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

Breast Cancer Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01857193
• Other study ID #: CLEE011X2106
• Status: Completed
• Phase: Phase 1
• Start date: September 6, 2013
• Est. completion date: April 16, 2020

Study information

• Verified date: April 2021
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 132
• Est. completion date: April 16, 2020
• Est. primary completion date: March 14, 2018
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms

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

Locations

Country	Name	City	State
Belgium	Novartis Investigative Site	Wilrijk
France	Novartis Investigative Site	Saint Herblain cedex
Hong Kong	Novartis Investigative Site	Hong Kong
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Hospitalet de LLobregat	Catalunya
United States	Massachusetts General Hospital Onc Dept	Boston	Massachusetts
United States	Karmanos Cancer Institute Dept of Onc	Detroit	Michigan
United States	Highlands Oncology Group	Fayetteville	Arkansas
United States	University of Texas MD Anderson Cancer Center Onc Dept	Houston	Texas
United States	Sylvester Comprehensive Cancer Center Main Center	Miami	Florida
United States	Memorial Sloan Kettering Oncology Dept.	New York	New York
United States	Oregon Health and Science University SC-5	Portland	Oregon
United States	Northwest Medical Specialties	Tacoma	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Belgium,  France,  Hong Kong,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	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	Dose Escalation: Number of participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)	Adverse events were collected for approximately 6.5 years for dose escalation including the 30 days safety follow-up period.	Approximately 6.5 years after FPFV
Secondary	Dose Escalation and Expansion: Overall Response Rate (ORR)	Overall Response Rate (ORR) is defined as the proportion of participants with a best overall response of complete response or partial response.	Approximately 6.5 years for Dose Escalation and 4.5 years for Dose Espansion after FPFV
Secondary	Dose Escalation and Expansion: Disease Control Rate (DCR)	Disease Control Rate (DCR) is the proportion of patients with a best overall response of Complete Response or Partial Response or Stable Disease.	Approximately 6.5 years for Dose Escalation and 4.5 years for Dose expansion after FPFV
Secondary	Dose Escalation and Expansion: Clinical Benefit Rate (CBR)	Clinical Benefit Rate (CBR) is the Complete Response, Partial Response, or Stable Disease lasting 24 weeks or longer	Approximately 6.5 years for Dose Escalation and 4.5 years for Dose Espansion after FPFV
Secondary	Dose Expansion: Duration of Response (DOR)	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	Approximately 4.5 years for dose expansion after FPFV
Secondary	Dose Expansion: Progression Free Survival (PFS)	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.	Approximately 4.5 years after FPFV
Secondary	Dose Escalation: Pharmacokinetics (PK) parameter: AUC0-24h at Day 1 of Cycle 1	AUC0-24h is the area under the drug concentration-time curve during a dosing interval (mass x time x volume-1).	6 Cycles of treatment (28 day cycles): Cycle 1 Day 1
Secondary	Dose Escalation: Pharmacokinetics (PK) parameter: AUC0-24h at at Day 15 of Cycle 1	AUC0-24h is the area under the drug concentration-time curve during a dosing interval (mass x time x volume-1).	6 Cycles of treatment (28 day cycles): Cycle 1 Day 15
Secondary	Dose Escalation: Pharmacokinetics (PK) parameter: Cmax at Day 1 of Cycle 1	Cmax is the maximum observed drug concentration after drug administration (mass x volume-1).	6 Cycles of treatment (28 day cycles): Cycle 1 Day 1
Secondary	Dose Escalation: Pharmacokinetics (PK) parameter: Cmax at Day 15 of Cycle 1	Cmax is the maximum observed drug concentration after drug administration (mass x volume-1).	6 Cycles of treatment (28 day cycles): Cycle 1 Day 15
Secondary	Dose Escalation: Pharmacokinetics (PK) parameter: Tmax at Day 1 of Cycle 1	Tmax is the time to reach maximum plasma/blood/serum drug concentration (time).	6 Cycles of treatment (28 day cycles): Cycle 1 Day 1
Secondary	Dose Escalation: Pharmacokinetics (PK) parameter: Tmax at Day 15 of Cycle 1	Tmax is the time to reach maximum plasma/blood/serum drug concentration (time).	6 Cycles of treatment (28 day cycles): Cycle 15 Day 1
Secondary	Dose Escalation: Pharmacokinetics (PK) parameter: Racc at Day 15 of Cycle 1	Racc is the accumulation ratio calculated as AUCtau,ss / AUCtau,sd	6 Cycles of treatment (28 day cycles): Cycle 15 Day 1

External Links

•   Results for CLEE011X2106 from the Novartis Clinical Trials Website