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Phosphatidylinositol 3-kinase (PI3K) Alpha iNhibition In Advanced Breast Cancer (PIKNIC)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02506556
Recruitment Status : Unknown
Verified July 2015 by Peter MacCallum Cancer Centre, Australia.
Recruitment status was:  Recruiting
First Posted : July 23, 2015
Last Update Posted : July 23, 2015
Novartis Pharmaceuticals
Information provided by (Responsible Party):
Peter MacCallum Cancer Centre, Australia

Tracking Information
First Submitted Date  ICMJE July 22, 2015
First Posted Date  ICMJE July 23, 2015
Last Update Posted Date July 23, 2015
Study Start Date  ICMJE July 2015
Estimated Primary Completion Date December 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 22, 2015)
Objective response rate [ Time Frame: > 6 months ]
The percentage of patients who achieve a complete or partial response as defined by RECIST 1.1 criteria.
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: July 22, 2015)
  • Clinical Benefit Rate [ Time Frame: > 6 months ]
    Defined as Complete or partial responses according to RECIST 1.1 criteria or stable disease for 6 months or greater
  • Progression free survival [ Time Frame: > 6 months ]
    Defined as the time from study entry until documented disease progression
  • Safety and tolerability [ Time Frame: > 6 months ]
    Safety and tolerability will be described using frequency of significant treatment related adverse events (AEs) using CTCAE 4.0 grade ≥3, all Serious Adverse Events and SUSARs. Safety analysis will include all patients who have received at least one dose of the drug and will be evaluated descriptively
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Phosphatidylinositol 3-kinase (PI3K) Alpha iNhibition In Advanced Breast Cancer
Official Title  ICMJE A Phase II Exploratory, Open-label, Single Arm Study of BYL719 Monotherapy, a Selective Phosphatidylinositol 3-kinase (PI3K) Alpha Inhibitor, in Adult Patients With Advanced Breast Cancer Progressing After First Line Therapy.
Brief Summary This is a phase II, exploratory, open-label, single arm study of BYL719 monotherapy, a selective phosphatidylinositol 3-kinase (PI3K) alpha inhibitor, in adult patients with advanced metastatic breast cancer progressing after first line therapy. Patients with advanced hormone receptor positive tumors will be required to have an alteration of the PI3K pathway. Those patients with advanced triple negative breast cancers are genetically unselected for this study.
Detailed Description The technology now exists to advance the concept of personalized medicine for all cancer patients. The advent of next generation sequencing can allow us to potentially characterize each individual's tumor for oncogenic driver mutations. It is unknown at present if a wide range of mutations in the phosphatidylinositol 3-kinase (PI3K) pathway predict for responsiveness to a PI3K inhibitor as would be expected in a situation of "oncogene addiction". In this study, we plan to explore two cohorts of patients and response to BYL719, an oral selective PI3K-alpha inhibitor: 1. Metastatic triple negative breast cancer (triple negative breast cancer [TNBC] which is defined as ER-/HER2-) and 2. PI3K pathway abnormal metastatic luminal breast cancer (ER+/HER2-). Both cohorts are eligible for this study after progression after standard first line therapy. In recent large sequencing efforts, for example The Cancer Genome Atlas [TCGA], primary breast cancers were found to have a large number of Pi3K pathway abnormalities- in TNBC there was a high rate of genetic abnormalities in the Pi3K pathway (combined mutations, amplifications and deletions in nearly 100% of TNBC)- as well as in ER+/HER2- disease. Therefore, in this study we plan to study responses to BYL719 and associations with genetic features that could signify Pi3K pathway activation in a cohort of fully molecular- characterized metastatic breast cancers in order to identify biomarkers of response to selective PI3K alpha inhibition in breast cancer.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Metastatic Breast Cancer
Intervention  ICMJE Drug: BYl719

Treatment: BYL719 350mg orally daily Treatment will be given daily until progression, undue adverse events or withdrawal of consent.

Dose reductions (two levels) are allowed. Each cycle is 28 days

Study Arms  ICMJE Experimental: experimental
BYL719 350 mg orally daily until progression, undue adverse events or withdrawal of consent.
Intervention: Drug: BYl719
Publications *

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Unknown status
Estimated Enrollment  ICMJE
 (submitted: July 22, 2015)
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2018
Estimated Primary Completion Date December 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 ≥ 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) ≥ 1.5 x 10^9/L
  • Platelets ≥ 100 x 10^9/L
  • Hemoglobin (Hgb) ≥ 9.0 g/dL
  • Serum creatinine ≤ 1.5 x ULN
  • Total serum bilirubin ≤ 1.5 x ULN (in patients with known Gilbert's syndrome, a total bilirubin ≤ 3.0 x ULN with direct bilirubin ≤ 1.5 x ULN)
  • AST and ALT ≤ 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 ≤ 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 ≤ 1 and/or from whom ≥ 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 ≤ 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 ≥ 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; Refer to Appendix 1
  • 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT02506556
Other Study ID Numbers  ICMJE LL14/02
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Peter MacCallum Cancer Centre, Australia
Study Sponsor  ICMJE Peter MacCallum Cancer Centre, Australia
Collaborators  ICMJE Novartis Pharmaceuticals
Investigators  ICMJE
Study Chair: Sherene Loi, MD,PhD Peter MacCallum Cancer Centre, East Melbourne, Victoria, AUSTRALIA
PRS Account Peter MacCallum Cancer Centre, Australia
Verification Date July 2015

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP