A Multicenter, Open Label, Randomized Phase II Trial of the MEK Inhibitor Pimasertib or Dacarbazine in Previously Untreated Subjects With N-Ras Mutated Locally Advanced or Metastatic Malignant Cutaneous Melanoma
1. Subjects with measurable, histologically or cytologically confirmed, locally advanced
or metastatic cutaneous melanoma (stage III c or M1ac) N-Ras mutated. If N-Ras
mutational status is unknown at screening, it must be prospectively defined before
inclusion. If N-Ras mutational status is already known before screening, it must be
retrospectively confirmed after inclusion by the sponsor.
2. Tumor lesions amenable to biopsy or available tumor tissue as archival samples.
3. Age ≥ 18 years.
4. Has read and understood the informed consent form and is willing and able to give
informed consent. Fully understands requirements of the trial and willing to comply
with all trial visits and assessments.
5. Women of childbearing potential must have a negative blood pregnancy test at the
screening visit. For the purposes of this trial, women of childbearing potential are
defined as: "All female subjects after puberty unless they are post-menopausal for at
least two years, or are surgically sterile".
6. Female subjects of childbearing potential and male subjects with female partners of
childbearing potential must be willing to avoid pregnancy by using an adequate method
of contraception for 2 weeks prior to, during and four weeks after the last dose of
trial medication. Effective contraception is defined as the method of contraception
with a failure rate of less than 1% per year. Adequate contraception is defined as
follows: two barrier methods or one barrier method with a spermicidal or intrauterine
device or oral contraception for female partners of male subjects.
1. Has previous systemic treatment for locally advanced or metastatic cutaneous melanoma
(excluding adjuvant treatment).
2. Has non-measurable lesions, disease not evaluable by RECIST v. 1.1
3. Has an Eastern Cooperative Oncology Group performance status (ECOG PS) >1.
4. Has bone marrow impairment as evidenced by Hemoglobin < 10.0 g/dL, Neutrophil count
<1.5 x 10^9/L, platelets < 100 x 10^9/L.
5. Has renal impairment as evidenced by calculated creatinine clearance <60 mL/min
(according to the Cockcroft-Gault formula).
6. Has liver function abnormality as defined by total bilirubin > 1.5 x ULN, or AST/ALT
>2.5 x ULN, for subjects with liver involvement AST/ALT >5 x ULN.
7. Has significant cardiac conduction abnormalities, including QTc prolongation of >480
ms and/or pacemaker or clinically relevant impaired cardiovascular function.
8. Has hypertension uncontrolled by medication
9. Has retinal degenerative disease (hereditary retinal degeneration or age-related
macular degeneration), history of uveitis, or history of retinal vein occlusion (RVO)
or any eye condition that would be considered a risk factor for RVO (e.g.,
uncontrolled glaucoma or ocular hypertension).
10. Has known active CNS metastases unless previously radiotherapy treated, stable by CT
scan for at least 3 months without evidence of cerebral edema and no requirements for
corticosteroids or anticonvulsants.
11. History of difficulty swallowing, malabsorption or other chronic gastro-intestinal
disease, or conditions that may hamper compliance and/or absorption of the tested
12. Known HIV positivity, active hepatitis C, or active hepatitis B.
13. Has undergone surgical intervention within 28 days from Day 1 of trial drug
14. Has received extensive prior radiotherapy on more than 30% of bone marrow reserves,
or prior bone marrow/stem cell transplantation within 5 years from Day 1 of trial
15. Has history of any other significant medical disease such as major gastric or small
bowel surgery, recent drainage of significant volumes of ascites or pleural effusion
or has a psychiatric condition that might impair the subject well-being or preclude
full participation in the trial.
16. Has known hypersensitivity to dacarbazine.
17. Is a pregnant or nursing female.
18. Participated in another clinical trial within the past 28 days.