recruiting
Detroit, Michigan, United States, 48201
Contact: Barbara the Ivers    +1 313 576 8096    iversb@karmanos.org   
Principal Investigator: Amy M Weise         
United States, Missouri
St. Luke's Cancer Institute Recruiting
Kansas City, Missouri, United States, 64111
Contact: Beth Humphrey    816-932-5793    bhumphrey@saint-lukes.org   
Principal Investigator: Timothy Pluard         
United States, New York
Memorial Sloan Kettering Cancer Center Oncology Dept. Recruiting
NY, New York, United States, 10065
Contact: Alan Lau    646-888-5341    laura1@mskcc.org   
Principal Investigator: Shanu N. Modi         
United States, Oregon
Oregon Health & Science University SC-5 Recruiting
Portland, Oregon, United States, 97239
Contact: Wendy Stitzel    503-418-9736    stitzelw@ohsu.edu   
Principal Investigator: Jacqueline Vuky         
United States, Texas
University of Texas/MD Anderson Cancer Center Onc Dept Recruiting
Houston, Texas, United States, 77030-4009
Contact: Daniela N. Westerhold    713-792-2921    diwesterhold@mdanderson.org   
Principal Investigator: Marianna Chavez-MacGregor         
United States, Washington
Northwest Medical Specialties Recruiting
Tacoma, Washington, United States, 98405
Contact: Sheila Marsh    253-428-8756    smarsh@nwmsonline.com   
Principal Investigator: Jorge M. Chaves         
Belgium
Novartis Investigative Site Recruiting
Wilrijk, Belgium, 2610
France
Novartis Investigative Site Recruiting
Saint Herblain cedex, France, 44805
Hong Kong
Novartis Investigative Site Recruiting
Hong Kong, Hong Kong
Italy
Novartis Investigative Site Recruiting
Cona, FE, Italy, 44100
Novartis Investigative Site Recruiting
Padova, PD, Italy, 35100
Spain
Novartis Investigative Site Recruiting
Barcelona, Catalunya, Spain, 08035
Novartis Investigative Site Recruiting
Hospitalet de LLobregat, Catalunya, Spain, 08907
Novartis Investigative Site Recruiting
Madrid, Spain, 28041
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01857193     History of Changes
Other Study ID Numbers: CLEE011X2106 
Study First Received: May 16, 2013
Last Updated: November 11, 2016
Health Authority: United States: Food and Drug Administration
Australia: Department of Health and Ageing Therapeutic Goods Administration
Belgium: Federal Agency for Medicinal Products and Health Products
Germany: Federal Institute for Drugs and Medical Devices
Hong Kong: Department of Health
Spain: Agencia Española de Medicamentos y Productos Sanitarios

Keywords provided by Novartis:
Open label; dose escalation; ER+; LEE011; CDK4/6; everolimus; advanced breast cancer; mTOR; HR positive; HER2 negative

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Hormones
Exemestane
Everolimus
Sirolimus
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Aromatase Inhibitors
Steroid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Estrogen Antagonists
Hormone Antagonists

ClinicalTrials.gov processed this record on December 09, 2016