Patient case: 73-year-old female with breast cancer; genetic feature: CDKN2A

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

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.

Eligibility: 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.

Relevance to patient case: not relevant