Phase II Trial of Pimasertib Versus Dacarbazine in N-Ras Mutated Cutaneous Melanoma
This study is ongoing, but not recruiting participants.
Information provided by (Responsible Party):
First received: September 14, 2012
Last updated: April 20, 2015
Last verified: April 2015
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.
N-Ras Mutated Locally Advanced or Metastasis Malignant Cutaneous Melanoma
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
||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
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 ] [ Designated as safety issue: No ]
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 ] [ Designated as safety issue: No ]
- 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 ] [ Designated as safety issue: No ]
- 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 ] [ Designated as safety issue: No ]
- Overall survival defined as the time from randomization to death from any cause [ Time Frame: every 6 months up to 2 years ] [ Designated as safety issue: No ]
- Overall survival rate at 12 months from the time of randomization [ Time Frame: up to 12 months ] [ Designated as safety issue: No ]
- 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 ] [ Designated as safety issue: No ]
- Number of subjects with treatment-emergent adverse events (TEAEs), serious adverse events (SAEs) and death [ Time Frame: up to 2 years ] [ Designated as safety issue: Yes ]
- 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 ] [ Designated as safety issue: Yes ]
- Plasma concentration of Pimasertib [ Time Frame: Day 8 and Day 15 of Cycle 1, and Day 1 of Cycle 2 ] [ Designated as safety issue: No ]
- Gene products and genetic alterations in tumor biopsies [ Time Frame: Day 1 of Cycle 1 ] [ Designated as safety issue: No ]
- Predictive markers in plasma [ Time Frame: Day 1 of Cycle 1 ] [ Designated as safety issue: No ]
- 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 ] [ Designated as safety issue: No ]
| Study Start Date:
| Estimated Study Completion Date:
| Estimated Primary Completion Date:
||December 2015 (Final data collection date for primary outcome measure)
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.
Active Comparator: 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
|Genders Eligible for Study:
|Accepts Healthy Volunteers:
- 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 ≥ 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.
- Has previous systemic treatment for locally advanced or metastatic cutaneous melanoma (excluding adjuvant treatment).
- Has non-measurable lesions, disease not evaluable by 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 x 10^9/L, platelets < 100 x 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 x ULN, or AST/ALT >2.5 x ULN, for subjects with liver involvement AST/ALT >5 x ULN.
- Has significant cardiac conduction abnormalities, including QTc prolongation of >480 ms 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 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 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 CPK level at baseline NCI CTCAE Grade ≥ 2 (i.e > 2.5 x 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).
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Please refer to this study by its ClinicalTrials.gov identifier: NCT01693068
||Merck Serono S.A., Geneva
No publications provided
History of Changes
|Other Study ID Numbers:
||EMR 200066-007, 2012-002669-37
|Study First Received:
||September 14, 2012
||April 20, 2015
||United States: Food and Drug Administration
Keywords provided by EMD Serono:
Additional relevant MeSH terms:
ClinicalTrials.gov processed this record on November 25, 2015
Neoplasms by Histologic Type
Neoplasms, Germ Cell and Embryonal
Neoplasms, Nerve Tissue
Nevi and Melanomas