BRAF/MEK Inhibition in Relapsed/Refractory Multiple Myeloma (BIRMA)

NCT02834364 | Completed Phase 2

• 2 other identifiers: CLGX818ADE01T2014-004597-42
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 7

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).

Conditions

Relapsed or Refractory Multiple Myeloma; Patients With BRAFV600 E or BRAFV600K Mutation

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (3)

• 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 Outcomes (3)

• 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)

• 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

Study Arms (1)

single arm

EXPERIMENTAL

Encorafenib 450 mg. p.o.once daily and Binimetinib 45 mg p.o. twice daily until disease progression or toxicity requiring discontinuation of treatment. 1 cycle is defined as 28 days.

Drug: Encorafenib; Drug: Binimetinib

Interventions

Encorafenib DRUG

450 mg p.o. once daily. One cycle is defined as 28 days

Also known as: LGX818

single arm

Binimetinib DRUG

45 mg p.o. twice daily. One cycle is defined as 28 days

Also known as: MEK162

single arm

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patient has provided a signed study Informed Consent Form prior to any study-specific procedure and is able to comply with protocol requirements
• 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)
• 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
• 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
• Age ≥18
• WHO performance status 0-3 (WHO 3 is allowed only when caused by MM and not by comorbid conditions) (see Appendix 3)

You may not qualify if:

• All patients must agree to abstain from donating blood while on study
• Adequate cardiac function: left ventricular ejection fraction (LVEF) ≥ 50% as determined by an echocardiogram, QTc interval ≤ 450 ms
• Ability of subject to take oral medications
• Ability of subject to understand character and individual consequences of clinical trial
• Patient with prior treatment with MEK and/or RAF inhibitors
• Systemic AL amyloidosis (except for patients with AL amyloidosis of the skin or the bone marrow)
• Patients with meningeosis or central nervous system lesion(s) caused by multiple myeloma. However, patients treated with stereotactic radiotherapy or surgery are eligible if patient remained without evidence of CNS disease progression ≥ 4 weeks.
• History or current evidence of retinal vein occlusion (RVO) or predisposing factors to RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes)
• History of retinal degenerative disease
• Plasma cell leukaemia which requires the presence of 20% of plasma cell in peripheral blood leukocytes and at least 2/nl.
• Patient has received radiotherapy (including therapeutic radioisotopes) ≤ 21 days, if not restricted to a single osteolytic lesion, or has not recovered from side effects of such therapy.
• Patient has had major surgery within 21 days prior to starting study drug or has not recovered from major side effects of the surgery. Kyphoplasty as prevention of skeletal related events is allowed.
• Patient is concurrently using other approved antineoplastic or any investigational agents in the last 14 days prior to start of treatment. Note: patients may have received a cumulative dose of up to 160 mg of dexamethasone or equivalent as emergency therapy within 4 weeks prior to study entry.
• Impaired cardiovascular function or clinical significant cardiovascular disease including any of the following: Symptomatic chronic heart failure, history or current evidence of clinically significant cardiac arrhythmia and/or conduction abnormality \<6 months prior to Screening except atrial fibrillation and paroxysmal supraventricular tachycardia;
• LVEF \< 50% as determined by ECHO, or uncontrolled hypertension despite medical treatment (please refer to WHO ISH guidelines)

Sponsors & Collaborators

• University of Heidelberg Medical Center: lead
• Array BioPharma: collaborator
• German Cancer Research Center: collaborator
• Coordinating Centre for Clinical Trials Heidelberg: collaborator
• University Hospital Heidelberg: collaborator

Study Sites (7)

Universitätsklinikum Köln, Klinik I Innere Medizin

Cologne, D-50937, Germany

Location

Mediz. Klinik und Poliklinik 1, Universitätsklinikum Dresden

Dresden, 01307, Germany

Location

Universitätsklinikum Frankfurt, Medizinische Klinik II

Frankfurt am Main, D-60590, Germany

Location

University Hospital Heidelberg, Med. Klinik V

Heidelberg, D-69120, Germany

Location

Universitätsklinikum Münster, Med. Klinik und Poliklinik A

Münster, 48149, Germany

Location

Universitätsklinikum Tübingen, Medizinische Klinik II

Tübingen, D-72076, Germany

Location

Universitätsklinikum Würzburg, Medizinische Klinik und Poliklinik II

Würzburg, D-97080, Germany

Location

Related Publications (1)

• Giesen N, Chatterjee M, Scheid C, Poos AM, Besemer B, Miah K, Benner A, Becker N, Moehler T, Metzler I, Khandanpour C, Seidel-Glaetzer A, Trautmann-Grill K, Kortum KM, Muller-Tidow C, Mechtersheimer G, Goeppert B, Stenzinger A, Weinhold N, Goldschmidt H, Weisel K, Raab MS. A phase 2 clinical trial of combined BRAF/MEK inhibition for BRAFV600E-mutated multiple myeloma. Blood. 2023 Apr 6;141(14):1685-1690. doi: 10.1182/blood.2022017789.

  PMID: 36608320 DERIVED

MeSH Terms

Conditions

Recurrence; Multiple Myeloma

Interventions

encorafenib; binimetinib

Condition Hierarchy (Ancestors)

Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases

Study Officials

• Marc S. Raab, PD Dr. med.

  Medizinische Klinik V, University Hospital Heidelberg

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: PD Dr. med

Study Record Dates

• First Submitted: June 13, 2016
• First Posted: July 15, 2016
• Study Start: June 1, 2016
• Primary Completion: March 29, 2023
• Study Completion: March 29, 2023
• Last Updated: November 24, 2023

Record last verified: 2023-11

Locations

DE (7)