A Study of BKM120 (Buparlisib) in Relapsed or Refractory Thymomas
Condition: Thymoma
MeSH terms: Thymoma; Thymus Neoplasms
Intervention: BKM120
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 14.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      Thymic tumors are rare tumors, but represent the most common tumors of the anterior
      mediastinum. Thymoma has an indolent course in advanced disease and has the propensity to
      spread to the pleura. In first line therapy, combination chemotherapy produces responses in
      approximately 80% of patients. A number of single agents have activity in recurrent disease,
      but none are curable. Patients with recurrent thymoma have limited treatment options, and
      thus novel target modalities are needed.

      At the Indiana University Simon Cancer Center (IUSCC), more patients with advance thymoma are
      seen than any other institution in the country. Our main hypothesis is the PI3K pathway is an
      important driver for growth and metastasis of thymoma and that inhibition of the PI3K pathway
      is expected to produce clinically meaningful response in patients with recurrent thymoma.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Histological confirmation of thymoma.

          2. At least one prior line of platin-based chemotherapy (unless refused or not
             tolerated).

          3. Documented progressive (clinical and/or objective) disease after the most recent
             systemic therapy regimen.

          4. Patients must not have received chemotherapy, radiation therapy, or undergone major
             surgery within 4 weeks prior to enrollment.

          5. Patients must have measurable disease, defined as at least one lesion that can be
             accurately measured in at least one dimension (longest diameter to be recorded for
             nonnodal lesions and short axis for nodal lesions) as >20 mm with conventional
             techniques or as >10 mm with spiral CT scan, MRI, or calipers by clinical exam. See
             Section 4 for the evaluation of measurable disease.

          6. Age ≥ 18 years

          7. ECOG performance status £ 2

          8. Patient must be able to swallow and retain oral medications

          9. Adequate bone marrow function as shown by: ANC ≥ 1.5 x 109/L, Platelets ≥ 100 x 109/L,
             Hb >9 g/dL

         10. Total calcium (corrected for serum albumin) within normal limits (biphosphonate use
             for malignant hypercalcemia control is not allowed)

         11. Magnesium ≥ the lower limit of normal

         12. Potassium within normal limits for the institution

         13. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) within normal
             range (or ≤ 3.0 x upper limit of normal (ULN) if liver metastases are present)

         14. 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 well documented Gilbert Syndrome)

         15. Serum creatinine ≤ 1.5 x ULN or 24-hour clearance ≥ 50 mL/min

         16. Serum amylase ≤ ULN

         17. Serum lipase ≤ ULN

         18. Fasting plasma glucose ≤ 120 mg/dL (6.7 mmol/L)

         19. HbA1c ≤ 8 %

         20. Negative serum pregnancy test within 72 hours before starting study treatment in women
             with childbearing potential

         21. Signed informed consent

         22. INR ≤ 2

        Exclusion Criteria:

          1. Patients who have received prior treatment with a P13K inhibitor.

          2. Patients with thymic carcinoma (formerly WHO Type C).

          3. Patients with a known hypersensitivity to BKM120 or to its excipients

          4. Patients with untreated brain metastases are excluded. However, patients with
             metastatic CNS tumors may participate in this trial, if the patient is > 4 weeks from
             therapy completion (incl. radiation and/or surgery), is clinically stable at the time
             of study entry and is receiving low dosage corticosteroid therapy

          5. Patients with acute or chronic liver, renal disease or pancreatitis

          6. Patients with the following mood disorders as judged by the Investigator or a
             psychiatrist, or as a result of patient's mood assessment questionnaire: • 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 with diarrhea ≥ CTCAE grade 2

          8. Patient has known active cardiac disease including any of the following:

             • Left ventricular ejection fraction (LVEF) < 50% as determined by Multiple Grated
             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

          9. Patient has a history of cardiac dysfunction including any of the following:

             • Myocardial infraction 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

         10. Patient has poorly controlled diabetes mellitus or steroid-induced diabetes mellitus

         11. Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g.,
             active or uncontrolled infection; uncontrolled hypertension) 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.

         12. 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

         13. Patients who have been 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

         14. Patients who are 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. Please refer to table 4 8 or a list of prohibited QT prolonging drugs with risk
             of Torsades de Pointes.

         15. Patients receiving chronic treatment with steroids or another immunosuppressive agent.
             • Note: Topical applications (e.g. rash), inhaled sprays (e.g. obstructive airways
             diseases), eye drops or local injections (e.g. intra-articular) are allowed. Patients
             with previously treated brain metastases, who are on stable low dose corticosteroid
             treatment (e,g dexamethasone 2 mg/day, predisolone 10 mg/day) for at least 14 days
             before start of study treatment are eligible.

         16. Patients who have 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.

         17. Patients who are 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
             4-7 for a list of prohibited inhibitors and inducers of CYP3A (Please note that
             co-treatment with weak inhibitors of CYP3A is allowed).

         18. Patients who have received chemotherapy or targeted anticancer therapy ≤ 4 weeks (6
             weeks for nitrosourea, antibodies or mitomycin-C) prior to starting study drug must
             recover to a grade 1 before starting the trial

         19. Patients who have received any continuous or intermittent small molecule therapeutics
             (excluding monoclonal antibodies) ≤ 5 effective half-lives prior to starting study
             drug or who have not recovered from side effects of such therapy

         20. Patients who have 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

         21. Patients who have undergone major surgery ≤ 2 weeks prior to starting study drug or
             who have not recovered from side effects of such therapy.

         22. Patients who are currently taking therapeutic doses of warfarin sodium or any other
             coumadin-derivative anticoagulant.

         23. Women who are pregnant or breast feeding or adults of reproductive potential not
             employing an effective method of birth control. 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.

               -  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.

               -  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:

        1. 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.

        2. 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.

        3. 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.

        4. 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.

               -  Fertile males, defined as all males physiologically capable of conceiving
                  offspring must use condoms during treatment, for 4 weeks (5 T1/2) after stopping
                  treatment and for an additional 12 weeks (1616 weeks in total after study drug
                  discontinuation) and should not father a child in this period.

               -  Female partner of male study subject should use highly effective contraception
                  during dosing of any study agent and for 16 weeks after final dose of study
                  therapy.

                  24. Known diagnosis of human immunodeficiency virus (HIV) infection 25. History
                  of another malignancy within 3 years, except cured basal cell carcinoma of the
                  skin or excised carcinoma in situ of the cervix 26. Patient is unable or
                  unwilling to abide by the study protocol or cooperate fully with the investigator