STAR Cape+BKM120 MBC With Brain Met
Condition: Brain Metastases; Breast Cancer; Metastatic Breast Cancer
MeSH terms: Breast Neoplasms; Neoplasm Metastasis; Brain Neoplasms
Intervention: BKM120; capecitabine; Trastuzumab
Intervention MeSH terms: Capecitabine; Trastuzumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 10.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Breast Cancer; Triple Negative Breast Cancer; Brain Metastases; Capecitabine; Metastatic Breast Cancer

Summary:

      This is a study to determine the safety and effectiveness of BKM120 plus capecitabine in
      breast cancer patients with brain metastases.

      Both capecitabine and BMK120 have previously shown activity in patients with breast cancer.
      Like capecitabine, BMK120 is also effective in crossing the blood brain barrier making it a
      preferred candidate for its evaluation in patients with metastatic breast cancer (MBC).
    

Eligibility criteria:

        Inclusion Criteria:

          1. Age ≥ 18 years

          2. Female

          3. Histologically and/or cytologically confirmed diagnosis of inoperable metastatic
             breast cancer

          4. ER+/HER2- OR HER2+ OR triple-negative breast cancer, assessed as ER-, PgR-, and
             HER2-negative by local laboratory testing; HER2 negative status (based on most
             recently analyzed biopsy) is defined as IHC status of 0, 1+ or 2+ (if IHC 2+, a
             negative FISH test is required, ie, HER2 FISH ratio < 2.0); ER-negative and
             PR-negative status is defined as ER and PgR <10% nuclei positive by IHC. HER2-positive
             status is defined as 3+ staining in ≥10% of cells by immunohistochemistry or a
             HER2/CEP17 ratio ≥2 or an average of ≥6 HER2 gene copies per cell by in situ
             hybridization (ISH)

          5. At least one CNS lesion that is at least 5mm in size in at least one dimension in the
             setting of prior WBRT

               -  Prior WBRT is required and may have been administered at any time in patient's
                  treatment history. Patients in the primary analysis will not have evidence of
                  progression of disease following WBRT. However, patients whose brain metastases
                  have progressed following WBRT are eligible. Patients must have completed WBRT at
                  least 3 weeks prior to study entry.

               -  Prior SRS is allowed, but previous treatment of the 5mm target CNS lesion with
                  SRS is not permitted

          6. ECOG performance status ≤ 2

          7. Adequate bone marrow function as shown by: ANC ≥ 1.5 x 109/L, Platelets ≥ 100 x 109/L,
             Hb >9 g/dL

          8. Total calcium (corrected for serum albumin) within normal limits (biphosphonate use
             for malignant hypercalcemia control is not allowed)

          9. Magnesium ≥ the lower limit of normal

         10. Potassium within normal limits for the institution

         11. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) within normal
             range (or ≤ 3.0 x upper limit of normal (ULN) if liver metastases are present)

         12. Serum bilirubin within normal range (or ≤ 1.5 x ULN if liver metastases are present;
             or total bilirubin ≤ 3.0 x ULN with direct bilirubin within normal range in patients
             with known Gilbert Syndrome)

         13. Serum creatinine ≤ 1.5 x ULN or 24-hour clearance ≥ 50 mL/min

         14. Serum amylase ≤ ULN

         15. Serum lipase ≤ ULN

         16. Fasting plasma glucose ≤ 120 mg/dL (6.7 mmol/L)

         17. Negative serum pregnancy test within 72 hours before starting study treatment in women
             with childbearing potential

         18. INR ≤ 2

         19. Life expectancy > 12 weeks

         20. Available tissue (blocks and/or slides) samples unless discussed in advance with study
             principal investigator

         21. Patient is able to swallow and retain oral medication

         22. Signed most recent patient informed consent form

         23. Signed Patient Authorization Form

        Exclusion Criteria:

          1. Patient received prior treatment with a P13K inhibitor.

          2. Patient with known hypersensitivity to BKM120, capecitabine, or their excipients.

          3. Patient has evidence of impending herniation on baseline brain imaging.

          4. Patient has evidence of diffuse leptomeningeal disease on brain MRI or by previously
             documented CSF.

          5. Patient has acute or chronic liver, renal disease or pancreatitis (liver metastases
             are allowed)

          6. Patients has a mood disorder as judged by the Investigator or a psychiatrist, or as a
             result of patient's mood assessment questionnaire (PHQ-9 and/or GAD-7):

               -  Medically documented history of or active major depressive episode, bipolar
                  disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of
                  suicidal attempt or ideation, or homicidal ideation (immediate risk of doing harm
                  to others) or patients with active severe personality disorders (defined
                  according to DSM- IV) are not eligible. Note: for patients with psychotropic
                  treatments ongoing at baseline, the dose and the schedule should not be modified
                  within the previous 6 weeks prior to start of study drug.

               -  ≥ CTCAE grade 3 anxiety

               -  Meets the cut-off score of ≥ 12 in the PHQ-9 or a cut-off of ≥ 15 in the GAD-7
                  mood scale, respectively, or selects a positive response of "1, 2, or 3" to
                  question number 9 regarding potential for suicidal thoughts in the PHQ-9
                  (independent of the total score of the PHQ-9)

          7. Patients has diarrhea ≥ CTCAE grade 2

          8. Patients with uncontrolled hypertension defined as systolic blood pressure 170 or
             greater or diastolic blood pressure over 100.

          9. Patient has active cardiac disease including any of the following:

               -  Left ventricular ejection fraction (LVEF) < 50% as determined by Multiple Gated
                  acquisition (MUGA) scan or echocardiogram (ECHO)

               -  QTc > 480 msec on screening ECG (using the QTcF formula)

               -  Angina pectoris that requires the use of anti-anginal medication

               -  Ventricular arrhythmias except for benign premature ventricular contractions

               -  Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled
                  with medication

               -  Conduction abnormality requiring a pacemaker

               -  Valvular disease with document compromise in cardiac function

               -  Symptomatic pericarditis

         10. Patient has a history of cardiac dysfunction including any of the following:

               -  Myocardial infarction within the last 6 months, documented by persistent elevated
                  cardiac enzymes or persistent regional wall abnormalities on assessment of LVEF
                  function

               -  History of documented congestive heart failure (New York Heart Association
                  functional classification III-IV)

               -  Documented cardiomyopathy

         11. Patient has poorly controlled diabetes mellitus or steroid-induced diabetes mellitus

         12. Patient has other concurrent severe and/or uncontrolled concomitant medical conditions
             (e.g., active or uncontrolled infection) that could cause unacceptable safety risks or
             compromise compliance with the protocol

               -  Significant symptomatic deterioration of lung function. If clinically indicated,
                  pulmonary function tests including measures of predicted lung volumes, DLco, O2
                  saturation at rest on room air should be considered to exclude pneumonitis or
                  pulmonary infiltrates.

         13. Impairment of gastrointestinal (GI) function or GI disease that may significantly
             alter the absorption of BKM120 (e.g., ulcerative diseases, uncontrolled nausea,
             vomiting, diarrhea, malabsorption syndrome, or small bowel resection). Patients with
             unresolved diarrhea will be excluded as previously indicated

         14. Patient was treated with any hematopoietic colony-stimulating growth factors (e.g.,
             G-CSF, GM-CSF) ≤ 2 weeks prior to starting study drug. Erythropoietin or darbepoetin
             therapy, if initiated at least 2 weeks prior to enrollment, may be continued

         15. Patient is currently receiving treatment with medication with a known risk to prolong
             the QT interval or inducing Torsades de Pointes and the treatment cannot either be
             discontinued or switched to a different medication prior to starting study drug.

         16. Patients receiving chronic treatment with steroids or another immunosuppressive agent.
             Patients must have been off all corticosteroids (except for physiologic doses of
             hydrocortisone as replacement therapy) for at least 2 weeks prior to study entry.

               -  Note: Single doses, or topical applications (e.g. rash), inhaled sprays (e.g.
                  obstructive airways diseases), eye drops or local injections (e.g.
                  intra-articular) are allowed.

         17. Patient has taken herbal medications and certain fruits within 7 days prior to
             starting study drug. 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. Fruits include the CYP3A inhibitors Seville oranges,
             grapefruit, pummelos, or exotic citrus fruits. Regular orange juice is permitted.

         18. Patient is currently treated with drugs known to be moderate and strong inhibitors or
             inducers of isoenzyme CYP3A, and the treatment cannot be discontinued or switched to a
             different medication prior to starting study drug. Please refer to Table 4-8 for a
             list of prohibited inhibitors and inducers of CYP3A (Please note that co-treatment
             with weak inhibitors of CYP3A is allowed).

         19. Patient received chemotherapy or targeted anticancer therapy ≤ 3 weeks (6 weeks for
             nitrosourea, antibodies or mitomycin-C) prior to starting study drug, and have related
             side effects must recover to a grade 1 or less before starting the trial

         20. Patient received any continuous or intermittent small molecule therapeutics (excluding
             monoclonal antibodies) with ≤ 5 effective half lives prior to starting study drug or
             who have not recovered from side effects of such therapy

         21. Patient received wide field radiotherapy ≤ 4 weeks or limited field radiation for
             palliation ≤ 2 weeks prior to starting study drug or who have not recovered from side
             effects of such therapy

         22. Patient underwent major surgery ≤ 2 weeks prior to starting study drug or who have not
             recovered from side effects of such therapy.

         23. Patient is currently taking therapeutic doses of warfarin sodium or any other
             coumadin-derivative anticoagulant.

         24. Patient is pregnant or breast feeding or is of reproductive potential and not
             employing an effective method of birth control.

               -  Note: Double barrier contraceptives must be used through the trial by both sexes.
                  Oral, implantable, or injectable contraceptives may be affected by cytochrome
                  P450 interactions, and are therefore not considered effective for this study.
                  Women of child-bearing potential, defined as sexually mature women who have not
                  undergone a hysterectomy or who have not been naturally postmenopausal for at
                  least 12 consecutive months (i.e., who has had menses any time in the preceding
                  12 consecutive months), must have a negative serum pregnancy test ≤ 72 hours
                  prior to initiating treatment.

               -  Note: Women are considered post-menopausal and not of child bearing potential if
                  they have had 12 months of natural (spontaneous) amenorrhea with an appropriate
                  clinical profile (e.g. age appropriate, history of vasomotor symptoms) or six
                  months of spontaneous amenorrhea with serum FSH levels > 40 mIU/mL [for US only:
                  and estradiol < 20 pg/mL] or have had surgical bilateral oophorectomy (with or
                  without hysterectomy) at least six weeks ago. In the case of oophorectomy alone,
                  only when the reproductive status of the woman has been confirmed by follow up
                  hormone level assessment is she considered not of child bearing potential.

               -  Note: Women of child-bearing potential, defined as all women physiologically
                  capable of becoming pregnant, must use highly effective contraception during
                  treatment for 4 weeks (5 T1/2) after stopping treatment. The highly effective
                  contraception is defined as either:

                  i. True abstinence: When this is in line with the preferred and usual lifestyle
                  of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal,
                  post-ovulation methods) and withdrawal are not acceptable methods of
                  contraception.

             ii. Sterilization: have had surgical bilateral oophorectomy (with or without
             hysterectomy) or tubal ligation at least six weeks ago. In case of oophorectomy alone,
             only when the reproductive status of the woman has been confirmed by follow up hormone
             level assessment.

             iii. Male partner sterilization (with the appropriate post-vasectomy documentation of
             the absence of sperm in the ejaculate). For female subjects on the study, the
             vasectomised male partner should be the sole partner for that patient.

             iv. Use of a combination of any two of the following (a+b):

               1. Placement of an intrauterine device (IUD) or intrauterine system (IUS)

               2. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or
                  cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository

                    -  Oral contraception, injected or implanted hormonal methods are not allowed
                       as BKM120 potentially decreases the effectiveness of hormonal
                       contraceptives.

         25. Patient has known diagnosis of human immunodeficiency virus (HIV) infection

         26. Patient has history of another malignancy within 5 years, except cured basal cell
             carcinoma of the skin or excised carcinoma in situ of the cervix

         27. Patient is unable or unwilling to abide by the study protocol or cooperate fully with
             the investigator

         28. Patient is concurrently using other approved or investigational antineoplastic agent.

         29. Patient taking or needing enzyme-inducing anti-epileptic medication.

         30. Patient has an acute viral hepatitis or a history of chronic or active HBV or HCV
             infection