Cancer
Conditions
Keywords
Metastatic melanoma, melanoma, BRAF mutant, Advanced melanoma
Brief 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.
Interventions
DRUGGSK2118436
150 mg twice daily
Intravenous (IV), 1000 mg/m2 every 3 weeks until initial progression
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) as Assessed by the Investigator | 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) | 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: Randomized Phase | 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) | 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
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With a Best Overall Response of Confirmed CR or PR as Assessed by an Independent Radiologist: Randomized Phase | From randomization until the first documented evidence of a confirmed complete response or partial response (median of 12.0 weeks) | 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 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) | 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 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) | 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. |
| Progression-free Survival (PFS2) as Assessed by the Investigator: Crossover Phase | 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) | 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. |
| Overall Survival | Time interval between the date of randomization and the date of death due to any cause (up to 22.1 months) | 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. |
| Duration of Response as Assessed by the Investigator: Crossover Phase | 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) | 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 | From Screening until study completion or discontinuation from the study (up to 9.9 months) | 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. |
| Agreement Rate for V600E Mutation Validation of the BRAF Mutation Assay | Screening | 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. |
| 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 | From randomization until the first documented evidence of a confirmed complete response or partial response (up to 6.4 months) | 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 Complete Response (CR) or Confirmed Partial Response (PR) as Assessed by the Investigator: Randomized Phase | From randomization until the first documented evidence of a confirmed complete response or partial response (median of 6.6 weeks) | 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. |
Countries
Australia, Canada, France, Germany, Hungary, Ireland, Italy, Netherlands, Poland, Russia, Spain, United States
Participant flow
Recruitment details
This was a Phase III randomized, open-label study to compare GSK2118436 to Dacarbazine (DTIC) in previously untreated participants (par.) with BRAF mutation positive advanced (Stage III) or metastatic (Stage IV) melanoma. This study was conducted at 70 centers in 12 countries.
Pre-assignment details
The study has 2 phases: Randomized and Crossover Phase. In Randomized Phase, a total of 250 par. were randomized in 3:1 to receive either oral dabrafenib 150 mg twice daily (BID) or intravenous DTIC 1000 milligram/meter square. Par. in DTIC arm with disease progression were considered for crossover to dabrafenib arm in Crossover Phase
Participants by arm
| Arm | Count |
|---|---|
| GSK2118436 150 mg BID Participants were randomly assigned to receive oral GSK2118436 150 mg BID. Dose reductions were permitted based on the severity of the hematological toxicity. Stopping recommendations for study treatment were also provided for cases of reoccurring skin toxicity, cardiovascular complication or abnormalities, and liver abnormalities. Participants continued on treatment until DP, death, the occurrence of an unacceptable AE, or withdrawal from the study. Participants who experienced investigator-reported DP but were benefitting from study treatment were permitted to continue GSK2118436 treatment upon approval of the GlaxoSmithKline Medical Monitor. | 187 |
| DTIC 1000 mg/m^2 in RP; GSK2118436 in Crossover Phase In the RP, par. received IV DTIC 1000 mg/m\^2 every 3 weeks. Dose reductions were permitted based on the severity of the hematological toxicity. Stopping recommendations for study treatment were also provided for cases of reoccurring skin toxicity, cardiovascular complication or abnormalities, and liver abnormalities. Par. continued on treatment until DP, death, the occurrence of an unacceptable AE, or withdrawal from the study. Par. who received DTIC in the RP and experienced DP had the option, at the discretion of the Investigator, of receiving GSK2118436 150 mg BID in the Crossover Phase. Par. who permanently discontinued DTIC treatment due to an AE, withdrawal of consent, or for any reason other than DP were not eligible for crossover to GSK2118436. Crossover par. continued on GSK2118436 until further DP was noted. After DP on GSK2118436, par. were followed for response, progression, survival, and further anti-cancer therapy. | 63 |
| Total | 250 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Crossover Phase | Adverse Event | 0 | 1 |
| Crossover Phase | Physician Decision | 0 | 3 |
| Crossover Phase | Progressive Disease | 0 | 31 |
| Crossover Phase | Study Terminated By Sponsor | 0 | 1 |
| Crossover Phase | Withdrawal by Subject | 0 | 1 |
| Randomized Phase (RP) | Adverse Event | 13 | 0 |
| Randomized Phase (RP) | Missing | 1 | 3 |
| Randomized Phase (RP) | Physician Decision | 13 | 5 |
| Randomized Phase (RP) | Progressive Disease | 135 | 52 |
| Randomized Phase (RP) | Study terminated by sponsor | 10 | 0 |
| Randomized Phase (RP) | Withdrawal by Subject | 15 | 3 |
Baseline characteristics
| Characteristic | GSK2118436 150 mg BID | DTIC 1000 mg/m^2 in RP; GSK2118436 in Crossover Phase | Total |
|---|---|---|---|
| Age, Continuous | 53.5 Years STANDARD_DEVIATION 13.76 | 51.6 Years STANDARD_DEVIATION 14.22 | 53.0 Years STANDARD_DEVIATION 13.87 |
| Race/Ethnicity, Customized Missing | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized White | 186 participants | 63 participants | 249 participants |
| Sex: Female, Male Female | 75 Participants | 26 Participants | 101 Participants |
| Sex: Female, Male Male | 112 Participants | 37 Participants | 149 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 5 / 187 | 0 / 59 | 1 / 37 |
| other Total, other adverse events | 181 / 187 | 51 / 59 | 37 / 37 |
| serious Total, serious adverse events | 64 / 187 | 14 / 59 | 9 / 37 |
Outcome results
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 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)
Population: ITT Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| GSK2118436 150 mg BID | Progression-free Survival (PFS) as Assessed by an Independent Radiologist: Randomized Phase | 6.7 Months |
| DTIC 1000 mg/m^2 in RP | Progression-free Survival (PFS) as Assessed by an Independent Radiologist: Randomized Phase | 2.9 Months |
95% CI: [0.2, 0.61]
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 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)
Population: Intent-to-Treat (ITT) Population: all randomized participants regardless of whether or not treatment was administered
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| GSK2118436 150 mg BID | Progression-free Survival (PFS) as Assessed by the Investigator | 6.9 Months |
| DTIC 1000 mg/m^2 in RP | Progression-free Survival (PFS) as Assessed by the Investigator | 2.7 Months |
p-value: <0.000195% CI: [0.26, 0.6]Log Rank
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.
Time frame: Screening
Population: V600E positive participants screened for BREAK-3 study
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| GSK2118436 150 mg BID | Agreement Rate for V600E Mutation Validation of the BRAF Mutation Assay | Agreement for V600E | 96.70 Percent agreement |
| GSK2118436 150 mg BID | Agreement Rate for V600E Mutation Validation of the BRAF Mutation Assay | Agreement for V600K | 90.00 Percent agreement |
| GSK2118436 150 mg BID | Agreement Rate for V600E Mutation Validation of the BRAF Mutation Assay | Agreement for mutation negative | 95.00 Percent agreement |
| GSK2118436 150 mg BID | Agreement Rate for V600E Mutation Validation of the BRAF Mutation Assay | Agreement for overall | 94.90 Percent agreement |
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 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)
Population: ITT Population. Only participants with a confirmed CR or PR were assessed for duration of response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| GSK2118436 150 mg BID | Duration of Response as Assessed by an Independent Radiologist: Randomized Phase | 5.5 Months |
| DTIC 1000 mg/m^2 in RP | Duration of Response as Assessed by an Independent Radiologist: Randomized Phase | NA 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 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)
Population: Crossover Population. Only participants with a confirmed CR or PR were assessed for duration of response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| GSK2118436 150 mg BID | Duration of Response as Assessed by the Investigator: Crossover Phase | 4.4 Months |
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 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)
Population: ITT Population. Only participants with a confirmed CR or PR were assessed for duration of response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| GSK2118436 150 mg BID | Duration of Response as Assessed by the Investigator: Randomized Phase | 9.2 Months |
| DTIC 1000 mg/m^2 in RP | Duration of Response as Assessed by the Investigator: Randomized Phase | 8.2 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.
Time frame: From randomization until the first documented evidence of a confirmed complete response or partial response (up to 6.4 months)
Population: Crossover Treatment Population. At the time data were analyzed for overall response, only 37 participants had crossed over from DTIC treatment to GSK25118436 treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| GSK2118436 150 mg BID | 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 | CR | 0 participants |
| GSK2118436 150 mg BID | 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 | PR | 12 participants |
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.
Time frame: From randomization until the first documented evidence of a confirmed complete response or partial response (median of 6.6 weeks)
Population: ITT Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| GSK2118436 150 mg BID | 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 | CR | 26 participants |
| GSK2118436 150 mg BID | 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 | PR | 86 participants |
| DTIC 1000 mg/m^2 in RP | 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 | CR | 4 participants |
| DTIC 1000 mg/m^2 in RP | 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 | PR | 11 participants |
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.
Time frame: From randomization until the first documented evidence of a confirmed complete response or partial response (median of 12.0 weeks)
Population: ITT Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| GSK2118436 150 mg BID | Number of Participants With a Best Overall Response of Confirmed CR or PR as Assessed by an Independent Radiologist: Randomized Phase | PR | 87 participants |
| GSK2118436 150 mg BID | Number of Participants With a Best Overall Response of Confirmed CR or PR as Assessed by an Independent Radiologist: Randomized Phase | CR | 6 participants |
| DTIC 1000 mg/m^2 in RP | Number of Participants With a Best Overall Response of Confirmed CR or PR as Assessed by an Independent Radiologist: Randomized Phase | CR | 1 participants |
| DTIC 1000 mg/m^2 in RP | Number of Participants With a Best Overall Response of Confirmed CR or PR as Assessed by an Independent Radiologist: Randomized Phase | PR | 3 participants |
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.
Time frame: From Screening until study completion or discontinuation from the study (up to 9.9 months)
Population: Safety Population: all randomized participants who received at least one dose of study drug, based on the actual treatment received, if this differed from that to which the participant was randomized
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| GSK2118436 150 mg BID | Number of Participants With Non-melanoma Skin Lesions: Randomized Phase | Number of Subjects with Event | 14 participants |
| GSK2118436 150 mg BID | Number of Participants With Non-melanoma Skin Lesions: Randomized Phase | Number of Events | 24 participants |
| DTIC 1000 mg/m^2 in RP | Number of Participants With Non-melanoma Skin Lesions: Randomized Phase | Number of Subjects with Event | 0 participants |
| DTIC 1000 mg/m^2 in RP | Number of Participants With Non-melanoma Skin Lesions: Randomized Phase | Number of Events | 0 participants |
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 frame: Time interval between the date of randomization and the date of death due to any cause (up to 22.1 months)
Population: ITT Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| GSK2118436 150 mg BID | Overall Survival | 20.0 Months |
| DTIC 1000 mg/m^2 in RP | Overall Survival | 15.6 Months |
95% CI: [0.57, 1.18]
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 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)
Population: Crossover Treatment Population: the subset of participants who were randomized to the DTIC arm, and who elected at the point of disease progression to receive GSK2118436. Only participants who received at least one dose of GSK2118436 were included in the Crossover Treatment Population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| GSK2118436 150 mg BID | Progression-free Survival (PFS2) as Assessed by the Investigator: Crossover Phase | 4.3 Months |