N-RAS mutated locally advanced or metastatic malignant cutaneous melanoma MedDRA version: 18.0 Level: LLT Classification code 10025655 Term: Malignant melanoma of skin System Organ Class: 100000004864
Conditions
Interventions
Product Name: pimasertib
Product Code: MSC1936369B
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Pimasertib
CAS Number: 1236361-78-6
Current Sponsor code: Pimasertib
Other descriptive name:
Sponsors
Merck Serono S.A. Geneva
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Subjects with measurable, histologically or cytologically confirmed, unresectable, locally advanced or metastatic cutaneous melanoma (stage III c or M1a-c) 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 for female subjects or female partners of male subjects is defined as follows: two barrier methods or one barrier method in combination with an intrauterine device or oral contraception. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 157 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 27
Exclusion criteria
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 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 (NYHA Class III/IV). 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 or anti-human CTLA-4 (CD152) monoclonal antibodies (such as ipilimumab).
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Timepoint(s) of evaluation of this end point: Baseline; Day 1 of cycles 3, 5, 7, 9, 11, 13 and every 4 cycles thereafter; EoT;Secondary Objective: Efficacy - Compare the objective response of subjects treated with either pimasertib or dacarbazine. - Compare the disease control of subjects treated with either pimasertib or dacarbazine. - Evaluate the overall survival of subjects treated with either pimasertib or dacarbazine. - Compare the Quality of Life of subjects treated with either pimasertib or dacarbazine. Safety - Compare the safety profile of subjects treated with pimasertib or dacarbazine. Pharmacokinetics - Assess the pharmacokinetics of pimasertib in melanoma subjects and to evaluate relationships between exposure and response as well as exposure and AEs. Pharmacogenetics and Biomarkers - Describe the relationship between basal tumor characteristics and circulating markers and pimasertib anti-tumor activity. Explore genes that are important in the drug metabolizing enzymes and transporters of pimasertib and identify potential genetic variations that may account for differences in PK profile.;Primary end point(s): Progression-free survival, defined as the time from randomization to the first documentation of objective disease progression (according to RECIST v. 1.1) as determined by the investigator or death, whichever comes first. Death will be considered as an event only if it is reported within 12 weeks after the last tumor assessment without progression.;Main Objective: To compare the progression-free survival (PFS) of previously untreated subjects with N-Ras mutated locally advanced or metastatic malignant cutaneous melanoma treated with either pimasertib or dacarbazine. | — |
Secondary
| Measure | Time frame |
|---|---|
| Timepoint(s) of evaluation of this end point: - OR & Disease control: Baseline; Day 1 of cycles 3, 5, 7, 9, 11, 13 and every 4 cycles thereafter; EoT - PFS rate: 6 months from time of randomization - OS: time of death from any cause. - OS rate: 12 months from time of randomization. - Change in patient-reported QoL: at last assessment prior to objective disease progression - TEAEs, SAEs, deaths.: Screening up to Post treatment assessment (30+/- 3 days after last drug intake). - Vital signs: Baseline; Pre-dose on day 1, 8 of cycle 1, 2; Day 1 of every cycles thereafter; EoT; PTP - PK: Day 8, 15 of cycle 1; Day 1 of cycle 2 - Gene products and genetic alterations: Baseline - Predictive markers in plasma: Day 1 of cycle 1 - Potential genetic variations: Cycle 1 day 1 for pimasertib arm only.;Secondary end point(s): *Efficacy All efficacy endpoints involving RECIST v. 1.1 criteria will be based upon investigator assessment. Independent central review of scans will be performed retrospectively for the purpose of sensitivity analyses. - Objective response defined as complete or partial tumor response according to RECIST v. 1.1 criteria. - Disease control defined as the proportion of subjects with complete response, partial response, or stable disease for > 3 months, according to RECIST v. 1.1 criteria. - Progression-free survival rate at six months from the time of randomization based upon objective disease progression (according to RECIST v. 1.1 as defined for PFS above. - Overall survival defined as the time from randomization to death from any cause. - Overall survival rate at 12 months from the time of randomization. - Change in patient-reported QoL (assessed by FACT-Melanoma) from baseline assessment to last assessment prior to objective disease progression (according to RECIST v. 1.1). *Safety - Treatment-emergent adverse events (TEAEs), SAEs, deaths. - Clinically significant changes in safety-related laboratory parameters according to NCI-C | — |
Countries
Australia, Belgium, France, Germany, Israel, Italy, Netherlands, New Zealand, Norway, South Africa, Spain, Sweden, Switzerland, United Kingdom, United States
Contacts
Public ContactCommunication Center Merck KGaA
Merck KGaA
Outcome results
None listed