To determine whether treatment with MEK162 prolongs PFS as compared to dacarbazine in patients with previously untreated, advanced unresectable, or metastatic NRAS mutation-positive melanoma who are previously untreated or who have progressed on or…
ID
Source
Brief title
Condition
- Skin neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
PFS, defined as the time from the date of randomization to the date of the
first documented disease progression or death due to any cause, whichever
occurs first. PFS will be determined based on tumor assessment (RECIST V1.1
criteria) as per BIRC and survival information.
The local Investigator*s assessments will be used as supportive analyses.
Secondary outcome
OS, calculated as the time from date of randomization to date of death due to
any cause
Background summary
Cutaneous melanoma is the most aggressive skin cancer. Although it accounts for
only 4 percent of all dermatologic cancers, it is responsible for 80 percent of
skin cancer deaths. The median age at diagnosis is 57 years, and up to 75% of
patients are younger than 70 years.
dacarbazine is considered the standard of care for most patients with
unresectable advanced or metastatic melanoma. However, the response rate with
dacarbazine is modest (7-15%), these responses are short-lived (e.g. median
duration of response of 6 months) and there is no associated increase in
survival.
Recently ipilimumab has obtained the FDA approval for the treatment of
unresectable or metastatic melanoma and the EMA approval for the treatment of
advanced (unresectable or metastatic) melanoma in adults who have received
prior therapy.
There are no targeted therapies approved specifically for the treatment of the
subset of patients with NRAS mutated melanoma (15-20% of melanoma). NRAS
activating mutations result in an aberrant downstream signaling, leading to
malignant transformation and tumor progression.
To date, MEK162 is the only MEK inhibitor of which the antitumor activity has
prospectively been assessed in patients with NRAS mutant advanced cutaneous
melanoma
Study objective
To determine whether treatment with MEK162 prolongs PFS as compared to
dacarbazine in patients with previously untreated, advanced unresectable, or
metastatic NRAS mutation-positive melanoma who are previously untreated or who
have progressed on or after prior first-line immunotherapy for metastatic
disease.
To compare Overall Survival (OS) between treatment arms
Study design
This is a two-arm, randomized, prospective, open-label, multi-center, phase III
study to compare the efficacy and safety of MEK162 (45 mg BID) versus
dacarbazine (1000 mg/m2 IV every 3 weeks) in patients with, advanced
unresectable or metastatic NRAS mutation-positive melanoma as confirmed by
central assessment.
A total of 393 patients will be randomized 2:1 to MEK162 or dacarbazine and
stratified according to AJCC stage ,ECOG Performance status and previously
treated or not
Intervention
MEK162 tablets of 15mg, Orally, continuous, daily
Startdose: 45mg / BID
or DTIC, 1000mg/m2 once every 3 weeks
Study burden and risks
Possible side effects of MEk162 are:
* skin irritation (acne-like rash or redness which may be itchy)
* diarrhea
* headache
* abdominal pain
* nausea (with or without vomiting)
* eye disorders with may include mild to moderate changes in vision, 'floaters"
or swelling in and around the eye
* increases in the blood levels of proteins (called creatinine kinase proteins)
* heartburn of indigestion
* mucositis (sores in the mouth or throat)
* edema (swelling or puffiness of parts of the body)
* loss of appetite
* muscle ache
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.
Possible toxicities due to Dacarbazine
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Listed location countries
Age
Inclusion criteria
1 Male or female patients, age * 18 years
2 Histologically confirmed diagnosis of locally advanced, unresectable or metastatic cutaneous or unknown primary melanoma AJCC Stage IIIC or IV (Uveal and mucosal melanoma are excluded)
3 Presence of NRAS Q61 mutation in tumor tissue prior to randomization, as determined by a central laboratory
4 Naïve untreated patients or patients who have progressed on or after prior treatment with any number of lines of immunotherapy for unresectable or metastatic melanoma;
5 Evidence of at least one measurable lesion as documented by radiological or photographic methods according to RECIST (version 1.1)
6 ECOG performance status of 0-1
7 Adequate bone marrow and organ function and laboratory parameters:
* ANC * 1.5 x 109/L
* Hemoglobin (Hgb) * 9 g/dL without transfusions
* Platelets (PLT) * 100 x 109/L without transfusions
* AST and/or ALT * 2.5 × upper limit of normal (ULN); patients with liver metastases * 5 ×ULN
* Total bilirubin * 2 × ULN
* Creatinine * 1.5 mg/dL
8 Adequate cardiac function:
* left ventricular ejection fraction (LVEF) * 50% as determined by a multigated acquisition (MUGA) scan or echocardiogram
* QTc interval * 480 ms
9 Negative serum * HCG test (female patients of childbearing potential only) performed locally within 72 hrs prior to first dose
Exclusion criteria
1 Any active central nervous system (CNS) lesion (i.e., those with radiographically unstable, symptomatic lesions). However, patients treated with radiotherapy or surgery are eligible if the patient remained without evidence of CNS disease progression * 3 months. Patients must be off corticosteroid therapy for * 3 weeks.
2 Uveal or mucosal melanoma
3 History of leptomeningeal metastases
4 History or current evidence of central serous retinopathy (CSR) or retinal vein occlusion (RVO) or predisposing factors to RVO or CSR
5 History of allogeneic bone marrow transplantation or organ transplantation
6 History of Gilbert*s syndrome
7 Previous or concurrent malignancy with the following exceptions:
* adequately treated basal cell or squamous cell carcinoma
* 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
8 Prior therapy with a MEK inhibitor
9 Patients with washout period < 12 weeks from the last dose of ipilimumab or other immunotherapy;
10 Impaired cardiovascular function or clinically significant cardiovascular diseases
11 Uncontrolled arterial hypertension, despite medicial treatment
12 Known positive serology for HIV, active Hepatitis B, and/or active Hepatitis C infection
13 Patients who have neuromuscular disorders that are associated with elevated CK
14 Impairment of gastrointestinal function or gastrointestinal disease
15 Pregnant or nursing (lactating) women
16 Women of child-bearing potential, unless they are using highly effective methods of contraception during dosing and for 8 weeks after stopping study treatment.
17 Sexually active males, unless they use a condom during intercourse while taking drug and for 8 weeks after stopping study medication.
Design
Recruitment
Medical products/devices used
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 | EUCTR2012-003593-51-NL |
| ClinicalTrials.gov | NCT01763164 |
| CCMO | NL42858.031.13 |