Trial document





This trial has been registered retrospectively.
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  DRKS00009626

Trial Description

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Title

A Study of MEK162 in NRAS mutated metastatic melanoma patients with brain metastases

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Trial Acronym

Brain-MEK-Study

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URL of the Trial

[---]*

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Brief Summary in Lay Language

Early results have shown that MEK162 induces high response rates in patients with metastatic melanoma carrying the NRAS mutation.
Recent data indicate that for patients with brain metastasis harboring NRAS mutations, MEK 162 might be an effective treatment option.
There is a need to conduct clinical trials assessing the efficacy of MEK162 in this patient population with poor prognosis and with the highest medical need.

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Brief Summary in Scientific Language

This is an open-label, pilot phase II study of MEK162 in NRAS mutated metastatic melanoma patients with brain metastases to evaluate safety and tolerability of MEK162 and to evaluate progression-free survival (PFS) of MEK 162 (given 45mg BID orally).

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Organizational Data

  •   DRKS00009626
  •   2015/11/11
  •   [---]*
  •   yes
  •   Approved
  •   2014-0105, Kantonale Ethikkommission Zürich Stampfenbachstrasse 121 CH-8090 Zürich
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Secondary IDs

  • [---]*
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Health Condition or Problem studied

  •   C43 -  Malignant melanoma of skin
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Interventions/Observational Groups

  •   MEK 162, 45mg
    Dose route: oral
    Dose regimen: twice daily (b.i.d)
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Characteristics

  •   Interventional
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  •   Single arm study
  •   Open (masking not used)
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  •   Uncontrolled/Single arm
  •   Treatment
  •   Single (group)
  •   II
  •   No
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Primary Outcome

Primary objective:
To evaluate safety and tolerability of MEK162 (45mg orally, b.i.d) in patients with metastatic melanoma with brain metastases (Stage IV; AJCC)
The following adverse events will be collected according to NCI CTCAE version 4.0 for the safety analysis of MEK162:
- all AEs
- AEs related to study medication
- AEs grade 3 or 4
- AEs of special interest
- AEs leading to treatment interruption and discontinuation
- serious adverse events (SAEs)
- premature discontinuation from study and treatment
- dermatological assessment
- laboratory parameters
- study medication

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Secondary Outcome

Secondary objectives:
- To evaluate Overall Response Rate (ORR (Complete response (CR) + Partial Response (PR)), duration of response, time to response
To evaluate progression-free survival (PFS) of MEK 162
To investigate PFS in brain metastasis and compare with results from other trials in patients with non-CNS lesions
- To determine overall survival (OS), record quality of life (QoL), record the use of supportive drugs, such as dexamethasone and narcotics during the therapy
- harvest of tumor tissue for tranlational research in case the patient signed the corresponding informed consent

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Countries of Recruitment

  •   Switzerland
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Locations of Recruitment

  • University Medical Center 
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Recruitment

  •   Actual
  •   2015/09/29
  •   25
  •   Monocenter trial
  •   National
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Inclusion Criteria

  •   Both, male and female
  •   18   Years
  •   no maximum age
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Additional Inclusion Criteria

1. Subjects must provide written informed consent prior to performance of study specific procedures or assessments, and must be willing to comply with treatment and follow-up. Procedures conducted as part of the subject’s routine clinical management (e.g., blood count, imaging study) and obtained prior to signing of informed consent may be utilized for screening or baseline purposes provided these procedures are conducted as specified in the protocol.

2. Male or female ≥ 18 years of age

3. Histologically confirmed metastatic melanoma (Stage IV, AJCC) with documented mutational status (NRAS mutation)

4. Presence of brain metastases (pretreated, not pretreated, asymptomatic patients that are not eligible in other clinical trials or symptomatic patients). Pretreated patients should have documented progression of disease after previous treatment to be included in the trial. Symptomatic patients should have a stable or decreasing steroid dose.

5. Prior PD-1 antibody blockers and any other prior immunotherapy are allowed

6. Stable or decreasing corticosteroids dose within 1 week prior to study entry

7. Patients with either measurable or non-measurable disease (RECIST Version 1.1)

8. Present lesions must be measurable (either by CT-scan, MRI, or PET/CT)

9. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2

10. Patients must have recovered from all side-effects of their most recent systemic or local treatment for metastatic melanoma

11. Adequate hematologic, renal and liver function as defined by the following laboratory values performed within 7 days prior to initiation of dosing
- Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
- Platelet count ≥ 100 x 109/L
- Hemoglobin ≥ 9 g/dL
- Serum creatinine ≤ 1.5 times the upper limit of normal (ULN) or creatinine clearance (CrCl) > 50 mL/h by the Cockroft–Gault formula
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 times ULN (≤ 5 times ULN if considered due to tumor)
- Serum bilirubin ≤ 1.5 times ULN
- Alkaline phosphatase ≤ 2.5 times ULN (≤ 5 times ULN if considered due to tumor)
12. Adequate cardiac function:
• left ventricular ejection fraction (LVEF) ≥ 50% as determined by a multigated acquisition (MUGA) scan or echocardiogram,
• QTc interval ≤ 480 ms;
13. Able to take oral medications;
14. Patient is deemed by the Investigator to have the initiative and means to be complaint with the protocol (treatment and follow-up);
15. Negative serum pregnancy test within 28 days prior to commencement of dosing in pre menopausal women or if she is of non-childbearing potential (i.e., physiologically incapable of becoming pregnant), including any female who has had a hysterectomy, a bilateral oophorectomy (ovariectomy), a bilateral tubal ligation, is post-menopausal.
16. Fertile men and women must use an effective method of contraception during treatment and for at least 2 months after completion of treatment as directed by their physician.
17. Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow up schedule

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Exclusion Criteria

1. Non-cutaneous melanoma;
2. Cutaneous melanoma with BRAF V600 mutation or NRAS wildtype/unknown;
3. Leptomeningeal disease
4. History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes);
5. History of retinal degenerative disease;
6. History of allogeneic bone marrow transplantation or organ transplantation;
7. History of Gilbert’s syndrome;
8. Previous or concurrent malignancy with the following exceptions:
• adequately treated basal cell or squamous cell carcinoma of the skin (adequate wound healing is required prior to study entry),
• in situ carcinoma of the cervix, treated curatively and without evidence of recurrence for at least 3 years prior to the study,
• a primary malignancy which has been completely resected and in complete remission for ≥5 years;
9. Prior therapy with a MEK- inhibitor;
10. Treatment with any cytotoxic and/or investigational cytotoxic drug or targeted therapy ≤ 2 weeks prior to Day 1 of study
11. Impaired cardiovascular function or clinically significant cardiovascular diseases, including any of the following:
• History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or stenting) <6 months prior to screening,
• 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;
12. Uncontrolled arterial hypertension despite medical treatment;
13. Known positive serology for HIV, active hepatitis B, and/or active hepatitis C infection
14. Patients who have neuromuscular disorders that are associated with elevated CK (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy);
15. Patients who are planning on embarking on a new strenuous exercise regimen after first dose of study treatment. NB: Muscular activities, such as strenuous exercise, that can result in significant increases in plasma CK levels should be avoided while on MEK162 treatment;
16. Impairment of gastrointestinal function or gastrointestinal disease (e.g., uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection);
17. Any other condition that would, in the Investigator’s judgment, contraindicate the patient’s participation in the clinical study due to safety concerns or compliance with clinical study procedures, e.g., infection/inflammation, intestinal obstruction, unable to swallow medication, social/ psychological issues, etc.;
18. Patients who have who have not recovered from side effects of major surgery procedures;
19. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test;
20. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception throughout the study and for 8 weeks after study drug discontinuation. Highly effective contraception methods include:
• Total abstinence including lesbians and nuns of any religious affiliation when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
• Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
• Male sterilization (at least 6 months prior to screening). For female patient on the study, the vasectomized male partner should be the sole partner for that patient
• Combination of any of the two following (a+b or a+c or b+c)
a. Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate
b. <1%), for example hormone vaginal ring or transdermal hormone contraceptionPlacement of an intrauterine device (IUD) or intrauterine system (IUS)
c. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository

In case of use of oral contraception women should have been stable on the same pill before taking study treatment.

Note: Oral contraceptives are allowed but should be used in conjunction with a barrier method of contraception due to unknown effect of drug-drug interaction.

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 have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation 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.
21. Sexually active males unless they use a condom during intercourse while taking the drug and for 8 weeks after stopping treatment and should not father a child in this period. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid;
22. 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.
23. Known hypersensitivity or allergy to MEK 162 or another MEK inhibitor

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Addresses

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    • UniversitätsSpital ZürichDermatologische KlinikSwitzerland
    • Mr.  Prof. Dr. med.  Reinhard  Dummer 
    • Gloriastrasse 31
    • 8091  Zürich
    • Switzerland
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    • UniversitätsSpital ZürichDermatologische Klinik
    • Ms.  Dr. med.  Simone Maria  Goldinger 
    • Gloriastr. 31
    • 8091  Zürich
    • Switzerland
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    • UniversitätsSpital ZürichDermatologische KlinikSwitzerland
    • Mr.  Prof. Dr. med.  Reinhard  Dummer 
    • Gloriastrasse 31
    • 8091  Zürich
    • Switzerland
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Sources of Monetary or Material Support

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    • UniversitätsSpital ZürichDermatologische KlinikSwitzerland
    • Mr.  Prof. Dr. med.  Reinhard  Dummer 
    • Gloriastrasse 31
    • 8091  Zürich
    • Switzerland
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    • Array Biopharma Inc.
    • 3200 Walnut Street, Boulder
    • 80301  Colorado
    • United States
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Status

  •   Recruiting ongoing
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Trial Publications, Results and other Documents

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* This entry means the parameter is not applicable or has not been set.