Clinical Trials /

BYL719 and Letrozole in Post-Menopausal Patients With Hormone Receptor-Positive Metastatic Breast Cancer

NCT01791478

Description:

This phase I trial studies the side effects and best dose of the PI3K inhibitor BYL719 when given together with letrozole in treating patients with hormone receptor-positive metastatic breast cancer. The PI3K inhibitor BYL719 may stop the growth of tumor cells by blocking some of the proteins needed for cell growth. Hormone therapy using letrozole may fight breast cancer by blocking the use of estrogen by the tumor cells. Giving the PI3K inhibitor BYL719 together with letrozole may kill more tumor cells

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: BYL719 and Letrozole in Post-Menopausal Patients With Hormone Receptor-Positive Metastatic Breast Cancer
  • Official Title: A Phase Ib Trial of BYL719 (an α-Specific PI3K Inhibitor) in Combination With Endocrine Therapy in Post-Menopausal Patients With Hormone Receptor-Positive Metastatic Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: VICC BRE 12101
  • SECONDARY ID: NCI-2013-00102
  • NCT ID: NCT01791478

Conditions

  • Estrogen Receptor-positive Breast Cancer
  • HER2-negative Breast Cancer
  • Invasive Ductal Breast Carcinoma
  • Progesterone Receptor-positive Breast Cancer
  • Recurrent Breast Cancer
  • Stage IV Breast Cancer

Interventions

DrugSynonymsArms
PI3K inhibitor BYL719BYL719, a-specific phosphoinositide 3-kinase inhibitor BYL719Treatment (PI3K inhibitor BYL719, letrozole)
letrozole112809-51-5, 4,4'-(1H-1,2,4triazol-1-ylmethylene)dibenzonitrile, 719345, CGS 20267,, Femara,LTZTreatment (PI3K inhibitor BYL719, letrozole)

Purpose

This phase I trial studies the side effects and best dose of the PI3K inhibitor BYL719 when given together with letrozole in treating patients with hormone receptor-positive metastatic breast cancer. The PI3K inhibitor BYL719 may stop the growth of tumor cells by blocking some of the proteins needed for cell growth. Hormone therapy using letrozole may fight breast cancer by blocking the use of estrogen by the tumor cells. Giving the PI3K inhibitor BYL719 together with letrozole may kill more tumor cells

Detailed Description

      PRIMARY OBJECTIVE: To determine the safety and tolerability of BYL719 given in combination
      with endocrine therapy in post-menopausal patients with hormone receptor-positive metastatic
      breast cancer by determining:

      I. Dose limiting toxicities (DLTs) during the first 4 weeks of treatment (cycle 1).

      II. Maximum tolerated dose (MTD) of BYL719 (PI3K inhibitor BYL719) given in combination with
      letrozole.

      III. Highest tolerated dose - ability to tolerate BYL719 with letrozole for a total of 8
      weeks without development of:

        -  Hyperglycemia (fasting glucose > 200 mg/dL) for more than 2 weeks in a row despite
           optimal medical treatment

        -  CTC Grade 3 or > rash for more than 2 weeks in a row despite optimal medical treatment

        -  CTC Grade 2 or > GI toxicity for more than 2 weeks in a row despite optimal medical
           treatment

        -  CTC Grade 2 or > serum creatinine, bilirubin, AST, ALT elevation from baseline for more
           than 2 weeks in a row despite optimal medical treatment

      SECONDARY OBJECTIVES: To determine the anti-tumor effect of the combinations of endocrine
      therapy with BYL719 in post-menopausal patients with hormone receptor-positive metastatic
      breast cancer by assessing:

      I. Progression free survival (PFS). II. Objective response rate (ORR). III. Clinical benefit
      rate (complete response [CR]+partial response [PR]+stable disease [SD] >= 6 months).

      EXPLORATORY OBJECTIVES:

      I. Pharmacokinetics of BYL719 in combination with letrozole: Plasma concentration-time
      profiles and derived basic pharmacokinetic (PK) parameters of BYL719 and letrozole, including
      but not limited to area under the plasma concentration-time curve from time zero to the last
      measurable concentration (AUC0-tlast), AUC curve to infinite time (AUC0-inf), maximum
      observed concentration (Cmax), time to peak concentration (Tmax), clearance over
      bioavailability (CL/F), apparent volume of distribution (Vz/F) and the terminal half-life
      (t1/2) and other PK parameters if deemed appropriate.

      II. Correlation of response with alterations of the PI3K pathway: Mutational analysis of
      PIK3CA (exons 9 and 20), phosphatase and tensin homolog (PTEN), and AKT1 in formalin-fixed
      paraffin blocks (FFPB) from previous surgeries or fresh-frozen biopsies (if available) on all
      patients enrolled in the trial.

      OUTLINE: This is an open-label phase Ib dose-escalation study of the PI3K inhibitor BYL719 in
      combination with letrozole in post-menopausal patients with ER+ metastatic breast cancer.

      Patients receive BYL719 orally (PO) once daily (QD) and letrozole PO QD. Courses repeat every
      4 weeks in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up for 4 weeks.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (PI3K inhibitor BYL719, letrozole)ExperimentalPatients receive PI3K inhibitor BYL719 PO QD and letrozole PO QD. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
  • PI3K inhibitor BYL719
  • letrozole

Eligibility Criteria

        Inclusion Criteria

          -  Patients must provide informed written consent.

          -  Patients must be >/= 18 years of age.

          -  ECOG performance status 0 - 1.

          -  Clinical stage IV invasive mammary carcinoma, ER-positive and/or PR-positive by
             immunohistochemistry (IHC) and HER2 negative (by IHC or ISH). Patients may have either
             measurable or non-measurable disease, both are allowed.

          -  A minimum of 10 patients in the trial (~50%) will need to have a PIK3CA mutation in
             their cancer

          -  Patients must have had at least one line of endocrine therapy in the metastatic
             setting, or be diagnosed with metastatic breast cancer during or within 1 year of
             adjuvant endocrine therapy. There is no limit on lines of prior treatment in the
             metastatic setting.

          -  Patients must have available tissue (archived formalin-fixed paraffin embedded blocks
             (FFPB) or fresh frozen tissue from original diagnosis or metastatic setting) for
             correlative studies. Tissue needs to be located and available at the time of
             registration (tissue needs to be submitted within 3 weeks of study initiation).
             Patients will not be able to start study drugs without tissue availability.

          -  Life expectancy ≥ 6 months

          -  Patients must have adequate hematologic, hepatic, and renal function. All laboratory
             tests must be obtained less than 1 week from study entry. This includes:

               1. ANC >/= 1,500/mm3

               2. platelet count >/=100,000/mm3

               3. HgB ≥ 9 g/dL

               4. Creatinine ≤ 1.5x ULN

               5. INR ≤ 2

               6. Fasting plasma glucose ≤ 140 mg/dL

               7. HgBA1C ≤ 8%

               8. Total Serum Bilirubin ≤ 1.5 x ULN (Patients with known Gilbert Syndrome, a total
                  bilirubin ≤ 3.0 x ULN, with direct bilirubin ≤ 1.5 x ULN)

               9. SGOT, SGPT ≤ 3 X ULN if no liver metastasis present

              10. SGOT, SGPT ≤ 5 X ULN if liver metastasis present

          -  Patients must be able to swallow and retain oral medication.

          -  Patients must be post-menopausal. Post-menopausal female subjects should be defined
             prior to protocol enrollment by any of the following:

               1. Subjects at least 55 years of age; OR

               2. Subjects under 55 years of age and naturally (spontaneous) amenorrhea for at
                  least 12 months or follicle-stimulating hormone (FSH) values ≥ 40 IU/L and
                  estradiol levels </= 20 IU/L; OR

               3. Prior bilateral oophorectomy; OR

               4. Prior radiation castration with amenorrhea for at least 6 months

                  NOTE: Treatment with a luteinizing hormone-releasing hormone (LH-RH) agonist
                  (such as goserelin acetate or leuprolide acetate) is not permitted for induction
                  of ovarian suppression.

          -  Patients must complete all screening assessments as outlined in the protocol.

        Exclusion Criteria

          -  Locally recurrent resectable breast cancer.

          -  Any kind of malabsorption syndrome significantly affecting gastrointestinal function.

          -  Patients with clinically manifest diabetes mellitus (treated and/or clinical signs or
             with fasting glucose >/= 140 mg/dL / 7.8 mmol/L), history of gestational diabetes
             mellitus or documented steroid-induced diabetes mellitus.

          -  Patients who have received radiation therapy </= 2 weeks prior to study entry.
             Patients who have received prior radiotherapy must have recovered from toxicity (≤
             grade 1) induced by this treatment.

          -  Patients who have received systemic anti-cancer therapy such as chemotherapy,
             immunotherapy and/or biologic therapy </= 4 weeks prior to study entry. Concurrent
             anti-cancer therapy (chemotherapy, immunotherapy, biologic therapy) other than the
             ones specified in the protocol is not permitted during study participation. Patients
             must have discontinued the above cancer therapies for 4 weeks prior to the first dose
             of study medication, as well as recovered from toxicity (to ≤ than grade 1, except for
             alopecia) induced by previous treatments. Any investigational drugs should be
             discontinued 4 weeks prior to the first dose of study medication.

          -  Prior hormonal / endocrine therapy </= 2 weeks prior to study entry. Patients must
             have recovered from toxicity > grade 1, except for alopecia.

          -  Prior therapy with a PI3K inhibitor. Prior use of Akt or mTOR inhibitors are allowed.

          -  Patients who have received herbal medications </= 2 weeks prior to study entry. Herbal
             medications include, but are not limited to: St. John's wort, Kava, ephedra (ma
             huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and
             ginseng.

          -  Use of drugs that are CYP3A4 modifiers

          -  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.

          -  Patients with a family history of congenital long QT syndrome

          -  Patients with abnormal calcium, potassium, or magnesium levels that cannot be
             adequately corrected to within normal range prior to initiation of study drugs

          -  Uncontrolled intercurrent illness including, but not limited to:

               1. ongoing or active infection requiring parenteral antibiotics

               2. impairment of lung function (COPD > grade 2, lung conditions requiring oxygen
                  therapy)

               3. symptomatic congestive heart failure (class III or IV of the New York Heart
                  Association classification for heart disease)

               4. Left Ventricular Ejection Fraction (LVEF) < 50%

               5. unstable angina pectoris, angioplasty, stenting, or myocardial infarction within
                  6 months

               6. uncontrolled hypertension within 2 weeks of study initiation (systolic blood
                  pressure > 180 mm Hg or diastolic blood pressure > 110 mm Hg, found on two
                  consecutive measurements separated by a 1 or 2-week period despite adequate
                  medical support)

               7. clinically significant cardiac arrhythmia (multifocal premature ventricular
                  contractions, bigeminy,trigeminy, ventricular tachycardia that is symptomatic or
                  requires treatment [National Cancer Institute -Common Terminology Criteria for
                  Adverse Events, Version 4.0, grade 3]

               8. QTcF ≥ 480 msec on screening EKG

               9. known history of QT/QTc prolongation or Torsades de Pointes (TdP)

              10. ST depression or elevation of ≥ 1.5 mm in 2 or more leads

              11. Diarrhea of any cause ≥ CTCAE grade 2

              12. psychiatric illness/social situations that would compromise patient safety or
                  limit compliance with study requirements including maintenance of a
                  compliance/pill diary

              13. patients with symptomatic brain metastases (patients with a history of brain
                  metastases must be clinically stable for more than 4 weeks from completion of
                  radiation treatment)

              14. patients with known history of chronic liver or renal failure

              15. patients with known history of chronic or acute pancreatitis

        Individuals of all races and ethnic groups are eligible for this trial. There is no bias
        towards age or race in the clinical trial outlined. This trial is open to the accrual of
        women.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose of BYL719 in combination with letrozole
Time Frame:4 weeks
Safety Issue:
Description:Highest dose of BYL719 tested in which a DLT is experienced by 0 out of 3 or 1 of 6 patients, based on the NCI Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0

Secondary Outcome Measures

Measure:Highest tolerated dose of BYL719 in combination with letrozole
Time Frame:8 weeks
Safety Issue:
Description:Highest dose of BYL719 without CTC Grade > 2 hyperglycemia(fasting glucose > 200 mg/dL) for > 2 weeks, Grade > 3 rash for > 2 weeks , Grade > 2 gastrointestinal toxicity for > 2 weeks and Grade > 2 creatinine, bilirubin, AST, ALT for > 2 weeks.
Measure:Clinical benefit rate
Time Frame:At 6 months of study treatment
Safety Issue:
Description:Per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1; percentage of patients with complete response (CR) + partial response (PR) + stable disease (SD) for more than 6 months.
Measure:Overall progression-free survival
Time Frame:Up to 4 weeks after interruption of study treatment
Safety Issue:
Description:Duration from on-study date to date of progressive disease.
Measure:Overall response
Time Frame:Every 8 weeks to interruption of treatment
Safety Issue:
Description:Per RECIST version 1.1. number of patients each with CR, PR, SD, and progressive disease (PD) as their best response.
Measure:Worst grade toxicities
Time Frame:Up to 4 weeks after interruption of study treatment
Safety Issue:
Description:Number of patients with worst-grade toxicity at each of five grades (grade 1, least severe; to grade 5, most severe) following NCI Common Toxicity Criteria 4.0.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Vanderbilt-Ingram Cancer Center

Trial Keywords

  • -Metastatic breast cancer, PI3K inhibitor, Endocrine therapy

Last Updated

October 19, 2017