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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

Phase 1
18 Years
Open (Enrolling)
Metastatic Breast Cancer

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Trial Information

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

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
- INR Syndrome, a total bilirubin
- AST and ALT
- Fasting plasma glucose (FPG) diabetes, HgBA1c needs to be
- 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 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 (
- 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
investigational drugs should be discontinued 2 weeks prior to the first dose of study

- Prior therapy with a PI3K specific inhibitor. Prior use of Akt or mTOR inhibitors are

- Use of any of the drugs (prohibited concomitant medications)

- Patients with the following mood disorders as judged by the Investigator or a

- 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

- 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

- 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

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum Tolerated Dose of BKM120 or BEZ235 given in combination with endocrine therapy

Outcome Description:

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.

Outcome Time Frame:

at 4 weeks

Safety Issue:


Principal Investigator

Ingrid Mayer, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Vanderbilt-Ingram Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

November 2010

Completion Date:

December 2013

Related Keywords:

  • Metastatic Breast Cancer
  • Breast Neoplasms



University of Alabama Birmingham, Alabama  
Vanderbilt-Ingram Cancer Center Nashville, Tennessee  37232-6838
Columbia University Medical Center New York, New York  10032
Massachusetts General Hospital, Dana Farber Cancer Center Boston, Massachusetts  02114
Vanderbilt Cool Springs Nashville, Tennessee  37067
Vanderbilt Breast Center One Hundred Oaks Nashville, Tennessee  37204