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

Cancer Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01227889
• Other study ID #: 113683
• Status: Completed
• Phase: Phase 3
• First received: October 21, 2010
• Last updated: September 6, 2017
• Start date: December 23, 2010
• Est. completion date: September 16, 2016

Study information

• Verified date: August 2017
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 251
• Est. completion date: September 16, 2016
• Est. primary completion date: December 19, 2011
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Cancer
• Melanoma

Intervention

Drug:
• GSK2118436
150 mg twice daily
• Dacarbazine (DTIC)
Intravenous (IV), 1000 mg/m2 every 3 weeks until initial progression

Locations

Country	Name	City	State
Australia	GSK Investigational Site	Adelaide	South Australia
Australia	GSK Investigational Site	Nedlands	Western Australia
Australia	GSK Investigational Site	Southport	Queensland
Australia	GSK Investigational Site	Westmead	New South Wales
Canada	GSK Investigational Site	Edmonton	Alberta
Canada	GSK Investigational Site	Kelowna	British Columbia
Canada	GSK Investigational Site	Montreal	Quebec
Canada	GSK Investigational Site	Toronto	Ontario
Canada	GSK Investigational Site	Toronto	Ontario
France	GSK Investigational Site	Bordeaux
France	GSK Investigational Site	Lille
France	GSK Investigational Site	Marseille Cedex 5
France	GSK Investigational Site	Nice
France	GSK Investigational Site	Paris
France	GSK Investigational Site	Paris cedex 18
France	GSK Investigational Site	Reims
France	GSK Investigational Site	Villejuif
Germany	GSK Investigational Site	Bonn	Nordrhein-Westfalen
Germany	GSK Investigational Site	Erfurt	Thueringen
Germany	GSK Investigational Site	Erlangen	Bayern
Germany	GSK Investigational Site	Essen	Nordrhein-Westfalen
Germany	GSK Investigational Site	Gera	Thueringen
Germany	GSK Investigational Site	Hannover	Niedersachsen
Germany	GSK Investigational Site	Heidelberg	Baden-Wuerttemberg
Germany	GSK Investigational Site	Homburg	Saarland
Germany	GSK Investigational Site	Jena	Thueringen
Germany	GSK Investigational Site	Kassel	Hessen
Germany	GSK Investigational Site	Kiel	Schleswig-Holstein
Germany	GSK Investigational Site	Koblenz	Rheinland-Pfalz
Germany	GSK Investigational Site	Koeln	Nordrhein-Westfalen
Germany	GSK Investigational Site	Ludwigshafen	Rheinland-Pfalz
Germany	GSK Investigational Site	Magdeburg	Sachsen-Anhalt
Germany	GSK Investigational Site	Mainz	Rheinland-Pfalz
Germany	GSK Investigational Site	Muenster	Nordrhein-Westfalen
Germany	GSK Investigational Site	Nuernberg	Bayern
Germany	GSK Investigational Site	Regensburg	Bayern
Germany	GSK Investigational Site	Ulm	Baden-Wuerttemberg
Germany	GSK Investigational Site	Wiesbaden	Hessen
Hungary	GSK Investigational Site	Budapest
Hungary	GSK Investigational Site	Debrecen
Hungary	GSK Investigational Site	Gyor
Hungary	GSK Investigational Site	Miskolc
Hungary	GSK Investigational Site	Pecs
Ireland	GSK Investigational Site	Cork
Ireland	GSK Investigational Site	Dublin
Ireland	GSK Investigational Site	Dublin
Ireland	GSK Investigational Site	Dublin
Ireland	GSK Investigational Site	Dublin
Ireland	GSK Investigational Site	Galway
Italy	GSK Investigational Site	Genova	Liguria
Italy	GSK Investigational Site	Modena	Emilia-Romagna
Italy	GSK Investigational Site	Padova	Veneto
Italy	GSK Investigational Site	Roma	Lazio
Italy	GSK Investigational Site	Roma	Lazio
Italy	GSK Investigational Site	Rozzano (MI)	Lombardia
Italy	GSK Investigational Site	Siena	Toscana
Italy	GSK Investigational Site	Terni	Umbria
Italy	GSK Investigational Site	Udine	Friuli-Venezia-Giulia
Netherlands	GSK Investigational Site	Amsterdam
Poland	GSK Investigational Site	Brzozow
Poland	GSK Investigational Site	Konin
Poland	GSK Investigational Site	Krakow
Poland	GSK Investigational Site	Slupsk
Poland	GSK Investigational Site	Warszawa
Russian Federation	GSK Investigational Site	Kazan
Russian Federation	GSK Investigational Site	Moscow
Russian Federation	GSK Investigational Site	Ryazan
Russian Federation	GSK Investigational Site	St. Petersburg
Russian Federation	GSK Investigational Site	St. Petersburg
Russian Federation	GSK Investigational Site	St. Petersburg
Russian Federation	GSK Investigational Site	Stavropol
Spain	GSK Investigational Site	Badalona
Spain	GSK Investigational Site	Barcelona
Spain	GSK Investigational Site	Barcelona
Spain	GSK Investigational Site	Hospitalet de Llobregat, Barcelona
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Pamplona
Spain	GSK Investigational Site	Sevilla
United States	GSK Investigational Site	Ann Arbor	Michigan
United States	GSK Investigational Site	Birmingham	Alabama
United States	GSK Investigational Site	Indianapolis	Indiana
United States	GSK Investigational Site	La Jolla	California
United States	GSK Investigational Site	Lebanon	New Hampshire
United States	GSK Investigational Site	Los Angeles	California
United States	GSK Investigational Site	Mobile	Alabama
United States	GSK Investigational Site	New York	New York
United States	GSK Investigational Site	Orlando	Florida
United States	GSK Investigational Site	San Francisco	California
United States	GSK Investigational Site	Vallejo	California

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Countries where clinical trial is conducted

United States,  Australia,  Canada,  France,  Germany,  Hungary,  Ireland,  Italy,  Netherlands,  Poland,  Russian Federation,  Spain, 

References & Publications (1)

Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, Rutkowski P, Blank CU, Miller WH Jr, Kaempgen E, Martín-Algarra S, Karaszewska B, Mauch C, Chiarion-Sileni V, Martin AM, Swann S, Haney P, Mirakhur B, Guckert ME, Goodman V, Chapman PB. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012 Jul 28;380(9839):358-65. doi: 10.1016/S0140-6736(12)60868-X. Epub 2012 Jun 25. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-free Survival (PFS) as Assessed by the Investigator	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.	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)
Primary	Progression-free Survival (PFS) as Assessed by an Independent Radiologist: Randomized Phase	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.	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)
Secondary	Overall Survival	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.	Time interval between the date of randomization and the date of death due to any cause (up to 22.1 months)
Secondary	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	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.	From randomization until the first documented evidence of a confirmed complete response or partial response (median of 6.6 weeks)
Secondary	Number of Participants With a Best Overall Response of Confirmed CR or PR as Assessed by an Independent Radiologist: Randomized Phase	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.	From randomization until the first documented evidence of a confirmed complete response or partial response (median of 12.0 weeks)
Secondary	Duration of Response as Assessed by the Investigator: Randomized Phase	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.	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)
Secondary	Duration of Response as Assessed by an Independent Radiologist: Randomized Phase	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. NA indicates that data is not available.	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)
Secondary	Progression-free Survival (PFS2) as Assessed by the Investigator: Crossover Phase	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.	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)
Secondary	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	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.	From randomization until the first documented evidence of a confirmed complete response or partial response (up to 6.4 months)
Secondary	Duration of Response as Assessed by the Investigator: Crossover Phase	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.	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)
Secondary	Number of Participants With Non-melanoma Skin Lesions: Randomized Phase	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.	From Screening until study completion or discontinuation from the study (up to 9.9 months)
Secondary	Agreement Rate for V600E Mutation Validation of the BRAF Mutation Assay	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 Clinical Trial Assay (CTA) to detect BRAF mutations to determine participant eligibility into the study. Skin tissue samples collected at the Screening visit were used for this analysis. Multiple specimen per participant were analyzed.	Screening