Metastatic melanoma MedDRA version: 20.0 Level: LLT Classification code 10027481 Term: Metastatic melanoma System Organ Class: 100000004864
Conditions
Sponsors
Novartis Pharma Services AG
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Subjects eligible for enrolment in the study must meet all of the following criteria: 1. = 18 years of age. 2. Signed written informed consent. 3. Histologically confirmed cutaneous melanoma that is either Stage IIIC (unresectable) or Stage IV (metastatic), and determined to be BRAF V600E/K mutation-positive using the bioMerieux (bMx) investigational use only (IUO) THxID BRAF Assay (IDE:G120011). Note: The IUO assay is currently approved (THxID BRAF assay). The assay will be tested in a central reference laboratory. Subjects with ocular or mucosal melanoma are not eligible. 4. Measurable disease (i.e., present with at least one measurable lesion per RECIST, version 1.1. Refer to Section 7.2.3.1 of the Protocol for the definition of a measurable lesion. 5. All prior anti-cancer treatment-related toxicities (except alopecia and laboratory values as listed on Table 2)) must be = Grade 1 according to the Common Terminology Criteria for Adverse Events version 4 (CTCAE version 4.0; National Cancer Institute ( NCI) 2009) at the time of randomization. 6. Able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels. 7. Women of childbearing potential must have a negative serum pregnancy test within 14 days prior to randomization and agree to use effective contraception, as defined in Section 7.3.3, throughout the treatment period, and for 6 months after the last dose of study treatment. Men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception as described in Section 7.3.3 from 14 days prior to administration of the first dose of study treatment, throughout the treatment period, and for 2 months after the last dose of study treatment. 8. An Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 [Oken 1982]. Refer to Appendix 1 of the protocol for details. 9. Adequate baseline organ function as defined in Table 2 (see inclusion criteria within the Protocol). 10. Subjects enrolled in France: In France, a subject will be eligible for inclusion in this study only if either affiliated to, or a beneficiary of, a social security category. 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 694 F.1.3 Elderly (>=65 years) F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: Subjects meeting any of the following criteria must not be enrolled in the study: 1. Prior treatment with a BRAF inhibitor (including but not limited to dabrafenib, vemurafenib, LGX818, and XL281/BMS-908662) or a MEK inhibitor (including but not limited to trametinib, AZD6244, and RDEA119). 2. Prior systemic anti-cancer treatment (chemotherapy, immunotherapy, biologic therapy, vaccine therapy, or investigational treatment) for Stage IIIC (unresectable) or Stage IV (metastatic) melanoma. Prior systemic treatment in the adjuvant setting is allowed. (Note: Ipilimumab treatment must end at least 8 weeks prior to randomization.) 3. Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity, biologic therapy, or immunotherapy within 21 days prior to randomization and/or daily or weekly chemotherapy without the potential for delayed toxicity within 14 days prior to randomization. 4. Taken an investigational drug within 28 days or 5 half-lives (minimum 14 days), whichever is shorter, prior to randomization. 5. Current use of a prohibited medication (Section 6.2). 6. History of another malignancy. Exception: Subjects who have been disease-free for 3 years, (i.e. subjects with second malignancies that are indolent or definitively treated at least 3 years ago) or subjects with a history of completely resected non-melanoma skin cancer. 7. Any serious or unstable pre-existing medical conditions (aside from malignancy exceptions specified above), psychiatric disorders, or other conditions that could interfere with the subject’s safety, obtaining informed consent, or compliance with study procedures. 8. Known HIV, Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection (subjects with laboratory evidence of cleared HBV and HCV infection will be permitted). 9. A history of glucose-6-phosphate dehydrogenase (G6PD) deficiency. 10. Brain metastasis are excluded unless: a. All known lesions have been definitively treated with surgery or stereotactic surgery (whole-brain radiation may be given as adjuvant treatment) b. Brain lesion(s), if still present, must be confirmed stable (i.e., no increase in lesion size) for = 12 weeks prior to randomization (stability must be confirmed with two consecutive magnetic resonance image (MRI) or computed tomography (CT) scans with contrast, separated by >6 weeks c. Asymptomatic with no corticosteroid requirements for = 4 weeks prior to randomization d. No enzyme inducing anticonvulsants for = 4 weeks prior to randomization In addition, for subjects that had brain metastases but currently have no evidence of disease (NED), NED for =12 weeks is required and must be confirmed by two consecutive scans, separated by =6 weeks, prior to randomization. 11. A history or evidence of cardiovascular risk including any of the following: a. Current LVEF 30 days prior to randomization are eligible d. A history (within 6 months prior to randomization) of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty; e. A history or evidence of current = Class II congestive heart failure as defined by the New York Heart Association (NYHA) guidelines (Appendix 4 of the Protocol); f. Trea
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: • To establish the superiority of dabrafenib and trametinib combination therapy with vemurafenib monotherapy with respect to overall survival (OS) for subjects with advanced/metastatic BRAF V600E/K mutation-positive cutaneous melanoma.;Secondary Objective: • To compare dabrafenib and trametinib combination therapy over vemurafenib monotherapy with respect to progression-free survival (PFS) for subjects with advanced/metastatic BRAF V600E/K mutation-positive cutaneous melanoma. • To compare dabrafenib and trametinib combination therapy over vemurafenib monotherapy with respect to overall response rate (ORR). • To compare dabrafenib and trametinib combination therapy over vemurafenib monotherapy with respect to duration of response • To characterize the safety of dabrafenib and trametinib combination therapy, including incidences of squamous cell carcinoma (SCC) and other proliferative cutaneous lesions ;Primary end point(s): • To establish the superiority of dabrafenib and trametinib combination therapy with vemurafenib monotherapy with respect to overall survival (OS) for subjects with advanced/metastatic BRAF V600E/K mutation-positive cutaneous melanoma.;Timepoint(s) of evaluation of this end point: •Overall survival (OS; defined as the time from randomization until death due to any cause). | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): •To evaluate and compare dabrafenib and trametinib combination therapy versus vemurafenib with respect to progression-free survival (PFS), overall response rate (ORR) and duration of response; • To characterize the safety of dabrafenib and trametinib combination therapy, including incidences of squamous cell carcinoma (SCC) and other proliferative skin diseases; Safety parameters to be measured: • Safety as measured by clinical assessments including vital signs and physical examinations, 12-lead electrocardiograms (ECG), echocardiogram (ECHO), chemistry and hematology laboratory values, and adverse events (AEs). ;Timepoint(s) of evaluation of this end point: • Progression-free survival (PFS; defined as the time from randomization until the earliest date of disease progression or death due to any cause) • Overall response rate (ORR; defined as the percentage of subjects with a confirmed complete response [CR] or partial response [PR] at any time per Response Evaluation Criteria in Solid Tumors [RECIST], • Duration of response (defined as the time from first documented evidence of CR or PR until disease progression or death due to any cause among subjects who achieve an overall response [i.e., confirmed CR or PR]). | — |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Canada, Czech Republic, Denmark, Finland, Hungary, Ireland, Israel, Italy, Korea, Republic of, Netherlands, New Zealand, Norway, Poland, Russian Federation, Spain, Sweden, Ukraine, United Kingdom, United States
Contacts
Public ContactClinical Trial Information Desk
Novartis Pharma Services AG
Outcome results
None listed