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

NCT01857193 | Completed Phase 1 FDA Drug

• 1 other identifier: CLEE011X2106
• Study Type: interventional
• Target: 132
• Locations: 5 countries
• Sites: 13

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).

Conditions

Breast Cancer

Keywords

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

Outcome Measures

Primary Outcomes (2)

• Dose Escalation: Incidence of Dose Limiting Toxicity (DLT)

  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.

  At the end of Cycle 1 (each cycle is 28 days)

• Dose Expansion: Number of participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)

  Adverse events were collected for approximately 4.5 years for dose expansion including the 30 days safety follow-up period.

  Approximately 4.5 years after FPFV

Secondary Outcomes (13)

• Dose Escalation: Number of participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)

  Approximately 6.5 years after FPFV

• Dose Escalation and Expansion: Overall Response Rate (ORR)

  Approximately 6.5 years for Dose Escalation and 4.5 years for Dose Espansion after FPFV

• Dose Escalation and Expansion: Disease Control Rate (DCR)

  Approximately 6.5 years for Dose Escalation and 4.5 years for Dose expansion after FPFV

• Dose Escalation and Expansion: Clinical Benefit Rate (CBR)

  Approximately 6.5 years for Dose Escalation and 4.5 years for Dose Espansion after FPFV

• Dose Expansion: Duration of Response (DOR)

  Approximately 4.5 years for dose expansion after FPFV

Study Arms (2)

L-R-E arm

EXPERIMENTAL

Participants who took ribociclib (LEE011), everolimus (RAD001) and exemestane triple combination

Drug: ribociclib (LEE011); Drug: Exemestane; Drug: Everolimus (RAD001)

L-E arm

EXPERIMENTAL

Participants who ribociclib (LEE011) and exemestane double combination

Drug: ribociclib (LEE011); Drug: Exemestane

Interventions

ribociclib (LEE011) DRUG

LEE011 is taken orally once per day for 21 days of each 28 day cycle. LEE011 comes in 50 mg and 200 mg capsules.

Also known as: LEE011

L-E arm; L-R-E arm

Exemestane DRUG

Exemestane is taken orally once per day. Exemestane comes in 25 mg tablets.

L-E arm; L-R-E arm

Everolimus (RAD001) DRUG

Everolimus is taken orally once per day. Everolimus comes in 1 mg, 2.5 mg, 5mg, and 7.5 mg tablets

Also known as: RAD001

L-R-E arm

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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)
• Group 1 - Patients must not have received prior treatment with any CDK4/6 inhibitors

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (13)

Highlands Oncology Group

Fayetteville, Arkansas, 72703, United States

Location

Sylvester Comprehensive Cancer Center Main Center

Miami, Florida, 33136, United States

Location

Massachusetts General Hospital Onc Dept

Boston, Massachusetts, 02114, United States

Location

Karmanos Cancer Institute Dept of Onc

Detroit, Michigan, 48201, United States

Location

Memorial Sloan Kettering Oncology Dept.

New York, New York, 10017, United States

Location

Oregon Health and Science University SC-5

Portland, Oregon, 97239, United States

Location

University of Texas MD Anderson Cancer Center Onc Dept

Houston, Texas, 77030, United States

Location

Northwest Medical Specialties

Tacoma, Washington, 98405, United States

Location

Novartis Investigative Site

Wilrijk, 2610, Belgium

Location

Novartis Investigative Site

Saint-Herblain, 44805, France

Location

Novartis Investigative Site

Hong Kong, Hong Kong

Location

Novartis Investigative Site

Barcelona, Catalonia, 08035, Spain

Location

Novartis Investigative Site

L'Hospitalet de Llobregat, Catalonia, 08907, Spain

Location

Related Links

• Results for CLEE011X2106 from the Novartis Clinical Trials Website

MeSH Terms

Conditions

Breast Neoplasms

Interventions

ribociclib; exemestane; Everolimus

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Sirolimus; Macrolides; Lactones; Organic Chemicals

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 16, 2013
• First Posted: May 20, 2013
• Study Start: September 6, 2013
• Primary Completion: March 14, 2018
• Study Completion: April 16, 2020
• Last Updated: April 13, 2021

Record last verified: 2021-04

Data Sharing

• IPD Sharing: Will not share

Locations

BE (1); ES (2); US (8); FR (1); HK (1)