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A Phase I Trial of BYL719 Plus Letrozole or Exemestane for Patients With Hormone-Receptor Positive Locally-Advanced Unresectable or Metastatic Breast Cancer


Phase 1
18 Years
N/A
Open (Enrolling)
Female
Metastatic or Locally-advanced Unresectable Breast Cancer

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Trial Information

A Phase I Trial of BYL719 Plus Letrozole or Exemestane for Patients With Hormone-Receptor Positive Locally-Advanced Unresectable or Metastatic Breast Cancer


Inclusion Criteria:



- Women age ≥ 18 years

- Willing and able to comply with scheduled visits, treatment plan and laboratory tests

- Willing and able to consent for biopsy of locally-advanced or metastatic breast
cancer prior to treatment

- Metastatic or locally-advanced unresectable breast cancer (includes metastatic or
locally-advanced unresectable breast cancer which is diagnosed while on adjuvant
letrozole or exemestane)

- Histologically documented HR+ breast cancer in either the primary or metastatic
setting, as defined by ER or PR ≥ 1%; results from the local lab are acceptable.
Eligibility will not be affected by HER2 status.

- The most recent treatment prior to enrollment must be one of the following (duration
of treatment ≥4 weeks), and must have been adequately tolerated according the
treating physician's judgment:

- Letrozole

- Exemestane

- Exemestane + everolimus (everolimus must be discontinued for ≥ 3 weeks prior to
starting study treatment)

- Letrozole or exemestane in combination with an experimental agent(s) on a clinical
trial, provided that the experimental agent(s) is not a PI3K inhibitor or AKT
inhibitor (experimental agent(s) must be discontinued for ≥ 3 weeks prior to starting
study treatment)

- Any number of prior endocrine therapies (including tamoxifen, fulvestrant and/or
aromatase inhibitors in either the adjuvant or metastatic setting) and any number of
prior chemotherapy regimens. Anti-cancer systemic therapy, such as chemotherapy or
biologics or endocrine therapy, other than the AI, must be discontinued for ≥ 3 weeks
prior to starting study treatment.

- For the dose-finding phase, patients may have stable disease OR progression of
disease on the most recent treatment. For the expansion phase, patients must have
progression of disease on the most recent treatment. Progression of disease is
defined as new or worsening disease on objective imaging. Progression of disease
includes recurrence diagnosed while on adjuvant letrozole or exemestane.

- Postmenopausal women, as defined by one of the following (estradiol assay cutoff
takes into account that the patient is on aromatase inhibitor therapy):

- Age ≥ 55 years and one year or more of amenorrhea

- Age < 55 years and one year or more of amenorrhea, with an estradiol assay within the
post-menopausal range

- Age < 55 years with prior hysterectomy but intact ovaries, with an estradiol assay
within the post-menopausal range

- Surgical menopause with bilateral oophorectomy

- Ovarian suppression with a LH-RH agonist, with an estradiol assay within the
post-menopausal range Measurable or non-measurable disease per RECIST criteria v1.1

- ECOG performance status 0-1

- Adequate organ function, as defined by all of the following:

Hematologic parameters:

- Absolute neutrophil count (ANC) ≥ 1500/μl (without growth factor support)

- Platelets ≥ 100,000/μl (no transfusion allowed within 2 weeks)

- Hemoglobin ≥ 9.0 g/dl (may be reached by transfusion)

- Liver function:

- Serum bilirubin ≤ 1.5 x upper limit of normal (ULN) unless attributable to Gilbert's
syndrome

- AST ≤ 2.5 x ULN, or ≤ 5 x ULN if liver metastases are present

- ALT ≤ 2.5 x ULN, or ≤ 5 x ULN if liver metastases are present

Kidney function:

- Creatinine ≤ 1.5 ULN

- Endocrine function:

- 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.

Exclusion Criteria:

- Pregnant patients or women who are breast-feeding (patients must be postmenopausal,
see Section 6.1.9)

Patients with central nervous system (CNS) involvement may participate if:

- 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

- Not receiving steroid therapy

- Not receiving enzyme inducing anti-epileptic medications that were started for brain
metastases (these include carbamazepine, phenytoin, phenobarbital, primidone,
oxcarbazepine, topiramate, and vigabatrin) Prior PI3K inhibitor or AKT inhibitor
(patients previously treated with everolimus are eligible, see rationale in Section
3.6)

- History of toxicity to the most recent AI (letrozole or exemestane) that warrants
cessation of the AI

- Patients who have received radiotherapy ≤ 2 weeks prior to starting study treatment

- Patients who have undergone major surgery ≤ 4 weeks prior to starting study
treatment, who have not recovered from side effects of such procedure

- Uncontrolled diabetes (as defined by fasting glucose ≥ 140mg/dL) and/or
insulin-dependent diabetes. Fasting glucose measurement must be obtained at least 8
hours after the most recent caloric intake. Patients currently requiring the use of
antiglycemic agents (other than insulin) may be enrolled if fasting glucose
<140mg/dL.

- Current need for chronic corticosteroid therapy (≥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) Active
infection or serious underlying medical condition that would impair the patient's
ability to receive protocol treatment

- Clinically significant cardiac disease or impaired cardiac function, such as:

- Congestive heart failure requiring treatment (e.g., New York Heart Association Class
II, III or IV) Acute coronary syndromes < 3 months prior to screening (including
myocardial infarction, unstable angina, coronary artery bypass graft, coronary
angioplasty, or stenting)

- Uncontrolled arterial hypertension defined by blood pressure > 140/100 mm Hg at rest
(average of 3 consecutive readings)

- History or current evidence of unstable, clinically significant cardiac arrhythmias
or patients that require medications with a narrow therapeutic window, atrial
fibrillation and/or conduction abnormality, e.g. congenital long QT syndrome,
high-Grade/complete AV-blockage

- Corrected QT interval (QTc) > 480 msec on screening ECG 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 treatment (see Section 9.6.3
and Appendix F)

- 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 assessment

- 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.

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

phase II dose of BYL719

Outcome Description:

Three patients will be enrolled onto Cohort 0 at the starting BYL719 dose of 300mg daily. All patients within a cohort will be observed for toxicity for one cycle (28 days) prior to entering additional patients.

Outcome Time Frame:

2 years

Safety Issue:

No

Principal Investigator

Maura Dickler, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Memorial Sloan-Kettering Cancer Center

Authority:

United States: Food and Drug Administration

Study ID:

13-027

NCT ID:

NCT01870505

Start Date:

May 2013

Completion Date:

May 2015

Related Keywords:

  • Metastatic or Locally-advanced Unresectable Breast Cancer
  • BYL719
  • Letrozole
  • Exemestane
  • 13-027
  • Breast Neoplasms

Name

Location

Memorial Sloan-Kettering Cancer CenterNew York, New York  10021