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

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

This is a Phase 2, multicenter, randomized, controlled, open-label trial of pimasertib versus dacarbazine aimed to confirm the activity of pimasertib in previously untreated subjects with N-Ras mutated locally advanced or metastatic malignant cutaneous melanoma by comparing the progression-free survival (PFS) of subjects treated with either pimasertib or dacarbazine and by getting a better understanding of the efficacy, safety, pharmacogenomics (PGx) and their relationship with pimasertib exposure.

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).