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

• Status: Completed
• Trial end date: 2020-04-16
• Target enrollment: 0
• Participant gender: Female

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).

• Phase: Phase 1
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Novartis Pharmaceuticals
• Treatments: Everolimus; Exemestane; Hormones; Sirolimus

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.