| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced non-resectable (Stage IIIc) or metastatic (Stage IV) melanoma |
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| E.1.1.1 | Medical condition in easily understood language |
| Melanoma, the most Dangerous form of skin cancer |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10053571 |
| E.1.2 | Term | Melanoma |
| E.1.2 | System Organ Class | 100000004864 |
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| 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 |
Part 1
To evaluate BGB324 safety in combination with dabrafenib/trametinib and to select the dose level of BGB324 for combination treatment with dabrafenib/trametinib in patients with advanced melanoma.
Part 2
To evaluate safety and efficacy of pembrolizumab and dabrafenib/trametinib in combination with BGB324 compared to pembrolizumab and dabrafenib/trametinib alone as first line treatment in patients with advanced melanoma.
Part 3
To explore safety and efficacy of pembrolizumab or dabrafenib/trametinib in combination with BGB324 and pembrolizumab or dabrafenib/trametinib alone as second line treatment in BRAF+ patients with advanced melanoma failing first line treatment in Part 2 of the study.
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| E.2.2 | Secondary objectives of the trial |
Part 1 and 2:
- PK of BGB324 in combination with pembrolizumab and dabrafenib/trametinib compared the PK of BGB324 monotherapy using data from previous clinical studies with BGB324
- PK of dabrafenib in combination With BGB324 compared to PK for dabrafenib administered in dabrafenib/trametinib combination (historical data)
- long term combined safety and efficacy profile of combination treatment of BGB324 and standard therapy to standard treatment alone
Part 3:
To evaluate safety and efficacy of BGB324 in combination with pembrolizumab or dabrafenib/trametinib as second line treatment in melanoma patients failing first line treatment with dabrafenib/trametinib or pembrolizumab respectively in combination with BGB324 as first line treatment in patients BRAF+ at randomisation
Exploratory
- evaluate the predictive value of candidate biomarkers in blood, urine or tissue
- assess effects of BGB324 on biological markers
- Health-related Quality of Life of melanoma patients
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion Criteria
1. Patients able to understand and willing to sign a written protocol specific informed consent and older than 18 years at the time of consent.
2. Histologically confirmed advanced cutaneous melanoma that is either non-resectable (Stage IIIc) or metastatic (Stage IV) with:
a. At least one measurable lesion as defined by RECIST 1.1 on CT or MRI scan and
b. Documented progression of ≥1 measurable lesion
3. ECOG performance status 0 to 2 at screening
4. Availability of fresh or archival tumour tissue sample suitable for evaluation of predictive biomarkers of response
5. Male patients with female partners of childbearing potential and female patients of childbearing potential willing to practice highly effective birth control while onfrom screening, throughout the study and for at least 3 months following the last dose of study treatment (and if female of childbearing potential, has a negative serum pregnancy test in the 7 days before the first dose of BGB324study treatment) |
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| E.4 | Principal exclusion criteria |
1.Prior first line systemic treatment for the treatment of Stage IIIb or Stage IIIc melanoma, including BRAF or MEK inhibitor
2.Symptomatic central nervous system metastatic lesions as determined by Investigator
3.History of malignancy other than melanoma within the last 2 years (basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix; isolated elevation in prostate specific antigen in the absence of histological or radiographic evidence of prostate cancer is allowed)
4.History of or current active autoimmune diseases. Patients with vitiligo, or other non-serious autoimmune diseases based on the Investigator’s assessment, are NOT excluded
5.FOR BRAF pos PATS: History of retinal vein occlusion (RVO) or ongoing retinal pigment epithelial detachment (RPED)
6.History of the following cardiac conditions:
a.Congestive cardiac failure of >Grade 2 severity according to the New York Heart Association (defined as symptomatic at less than ordinary levels of activity)
b.Ischemic cardiac event including myocardial infarction within 3 months prior to first dose of study treatment
c.Uncontrolled cardiac disease, including unstable angina, uncontrolled hypertension or need to change medication within 6 weeks of provision of consent due to lack of disease control
d.History or presence of sustained bradycardia (≤55 bpm), left bundle branch block, cardiac pacemaker or ventricular arrhythmia. Note: Patients with a supraventricular arrhythmia requiring medical treatment, but with a normal ventricular rate are eligible
e.Family history of long QTc syndrome; personal history of long QTc syndrome or previous drug-induced QTc prolongation
7.Abnormal left ventricular ejection fraction on echocardiography or Multi Gated Acquisition (MUGA) Scan (MUGA) (less than the lower limit of normal for a patient of that age at the treating institution or <45%, whichever is lower)
8.Current treatment with any agent known to cause Torsade de Points which cannot be discontinued at least five half-lives or two weeks prior to the first dose of study treatment
9.Screening 12-lead ECG with a measurable QTc interval calculated according to Fridericia’s correction (QTcF) >450ms
10.Inadequate organ function as defined by the following laboratory values:
a.Haematological: absolute neutrophil count ≤1.5 x 109/L, platelets ≤100 x 109/L, haemoglobin ≤9.0 g/dL
b.Renal: serum creatinine ≥1.5 x institutional upper limit of normal (ULN) and estimated glomerular filtration rate of ≤50 mL/minute
c.Hepatic: total bilirubin ≥1.5 x institutional ULN, alanine transaminase and aspartate transaminase ≥2.5 x institutional ULN or ≥5.0 x institutional ULN if liver metastases are present
d.Coagulation: international normalized ratio or prothrombin time and activated partial thromboplastin time ≥1.5 x institutional ULN if not using anticoagulants (if patient is receiving anticoagulant therapy value must be within therapeutic range for the condition being treated)
11.Ongoing infection requiring systemic treatment. Patients who are on prophylactic anti infectives or who have been afebrile for 48 hours following the initiation of treatment are eligible
12.Known active infection with human immunodeficiency virus (HIV), hepatitis B or C viruses (screening not required)
•Patients who have a history of hepatitis B infection are eligible provided they are hepatitis B surface antigen negative
•Patients who have a history of hepatitis C infection are eligible provided they have no evidence of hepatitis C ribonucleic acid using a quantitative polymerase chain reaction assay at least 6 months after completing treatment for hepatitis C infection
13.Any conditions which may have significant impact on absorption of BGB324 or dabrafenib or trametinib from the gastrointestinal tract
14.Any severe or uncontrolled medical conditions which may jeopardise patient safety, compliance with the protocol, or interpretation of study results in the opinion of the Investigator
15Current or recent (within last year) systemic treatment with immunosuppressive or immunomodulating agents, or other medications known to have significant impact on the immune system. Topical agents and inhaled steroids are permitted
16.Treatment with any medication with a narrow therapeutic index which is predominantly metabolised by cytochrome P450 (CYP)3A4 and cannot be stopped before the first dose of study treatment
17.Known hypersensitivity to pembrolizumab or BGB324 or excipients (including lactose intolerance)
18.FOR BRAF POS PATS: Known hypersensitivity to dabrafenib or trametinib (including lactose intolerance)
19.Treatment with histamine receptor 2 inhibitors, proton pump inhibitors or antacids in the 7 days before the first dose of study treatm.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Efficacy Endpoint
Objective Response Rate (ORR) assessed according to RECIST Version 1.1
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Primary Efficacy Endpoint
Objective Response Rate (ORR) assessed according to RECIST Version 1.1 - To be evaluated every third cycle of study treatment |
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| E.5.2 | Secondary end point(s) |
Secondary Efficacy Endpoints
• Progression Free Survival (PFS)
• Duration of response- defined as time from objective response until disease progression (clinical or RECIST confirmed)
• Overall Survival (OS)
Exploratory Efficacy Endpoints
• ORR assessed according to irRC
• Biomarkers
• HRQoL using the EuroQoL instrument and European Organisation for Research and Treatment Cancer (EORTC) quality of life questionnaire core (QLQ-C30)
Pharmacokinetic Endpoints
Plasma concentrations of BGB324 and dabrafenib, Area Under the Curve within a dosing interval (AUC0-T) and Average Concentration (Cav) estimated at steady state.
Safety Endpoints
Safety endpoints are based on continuous monitoring of adverse events and other safety parameters (laboratory safety assessments, vital signs 12-lead ECGs, physical examination and skin examination and performance status using the ECOG score).
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| 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 | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| first administration to new population/indication |
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| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| 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 | Yes |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| 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
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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