Patients With BRAFV600 E or BRAFV600K Mutation, Relapsed or Refractory Multiple Myeloma
Conditions
Brief summary
Trial for patients with refractory multiple myeloma after failure of at least two treatment regimens and with BRAFV600E/K Mutation to evaluate the efficacy of the kinase inhibitors Encorafenib (LGX818 in) combination with Binimetinib (MEK162).
Detailed description
An open-label, single-arm, multi-centre phase II trial for patients with refractory multiple myeloma and with BRAFV600E/K Mutation to evaluate the efficacy of the kinase inhibitors Encorafenib (LGX818 in) combination with Binimetinib (MEK162). The patients must have received at least two prior therapy regimen (at least one immunomodulatory drug and one proteasome inhibitor). The subjects receive LGX 818 450 mg. p.o. once daily and MEK 162 45 mg p.o. twice daily until disease progression or toxicity requiring discontinuation of treatment. 1 cycle is defined as 28 days.
Interventions
DRUGEncorafenib
450 mg p.o. once daily. One cycle is defined as 28 days
DRUGBinimetinib
45 mg p.o. twice daily. One cycle is defined as 28 days
Sponsors
Array BioPharma
German Cancer Research Center
Coordinating Centre for Clinical Trials Heidelberg
University Hospital Heidelberg
University of Heidelberg Medical Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patient has provided a signed study Informed Consent Form prior to any study-specific procedure and is able to comply with protocol requirements 2. Patients with multiple myeloma,relapsed or refractory after failure of two or more lines of systemic treatments. All patients must have received at least one immunomodulatory drug (IMiD) and a proteasome inhibitor. Multiple myeloma requiring systemic therapy must have been confirmed in the medical history of the patients with criteria established by the International Myeloma Working Group (IMWG) (Rajkumar V et al. Lancet International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet 2014; 15: 538-548) 3. Written confirmation of BRAFV600E mutation or BRAFV600K mutation in in the majority of myeloma cells, defined by positive IHC staining with mutations specific antibody of ≥ 50% in the respective biopsy, confirmed by DNA sequencing of the corresponding codon 4. Measurable disease, as defined as: Measurable levels of myeloma paraprotein in serum (≥ 0.5 g/dL) or urine (≥ 0.2 g/24 hours) or FLC of involved light chain \> 100mg/l and abnormal FLC-ratio 5. Age ≥18 6. WHO performance status 0-3 (WHO 3 is allowed only when caused by MM and not by comorbid conditions) (see Appendix 3) 7. Negative pregnancy test within 72 hours of inclusion (women of childbearing potential): For all men and women of childbearing potential: patients must be willing and capable to use adequate contraception during the complete therapy (see also
Exclusion criteria
). 8. All patients must agree to abstain from donating blood while on study 9. Adequate cardiac function: left ventricular ejection fraction (LVEF) ≥ 50% as determined by an echocardiogram, QTc interval ≤ 450 ms 10. Ability of subject to take oral medications 11. Ability of subject to understand character and individual consequences of clinical trial
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Response is assessed by quantification of monoclonal protein in serum and urine and by immunofixation of serum and urine | response assessment is performed after each cycle of therapy (28 days) |
Secondary
| Measure | Time frame |
|---|---|
| Correlation of overall survival with cytogenetic characteristics deletion 17p and translocation 4;14 | Time from start of therapy until timepoint of death will be measured for all patients up to 30 months. |
| MEK162 Response will be categorized according to International Myeloma Working Group (IMWG) Uniform Response Criteria | response assessment after each cycle of therapy (28 days) |
| To evaluate the adverse events profile of LGX818/MEK162 in this indication (with respect to all adverse events and serious adverse events) | Observation period starts with the first administration of study drug and ends 30 days after the last administration of study drug or upon start of of the subsequent therapy, whatever comes first. |
Other
| Measure | Time frame |
|---|---|
| Target inhibition will be analyzed in bone marrow biopsies by detection of BRAF/MEK inhibition using immunochemistry and whole genome sequencing. | at day 28 of the first treatment cycle and at time of progression, assessed up to 30 months |
| Comparative genome sequencing at start of study treatment and at timepoint of progression to investigate the potential mechanism of resistance to combined BRAF/MEK inhibition | start of study treatment and at timepoint of progression, assessed up to 30 months |
| Correlation of response rates and Adverse Events rates with the cytogenetic characteristics deletion 17p and translocation 4;14 | 9 months after end of study (final data analysis) |
Countries
Germany
Outcome results
None listed