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
Overview
- Phase
- Phase 1
- Status
- Completed
- Sponsor
- Haukeland University Hospital
- Enrollment
- 74
- Locations
- 5
- Primary Endpoint
- Objective Response Rate (ORR) assessed according to RECIST Version 1.1
Overview
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,
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
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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
Arms & Interventions
dabrafenib and trametinib
Dabrafenib capsules:150 mg twice daily Trametinib tablets: 2 mg once daily
Treatment until disease progression, or unacceptable toxicity
Intervention: dabrafenib and trametinib (Drug)
BGB324 + pembrolizumab
BGB324 capsules, 200 mg once daily + pembrolizumab 2 mg/kg IV every 3. week
Treatment until disease progression, or unacceptable toxicity
Intervention: BGB324+pembrolizumab (Drug)
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
Intervention: BGB324+dabrafenib and trametinib (Drug)
pembrolizumab
Pembrolizumab 2 mg/kg IV every 3. week
Treatment until disease progression, or unacceptable toxicity
Intervention: pembrolizumab (Drug)
Outcomes
Primary Outcomes
Objective Response Rate (ORR) assessed according to RECIST Version 1.1
Time Frame: through study completion, an average of 1 year
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Time Frame: through study completion, an average of 1 year
Secondary Outcomes
- Progression Free Survival (PFS)(ongoing evaluation, assessed up to 5 years)
- Duration of response(ongoing evaluation, an average of 1 year)
- Overall Survival (OS)(ongoing evaluation, an average of 2 year)