Phase Ib/II Trial of LEE011 With Everolimus (RAD001) and Exemestane in the Treatment of ER+ Her2- Advanced 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:
NCT01857193
First received: May 16, 2013
Last updated: September 25, 2014
Last verified: September 2014
  Purpose

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


Condition Intervention Phase
Breast Cancer
Drug: LEE011
Drug: Exemestane
Drug: Everolimus
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 Trial of LEE011 in Combination With Everolimus (RAD001) and Exemestane in the Treatment of Postmenopausal Women With Estrogen Receptor Positive, Her2- 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).

  • Progression Free Survival (PFS)- Phase II [ Time Frame: Approximately 26 months after FPFV ] [ Designated as safety issue: No ]
    PFS is defined as the date of randomization to the date of the first radiologically documented disease progression (PD) or death due to any cause per local investigator assessment as per RECIST.


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/II [ 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). Phase 2: Cycle 1/Days 1 and 15. Cycles 2, 3, 4, 5, and 6 on Day 1 of each cycle (if applicable).

  • Overall Response Rate (ORR)- Phase Ib and Phase II [ 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, Phase II [ 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.

  • Overall Survival (OS) - Phase II [ Time Frame: Approximately 26 months after FPFV ] [ 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.

  • Plasma concentration-time profiles: AUCtau - Phase Ib/II [ 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). Phase 2: Cycle 1/Days 1 and 15. Cycles 2, 3, 4, 5, and 6 on Day 1 of each cycle (if applicable).

  • Plasma concentration-time profiles - Cmin Phase Ib/II [ 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). Phase 2: Cycle 1/Days 1 and 15. Cycles 2, 3, 4, 5, and 6 on Day 1 of each cycle (if applicable).

  • Plasma concentration-time profiles - Cmax Phase Ib/II [ 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). Phase 2: Cycle 1/Days 1 and 15. Cycles 2, 3, 4, 5, and 6 on Day 1 of each cycle (if applicable).

  • Plasma concentration-time profiles - Tmax Phase Ib/II [ 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). Phase 2: Cycle 1/Days 1 and 15. Cycles 2, 3, 4, 5, and 6 on Day 1 of each cycle (if applicable).

  • Plasma concentration-time profiles - Racc Phase Ib/II [ 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). Phase 2: Cycle 1/Days 1 and 15. Cycles 2, 3, 4, 5, and 6 on Day 1 of each cycle (if applicable).

  • Disease Control Rate (DCR) - Phase Ib, Phase II [ 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: 185
Study Start Date: September 2013
Estimated Study Completion Date: May 2016
Estimated Primary Completion Date: May 2016 (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.
Active Comparator: R-E arm
everolimus + exemestane double combination
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

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 phase II part of the study will evaluate the triple combination of LEE011 + everolimus + exemestane and the double combination of LEE011 + exemestane in comparison to everolimus + exemestane. Safety, tolerability and PK (in a subset of patients) will also be assessed.

  Eligibility

Ages Eligible for Study:   18 Years and older
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 not amenable to curative treatment by surgery or radiotherapy
  • Histological or cytological confirmation of estrogen-receptor positive (ER+) breast cancer
  • A representative tumor specimen must be available for molecular testing. An archival tumor sample may be submitted; if one is not available, a newly obtained tumor specimen must be submitted instead
  • 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.

    • Exception for Phase Ib patients: measurable disease is not required

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 CDK4/6 inhibitors, exemestane or mTOR inhibitors*.
  • History of active or symptomatic brain or other CNS metastases.
  • Impaired cardiac function or clinically significant cardiac diseases, including any of the following:
  • Left ventricular ejection fraction (LVEF) < 45% or less than the institution lower limit of normal as determined by multiple gated acquisition scan (MUGA) or echocardiogram (ECHO)
  • Congenital long QT syndrome or family history of unexpected sudden cardiac death
  • QT corrected with Fredericia's (QTcF) >470 ms for females on screening ECG
  • Any other clinically significant heart disease such as angina pectoris, resting bradycardia, left bundle branch block, ventricular tachyarrhythmia, unstable atrial fibrillation, Right bundle branch block with left anterior hemiblock (bifascicular block), acute myocardial infarction or any heart disease that requires the use of a cardiac pacemaker or implantable cardioverter defibrillator ≤ 3 months prior to starting study drug.
  • Patients who are currently receiving treatment with agents that are known to cause QTc prolongation in humans.
  • Patients who are currently receiving treatment (within five days prior to randomization) with agents that are metabolized predominantly through CYP3A4 and that have a narrow therapeutic window. Agents that are known strong inducers or inhibitors CYP3A4 are prohibited (Refer to Appendix 4) * Exceptions for Phase Ib patients:

    1. Patients who received more than two prior lines of chemotherapy are eligible
    2. Patients who received CDK4/6 inhibitors, exemestane or mTOR inhibitors are eligible
  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

  Show 39 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: NCT01857193     History of Changes
Other Study ID Numbers: CLEE011X2106
Study First Received: May 16, 2013
Last Updated: September 25, 2014
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+; Her2-

Additional relevant MeSH terms:
Breast Neoplasms
Breast Diseases
Neoplasms
Neoplasms by Site
Skin Diseases
Everolimus
Exemestane
Sirolimus
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Antineoplastic Agents
Aromatase Inhibitors
Enzyme Inhibitors
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on October 23, 2014