To find out if MEK162 is safe and what effects (good of bad) it has on the patient.. To understand what MEK162 does in the patient and assess what the patient does to clear the studymedication from the system. And last but not least to find out what…
ID
Source
Brief title
Condition
- Skin neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To estimate the objective response rate (ORRs) of MEK162 in adult patients with
advanced, unresectable, cutaneous malignant melanoma, i) harboring BARFV600 of
ii) harboring NRAS mutations
Secondary outcome
* To assess the effect of oral MEK162 on time-related efficacy parameters
(progression free survival (PFS) and duration of response)
* To characterize the safety and tolerability of oral MEK162
* To assess the effect of MEK162 on MEK/MAPK signaling, (PD changes of
molecular status of ERK, DUSP6, MEK) in pre- vs. post-dose tumor biopsies
* To characterize the baseline status of molecules relevant to MEK/MAPK
signaling (PTEN, p53) in tumor tissue and potential correlation with clinical
outcomes
* To measure plasma concentrations of MEK162 and the pharmacologically active
metabolite, AR00426032
Background summary
Cutaneous malignant melanoma is a highly invasive form of skin cancer. The
incidence of malignant melanoma is rapidly increasing throughout the world.
Clinical outcome is dependent on the extent of disease at diagnosis with
excellent survival rates (approximately 90% at 5 years) described for patients
with stage I disease. By contrast, very poor survival rates (ranging from 6.7%
to 18% at 5 years) with median survival of 6 to 9 months are reported for those
patients with metastatic (stage IV) disease. The poor survival of patients with
metastatic melanoma appears to result from the disease*s chemoinsensitivity.
Recent advances in the understanding of the genetic basis of melanoma have
motivated the development of new therapies for this disease. Previous studies
implicated mutations in NRAS in the pathogenesis of melanoma. More recently,
activating somatic mutations in the BRAF gene have been observed in a wide
variety of human tumors, most notably melanoma. Somatic mutations in BRAF have
been detected in approximately two-thirds of melanoma tumors and cell lines.
BRAF is a member of the Ras/Raf/MEK/ERK pathway. This pathway plays a prominent
role in controlling several key cellular functions including growth,
proliferation, and survival. These findings suggest that inhibition of the
Ras/Raf/MEK/ERK pathway would have therapeutic benefit in melanoma patients.
Specifically, the high frequency of BRAF (V600E) mutations in patients with
melanoma has led to the development of new drugs targeting this mutant BRAF
protein. Mek162 is a novel, orally active molecule with potent inhibitory
activity against mutant BRAF and NRAS kinase and additional anti-angiogenic
activity through inhibition of vascular endothelial growth factor receptor type
2 (VEGFR-2).
MEK162 is an experimental drug that could be an alternative for patients with
advanced melanoma, whose tumors have a mutation of the NRAS or BRAF gene and
who do not repond to the current therapy or for who no standard therapy
exists.It is expected that because of the selective profile less toxicity could
occur.
Study objective
To find out if MEK162 is safe and what effects (good of bad) it has on the
patient.. To understand what MEK162 does in the patient and assess what the
patient does to clear the studymedication from the system. And last but not
least to find out what effects MEK162 is having on the cancer.
Study design
This is a multi-center, open-label, 2-arm, Phase II study to determine the
anti-tumor efficacy of oral MEK162 in adults with advanced BRAFV600E / NRAS
mutated cutaneous malignant melanoma. Patients will be assigned according to
their mutation status at baseline:
Arm 1: BRAFV600 (n=28) MEK162 45 mg BID
Arm 2: NRAS (n= 96) MEK162 45mg BID
Arm 3: BRAFV600 (n=28) MEK162 60 mg BID
Intervention
MEK162 tablets 15mg
Orally, daily, continue
Startdosis: 45mg / twice daily or 60 mg / twice daily, depending on the arm
Study burden and risks
Possible side effects of MEk162 are:
Most likely side effects (greater than 20% incidence) are:
• Rash, acne or skin irritation including redness, raised bumps, dryness or
itching
• Swelling due to fluid retention or a worsening of pre-existing fluid
retention in specific areas of the body. This can occur throughout your body or
in specific areas such as your abdomen, arms, legs, hands, feet, face or eyes.
• Alteration of the light sensing part of the back of the eye that may effect
your vision
• Feeling weak, tired, or lacking in energy
Less likely side effects (greater than 10% up to 20% incidence):
• Blurred or impaired vision
• Fever
• High blood pressure
• Increase in lab test results that check how well the liver is working
• Muscle spasms, muscle pain or inflammation
• Stomach pain
Other risks:
Taking blood and tumorbiopsies may cause pain, bleeding, and/or bruising.
Patients will be exposed to radiation (CT-scan, MUGA-scan and/or X-rays). The
radiation exposure will not exceed the maximum ranges that are set within the
Netherlands.
Allergic reaction on contrast used for CT-scan.
Cambridge park drive 100
Cambridge MA 02140
US
Cambridge park drive 100
Cambridge MA 02140
US
Listed location countries
Age
Inclusion 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
3. Must have documented presence of somatic BRAFV600 or NRAS mutation in tumor tissue
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
6. WHO performance status of 0-2
7. Adequate organ function and laboratory parameters:
•ANC >= 1.5 x 109/L
•Hemoglobin (Hgb) >= 10 g/dL
•Platelets (PLT) >= 75 x 109/L
•AST and/or ALT <= 2.5 × upper limit of normal (ULN); patients with liver metastases <= 5 ×ULN
•Bilirubin <= 2 × ULN
•Calculated or directly measured creatinine clearance >= 60 mL/min/1.73m2
8. LVEF >= 50% as determined by MUGA scan or TTE
Exclusion criteria
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 symptomatic CNS metastasis.
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
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.
10.Women may not become pregnant. Reliable contraception should be maintained throughout the study and for 3 months after study drug discontinuation
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2010-023412-13-NL |
| ClinicalTrials.gov | NCT01320085 |
| CCMO | NL35299.031.11 |