None listed
Conditions
Brief summary
The primary purpose of this study is to determine whether BYL719, an oral selective PI3K alpha specific inhibitor, is a safe and effective drug treatment for adult patients with advanced breast cancer who have progressed after first line anti-cancer therapy. Patients who enrol in this study are required to have their breast cancer genetically characterised so we can understand the mutational profiles of their tumor. Who is it for? You may be eligible to join this study if you are over 18 years old, male or female, with advanced metastatic or locally recurring breast cancer which has progressed after first line therapy. It is a requirement of the study that some of your tumor tissue will evaluated in the laboratory for genetic alterations in their DNA. Regular blood tests will also be required to try to understand if we can detect the breast cancer's abnormal DNA in the blood. Study details All participants enrolled in this study will take the study drug, BYL719, which is an oral selective PI3K alpha specific inhibitor. Dose will commence at 350mg orally daily. This will involve taking tablets daily. Even though the study medication is taken daily, cycles are considered every 4 weeks. Visits to the Oncologist will be required every 4 weeks. Study medication will be continued until disease progression, unacceptable toxicity or requirement for new anti-cancer therapy. Participants will attend regular follow-up visits for up to 2 years in order to evaluate objective response rate, clinical benefit rate, progression free survival, safety and tolerability of treatment. Regular CT and/ or bone scans as well as blood tests will be performed. There will be two cohorts of participants involved in this study – those with advanced/ metastatic TNBC and those with advanced/metastatic ER+/HER2- breast cancers with a genetic mutation in the PI3K pathway. We plan to evaluate the efficacy and safety of BYL719 in these patients and associations with genetic features in order to try to identify biomarkers that can indicate those breast cancers more likely to respond to the study medication.
Interventions
BYL719 is administered at one tablet at 350mg orally daily. Each cycle is 4 weeks though the drug is administered continuously.
Patients will return drug bottles to monitor compliance.
Drug will be continued until disease progression, unacceptable toxicity or requirement for new anti-cancer therapy. The latter decision will be made by the consultant oncologist. Dose reductions may be considered if significant toxicity is experienced, as assessed by the consultant oncologist
Sponsors
Peter MacCallum Cancer Centre
Study design
Allocation
Non-randomised trial
Intervention model
Single group
Primary purpose
Treatment
Masking
Open (masking not used)
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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/L
Exclusion criteria
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 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; Patient with impaired gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral BYL719 (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection). Patient with known positive serology for human immunodeficiency virus (HIV). 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. Pregnant or nursing (lactating) woman, 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
Outcome results
None listed