A Phase II exploratory, open-label, single arm study of BYL719 monotherapy, a selective PI3K alpha inhibitor, in adult patients with advanced breast cancer progressing after first line therapy
- Conditions
- breast cancerCancer - Breast
- Registration Number
- ACTRN12615000850572
- Lead Sponsor
- Peter MacCallum Cancer Centre
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Completed
- Sex
- All
- Target Recruitment
- 45
Patients eligible for inclusion in this study have to meet all of the following criteria:
Males and females of any menopausal status
Patient has signed the Informed Consent Form (ICF) prior to any screening procedures being performed and is able to comply with protocol requirements
Age > or = 18 years old
Eastern Cooperative Oncology Group (ECOG) 0-2 that the investigator believes is stable at the time of screening
Patient has locally recurrent (incurable) or metastatic disease
Patient is able to swallow and retain oral medication
Known HER2 status (local lab) that is negative on IHC (IHC=0) and/or non-amplified.
Known estrogen receptor (ER) and progesterone receptor (PR) status (local lab)
Recent tumor tissue must be available from a metastatic or recurrent lesion for next generation sequencing targeted gene panel
Patients with TNBC disease (ER<1%, HER2-negative) should have documented progression on at least one line of prior systemic therapy in the metastatic setting or within 12 months of adjuvant therapy completion. There is no limit on previous therapies. There will be no molecular selection of these patients.
Patients with ER-positive (ER=1%, HER2-negative) disease should have documented progression on at least one line of prior systemic endocrine therapy in the metastatic setting. There is no limit on previous therapies. Prior everolimus is allowed.
*Patients are defined as PI3K abnormal” if they have documented gene mutation in AKT1,2,3,ALK, EGFR, ERBB2,3,4, HRAS, INPP4B, KRAS, NRAS, PTEN, PIK3CA, PIK3R1, PIK3R3, PTEN or gene amplification in EGFR, PIK3CA, PIK3R1 or loss in PTEN and INPP4B as per a next generation targeted gene sequencing panel
Measurable disease by RECIST v 1.1 criteria or non- measurable disease that is clinically evaluable (bone only disease allowed if evaluable)
Patient has adequate bone marrow and organ function assessed within 72 hours prior to first dose:
*Absolute neutrophil count (ANC) > or = 1.5 x 109/L
*Platelets > or = 100 x 109/L
*Hemoglobin (Hgb) > or = 9.0 g/dL
*Serum creatinine > or = 1.5 x ULN
*Total serum bilirubin > or = 1.5 x ULN (in patients with known Gilbert's syndrome, a total bilirubin < or = 3.0 x ULN with direct bilirubin < = 1.5 x ULN)
*AST and ALT < or = 2.5 x ULN (alternatively < 5 x ULN if evidence of liver metastases)
*Fasting blood glucose < = 140mg/dL or <= 7.8 mmol/
Patients eligible for this study must not meet any of the following criteria:
Patient has a primary CNS tumor or CNS tumor involvement.
*However patients with metastatic CNS tumors may participate in this study if the patient is:
*Four weeks from prior therapy completion (including radiation and surgery) to starting study treatment
*Clinically stable with respect to the CNS tumor at the time of screening
*Not receiving steroid therapy
Patient with diabetes mellitus (fasting glucose >120mg/dl or 6.7 mmol/L), or documented steroid-induced diabetes mellitus
Patient has a history of another malignancy within 2 years prior to starting study treatment, except for cured basal cell carcinoma of the skin or excised carcinoma in situ of the cervix.
Patient who has not recovered to grade 1 or better (except alopecia) from related side effects of any prior antineoplastic therapy
Patient who has had systemic chemotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to study entry.
Patient who has received radiotherapy < or = 4 weeks prior to starting study drugs, with exception of palliative radiotherapy (= 2 weeks prior to starting study drugs), who has not recovered from side effects of such therapy to baseline or Grade < or = 1 and/or from whom > or = 30% of the bone marrow was irradiated. Target lesions should not have had previous irradiation unless have progressed post treatment.
Patient who has undergone major surgery < or = 4 weeks prior to starting study treatment or who has not recovered from side effects of such procedure.
Patient has a clinically significant cardiac disease or impaired cardiac function, such as:
*Congestive heart failure (CHF) requiring treatment (New York Heart Association (NYHA) Grade > or = 2), left ventricular ejection fraction (LVEF) < 50% as determined by multi-gated acquisition (MUGA) scan or echocardiogram (ECHO)
*History or current evidence of clinically significant cardiac arrhythmias, atrial fibrillation and/or conduction abnormality, e.g. congenital long QT syndrome, high-grade/complete AV-blockage
*Acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass graft (CABG), coronary angioplasty, or stenting), < 3 months prior to screening
*QT interval adjusted according to Fredericia (QTcF) > 480 msec on screening ECG.
Patient who has any severe and/or uncontrolled medical conditions such as:
*Active or uncontrolled severe infection,
*Liver disease such as cirrhosis, decompensated liver disease, and chronic hepatitis (i.e. quantifiable HBV-DNA and/or positive HbsAg, quantifiable HCV-RNA)
*Known severely impaired lung function (spirometry and DLCO 50% or less of normal and O2 saturation 88% or less at rest on room air)
*Active, bleeding diathesis;
*Uncontrolled arterial hypertension defined by blood pressure > 140/100 mm Hg at rest (average of 3 consecutive readings 5 min apart)
*Chronic treatment with corticosteroids or other immunosuppressive agent
*Patient who is 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.
Patient who has participated in a prior investigational study within 30 days prior to enrollment.
Patient who is currently receiving treatment with drugs known to be moderate or strong inhibitors or induc
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method The primary endpoint in this trial is objective response rate (ORR). This is defined as the percentage of patients who have achieved a complete and partial response by RECIST v 1.1 per ER+/HER2- and TNBC cohorts separately.[Response is assessed every 2 cycles for the first 24 weeks and every 12 weeks after that or as clinically indicated.]
- Secondary Outcome Measures
Name Time Method Clinical Benefit Rate (CBR)- defined as Complete or partial responses according to RECIST 1.1 criteria or stable disease for 6 months or greater[Response is assessed every 2 cycles for the first 24 weeks and every 12 weeks after that or as clinically indicated.];Progression free survival- defined as the time from study entry until documented disease progression[Defined as the time from study entry until documented disease progression. Patients will be followed up for a maximum of 2 years.];Safety and tolerability of single agent BYL719[Safety and tolerability is assessed by incident of adverse events according to NCI CTCAE version 4 thoughout the study whilst on study medication. Visits to the oncologist are at the start of each cycle which is 4 weekly.]