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

• ClinicalTrials.gov Identifier: NCT01857193
• Recruitment Status: Completed
• First Posted: May 20, 2013
• Last Update Posted: April 13, 2021
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: May 16, 2013
• First Posted Date: May 20, 2013
• Last Update Posted Date: April 13, 2021
• Actual Study Start Date: September 6, 2013
• Actual Primary Completion Date: March 14, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 8, 2021)

• Dose Escalation: Incidence of Dose Limiting Toxicity (DLT) [ Time Frame: At the end of Cycle 1 (each cycle is 28 days) ]
  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.
• Dose Expansion: Number of participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Approximately 4.5 years after FPFV ]
  Adverse events were collected for approximately 4.5 years for dose expansion including the 30 days safety follow-up period.

Original Primary Outcome Measures (submitted: May 16, 2013)

• Incidence of dose limiting toxicity (DLT)- Phase Ib [ Time Frame: Day 1- Day 28 of Cycle 1 (28 day cycle) ]
  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 ]
  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.

Current Secondary Outcome Measures (submitted: April 8, 2021)

• Dose Escalation: Number of participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Approximately 6.5 years after FPFV ]
  Adverse events were collected for approximately 6.5 years for dose escalation including the 30 days safety follow-up period.
• Dose Escalation and Expansion: Overall Response Rate (ORR) [ Time Frame: Approximately 6.5 years for Dose Escalation and 4.5 years for Dose Espansion after FPFV ]
  Overall Response Rate (ORR) is defined as the proportion of participants with a best overall response of complete response or partial response.
• Dose Escalation and Expansion: Disease Control Rate (DCR) [ Time Frame: Approximately 6.5 years for Dose Escalation and 4.5 years for Dose expansion after FPFV ]
  Disease Control Rate (DCR) is the proportion of patients with a best overall response of Complete Response or Partial Response or Stable Disease.
• Dose Escalation and Expansion: Clinical Benefit Rate (CBR) [ Time Frame: Approximately 6.5 years for Dose Escalation and 4.5 years for Dose Espansion after FPFV ]
  Clinical Benefit Rate (CBR) is the Complete Response, Partial Response, or Stable Disease lasting 24 weeks or longer
• Dose Expansion: Duration of Response (DOR) [ Time Frame: Approximately 4.5 years for dose expansion after FPFV ]
  Duration of Response (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. The DOR is not applicable as none of the patients in the expansion treatment groups (triplet treatment naive, triplet treatment refractory and doublet treatment refractory) had a CR or PR
• Dose Expansion: Progression Free Survival (PFS) [ Time Frame: Approximately 4.5 years after FPFV ]
  Progression Free Survival (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.
• Dose Escalation: Pharmacokinetics (PK) parameter: AUC0-24h at Day 1 of Cycle 1 [ Time Frame: 6 Cycles of treatment (28 day cycles): Cycle 1 Day 1 ]
  AUC0-24h is the area under the drug concentration-time curve during a dosing interval (mass x time x volume-1).
• Dose Escalation: Pharmacokinetics (PK) parameter: AUC0-24h at at Day 15 of Cycle 1 [ Time Frame: 6 Cycles of treatment (28 day cycles): Cycle 1 Day 15 ]
  AUC0-24h is the area under the drug concentration-time curve during a dosing interval (mass x time x volume-1).
• Dose Escalation: Pharmacokinetics (PK) parameter: Cmax at Day 1 of Cycle 1 [ Time Frame: 6 Cycles of treatment (28 day cycles): Cycle 1 Day 1 ]
  Cmax is the maximum observed drug concentration after drug administration (mass x volume-1).
• Dose Escalation: Pharmacokinetics (PK) parameter: Cmax at Day 15 of Cycle 1 [ Time Frame: 6 Cycles of treatment (28 day cycles): Cycle 1 Day 15 ]
  Cmax is the maximum observed drug concentration after drug administration (mass x volume-1).
• Dose Escalation: Pharmacokinetics (PK) parameter: Tmax at Day 1 of Cycle 1 [ Time Frame: 6 Cycles of treatment (28 day cycles): Cycle 1 Day 1 ]
  Tmax is the time to reach maximum plasma/blood/serum drug concentration (time).
• Dose Escalation: Pharmacokinetics (PK) parameter: Tmax at Day 15 of Cycle 1 [ Time Frame: 6 Cycles of treatment (28 day cycles): Cycle 15 Day 1 ]
  Tmax is the time to reach maximum plasma/blood/serum drug concentration (time).
• Dose Escalation: Pharmacokinetics (PK) parameter: Racc at Day 15 of Cycle 1 [ Time Frame: 6 Cycles of treatment (28 day cycles): Cycle 15 Day 1 ]
  Racc is the accumulation ratio calculated as AUCtau,ss / AUCtau,sd

Original Secondary Outcome Measures (submitted: May 16, 2013)

• Incidence of adverse drug reactions [ Time Frame: Every cycle (1 cycle = 28 days) until study evlauation completion visit ]
  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 ]
  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) ]
  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 ]
  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 ]
  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 ]
  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) ]
  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) ]
  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) ]
  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) ]
  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) ]
  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 ]
  DCR is the proportion of patients with a best overall response of CR or PR or SD.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

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

Brief Summary

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).

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.

• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Breast Cancer

Intervention

• Drug: ribociclib (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.
  Other Name: LEE011
• Drug: Exemestane
  Exemestane is taken orally once per day. Exemestane comes in 25 mg tablets.
• Drug: Everolimus (RAD001)
  Everolimus is taken orally once per day. Everolimus comes in 1 mg, 2.5 mg, 5mg, and 7.5 mg tablets
  Other Name: RAD001

Study Arms

• Experimental: L-R-E arm
  Participants who took ribociclib (LEE011), everolimus (RAD001) and exemestane triple combination
  Interventions:

  • Drug: ribociclib (LEE011)
  • Drug: Exemestane
  • Drug: Everolimus (RAD001)
• Experimental: L-E arm
  Participants who ribociclib (LEE011) and exemestane double combination
  Interventions:

  • Drug: ribociclib (LEE011)
  • Drug: Exemestane

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: November 9, 2017): 132
• Original Estimated Enrollment (submitted: May 16, 2013): 185
• Actual Study Completion Date: April 16, 2020
• Actual Primary Completion Date: March 14, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Adult women (≥ 18 years of age) with metastatic or locally advanced breast cancer
• Histological or cytological confirmation of ER+ breast cancer in dose escalation and HR+ breast cancer in dose expansion
• 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
• 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.

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Belgium, France, Hong Kong, Spain, United States
• Removed Location Countries: Australia, Germany, Italy, United Kingdom

Administrative Information

• NCT Number: NCT01857193
• Other Study ID Numbers: CLEE011X2106
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Original Responsible Party: Same as current
• Current Study Sponsor: Novartis Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

• PRS Account: Novartis
• Verification Date: April 2021