Phase II Trial of Pimasertib Versus Dacarbazine in N-Ras Mutated Cutaneous Melanoma
Condition: N-Ras Mutated Locally Advanced or Metastasis Malignant Cutaneous Melanoma
MeSH terms: Melanoma; Skin Neoplasms
Intervention: Pimasertib; Dacarbazine
Intervention description: Subjects will receive pimasertib orally as monotherapy at a dose of 60 milligram (mg) twice daily continuously. Treatment will consist of repeated 21-day cycles which will continue until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurs first.; Subjects will receive dacarbazine intravenously at dose of 1000 milligram per square meter (mg/m^2) of body surface area every 3 weeks on Day 1 of each 21-days cycle until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurs first. Eligible subjects with documented tumor progression on dacarbazine will offer to switch to pimasertib treatment.
Intervention MeSH terms: Dacarbazine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 194.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Cutaneous Melanoma; Dacarbazine; Pimasertib; N-Ras

Summary:

      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.
    

Eligibility criteria:

        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).