Phase II Trial of Pimasertib Versus Dacarbazine in N-Ras Mutated Cutaneous Melanoma

Inclusion Criteria:

- 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.

- Tumor lesions amenable to biopsy or available tumor tissue as archival samples.

- Age greater than or equal to (>=) 18 years.

- 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.

- 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".

- 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.

Exclusion Criteria:

- Has previous systemic treatment for locally advanced or metastatic cutaneous melanoma
(excluding adjuvant treatment).

- Has non-measurable lesions, disease not evaluable by Response Evaluation Criteria in
Solid Tumors (RECIST) v. 1.1

- Has an Eastern Cooperative Oncology Group performance status (ECOG PS) >1.

- Has bone marrow impairment as evidenced by Hemoglobin <10.0 g/dL, Neutrophil count
<1.5 * 10^9/L, platelets <100 * 10^9/L.

- Has renal impairment as evidenced by calculated creatinine clearance <60 mL/min
(according to the Cockcroft-Gault formula).

- Has liver function abnormality as defined by total bilirubin >1.5 * Upper Limit of
Normal (ULN), or aspartate aminotransferase (AST)/alanine aminotransferase (ALT) >2.5
* ULN, for subjects with liver involvement AST/ALT >5 * ULN.

- Has significant cardiac conduction abnormalities, including QTc prolongation of >480
milliseconds and/or pacemaker or clinically relevant impaired cardiovascular function.

- Has hypertension uncontrolled by medication

- 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).

- Has known active central nervous system (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.

- History of difficulty swallowing, malabsorption or other chronic gastro-intestinal
disease, or conditions that may hamper compliance and/or absorption of the tested
product.

- Known human immunodeficiency virus (HIV) positivity, active hepatitis C, or active
hepatitis B.

- Has undergone surgical intervention within 28 days from Day 1 of trial drug treatment.

- 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 drug
treatment.

- 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.

- Has known hypersensitivity to dacarbazine.

- Is a pregnant or nursing female.

- Participated in another clinical trial within the past 28 days.

- Has creatine phosphokinase (CPK) level at baseline National Cancer Institute Common
Terminology Criteria for Adverse Events (NCI CTCAE) Grade >=2 (i.e > 2.5 * ULN),
and/or has a previous history of myositis or rhabdomyolysis.

- Is suitable for treatment with an approved B-Raf inhibitor (exclusion criteria
implemented in German amendment only).