Clinical Trials /

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

NCT02506556

Description:

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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Unknown status

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Phosphatidylinositol 3-kinase (PI3K) Alpha iNhibition In Advanced Breast Cancer
  • Official Title: 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.

Clinical Trial IDs

  • ORG STUDY ID: LL14/02
  • NCT ID: NCT02506556

Conditions

  • Metastatic Breast Cancer

Interventions

DrugSynonymsArms
BYl719experimental

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
experimentalExperimentalBYL719 350 mg orally daily until progression, undue adverse events or withdrawal of consent.
  • BYl719

Eligibility Criteria

        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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response rate
Time Frame:> 6 months
Safety Issue:
Description:The percentage of patients who achieve a complete or partial response as defined by RECIST 1.1 criteria.

Secondary Outcome Measures

Measure:Clinical Benefit Rate
Time Frame:> 6 months
Safety Issue:
Description:Defined as Complete or partial responses according to RECIST 1.1 criteria or stable disease for 6 months or greater
Measure:Progression free survival
Time Frame:> 6 months
Safety Issue:
Description:Defined as the time from study entry until documented disease progression
Measure:Safety and tolerability
Time Frame:> 6 months
Safety Issue:
Description: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

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Peter MacCallum Cancer Centre, Australia

Trial Keywords

  • Pi3K pathway

Last Updated

July 22, 2015