The study will enrol adult female and male patients with BRAF wild-type melanoma and brain
metastases who are not eligible for surgery or radiosurgery and failed prior therapy with
ipilimumab, and patients with BRAF V600 mutation-positive melanoma and brain metastases who
are not eligible for surgery or radiosurgery and who failed prior therapy with a BRAF
inhibitor.
1. Patient has signed the Informed Consent (ICF) prior to any screening procedures being
performed and is able to comply with protocol requirements.
2. Patient has adequate bone marrow and organ function as defined by the following
laboratory values; (Clinical labs - performed within 14 days prior to enrolment)
Hematology
1. Absolute Neutrophil Count (ANC) ≥ 1.0 x 109/L
2. Platelet count ≥ 100 x 109/L (For patients with haematologic malignancies
involving the bone marrow, platelet count > 75 x 109/L)
3. Haemoglobin ≥ 9.0 g/dL Coagulation
4. INR ≤ 1.5
Biochemistry e. Potassium and calcium (corrected for albumin), within normal limits
for the institution, or ≤ Grade 1 if judged not clinically significant by the
investigator f. Serum creatinine ≤ 1.5 x ULN and/or creatinine clearance > 50% LLN
(Lower Limit of Normal) g. Total Serum bilirubin ≤ ULN (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's Syndrome, which is defined as
presence of several episodes of unconjugated hyperbilirubinemia with normal results
from CBC count (including normal reticulocyte count and blood smear), normal liver
function test results, and absence of other contributing disease processes at the time
of diagnosis h. AST (SGOT) and ALT (SGPT) below or equal upper limit of normal range
or (≤ 3.0 x ULN if liver metastases are present) i. Fasting plasma glucose (FPG) ≤
120mg/dL or ≤ 6.7 mmol/L j. HbA1c ≤ 8%
3. Patient is able to swallow and retain oral medication
4. Patient must be at least 18 years old
5. Patient must have an estimated life expectancy > 8 weeks in the opinion of the
investigator
6. Patient must have ECOG performance status < 2
Nature of illness and treatment history
7. Histologically confirmed diagnosis of melanoma
8. Patient must has shown evidence for PD in the brain by MRI without leptomeningeal
disease
9. Contrast enhanced brain MRI and CT for chest / abdomen / pelvis or MRI for abdomen /
pelvis must be performed within 28 days before first dose of study treatment
10. Patient is able to be assessed by periodic MRI and CT scan
11. Patients BRAF V600 wildtype:
- must have objective evidence of progressive disease during or
- following treatment with anti-CTLA-4 containing therapy for advanced melanoma
12. Patients BRAF V600 mutation positive:
- must have objective evidence of progression of disease during or
- following treatment with a BRAF inhibitor
- not be eligible for surgery or radiosurgery
13. Time interval between last day of previous anti-tumour local or systemic treatment and
first dose of buparlisib:
- 14 days elapsed from last treatment with surgery or radiosurgery
- 28 days elapsed from last treatment with whole brain radiation
- 28 days have elapsed from last dose of approved or investigational chemo-,
cytokine-, immune-, biological-, or vaccine-therapy
14. Participants must have recovered to a grade 0 or 1 from the toxic effects of prior
therapy
Exclusion Criteria:
1. Patient has a known hypersensitivity to any of the excipients of buparlisib
2. Patient who has received wide field radiotherapy ≤ 4 weeks or limited field radiation
for palliation ≤ 2 weeks prior to starting study drug or who have not recovered to
Grade 1 or better from related side effects of such therapy (except alopecia)
3. Patient has not recovered to Grade 1 or better (except alopecia) from related side
effects of any prior antineoplastic therapy
4. Patient has had major surgery within 14 days prior to starting study drug or has not
recovered from major side effects
5. Patient is currently receiving increasing or chronic treatment (> 5 days) with
corticosteroids or another immunosuppressive agent;
1. The following uses of corticosteroids are permitted: single doses; e.g. with
standard premedication for taxanes; topical applications (e.g., rash), inhaled
sprays (e.g., obstructive airways diseases), eye drops or local injections (e.g.,
intra-articular)
2. Patient taking an enzyme-inducing anti-epileptic drug (EIAED): phenobarbital,
phenytoin, fosphenytoin, primidone, rufinamide carbamazepine, oxcarbazepine,
eslicarbazepine, felbamate, and topiramate (only when daily dose exceeds 200 mg).
Participant must be off any EIAEDs for at least two weeks prior to starting study
3. Requirement of more than 4 mg dexamethasone daily
6. Patient is being treated at start of study treatment with any of the following drugs:
1. Drugs known to be strong inhibitors or inducers of isoenzyme CYP3A including
herbal medications.
2. Drugs with a known risk to induce Torsades de Pointes
3. Note: The patient must have discontinued strong inducers for at least one week
and must have discontinued strong inhibitors before the treatment is initiated.
Switching to a different medication prior to starting study treatment is allowed.
4. Patient who has received prior treatment with a PI3K inhibitor, AKT inhibitor or
mTOR inhibitor
5. Patient who have received anti-angiogenic or anti-VEGF targeted agents
7. Patient is currently receiving warfarin or any other coumarin-derivative anticoagulant
for treatment, prophylaxis or otherwise. Therapy with heparin, low molecular weight
heparin (LMWH), or fondaparinux is allowed
8. Patient who has who have other concurrent severe and/or uncontrolled medical
conditions that would, in the investigator's judgment, contraindicate patient
participation in the clinical study (e.g., active or uncontrolled severe infection,
chronic active hepatitis, immuno-compromised, acute or chronic pancreatitis,
uncontrolled high blood pressure, interstitial lung disease, etc.)
9. Patient has a known history of human immunodeficiency virus (HIV) infection (testing
not mandatory)
10. Patient has any of the following cardiac abnormalities:
a. symptomatic congestive heart failure
1. history of documents congestive heart failure (New York Heart Association NYHA
functional classification III-IV, see Appendix 6), Documented cardiomyopathy
2. Left Ventricular Ejection Fraction (LVEF) <50% as determined by Multiple Gated
acquisition (MUGA) scan or echocardiogram (ECHO)
b. Myocardial infarction < 6 months prior to enrolment c. unstable angina pectoris d.
serious uncontrolled cardiac arrhythmia e. Symptomatic pericarditis f. QTcF > 450 msec
on the screening ECG (using the QTcF formula) g. Currently receiving treatment with
medication that has a known risk to prolong the QT interval or inducing Torsades de
Pointes, and the treatment cannot be discontinued or switched to a different
medication prior to starting study drug.
11. Patient has impairment of gastrointestinal (GI) function or GI disease that may
significantly alter the absorption of study drug (e.g., ulcerative diseases,
uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel
resection)
12. Participants with the following mood disorders as judged by the Investigator or a
psychiatrist, or as result of participant's mood assessment questionnaire:
a. Patient has a score of ≥ 12 in the PHQ-9 questionnaire, see Appendix 7 b. Patient
selects a response of '1, 2, or 3' to question number 9 on the PHQ-9 questionnaire
regarding potential for suicidal thoughts or ideation (independent of the total score
of the PHQ-9) c. Patient has GAD mood scale score of ≥ 15 d. Patient has a 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.
e. Patient has anxiety ≥ CTCAE grade 3
13. Patient has other prior or concurrent malignancy (except for the following adequately
treated basal cell or squamous cell skin cancer , or GI cancer resected completely by
endoscopy procedures or any other cancer from which the patient has been disease free
for ≥ 3 years)
14. Patient has a history of non-compliance to medical regimen or inability to grant
consent
15. Patient is concurrently using other approved or investigational antineoplastic agent.
16. Pregnant or nursing (lactating) women, 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). Patients with elevated hCG at baseline that
is judged to be related to the tumor are eligible if hCG levels do not show the
expected doubling when repeated 5-7 days later, or pregnancy has been ruled out by
vaginal ultrasound
17. Patient who does not apply highly effective contraception during during the study and
through the duration as defined below after the final dose of study treatment:
a. Sexually active males should use a condom during intercourse while taking drug and
for 16 weeks after the final dose of study treatment and should not father a child in
this period, but may be recommended to seek advice on conservation of sperm. A condom
is required to be used also by vasectomized men in order to prevent delivery of the
drug via seminal fluid.
b. Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, must use highly effective contraception during the study and
through at least 4 weeks after the final dose of study treatment c. Highly effective
contraception is defined as either: i. Total abstinence: When this is in line with the
preferred and usual lifestyle of the subject. [Periodic abstinence (e.g., calendar,
ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable
methods of contraception].
ii. Female sterilization: have had surgical bilateral oophorectomy (with or without
hysterectomy) or tubal ligation at least six weeks before taking study treatment. 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 study
subjects, the vasectomized male partner should be the sole partner for that patient] iv.
Use a combination of the following (both 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.
3. Note: Hormonal contraception methods (e.g. oral, injected, and implanted) are not
allowed as buparlisib decreases the effectiveness of hormonal contraceptives.
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 have had surgical bilateral oophorectomy
(with or without hysterectomy) at least six weeks ago.
For women with therapy-induced amenorrhea, oophorectomy or serial measurements of FSH
and/or estradiol are needed to ensure postmenopausal status.
NOTE: Ovarian radiation or treatment with a luteinizing hormone-releasing hormone (LH-RH)
agonist (goserelin acetate or leuprolide acetate) is not permitted for induction of ovarian
suppression.
1. Intracranial disease control rate (Time Frame - 6 weeks): Intracranial disease control rate - defined as the percentage of patients whose intracranial response is a confirmed complete response, partial response or stable disease assessed by investigators using modified RECIST 1.1 criteria
Secondary outcome:
1. Overall response rate (Time Frame - 12 weeks)
2. Duration of response for the subsets of patients with confirmed intracranial CR or PR (Time Frame - Up to 60 weeks)
3. Duration of response for the subsets of patients with confirmed overall CR or PR (Time Frame - Up to 60 weeks)
6. Number of Adverse Events (Time Frame - Up to 104 weeks): e.g. clinically significant laboratory abnormalities, vital signs, ECG, ECHO and clinical monitoring/observation.
Buparlisib: Patients will receive oral buparlisib 100 mg once daily and continue on study treatment until evidence of disease progression, death, or unacceptable adverse events
Quelle: ClinicalTrials.gov
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