A Study Comparing GSK2118436 to Dacarbazine (DTIC) in Previously Untreated Subjects With BRAF Mutation Positive Advanced (Stage III) or Metastatic (Stage IV) Melanoma

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT01227889
First received: October 21, 2010
Last updated: June 12, 2014
Last verified: June 2014
  Purpose

BRF113683 is a Phase III, randomized, open-label study comparing the efficacy, safety, and tolerability of GSK2118436 to dacarbazine (DTIC), in subjects with BRAF mutant advanced (Stage III) or metastatic (Stage IV) melanoma. Subjects will be randomized to receive 150 mg of GSK2118436 twice daily or 1000 mg/m2 DTIC every 3 weeks and continue on treatment until disease progression, death, or unacceptable adverse event. Subjects who progress on DTIC will be allowed to crossover to an optional extension arm of the study to receive GSK2118436.


Condition Intervention Phase
Cancer
Drug: GSK2118436
Drug: Dacarbazine (DTIC)
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase III Randomized, Open-label Study Comparing GSK2118436 to Dacarbazine (DTIC) in Previously Untreated Subjects With BRAF Mutation Positive Advanced (Stage III) or Metastatic (Stage IV) Melanoma

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Progression-free Survival (PFS) as Assessed by the Investigator [ Time Frame: Time interval between the date of randomization and the earlier of the date of disease progression or the date of death due to any cause (up to 9.9 months) ] [ Designated as safety issue: No ]
    PFS is defined as the interval of time between the date of randomization and the earlier of the date of disease progression or the date of death due to any cause. Disease progression was based on radiographic or photographic evidence, and assessments were made by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 millimeters (mm). For participants who did not progress or die, PFS was censored at the date of last contact. Data are presented as median and 96% confidence interval.

  • Progression-free Survival (PFS) as Assessed by an Independent Radiologist [ Time Frame: Time interval between the date of randomization and the earlier of the date of disease progression or the date of death due to any cause (up to 9.9 months) ] [ Designated as safety issue: No ]
    PFS is defined as the interval of time between the date of randomization and the earlier of the date of disease progression or the date of death due to any cause. Disease progression was based on radiographic or photographic evidence, and assessments were made by an independent radiologist according to RECIST version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm. For participants who did not progress or die, PFS was censored at the date of last contact.


Secondary Outcome Measures:
  • Overall Survival [ Time Frame: Time interval between the date of randomization and the date of death due to any cause (up to 22.1 months) ] [ Designated as safety issue: No ]
    Overall survival is defined as the interval of time between the date of randomization and the date of death due to any cause. For participants who did not die, overall survival was censored at the date of last contact.

  • Number of Participants With a Best Overall Response of Confirmed Complete Response (CR) or Confirmed Partial Response (PR) as Assessed by the Investigator: Randomized Phase [ Time Frame: From randomization until the first documented evidence of a confirmed complete response or partial response (median of 6.6 weeks) ] [ Designated as safety issue: No ]
    A participant was defined as a responder if he/she achieved either a CR (the disappearance of all target lesions. Any pathological lymph nodes must be <10 mm in the short axis.) or PR (at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]). Response was evaluated by an investigator per RECIST, version 1.1. A participant without a post-Baseline assessment of response was considered a non-responder. Confirmation, per RECIST version 1.1, requires a confimatory disease assessment of CR or PR at least 28 days after the initial disease assessment of CR or PR.

  • Number of Participants With a Best Overall Response of Confirmed CR or PR as Assessed by an Independent Radiologist: Randomized Phase [ Time Frame: From randomization until the first documented evidence of a confirmed complete response or partial response (median of 12.0 weeks) ] [ Designated as safety issue: No ]
    A participant was defined as a responder if he/she achieved either a CR (the disappearance of all target lesions. Any pathological lymph nodes must be <10 mm in the short axis.) or PR (at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]). Response was evaluated by an independent radiologist per RECIST, version 1.1. A participant without a post-Baseline assessment of response was considered a non-responder. Confirmation, per RECIST version 1.1, requires a confimatory disease assessment of CR or PR at least 28 days after the initial disease assessment of CR or PR.

  • Duration of Response as Assessed by the Investigator: Randomized Phase [ Time Frame: Time from the first documented evidence of PR or CR until the first documented sign of disease progression or death due to any cause (up to 65.6 weeks) ] [ Designated as safety issue: No ]
    Duration of response for participants with either a CR (the disappearance of all target lesions. Any pathological lymph nodes must be <10 mm in the short axis.) or PR (at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]) was defined as the time from the first documented evidence of a PR or CR until the first documented sign of PD or death due to any cause. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm.

  • Duration of Response as Assessed by an Independent Radiologist: Randomized Phase [ Time Frame: Time from the first documented evidence of PR or CR until the first documented sign of disease progression or death due to any cause (up to 7.4 months) ] [ Designated as safety issue: No ]
    Duration of response for participants with either a CR (the disappearance of all target lesions. Any pathological lymph nodes must be <10 mm in the short axis.) or PR (at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]) was defined as the time from the first documented evidence of a PR or CR until the first documented sign of PD or death due to any cause. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm.

  • Progression-free Survival (PFS2) as Assessed by the Investigator: Crossover Phase [ Time Frame: Time from first dose of GSK2118436 in participants who crossover after initial progression to the earliest date of radiographical or photographical PD or death due to any cause (up to 6.4 months) ] [ Designated as safety issue: No ]
    PFS2 is defined as the time from the first dose of GSK2118436, in participants randomized to DTIC who crossed over to GSK2118436 after initial progression, to the earliest date of radiographic or photographic disease progression or death due to any cause. Disease progression was based on radiographic or photographic evidence, and assessments were made by the investigator according to RECIST version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm. For participants who did not progress or die, PFS was censored at the date of last contact.

  • Number of Participants With a Best Overall Response of Confirmed Complete Response (CR) or Confirmed Partial Response (PR) as Assessed by the Investigator: Crossover Phase [ Time Frame: From randomization until the first documented evidence of a confirmed complete response or partial response (up to 6.4 months) ] [ Designated as safety issue: No ]
    A participant was defined as a responder if he/she achieved either a CR (the disappearance of all target lesions. Any pathological lymph nodes must be <10 mm in the short axis.) or PR (at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]). Response was evaluated by an investigator per RECIST, version 1.1. A participant without a post-Baseline assessment of response was considered a non-responder. Confirmation, per RECIST version 1.1, requires a confimatory disease assessment of CR or PR at least 28 days after the initial disease assessment of CR or PR.

  • Duration of Response as Assessed by the Investigator: Crossover Phase [ Time Frame: Time from the first documented evidence of PR or CR until the first documented sign of disease progression or death due to any cause (up to 6.4 months) ] [ Designated as safety issue: No ]
    Duration of response for participants with either a CR (the disappearance of all target lesions. Any pathological lymph nodes must be <10 mm in the short axis.) or PR (at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]) was defined as the time from the first documented evidence of a PR or CR until the first documented sign of PD or death due to any cause. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm.

  • Number of Participants With Non-melanoma Skin Lesions: Randomized Phase [ Time Frame: From Screening until study completion or discontinuation from the study (up to 9.9 months) ] [ Designated as safety issue: No ]
    Dermatological examinations were performed by the investigator, or at the discretion of the investigator, referred to a dermatologist. The number of participants with non-melanoma skin lessions was assessed from the time of Screening until study completion or discontinuation from the study for any reason.

  • Validation of the BRAF Mutation Assay [ Time Frame: Screening ] [ Designated as safety issue: No ]
    Analytical and clinical validation of the companion diagnostic (cDx) assay was performed to determine the extent of agreement between the bioMerieux cDx assay (THxID BRAF Assay) and the Response Genetic Incorporated Investigational Use Only assay used to detect BRAF mutations to determine participant eligibility into the study. Skin tissue samples collected at the Screening visit were used for this analysis. However, assay validation is ongoing; no data are available at this time.


Enrollment: 250
Study Start Date: December 2010
Estimated Study Completion Date: September 2016
Primary Completion Date: December 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: GSK2118436
Subjects in this arm will receive GSK2118436 150 mg twice daily.
Drug: GSK2118436
150 mg twice daily
Active Comparator: Dacarbazine (DTIC)
Subjects will receive intravenous dacarbazine (DTIC) 1000 mg/m2 every 3 weeks
Drug: Dacarbazine (DTIC)
Intravenous (IV), 1000 mg/m2 every 3 weeks until initial progression
Experimental: Crossover
Subjects who initially receive DTIC will be allowed to receive GSK2118436 after initial progression.
Drug: GSK2118436
150 mg twice daily

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Adults at least 18 years of age
  • Has advanced (unresectable Stage III) or metastatic (Stage IV) melanoma that is BRAF mutation positive (V600E)
  • Is treatment naive for advanced (unresectable) or metastatic melanoma, with the exception of Interleukin 2 (IL-2) which is allowed.
  • Has measurable disease according to RECIST 1.1 criteria.
  • Women of child-bearing potential must have a negative pregnancy test within 14 days prior to the first dose of study treatment.
  • Women with reproductive potential must be willing to practice acceptable methods of birth control during the study and for up to 4 weeks after the last dose of study medication.
  • Men with reproductive potential must be willing to practice acceptable methods of birth control during the study and for up to 16 weeks after the last dose of study medication.
  • Must have adequate organ function.
  • Must have Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1.

Exclusion Criteria:

  • Currently receiving cancer therapy (chemotherapy, radiation therapy, immunotherapy, biologic therapy or surgery).
  • Evidence of active central nervous system (CNS) disease.
  • Previous treatment for metastatic melanoma, including treatment with BRAF or MEK inhibitor.
  • A history of other malignancy. Subjects who have been disease-free for 5 years or subjects with a history of complete resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible.
  • History of Human Immunodeficiency Virus (HIV) infection.
  • Certain cardiac abnormalities
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01227889

  Show 94 Study Locations
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

No publications provided by GlaxoSmithKline

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT01227889     History of Changes
Other Study ID Numbers: 113683
Study First Received: October 21, 2010
Results First Received: June 6, 2013
Last Updated: June 12, 2014
Health Authority: Italy: AIFA - Italian Ministry of Health
France: Ministry of Health
Italy: Comitato Etico Fondazione Centro San Raffaele del Monte Tabor - Via Olgettina, 60 - 20132 Milano
Canada: Health Canada
Hungary: National Institute of Pharmacy
Spain: Ministry of Health and Consumption
Ireland: Irish Medicines Board
United States: Food and Drug Administration
Russia: Russian Ministry of Health
Poland: Ministry of Health
Germany: Bundesinstitut für Arzneimittel und Medizinprodukte
Netherlands: Medical Ethics Review Committee (METC)
Australia: Therapeutic Goods Administration

Keywords provided by GlaxoSmithKline:
Metastatic melanoma
melanoma
BRAF mutant
Advanced melanoma

Additional relevant MeSH terms:
Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Dacarbazine
Dabrafenib
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Protein Kinase Inhibitors
Enzyme Inhibitors

ClinicalTrials.gov processed this record on August 18, 2014