E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
locally advanced and unresectable or metastatic malignant cutaneous melanoma, harboring BRAFV600 or NRAS mutations |
lokaal gevorderd en inoperabel of gemetastaseerd cutaan melanoom, met een BRAFV600 of NRAS mutatie |
|
E.1.1.1 | Medical condition in easily understood language |
specific subtypes of locally advanced or metastatic malignant cutaneous
melanoma |
specifieke subtypes van lokaal gevorderd of gemetastaseerd maligne cutaan melanoom |
|
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 | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10027480 |
E.1.2 | Term | Metastatic malignant melanoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
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 |
To estimate the objective response rates (ORRs) of MEK162 when
administered orally as 45mg bid, to adult patients with advanced,
unresectable cutaneous malignant melanoma, i) harboring BRAFV600 or
ii) harboring NRAS mutations and iii) when administered orally as 60mg
bid, to adult patients with advanced, unresectable cutaneous malignant
melanoma, harboring BRAFV600 mutations |
|
E.2.2 | Secondary objectives of the trial |
To assess the effect of oral MEK162 on time-related efficacy
parameters (progression free survival (PFS) and duration of response)
• To further assess the effect of MEK162 on other time related efficacy
parameters
• To characterize the safety and tolerability of oral MEK162
• To assess the effects of MEK162 on MEK/MAPK signaling (PD changes
of molecular status of pERK, and DUSP6
• To measure plasma concentrations of MEK162 and the
pharmacologically active metabolite, AR00426032 |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patients eligible for inclusion in this study have to meet all of the following criteria:
1. Male or female patients age ≥ 18 years
2. Histologically confirmed diagnosis of locally advanced or metastatic cutaneous melanoma AJCC Stage IIIB to IV, not potentially curable with surgery (Appendix 1)
3. Must have documented presence of somatic BRAFV600 or NRAS mutation in tumor tissue (*melanoma histologies positive for other activating BRAF mutations may be considered upon approval by the Array Medical Monitor).
4. All patients enrolled should provide sufficient fresh or archival tumor sample at baseline to enable central confirmation of BRAF or NRAS mutations and the additional analyses described in the protocol
5. Evidence of measurable tumor disease as per RECIST (Appendix 2), defined as at least one lesion that can accurately be measured in at least one dimension as ≥ 20 mm by conventional radiological technique or ≥ 10 mm with spiral CT-scan. Cutaneous lesions must have clearly defined margins and measure ≥ 5 mm in at least one diameter and be documented by color photography. Target lesions should not be selected in previously irradiated fields unless there is clear evidence of progression in such lesions.
6. WHO performance status of 0-2
7. Adequate organ function and laboratory parameters as defined in teh protocol
8. Recovery from all reversible adverse events of previous anti-cancer therapies to baseline or to Grade ≤ 1, except for alopecia and Grade <2 sensory PNP
9. LVEF ≥ 50% as determined by MUGA scan or TTE
10. Patient is deemed by the Investigator to have the initiative and means to be compliant with the protocol (treatment and follow-up) and be within geographical proximity to make the required study visits
11. Negative serum β-HCG test (female patients of childbearing potential only) within 72 hrs prior to first dose
12. Written informed consent obtained prior to any screening procedures.
|
|
E.4 | Principal exclusion criteria |
Patients eligible for this study must not meet any of the following criteria at screening:
1. History or current evidence of central serous retinopathy (CSR), retinal vein occlusion (RVO) or ophthalmopathy visible at screening that would be considered a risk factor for CSR or RVO
2. Patients with CNS metastasis unless previously treated with surgery, whole-brain radiation or stereotactic radiosurgery and the disease has been stable for at least 2 months without steroid use or on a stable dose of steroids for at least 1 month prior to the first dose of MEK162
3. Prior therapy with a MEK- inhibitor
4. Impaired cardiovascular function or clinically significant cardiovascular diseases, including any of the following:
• History/evidence of acute coronary syndromes (including MI, unstable angina, CABG, coronary angioplasty, or stenting) <6 months prior to screening
• Symptomatic CHF, history or current evidence of clinically significant cardiac arrhythmia and/or conduction abnormality
• Uncontrolled arterial hypertension, defined as BP > 140/100 mmHg (average of 3 consecutive readings)
5. Known positive serology for HIV, active Hepatitis B, and/or active Hepatitis C infection
6. Any other condition that would, in the Investigator’s judgment, contraindicate 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.
7. Patients who have received prior systemic anti-cancer treatment within the following time frames:
• Patients who have received cyclical chemotherapy within a period of time that is shorter than the cycle length used for that treatment (e.g., 6 weeks for nitrosourea, mitomycin-C) prior to starting study drugs
• Patients who have received biologic therapy (e.g., antibodies) within 4 weeks prior to starting study drug
• Patients who have been treated with continuous or intermittent small molecule therapeutics within ≤ 5 t1/2 of the agent, or ≤ 4 weeks prior to starting study drug where half life is unknown
• Patients who have received any other investigational agents within a period of time that is less than the cycle length used for that treatment or ≤ 4 weeks (whichever is shorter) prior to starting study drugs
• Treatment with prior radiotherapy within 28 days of the first dose of study drug; however, if the radiation portal covered ≤ 10% of the bone marrow reserve, the patient may be enrolled irrespective of the end date of radiotherapy
8. Patients who have undergone major surgery ≤ 4 weeks prior to starting study drug or who have not recovered from side effects of such procedure
9. 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 (> 5 mIU/mL)
10. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, UNLESS they are:
• women whose sexual orientation precludes intercourse with a male partner
• women whose partners have been sterilized by vasectomy or other means
• using a highly effective method of birth control (i.e. one that results in a less than 1% per year failure rate when used consistently and correctly, such as implants, injectables, combined oral contraceptives, and some intrauterine devices (IUDs); periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) is not acceptable). Reliable contraception should be maintained throughout the study and for 3 months after study drug discontinuation
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 [for US only: and estradiol < 20 pg/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
11. 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. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Overall Response Rate [ORR] (Complete Responses [CR] and Partial Responses [PR]) according to RECIST |
ORR volgens RECIST |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
at baseline and at the end of every 2nd cycle/every 8 weeks until
progression (as per RECIST) |
op baseline en op het einde van elke volgende 8 weken (2 kuren) tot aan progressie volgens RECIST |
|
E.5.2 | Secondary end point(s) |
PFS according to RECIST
- Safety: Adverse drug reactions and serious adverse drug reactions,
changes in hematology and chemistry values, vital signs, ECGs and
assessment of physical and ocular examinations graded according to the NCI CTCAE v4.0
- OS, duration of response, time to response |
PFS volgens RECIST
Veiligheid: bijwerkingen en SAEs, hematologische en biochemische veranderingen, vitale functies, ECGs en oogtesten volgens CTCAE v 4
- OS, Duration of Response, Time to reponse |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
- PFS: at the end of every 2nd cycle/every 8 weeks until progression (as
per RECIST)
- Safety: throughout all cycles
- 18 months |
PFS: aan het einde van elke 2 kuren
Veiligheid: gedurende alle kuren
- 18 maanden |
|
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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
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 | Information not present in EudraCT |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 9 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
United States |
Germany |
Italy |
Netherlands |
Switzerland |
|
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
|
End of study will be when (at least) 80% of the patients in the study have died, or 24 months after last patient first visit, whichever occurs earlier.
As of protocol version 5, due to several patients continuing to receive treatment, the end of the study will occur when the last patient completes the 30-day safety follow-up visit. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 7 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 7 |
E.8.9.2 | In all countries concerned by the trial months | 7 |
E.8.9.2 | In all countries concerned by the trial days | 0 |