| Eligibility |
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
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