BGB324 in Combination With Pembrolizumab or Dabrafenib/Trametinib in Metastatic Melanoma

Sponsor

Haukeland University Hospital (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT02872259

Collaborator

BerGenBio ASA (Industry)

Enrollment

Locations

Arms

77.5

Anticipated Duration (Months)

14.8

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of the study is to assess the safety and efficacy of BGB324 given together with standard treatment, pembrolizumab or dabrafenib and trametinib, compared to standard treatment alone,

Condition or Disease	Intervention/Treatment	Phase
Melanoma	Drug: BGB324+pembrolizumab Drug: BGB324+dabrafenib and trametinib Drug: pembrolizumab Drug: dabrafenib and trametinib	Phase 1/Phase 2

Detailed Description

This is an investigator initiated randomized randomized clinical phase 1b/2 clinical trial comparing safety and efficacy of the Axl inhibitor BGB324 in combination with pembrolizumab or dabrafenib+trametinib with that of pembrolizumab or dabrafenib+trametinib alone. Patients with non-resectable stage III or stage IV melanoma will be stratified based on BRAF mutation and tumor load to start dabrafenib+trametinib (BRAF mutation and high tumor load) or pembrolizumab (BRAF wild type or BRAF mutation and low tumor load) in first line. The patients will be randomized 2:1 to receive BGB324 in combination with pembrolizumab or dabrafenib+trametinib or to receive pembrolizumab or dabrafenib+trametinib alone. A 3+3 dose escalation will be performed for the combination of BGB324 and dabrafenib+trametinib. There is a major focus on predictive markers of treatment response evaluated in blood samples and biopsies.

Study Design

Study Type:

Interventional

Actual Enrollment :

74 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase Ib/II Randomised Open Label Study of BGB324 in Combination With Pembrolizumab or Dabrafenib/Trametinib Compared to Pembrolizumab or Dabrafenib/Trametinib Alone, in Patients With Advanced Non-resectable (Stage IIIc) or Metastatic (Stage IV) Melanoma

Actual Study Start Date :

Feb 13, 2017

Anticipated Primary Completion Date :

Aug 1, 2023

Anticipated Study Completion Date :

Aug 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: BGB324 + pembrolizumab BGB324 capsules, 200 mg once daily + pembrolizumab 2 mg/kg IV every 3. week Treatment until disease progression, or unacceptable toxicity	Drug: BGB324+pembrolizumab Combination Other Names: Keytruda
Experimental: BGB324 + dabrafenib and trametinib BGB324 capsules: Dose finding part of the study will determine if 100 mg once daily should be used for main part of the study or if 200 mg once daily once daily should be used. Dabrafenib capsules: 150 mg twice daily Trametinib tablets: 2 mg once daily Treatment until disease progression, or unacceptable toxicity	Drug: BGB324+dabrafenib and trametinib Combination Other Names: Tafinlar Mekinist
Active Comparator: pembrolizumab Pembrolizumab 2 mg/kg IV every 3. week Treatment until disease progression, or unacceptable toxicity	Drug: pembrolizumab Monotherapy Other Names: Keytruda
Active Comparator: dabrafenib and trametinib Dabrafenib capsules:150 mg twice daily Trametinib tablets: 2 mg once daily Treatment until disease progression, or unacceptable toxicity	Drug: dabrafenib and trametinib Combination Other Names: Tafinlar Mekinist

Outcome Measures

Primary Outcome Measures

Objective Response Rate (ORR) assessed according to RECIST Version 1.1 [through study completion, an average of 1 year]
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [through study completion, an average of 1 year]

Secondary Outcome Measures

Progression Free Survival (PFS) [ongoing evaluation, assessed up to 5 years]
From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 5 years
Duration of response [ongoing evaluation, an average of 1 year]
through study completion, an average of 1 year
Overall Survival (OS) [ongoing evaluation, an average of 2 year]
through study completion, an average of 2 year

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients able to understand and willing to sign a written protocol specific informed consent and 18 years or older at the time of consent
Histologically confirmed advanced cutaneous melanoma that is either non-resectable (Stage IIIc) or metastatic (Stage IV) with:
At least one measurable lesion as defined by RECIST 1.1 on CT or MRI scan and
Documented progression of ≥1 measurable lesion
ECOG score 0 to 2 at screening
Availability of fresh or archival tumour tissue sample suitable for evaluation of predictive biomarkers of response
Male patients with female partners of childbearing potential and female patients of childbearing potential willing to practice highly effective birth control from 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 study treatment)

Exclusion Criteria:

Prior first line systemic treatment for the treatment of Stage IIIb or Stage IIIc melanoma, including BRAF or MEK inhibitor (adjuvant immunomodulating agent treatment more than 6 months prior to first dose of study treatment is allowed)
Symptomatic central nervous system metastatic lesions as determined by the Investigator (patients with radiographically stable, asymptomatic lesions previously irradiated or surgically resected are eligible provided there is no need for systemic corticosteroids and treatment was completed at least 4 weeks before the first dose of study treatment)
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)
History of or current active autoimmune diseases, including but not limited to inflammatory bowel diseases, rheumatoid arthritis, autoimmune thyroiditis, autoimmune hepatitis, systemic sclerosis (scleroderma and variants), systemic lupus erythematosus, autoimmune vasculitis, autoimmune neuropathies (e.g. Guillain-Barré syndrome). Patients with vitiligo, or other non-serious autoimmune diseases based on the Investigator's assessment, are NOT excluded
ONLY FOR BRAF POSITIVE PATIENTS: History of retinal vein occlusion (RVO) or ongoing retinal pigment epithelial detachment (RPED)
History of the following cardiac conditions:
Congestive cardiac failure of >Grade 2 severity (see Appendix 1) according to the New York Heart Association (defined as symptomatic at less than ordinary levels of activity)
Ischemic cardiac event including myocardial infarction within 3 months prior to first dose of study treatment
Uncontrolled cardiac disease, including unstable angina, uncontrolled hypertension (i.e. sustained systolic blood pressure >160 mmHg or diastolic blood pressure >90 mmHg), or need to change medication within 6 weeks of provision of consent due to lack of disease control
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
Family history of long QTc syndrome; personal history of long QTc syndrome or previous drug-induced QTc prolongation
Known abnormal left ventricular ejection fraction on echocardiography or Multi Gated Acquisition (MUGA) scan (less than the lower limit of normal for a patient of that age at the treating institution or <45%, whichever is lower)
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
Screening 12-lead ECG with a measurable QTc interval calculated according to Fridericia's correction (QTcF) >450 ms
Inadequate organ function as defined by the following laboratory values:
Haematological: absolute neutrophil count ≤1.5 x 109/L, platelets ≤100 x 109/L, haemoglobin ≤9.0 g/dL
Renal: serum creatinine ≥1.5 x institutional upper limit of normal (ULN) and creatinine clearance ≥50 mL/minute
Hepatic: total bilirubin ≥1.5 x institutional ULN, alanine transaminase (ALT) and aspartate transaminase (AST) ≥2.5 x institutional ULN or ≥5.0 x institutional ULN if liver metastases are present
Coagulation: international normalised 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)
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
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

Any conditions which may have significant impact on absorption of BGB324 or dabrafenib or trametinib from the gastrointestinal tract (including but not limited to, celiac disease or Crohn's disease, gastric or bowel resection)
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
Current or recent (within last year) systemic treatment with immunosuppressive or immunomodulating agents (including systemic steroids intended for immunosuppressive effect), or other medications known to have significant impact on the immune system. Topical agents and inhaled steroids are permitted
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
Known hypersensitivity to pembrolizumab or BGB324 or excipients (including lactose intolerance)
ONLY FOR BRAF POSITIVE PATIENTS: Known hypersensitivity to dabrafenib or trametinib (including lactose intolerance)
Treatment with histamine receptor 2 inhibitors, proton pump inhibitors or antacids in the 7 days before the first dose of study treatment
Treatment with more than 40 mg prednisolone (or equivalent dose of systemic corticosteroid) which cannot be discontinued up to one week prior to starting BGB324. During the study this exclusion criteria is only applicable for patients receiving BGB324.

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Haukeland University Hospital	Bergen	Norway	5021
2	Akershus Univerisity Hospital	Lørenskog	Norway	1478
3	Oslo University Hospital, Radiumhospitalet	Oslo	Norway	0424
4	University Hospital of North Norway	Tromsø	Norway	9038
5	St. Olavs Hospital	Trondheim	Norway	7006