| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| metastatic melanoma with brain metastases |
| zerebral metastasiertes malignes Melanom |
|
| E.1.1.1 | Medical condition in easily understood language |
| metastatic melanoma with brain metastases not eligible for surgery or radiosurgery |
| zerebral metastasiertes malignes Melanom bei Patienten, bei denen ein chirurgischer oder radiochirurgischer Eingriff nicht in Frage kommt |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary objective of the study is to assess the intracranial disease control rate (IC-DCR), defined as the proportion of patients with confirmed complete intracranial responses (CR), partial intracranial responses (PR) or stable intracranial disease (SD) assessed by investigators in patients with melanoma-derived brain metastases treated with oral buparlisib.
|
| Das primäre Ziel dieser klinischen Prüfung ist die Bestimmung der intrakranialen Tumorwachstumskontrollrate (intracranial disease control rate, IC-DCR), definiert als Prozentsatz der Patienten mit bestätigter kompletter intrakranialer Remission (CR), partieller intrakranialer Remission (PR) oder intrakranialer Stable Disease (SD), gemäß Beurteilung durch den Prüfarzt bei Patienten mit zerebral metastasiertem malignem Melanom, die eine perorale Behandlung mit BKM120 erhalten. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study is to
• estimate the overall response rate (ORR)
• estimate duration of response of intracranial disease and OR
• estimate progression-free survival (PFS)
• estimate overall survival (OS)
• to characterize the safety and tolerability of buparlisib throughout the study
|
Die Studie hat die folgenden sekundären Ziele:
• Schätzung der Gesamtremissionsrate (overall response rate, ORR)
• Schätzung der Remissionsdauer (intrakranial und insgesamt)
• Schätzung des progressionsfreien Überlebens (progression-free survival, PFS)
• Schätzung des Gesamtüberlebens (overall survival, OS)
• Charakterisierung der Sicherheit und der Verträglichkeit von BKM120 während der gesamten Studiendauer
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients eligible for inclusion in this study have to meet all of the following 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 enrollment)
Hematology
a. Absolute Neutrophil Count (ANC) ≥ 1.0 x 109/L
b. Platelet count ≥ 100 x 109/L (For patients with hematologic malignancies involving the bone marrow, platelet
count > 75 x 109/L)
c. Hemoglobin ≥ 9.0 g/dL
Coagulation
d. 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 Checkpoint-inhibitors 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 |
|
| E.4 | Principal 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
a. 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
b. 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
c. Requirement of more than 4 mg dexamethasone daily
6. Patient is being treated at start of study treatment with any of the following drugs:
a. Drugs known to be strong inhibitors or inducers of isoenzyme CYP3A including herbal medications.
b. Drugs with a known risk to induce Torsades de Pointes (List of prohibited QT prolonging drugs
c. 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.
d. Patient who has received prior treatment with a PI3K inhibitor, AKT inhibitor or mTOR inhibitor
e. 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
b. Myocardial infarction < 6 months prior to enrolment
c. unstable angina pectoris
d. serious uncontrolled cardiac arrhythmia
e. Symptomatic pericarditis
f. QTcF > 480 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 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. Patient with poorly controlled diabetes mellitus (glycosolated hemoglobin > 8%) or poorly controlled steroid-
induced diabetes mellitus (glycosolated hemoglobin > 8%)
17. Patients with an acute viral hepatitis or a history of chronic or active HBV or HCV infection |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint of this study is the intracranial disease control rate (IC-DCR), which is defined as the percentage of patients whose intracranial response is a confirmed complete response (CR), partial response (PR) or stable disease (SD) assessed by investigators using modified RECIST 1.1 criteria. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Week 4, 8 and every week 8 |
|
| E.5.2 | Secondary end point(s) |
The secondary endpoints of this study are:
• Overall response rate, defined as the percentage of patients with a confirmed investigator-assessed overall CR, PR
using RECIST 1.1 criteria
• Duration of response for the subsets of patients with confirmed intracranial CR or, PR defined as the time from first
documented evidence of intracranial CR or PR until time of first documented intracranial disease progression or
death due to any cause
• Progression Free Survival (PFS), defined as the interval between the date of the first dose of study treatment and
the earliest date of intracranial or extra- cranial disease progression or death due to any cause
• Overall survival (OS), defined as the time from first dose of study treatment until death due to any cause
• The safety endpoint of this study is the assessment of safety and tolerability of buparlisib, as measured by the
nature and events, clinically significant laboratory abnormalities, vital signs, ECG, ECHO and clinical
monitoring/observation.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| weeks, 4, 8 and every 8 weeks, safety parameter every 4 weeks |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | No |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 28 |
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