This is a Phase I study. The purpose of this study is to determine what is the best dose of
the study drug BYL719 in combination with the study drug LJM716 and traztuzumab (Herceptin®).
The study will test the safety of the combination of these three drugs, and to find out the
effects, good and/or bad, that these three drugs have on the patient and breast cancer.
- Age ≥ 18 years
- Willing and able to comply with scheduled visits, treatment plan and laboratory tests,
- Patients with a histologically or cytologically confirmed diagnosis of breast cancer.
Patients must have metastatic HER2+ disease.
- Documented HER2+ breast cancer defined as: 3+ by IHC or with amplification by in situ
hybridization with ratio ≥ 2.0 ; results from the local lab are acceptable.
Eligibility will not be affected by hormone receptor status.
- For the dose-escalation phase, a PIK3CA mutation is also required. MSKCC or outside
documentation is acceptable.
There is no upper limit on prior chemotherapy, targeted therapy, or endocrine therapy.
- HER2+ patients must have received pertuzumab and TDM-1 (ado-trastuzumab emtansine) prior
to trial enrollment. unless deemed ineligible for these therapies, and with the exceptions
- Patients with metastatic breast cancer who have not received prior pertuzumab are
eligible if: heavily pretreated prior to FDA approval of pertuzumab (6/8/2012) for
first-line treatment of HER2+ MBC
- Patients with metastatic breast cancer who have not received ado-trastuzumab emtansine
are eligible if: heavily pretreated prior to FDA approval of ado-trastuzumab emtansine
(2/22/2013) for the treatment of patients with HER2+ MBC who previously received
trastuzumab and a taxane separately or in combination - For the dose-escalation phase,
measurable or non-measurable disease per RECIST criteria v1.1 is permitted. For the
dose expansion phase, patients must have measurable disease by RECIST v1.1.
Patients must have archived tumor specimens available unless pre-treatment biopsy is being
performed. If pre-treatment biopsy is being performed, availability of archived specimen
must still be assessed and collected if available.
- ECOG performance status 0-1
- Adequate organ function, as defined by all of the following:
i. Hematologic parameters:
1. Absolute neutrophil count (ANC) ≥ 1500/μl (without growth factor support)
2. Platelets ≥ 100,000/μl (no platelet transfusion allowed within 2 weeks)
3. Hemoglobin ≥ 9.0 g/dl (may be reached by transfusion) ii. Liver function:
1. Serum bilirubin ≤ 1.5 x upper limit of normal (ULN) unless attributable to
2. AST ≤ 2.5 x ULN, or ≤ 5 x ULN if liver metastases are present
3. ALT ≤ 2.5 x ULN, or ≤ 5 x ULN if liver metastases are present iii. Kidney
1. Creatinine ≤ 1.5 x ULN iv. Coagulation function:
1. INR ≤ 1.5 v. Endocrine function:
1. Fasting plasma glucose <140 mg/dl (may be on antiglycemic agents other than
insulin). Fasting glucose measurement must be obtained at least 8 hours after the most
recent caloric intake.
- Ability to swallow oral medication
- Willing to discontinue all herbal preparations / medications at least 7 days prior to
the first dose of study drug and throughout the study. These include, but not limited
to, St. John's wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone
(DHEA), yohimbe, saw palmetto, and ginseng.
- Negative serum pregnancy test in women of childbearing potential within 2 weeks of
- Patients with untreated or symptomatic metastatic central nervous system (CNS)
disease. However patients with CNS involvement may participate if:
i. Clinically stable with respect to the CNS tumor at the time of screening and >4
weeks from prior therapy completion (including radiation and/or surgery) to the start
of study treatment ii. Not receiving steroid therapy iii. Not receiving enzyme
inducing anti-epileptic medications that were started for brain metastases (these
include carbamazepine, phenytoin, phenobarbital, primidone, oxcarbazepine, topiramate,
- Patients who have received chemotherapy within 3 weeks prior to the initiation of
study treatment, or endocrine therapy within 2 weeks prior to the initiation of study
- Current grade ≥ 1 toxicity (except alopecia) from prior therapy
- History of prior grade 3 or 4 hypersensitivity or any toxicity to trastuzumab that
warranted permanent cessation of this antibody
- Patients who have received radiotherapy ≤ 2 weeks prior to starting study treatment
and/or from whom ≥ 30% of the bone marrow was irradiated as determined by the
- Patients who have undergone major surgery ≤ 4 weeks prior to starting study treatment,
who have not recovered from side effects of such procedure
- Patient with diabetes mellitus that is suboptimally controlled (fasting plasma glucose
≥ 140, glycosylated hemoglobin >7.0) despite oral medication, insulin-dependent
diabetes, or documented steroid-induced diabetes mellitus
- Current need for chronic corticosteroid therapy or other immunosuppressive agents
(≥10mg of prednisone daily or an equivalent dose of other corticosteroid), or patients
who have received systemic corticosteroids ≤ 2 weeks prior to starting study drug
- Current therapeutic anticoagulation with warfarin (or coumarin derivatives) Prior
treatment with a PI3K or AKT inhibitor. Patients previously treated with an mTOR
inhibitor are eligible.
- Clinically significant cardiac disease or impaired cardiac function, such as:
i. Baseline LVEF < 50% on baseline echocardiogram or MUGA ii. Congestive heart failure
requiring treatment (e.g., New York Heart Association Class II, III or IV) within 6
months prior to screening iii. Acute coronary syndromes < 3 months prior to screening
(including myocardial infarction, unstable angina, coronary artery bypass graft,
coronary angioplasty, or stenting) iv. Uncontrolled arterial hypertension defined by
blood pressure > 140/100 mm Hg at rest (average of 3 consecutive readings) v. History
or current evidence of unstable, clinically significant cardiac arrhythmias vi.
Patients that require medications with a narrow therapeutic window vii. Clinically
significant conduction abnormality, e.g. congenital long QT syndrome,
high-Grade/complete AV-blockage viii. Corrected QT interval (QTc) > 480 msec on
- Patients who are currently receiving medication with a known risk of prolonging the QT
interval or inducing Torsades de Pointes (TdP) and the treatment cannot either be
discontinued or switched to a different medication prior to starting study drug
- Impaired gastrointestinal function or poorly controlled gastrointestinal disease that
may significantly alter the absorption of oral BYL719 (e.g. Crohn's disease,
ulcerative colitis, malabsorption syndrome, small bowel resection, uncontrolled nausea
or vomiting, or grade ≥ 3 diarrhea of any etiology) based on treating physician
- Patients may not have a "currently active" second malignancy other than non-melanoma
skin cancers. Patients are not considered to have a "currently active" malignancy if
they have completed therapy and are considered by their physician to be at less than
30% risk of relapse.
- Patients with known HIV or active infection with hepatitis C virus or Hepatitis B
virus (testing is not mandatory)
- Active infection or serious underlying medical condition that would impair the
patient's ability to receive protocol treatment
- Patients who are currently receiving treatment with drugs known to be moderate or
strong inhibitors or inducers of isoenzymes CYP34A or CYP2C8. The patient must have
discontinued moderate and strong inducers of both enzymes for at least one week and
must have discontinued strong and moderate inhibitors before the start of treatment.
Switching to a different medication prior to start of treatment is allowed; Refer to
- Patients who have received live attenuated vaccines within 1 week of start of study
drug and during the study. Patient should also avoid close contact with others who
have received live attenuated vaccines. Examples of live attenuated vaccines include
intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever,
varicella and TY21a typhoid vaccines.
- Patients who have participated in a prior investigational study within 3 weeks prior
to initiation of study treatment.
- Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a
female after conception and until the termination of gestation, confirmed by a
positive hCG laboratory test (> 5 mIU/mL).
- Patient who does not apply highly effective contraception during the study and through
the duration as defined below after the final dose of study treatment.
- Sexually active males should use a condom during intercourse while taking drug and for
8 weeks after the final dose of study treatment and should not father a child in this
period. A condom is required to be used also by vasectomized men in order to prevent
delivery of the drug via seminal fluid.
- Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, unless they are using highly effective methods of contraception
during dosing and 8 weeks after the final dose of study treatment. Highly effective
contraception methods include:
i. Total abstinence (when this is in line with the preferred and usual lifestyle of
the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal,
post-ovulation methods) and withdrawal are not acceptable methods of contraception ii.
Female sterilization (have had surgical bilateral oophorectomy with or without
hysterectomy) or tubal ligation at least six weeks before taking study treatment. In
case of oophorectomy alone, only when the reproductive status of the woman has been
confirmed by follow up hormone level assessment iii. Male partner sterilization (at
least 6 months prior to screening). For female subjects on the study the vasectomized
male partner should be the sole partner for that subject.
iv. Combination of the following methods:
1. Placement of an intrauterine device (IUD) or intrauterine system (IUS)
2. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault
caps) with spermicidal foam/gel/film/cream/vaginal suppository
Note: Post-menopausal women are allowed to participate in this study. Women are considered
post-menopausal and not of child bearing potential if they are:
- Aged ≥60;
- or aged < 60 and have had 12 months of natural (spontaneous, in the absence of
chemotherapy, tamoxifen, toremifene, or ovarian suppression) amenorrhea with and FSH
and estradiol in the postmenopausal range (serum FSH > 40 mIU/mL and estradiol <10
pg/mL or according to the postmenopausal range definition for the local laboratory
- or have had surgical bilateral oophorectomy (with or without hysterectomy) For women
with therapy-induced amenorrhea, oophorectomy or serial measurements of FSH and/or
estradiol are needed to ensure postmenopausal status. NOTE: Ovarian radiation or
treatment with a luteinizing hormone-releasing hormone (LH-RH) agonist (goserelin
acetate or leuprolide acetate) is not permitted for induction of ovarian suppression.