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

This study has been completed.
Merck KGaA
Information provided by (Responsible Party):
EMD Serono Identifier:
First received: September 14, 2012
Last updated: February 11, 2016
Last verified: February 2016
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.

Condition Intervention Phase
N-Ras Mutated Locally Advanced or Metastasis Malignant Cutaneous Melanoma
Drug: Pimasertib
Drug: Dacarbazine
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:

Further study details as provided by EMD Serono:

Primary Outcome Measures:
  • Progression-free survival (PFS), defined as the first documentation of objective disease progression, according to Response Evaluation Criteria in Solid Tumors (RECIST v.1.1) [ Time Frame: every 6 weeks up to Cycle 13, then every 12 weeks up to 2 years ]

Secondary Outcome Measures:
  • Objective response defined as complete or partial tumor response, according to RECIST v.1.1 criteria [ Time Frame: every 6 weeks up to Cycle 13, then every 12 weeks up to 2 years ]
  • Disease control defined as the proportion of subjects with complete response, partial response, or stable disease for more than 3 months, according to RECIST v.1.1 criteria [ Time Frame: every 6 weeks up to Cycle 13, then every 12 weeks up to 2 years ]
  • Progression-free survival rate at six months from the time of randomization based upon observation of objective disease progression at this time point, according to RECIST v.1.1 criteria [ Time Frame: up to 6 months ]
  • Overall survival defined as the time from randomization to death from any cause [ Time Frame: every 6 months up to 2 years ]
  • Overall survival rate at 12 months from the time of randomization [ Time Frame: up to 12 months ]
  • Change in patient-reported Quality of life (assessed by FACT-Melanoma) from baseline assessment to last assessment prior to objective disease progression, according to RECIST v.1.1 [ Time Frame: Day 1 of every cycle up to 2 years ]
  • Number of subjects with treatment-emergent adverse events (TEAEs), serious adverse events (SAEs) and death [ Time Frame: up to 2 years ]
  • Clinically significant changes in safety related to National Cancer Institute- Common Toxicity Criteria Version 4.0 (NCI-CTC v 4.0) and abnormal vital signs [ Time Frame: up to 2 years ]
  • Plasma concentration of Pimasertib [ Time Frame: Day 8 and Day 15 of Cycle 1, and Day 1 of Cycle 2 ]
  • Gene products and genetic alterations in tumor biopsies [ Time Frame: Day 1 of Cycle 1 ]
  • Predictive markers in plasma [ Time Frame: Day 1 of Cycle 1 ]
  • Potential genetic variations in genomic deoxyribonucleic acid (gDNA) obtained from Peripheral Blood Mononuclear Cell (PBMC) associated with differences in pharmacokinetic and profile of pimasertib [ Time Frame: Day 1 of Cycle 1 ]

Enrollment: 194
Study Start Date: December 2012
Study Completion Date: January 2016
Primary Completion Date: July 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Pimasertib Drug: Pimasertib
Pimasertib will be administered as oral capsule at a dose of 60 milligram (mg) twice daily continuously. Treatment will consist of repeated 21-day cycles which will be continued until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever comes first.
Other Names:
  • MSC1936369B
  • AS703026
Active Comparator: Dacarbazine Drug: Dacarbazine

Dacarbazine will be administered intravenously at dose of 1000 mg per square meter of body surface area on Day 1 of each 21-days cycle. Treatment will be continued until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever comes first.

Eligible subjects with documented tumor progression on dacarbazine will be offered to switch to pimasertib treatment at the end of the treatment.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  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.

Exclusion Criteria:

  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 product.
  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 treatment.
  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 drug treatment.
  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.
  19. Has CPK level at baseline NCI CTCAE Grade ≥ 2 (i.e > 2.5 x ULN), and/or has a previous history of myositis or rhabdomyolysis.
  20. Is suitable for treatment with an approved B-Raf inhibitor (exclusion criteria implemented in German amendment only).
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Please refer to this study by its identifier: NCT01693068

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Sponsors and Collaborators
EMD Serono
Merck KGaA
Study Director: Study Director EMD Serono Inc., a business of Merck KGaA, Darmstadt, Germany
  More Information

Responsible Party: EMD Serono Identifier: NCT01693068     History of Changes
Other Study ID Numbers: EMR 200066-007
2012-002669-37 ( EudraCT Number )
Study First Received: September 14, 2012
Last Updated: February 11, 2016

Keywords provided by EMD Serono:
Cutaneous Melanoma

Additional relevant MeSH terms:
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Nerve Tissue
Nevi and Melanomas
Vitamin B Complex
Growth Substances
Physiological Effects of Drugs processed this record on March 27, 2017