Clinical Trials /

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

NCT02834364

Description:

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).

Related Conditions:
  • Multiple Myeloma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: BRAF/MEK Inhibition in Relapsed/Refractory Multiple Myeloma (BIRMA)
  • Official Title: LGX818 in Combination With MEK162 in Refractory or Relapsed Multiple Myeloma Patients With BRAFV600E or BRAFV600K Mutation

Clinical Trial IDs

  • ORG STUDY ID: CLGX818ADE01T
  • SECONDARY ID: 2014-004597-42
  • NCT ID: NCT02834364

Conditions

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

Interventions

DrugSynonymsArms
EncorafenibLGX818single arm
BinimetinibMEK162single arm

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
single armExperimentalEncorafenib 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.
  • Encorafenib
  • Binimetinib

Eligibility Criteria

        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

        Exclusion Criteria:

          1. Patient with prior treatment with MEK and/or RAF inhibitors

          2. Systemic AL amyloidosis (except for patients with AL amyloidosis of the skin or the
             bone marrow)

          3. 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.

          4. 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)

          5. History of retinal degenerative disease

          6. Plasma cell leukaemia which requires the presence of 20% of plasma cell in peripheral
             blood leukocytes and at least 2/nl.

          7. 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.

          8. 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.

          9. 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.

         10. 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;

               1. LVEF < 50% as determined by ECHO, or uncontrolled hypertension despite medical
                  treatment (please refer to WHO ISH guidelines)

               2. Clinically significant resting bradycardia, unstable angina pectoris ≤ 3 months
                  prior to starting study drug, history of acute coronary syndromes (including
                  myocardial infarction, coronary artery bypass grafting, coronary angioplasty, or
                  stenting) <6 months prior to screening

               3. QTcF > 450 msec

               4. patients with acute diffuse infiltrative pulmonary and pericardial disease

         11. Significant hepatic dysfunction (serum bilirubin ≥ 2 mg/dl or ASAT and/or ALAT ≥ 2.5
             times normal level), unless related to myeloma

         12. Active hepatitis B, and/or active hepatitis C infection

         13. Impairment of gastrointestinal (GI) function or GI disease that may significantly
             alter the absorption of oral LGX818/MEK162 (e.g., ulcerative diseases, uncontrolled
             nausea,vomiting, diarrhea, malabsorption syndrome, small bowel resection).

         14. Gilbert´s syndrome

         15. Patients who have neuromuscular disorders that are associated with elevated CK (e.g.,
             inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal
             muscular atrophy)

         16. Patients who are planning on embarking on a new strenuous exercise regimen after first
             dose of study treatment. Note: Muscular activities, such as strenuous exercise, that
             can result in significant increases in plasma CK levels should be avoided while on
             MEK162 treatment

         17. Patients known to be HIV-positive

         18. Patients with active, uncontrolled infections (patients successful treated with
             antimicrobial therapy may be enrolled at the discretion of the investigator).

         19. Patient is receiving chronic treatment with systemic steroids or another
             immuno-suppressive agent at start of study treatment. Note: Topical applications
             (e.g., rash), inhaled sprays (e.g., obstructive airways diseases), eye drops or local
             injections (e.g., intra-articular) and the use of systemic steroids up to a prednisone
             equivalent of 10 mg daily are allowed.

         20. Patient has consumed Seville oranges, grapefruit, grapefruit hybrids, pomelos and
             exotic citrus fruits (as well as their juices) during the last 7 days prior to start
             of treatment. Regular orange juice is permitted.

         21. Second malignancy within the past 3 years except:

               1. Adequately treated basal cell or squamous cell skin cancer (adequate wound
                  healing is required prior to entry in the study)

               2. Adequately treated carcinoma in situ of the cervix,

               3. Prostate Cancer not requiring systemic treatment or under anti-hormonal treatment
                  and PSA-level below upper level of normal range.

               4. Ductal breast carcinoma in situ with full surgical resection (i.e., negative
                  margins),

               5. solid tumor treated curatively, and without evidence of recurrence for at least 3
                  years prior to study entry

               6. Similar condition with an expectation of > 95 % 5-year disease free survival

         22. Patients with any of the following laboratory values at Screening/Baseline.

               1. Absolute neutrophil count (ANC) <1,000/mm3 [1.0 x 109/L] without Growth factor
                  support in the last 7 days

               2. Platelets ≤ 50000/mm3 [50 x 109/L] ; patients with platelets 75000- 50000/ mm3
                  are eligible if thrombocytopenia is confirmed as related to myeloma bone marrow
                  infiltration and pt. is able to receive thrombocyte concentrates

               3. Hemoglobin < 8.0 g/ dl (unless confirmed related to myeloma bone marrow
                  infiltration and pt. able to receive blood transfusions)

               4. Serum creatinine >2 x ULN or calculated or directly measured CrCl ≤ 45 ml/min;
                  patients with creatinin-clearance between 30-45 ml/min can be enrolled with
                  approval by the coordinating investigator.

         23. Clinically significant autoimmune haemolytic anaemia with positive Coombs test or
             immune thrombocytopenia

         24. Patient is a woman of child-bearing potential, UNLESS they are using a double barrier
             method for birth control throughout the trial.

               1. Hormonal contraceptives may be affected by cytochrome P450 interactions, and are
                  therefore considered neither indicated nor effective.

               2. Adequate barrier methods of contraception include: diaphragm, condom (by the
                  partner), intrauterine device (copper), sponge or spermicide.

               3. Reliable contraception has to be maintained throughout the study and for 12 weeks
                  after study drug discontinuation.

               4. Women are considered post-menopausal and not of child bearing potential if they
                  have had 12 months of natural (spontaneous) amenorrhea with an appropriate
                  clinical profile (e.g., age appropriate, history of vasomotor symptoms) or six
                  months of spontaneous amenorrhea with serum FSH levels > 40 mIU/mL or have had
                  surgical bilateral oophorectomy (with or without hysterectomy) at least six weeks
                  ago. In the case of oophorectomy alone, only when the reproductive status of the
                  woman has been confirmed by follow up hormone level assessment is she considered
                  not of child bearing potential

         25. Sexually active males unless they agree to use a condom during intercourse while
             taking the drug. This practice should be continued for another 12 weeks after stopping
             treatment. Also they should not father a child during the study period or the 12 weeks
             post study time.

             A condom is also required to be used by vasectomized men in order to prevent delivery
             of the drug via seminal fluid;

         26. Medical, psychiatric, cognitive or other conditions that may compromise the patient's
             ability to understand the patient information, give informed consent, comply with the
             study protocol or complete the study.

         27. Patients taking non-topical medication known to be a strong inhibitor of CYP3A4.
             However patients who either discontinue their treatment or switch to another
             medication at least three days prior to registration are eligible.

         28. Participation in other clinical trials within 1 month prior to enrolment except
             patients for supportive care studies and vaccination studies. This does not include
             long-term follow-up periods without active drug treatment of previous studies during
             the last 6 months.

         29. Patient has other concurrent severe and/or uncontrolled medical condition that would,
             in the investigator's judgment contraindicate her participation in the clinical study
             (e.g. uncontrolled diabetes, chronic pancreatitis, active chronic hepatitis ).

        No subject will be allowed to be enrolled in this trial more than once.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Response is assessed by quantification of monoclonal protein in serum and urine and by immunofixation of serum and urine
Time Frame:response assessment is performed after each cycle of therapy (28 days)
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Correlation of overall survival with cytogenetic characteristics deletion 17p and translocation 4;14
Time Frame:Time from start of therapy until timepoint of death will be measured for all patients up to 30 months.
Safety Issue:
Description:
Measure:MEK162 Response will be categorized according to International Myeloma Working Group (IMWG) Uniform Response Criteria
Time Frame:response assessment after each cycle of therapy (28 days)
Safety Issue:
Description:
Measure:To evaluate the adverse events profile of LGX818/MEK162 in this indication (with respect to all adverse events and serious adverse events)
Time Frame: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.
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of Heidelberg Medical Center

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