Buparlisib in Melanoma Patients Suffering From Brain Metastases (BUMPER)

Inclusion Criteria

• •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
• •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.
• •18\. Patient with poorly controlled diabetes mellitus (glycosolated hemoglobin \> 8%) or poorly controlled steroid-induced diabetes mellitus (glycosolated hemoglobin \> 8%)