| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed or refractory Multiple Myeloma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Relapsed or refractory Multiple Myeloma |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.1 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10028229 |
| E.1.2 | Term | Multiple myelomas |
| E.1.2 | System Organ Class | 100000004851 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| • The primary objective of this study is to demonstrate the therapeutic efficacy of LGX818/MEK162 to decrease myeloma tumour burden |
|
| E.2.2 | Secondary objectives of the trial |
• To provide information on survival related parameters for patients being treated with LGX818/MEK162
• To further characterize responses after treatment with LGX818/MEK162
• To evaluate the adverse events profile of LGX818/MEK162 in this indication (with respect to related adverse events of CTCAE grade 1 and 2 and all adverse events of grade 3 and 4 and SAEs)
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Patient has provided a signed study Informed Consent Form prior to any studyspecific 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 BRAFV600Emutation 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 and confirmed by DNA sequencing of the respective 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 co-morbid conditions) (see Appendix III)
7.Negative pregnancy test within 72 hours of inclusion (women of childbearing potential)
8. 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).
9.All patients must agree to abstain from donating blood while on study
10.Adequate cardiac function:
• left ventricular ejection fraction (LVEF) ≥ 50% as determined by a echocardiogram
• QTc interval ≤ 450 ms
11.Ability of subject to take oral medications
12.Ability of subject to understand character and individual consequences of clinical trial
|
|
| E.4 | Principal 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
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.
9.Patient is concurrently using other approved antineoplastic or any investigational agents in the last 14 days prior to start of treatment.
10.Impaired cardiovascular function or clinical significant cardiovarscular 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;
a.LVEF < 50% as determined by ECHO, or uncontrolled hypertension despite medical treatment (please refer to WHO ISH guidelines)
b.Clinically significant resting bradycardia, unstable angina pectoris ≤ 3 months prior to starting study drug, history of acute coronary syndromes <6 months prior to screening
c.QTcF > 450 msec
d.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)
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
14.Gilbert´s Syndrom
15.Patients who have neuromuscular disorders that are associated with elevated CK
16.Patients who are planning on embarking on a new strenuous exercise regimen after first dose of study treatment
17.Patients known to be HIV-positive
18.Patients with active, uncontrolled infections
19.Patient is receiving chronic treatment with systemic steroids or another immuno-suppressive agent at start of study treatment.
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.
21.Second malignancy within the past 3 years except:
a. Adequately treated basal cell or squamous cell skin cancer
b. Adequately treated carcinoma in situ of the cervix,
c. Prostate Cancer not requiring systemic treatment or under anti-hormonal treatment and PSA-level below upper level of normal range.
d. Ductal breast carcinoma in situ with full surgical resection (i.e., negative margins),
e. solid tumor treated curatively, and without evidence of recurrence for at least 3 years prior to study entry
f. Similar condition with an expectation of > 95 % 5-year disease free survival
22.Patients with any of the following laboratory values at Screening/Baseline.
a. Absolute neutrophil count (ANC) <1,000/mm3 [1.0 x 109/L] without Growth factor support in the last 7 days
b. Platelets ≤ 50000/mm3 [50 x 109/L]
c. Hemoglobin < 8.0 g/ dl
d. Serum creatinine >2 x ULN or calculated or directly measured CrCl ≤ 45 ml/min;
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.
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.
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.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| • The first primary endpoint is best ORR during treatment. |
|
| E.5.2 | Secondary end point(s) |
• Progression-free survival
• Overall survival
• Time-to-progression (TTP)
• Duration of response (DOR)
• Disease-free survival (DFS)
• Time-to best-objective response
• Time-to-objective Response
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The study is considered completed 3 months after all patients have experienced a progressive disease event. This includes progressive disease during study treatment as well as after discontinuation of the study drug for toxicity or other reasons. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
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