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 January 2016 by Novartis
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT01857193
First received: May 16, 2013
Last updated: January 19, 2016
Last verified: January 2016

May 16, 2013
January 19, 2016
September 2013
November 2016   (final data collection date for primary outcome measure)
  • 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
  • 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.
Complete list of historical versions of study NCT01857193 on ClinicalTrials.gov Archive Site
  • 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.
  • 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. 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. 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. 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. 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. 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. 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.
Not Provided
Not Provided
 
Phase Ib Trial of LEE011 With Everolimus (RAD001) and Exemestane in the Treatment of Hormone Receptor Positive HER2 Negative Advanced Breast Cancer
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

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).

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.

Interventional
Phase 1
Phase 2
Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Breast Cancer
  • 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-R-E arm
    LEE011 + everolimus + exemestane triple combination
    Interventions:
    • Drug: LEE011
    • Drug: Exemestane
    • Drug: Everolimus
  • Experimental: L-E arm
    LEE011 + exemestane double combination
    Interventions:
    • Drug: LEE011
    • Drug: Exemestane
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
142
November 2016
November 2016   (final data collection date for primary outcome measure)

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.

Female
18 Years and older
No
Contact: Novartis Pharmaceuticals 1-888-669-6682
Contact: Novartis Pharmaceuticals
United States,   Belgium,   France,   Hong Kong,   Spain
Australia,   Germany,   Italy,   United Kingdom
 
NCT01857193
CLEE011X2106
No
Not Provided
Not Provided
Novartis ( Novartis Pharmaceuticals )
Novartis Pharmaceuticals
Not Provided
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
Novartis
January 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP