PhIb BKM120 or BEZ235+Endocrine Treatment in Post-Menopausal Patients With Hormone Receptor + Metastatic Breast Cancer

Study Overview
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Brief Summary
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This is an open-label phase Ib multi-institution trial that evaluates the safety profile/tolerability and preliminary anti-tumor effect of BKM120 (a PI3K inhibitor) and endocrine therapy combination and BEZ235 (a PI3K/ mTOR inhibitor) and endocrine therapy combination in postmenopausal patients with hormone receptor-positive metastatic breast cancer.

Official Title
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A Phase Ib Trial of BKM120 (a PI3K Inhibitor) or BEZ235 (a PI3K/mTOR Inhibitor) in Combination With Endocrine Therapy in Post-Menopausal Patients With Hormone Receptor-Positive Metastatic Breast Cancer

Conditions
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Metastatic Breast Cancer

Intervention / Treatment
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* Drug: BEZ235
* Drug: BKM 120
* Drug: Letrozole
* Drug: BKM120


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must provide informed written consent. Patients must be >/= 18 years of age. ECOG performance status 0-1. Clinical stage IV invasive mammary carcinoma, ER-positive and/or PR-positive by immunohistochemistry (IHC). Patients may have either measurable or nonmeasurable disease, both are allowed. Patients whose breast cancers are also HER2-overexpressed (IHC 3+ or FISHpositive)need to have had previous treatment exposure to trastuzumab (Herceptin®) Prior endocrine therapy (any) is allowed. There is not limit on lines of prior treatment in the metastatic setting. Patients must have available tissue (archived formalin-fixed paraffin embedded blocks (FFPB) or fresh frozen tissue from original diagnosis or metastatic setting) for correlative studies. Tissue needs to be submitted at the time of registration. Patients will not be able to start study drugs without tissue availability. Life expectancy >/= 6 months Patients must have adequate hematologic, hepatic, and renal function. All tests must be obtained less than 4 weeks from study entry. This includes: ANC >/= 1500/mm3 Platelet count >/= 100,000/mm3 HgB >/= 9 g/dL Creatinine </= 1.5X upper limits of normal INR </= 2Total serum bilirubin </= 1.5 x ULN (in patients with known Gilbert Syndrome, a total bilirubin </= 3.0 x ULN, with direct bilirubin </= 1.5 x ULN) AST and ALT </= 3 x ULN (or </= 5.0 x ULN if hepatic metastases are present) Fasting plasma glucose (FPG) </= 140 mg/dL [7.8 mmol/L]. For patients with known diabetes, HgBA1c needs to be </= 8% Patients must be able to swallow and retain oral medication. Post-menopausal female subjects should be defined prior to protocol enrollment by any of the following: Subjects at least 55 years of age Subjects under 55 years of age and amenorrheic for at least 12 months or follicle-stimulating hormone (FSH) values >/= 40 IU/L and estradiol levels </= 20 IU/L; Prior bilateral oophorectomy Prior radiation castration with amenorrhea for at least 6 months Current use of an LHRH agonist for more than 12 months Patients may have received radiation therapy to painful bone metastases or areas of impending bone fracture as long as radiation therapy is completed >/= 2 weeks prior to study entry. Patients who have received prior radiotherapy must have recovered from toxicity (</= grade 1) induced by this treatment Patients must be disease-free of prior invasive cancers for > 5 years with the exception of basal or squamous cancer of the skin or cervical carcinoma in situ. Patients must complete all screening assessments as outlined in the protocol. Exclusion Criteria: Locally recurrent resectable breast cancer. Any kind of malabsorption syndrome significantly affecting gastrointestinal function. Concurrent anti-cancer therapy (chemotherapy, radiation therapy, surgery, immunotherapy, hormonal therapy, biologic therapy) other than the ones specified in the protocol. Patients must have discontinued the above cancer therapies for 1 week prior to the first dose of study medication, as well as recovered from toxicity (to </= than grade 1, except for alopecia) induced by previous treatments. Any investigational drugs should be discontinued 2 weeks prior to the first dose of study medication. Prior therapy with a PI3K specific inhibitor. Prior use of Akt or mTOR inhibitors are allowed. Use of any of the drugs (prohibited concomitant medications) Patients with the following mood disorders as judged by the Investigator or a psychiatrist: medically documented history of or active major depressive episode, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of suicidal attempt or ideation, or homicidal ideation (immediate risk of doing harm to others) >/= CTCAE grade 3 anxiety Meets the cut-off score of >/= 10 in the PHQ-9 or a cut-off of >/= 15 in the GAD-7 mood scale, respectively, or selects a positive response of 1, 2, or 3 to question number 9 regarding potential for suicidal thoughts in the PHQ-9 (independent of the total score of the PHQ-9) will be excluded from the study unless overruled by the psychiatric assessment Uncontrolled intercurrent illness including, but not limited to: ongoing or active infection requiring parenteral antibiotics impairment of lung function (COPD > grade 2, lung conditions requiring oxygen therapy) symptomatic congestive heart failure (class III or IV of the New York Heart Association classification for heart disease) Left Ventricular Ejection Fraction (LVEF) < 50% unstable angina pectoris, angioplasty, stenting, or myocardial infarction within 6 months uncontrolled hypertension (systolic blood pressure >160 mm Hg or diastolic blood pressure > 100 mm Hg, found on two consecutive measurements separated by a 1 or 2-week period despite adequate medical support) clinically significant cardiac arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia that is symptomatic or requires treatment [National Cancer Institute -Common Terminology Criteria for Adverse Events, Version 4.0, grade 3] QTcF >/= 480 msec on screening EKG known history of QT/QTc prolongation or Torsades de Pointes (TdP) ST depression or elevation of ≥ 1.5 mm in 2 or more leads Diarrhea of any cause >/= CTCAE grade 2 psychiatric illness/social situations that would compromise patient safety or limit compliance with study requirements including maintenance of a compliance/pill diary patients with symptomatic brain metastases (patients with a history of brain metastases must be clinically stable for more than 4 weeks from completion of radiation treatment and 4 weeks from steroid tapering) patients with known history of chronic liver or renal failure patients with known history of chronic pancreatitis

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BEZ235 + Letrozole<br> | Drug: BEZ235<br>* Dose level 1: 400mg PO BID Dose level -1: 400mg PO in AM and 200mg PO in PM Dose level -2: 200mg PO BID<br>Drug: Letrozole<br>* All levels: 2.5mg/day PO<br>|
| Experimental: BKM120 + Letrozole<br> | Drug: BKM 120<br>* Dose Level 1: BKM120, 100 mg PO daily Dose level -1: BKM120, 80 mg PO daily Dose Level -2: BKM120, 60 mg PO daily<br>Drug: Letrozole<br>* All levels: 2.5mg/day PO<br>|
| Experimental: Intermittent BKM120 + Letrozole<br> | Drug: Letrozole<br>* All levels: 2.5mg/day PO<br>Drug: BKM120<br>* Dose Level 1: BKM120, 100 mg PO from Mondays through Fridays, weekly Dose level -1: BKM120, 80 mg PO from Mondays through Fridays, weekly Dose Level -2: BKM120, 60 mg PO from Mondays through Fridays, weekly<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose of BKM120 or BEZ235 given in combination with endocrine therapy | The maximum tolerated dose for each of the arms will be defined as the highest dose tested in which a DLT is experienced by 0 out of 3 or 1 out of 6 patients among the dose levels. The first cohort of patients (3 patients) in each arm will be started at dose level 1, and each patient will be observed for 4 weeks on the specified dose. | at 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients with Progression-free survival (PFS) | The overall PFS data will be estimated using the Kaplan-Meier method with the 95% confidence interval. The Cox proportional hazards model will be applied to investigate potential prognostic factors, such as disease free interval after completion of adjuvant endocrine therapy on the time to event data. The adjusted p-values as well as the adjusted 95% confidence intervals from the Cox model will be reported. | 4 weeks after off-treatment date | 
| Response Rate (RR) | All of the patients who met the eligibility criteria (with the possible exception of those who received no study medication) should be included in the main analysis of the response rate. | 4 weeks after off-treament date |