Malignant Melanoma
Conditions
Keywords
dabrafenib, trametinib, adjuvant, Stage III melanoma, combination treatment, pyrexia
Brief summary
The main purpose of this study was to evaluate the impact on pyrexia-related outcomes of an adapted pyrexia adverse event (AE)-management algorithm, as well as safety, efficacy and health-related outcomes.
Detailed description
This was an open-label Phase IIIb study of dabrafenib in combination with trametinib in the adjuvant treatment of melanoma after complete resection. Patients with completely resected, histologically confirmed, BRAF V600E/K mutation-positive, high-risk cutaneous melanoma were screened for eligibility. This study consisted of two periods: 1. Treatment Period - patients received up to 12 months of dabrafenib (150 mg twice daily) and trametinib (2 mg once daily). In the adapted pyrexia management algorithm, dabrafenib and trametinib were interrupted promptly at the onset of pyrexia (≥38°C) and were restarted upon the improvement of symptoms at the same dose if patients remained symptom free (temperature \<38°C) for at least 24 hours. In addition, dabrafenib and trametinib could be interrupted in the presence of pyrexia syndrome (i.e. chills, rigours, night sweats, or influenza-like symptoms) without documented temperature ≥38°C for cases of suspected recurrent pyrexia, at the investigators' discretion. 2. Follow-up Period - patients were followed for disease relapse through 24 months from first dose date. Moreover, patients were followed for overall survival through withdrawal, lost to follow-up, death, or the end of study, whichever occurs first. The follow-up period started once treatment was completed or treatment was prematurely discontinued.
Interventions
DRUGDabrafenib
Supplied as dabrafenib 50 mg and 75 mg capsules for oral administration
DRUGTrametinib
Supplied as trametinib 0.5mg, and 2.0mg tablets for oral administration
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Completely resected histologically confirmed cutaneous melanoma stage IIIA (LN metastasis \>1 mm), IIIB, IIIC, IIID \[AJCC (ed 8)\] no more than 12 weeks, from last surgery, before Day 1 1. Subjects presenting with initial resectable lymph node recurrence after a diagnosis of Stage I or II melanoma were eligible. 2. Subjects who had previously had Stage III melanoma at any time were not eligible. 3. Recovered from definitive surgery (e.g. no uncontrolled wound infections or indwelling drains). * V600E/K mutation positive using a validated local test * Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1 Key
Exclusion criteria
* Uveal or mucosal melanoma * Evidence of metastatic disease including unresectable in-transit metastasis * Received any prior adjuvant or neoadjuvant treatment, including but not limited to chemotherapy, checkpoint inhibitors, targeted therapy \[e.g., BRAF and/or MEK inhibitors\], biologic therapy, vaccine therapy, investigational treatment, or radiotherapy for melanoma * Malignant disease, other than that being treated in this study. Exceptions to this exclusion include the following: malignancies that were treated curatively and had not recurred within 2 years prior to study treatment; completely resected basal cell and squamous cell skin cancers and any completely resected carcinoma in situ * History or current evidence of cardiovascular risk * A history or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Composite Rate of Pyrexia Related Events | Baseline up to 12 months | The composite rate of pyrexia related events was calculated as the total number of participants experiencing at least one of the three components of the composite endpoint (i.e., grade 3/4 pyrexia, hospitalization due to pyrexia, or permanent treatment discontinuation due to pyrexia), divided by the total number of participants treated in the study and multiplied by 100. Pyrexia is defined as fever ≥ 38 °C. Pyrexia events were graded by the investigator using Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 as Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (Life-threatening) and Grade 5 (Death) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Relapse Free Survival (RFS) Rate | At 12 and 24 months | RFS is defined as the time from the date of first dose of the study treatment to the date of the first documented disease recurrence or death due to any cause whichever comes first. Treatment emergent malignancies other than second melanomas were not considered as events. RFS rate is the estimated percent probability that a patient will remain event-free up to the specified time point. RFS rate was obtained from the Kaplan-Meier survival estimates. RFS was censored if no RFS event was observed before the first to occur between: (i) the analysis cut-off date, and (ii) the date when a new anti-cancer therapy is started. The censoring date was the date of the last adequate tumor assessment prior to data cut-off date/start of new anti-cancer therapy date. |
| Overall Survival (OS) Rate | At 12 and 24 months | OS is defined as the time from date of the first dose of study medication to date of death due to any cause, whichever comes first. If a patient was not known to have died, then OS rate is the estimated probability that a patient will remain event-free up to the specified time point. OS rate was obtained from the Kaplan-Meier survival estimates. OS was censored at the last contact date when the patient was known to be alive (on or before the cut-off date). |
| Percentage of Participants Who Required Management of Pyrexia | Baseline up to 12 months | Percentage of patients who experienced pyrexia and required intervention including hospitalizations, concomitant medications, and study treatment modifications (dose reductions, permanent discontinuations and/or interruptions) due to pyrexia. Pyrexia is defined as fever ≥ 38 °C |
| Percentage of Participants Who Permanently Discontinued Treatment Due to Any Adverse Event (AE) | Baseline up to 12 months | Percentage of participants who permanently discontinued treatment due to any AE during treatment. An AE is any untoward medical occurrence (e.g., any unfavorable and unintended sign, symptom or disease) in a subject or clinical investigation subject after providing written informed consent for participation in the study. |
| Change From Baseline in Subject-reported Quality of Life (QoL) Assessed by Functional Assessment Cancer Therapy - Melanoma Subscale Score (FACT-M MS) | Baseline up to 24 months | The FACT-M is a questionnaire that assesses participant health-related quality of life. It includes a melanoma specific (FACT-M MS) subscale that consists in 16 items related to signs, symptoms, physical/social activities most relevant to participants with advanced-stage melanoma. Each item ranges from 0 (not at all) to 4 (very much). FACT-M MS score ranges from 0 to 64, with higher score indicating better quality of life. If a patient discontinued the study treatment at Month 1 or Month 2, then the follow-up assessments started at Month 3 follow-up and continued until Month 24 follow-up or at withdrawal, lost to follow-up, death, or end of study. If a patient discontinued the study treatment from Month 3 through Month 5, the follow-up assessments started at Month 6 follow-up. If a patient discontinued from Month 6 through Month 11, the follow-up assessments started from Month 12 follow-up. For patients who completed treatment, the follow-up assessments started from Month 15 follow-up |
Countries
Argentina, Australia, Brazil, Canada, Czechia, Finland, France, Greece, Hungary, Israel, Italy, Japan, Latvia, Lithuania, Norway, Poland, Portugal, Russia, Slovakia, Slovenia, Sweden, Turkey (Türkiye), United Kingdom
Participant flow
Recruitment details
Patients in this study were enrolled at 103 centers across 23 countries
Pre-assignment details
A total of 748 patients were screened. Of the screened patients, 552 patients were treated.
Participants by arm
| Arm | Count |
|---|---|
| Dabrafenib+Trametinib Subjects received dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) orally for up to 12 months. | 552 |
| Total | 552 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 88 |
| Overall Study | Disease relapse | 18 |
| Overall Study | Lost to Follow-up | 3 |
| Overall Study | Patient decision | 5 |
| Overall Study | Physician Decision | 4 |
| Overall Study | Pregnancy | 1 |
| Overall Study | Protocol deviation | 1 |
| Overall Study | Technical problems | 1 |
| Overall Study | Withdrawal of informed consent | 6 |
Baseline characteristics
| Characteristic | Dabrafenib+Trametinib |
|---|---|
| Age, Continuous | 53.4 Years STANDARD_DEVIATION 13.09 |
| Race/Ethnicity, Customized Asian | 3 Participants |
| Race/Ethnicity, Customized Missing | 172 Participants |
| Race/Ethnicity, Customized White | 377 Participants |
| Sex: Female, Male Female | 255 Participants |
| Sex: Female, Male Male | 297 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 552 | 47 / 537 |
| other Total, other adverse events | 526 / 552 | 0 / 0 |
| serious Total, serious adverse events | 121 / 552 | 0 / 0 |
Outcome results
Primary
Composite Rate of Pyrexia Related Events
The composite rate of pyrexia related events was calculated as the total number of participants experiencing at least one of the three components of the composite endpoint (i.e., grade 3/4 pyrexia, hospitalization due to pyrexia, or permanent treatment discontinuation due to pyrexia), divided by the total number of participants treated in the study and multiplied by 100. Pyrexia is defined as fever ≥ 38 °C. Pyrexia events were graded by the investigator using Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 as Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (Life-threatening) and Grade 5 (Death)
Time frame: Baseline up to 12 months
Population: All subjects who received at least one dose of any study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dabrafenib+Trametinib | Composite Rate of Pyrexia Related Events | 7.6 Percentage of participants |
Secondary
Change From Baseline in Subject-reported Quality of Life (QoL) Assessed by Functional Assessment Cancer Therapy - Melanoma Subscale Score (FACT-M MS)
The FACT-M is a questionnaire that assesses participant health-related quality of life. It includes a melanoma specific (FACT-M MS) subscale that consists in 16 items related to signs, symptoms, physical/social activities most relevant to participants with advanced-stage melanoma. Each item ranges from 0 (not at all) to 4 (very much). FACT-M MS score ranges from 0 to 64, with higher score indicating better quality of life. If a patient discontinued the study treatment at Month 1 or Month 2, then the follow-up assessments started at Month 3 follow-up and continued until Month 24 follow-up or at withdrawal, lost to follow-up, death, or end of study. If a patient discontinued the study treatment from Month 3 through Month 5, the follow-up assessments started at Month 6 follow-up. If a patient discontinued from Month 6 through Month 11, the follow-up assessments started from Month 12 follow-up. For patients who completed treatment, the follow-up assessments started from Month 15 follow-up
Time frame: Baseline up to 24 months
Population: All subjects who received at least one dose of any study treatment. Number analyzed represents participants with data available at the specified data points
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dabrafenib+Trametinib | Change From Baseline in Subject-reported Quality of Life (QoL) Assessed by Functional Assessment Cancer Therapy - Melanoma Subscale Score (FACT-M MS) | Month 3 | -2.26 Score on a scale | Standard Deviation 4.789 |
| Dabrafenib+Trametinib | Change From Baseline in Subject-reported Quality of Life (QoL) Assessed by Functional Assessment Cancer Therapy - Melanoma Subscale Score (FACT-M MS) | Month 7 | -2.39 Score on a scale | Standard Deviation 5.873 |
| Dabrafenib+Trametinib | Change From Baseline in Subject-reported Quality of Life (QoL) Assessed by Functional Assessment Cancer Therapy - Melanoma Subscale Score (FACT-M MS) | Month 8 | -2.32 Score on a scale | Standard Deviation 5.609 |
| Dabrafenib+Trametinib | Change From Baseline in Subject-reported Quality of Life (QoL) Assessed by Functional Assessment Cancer Therapy - Melanoma Subscale Score (FACT-M MS) | End of treatment | -3.36 Score on a scale | Standard Deviation 5.944 |
| Dabrafenib+Trametinib | Change From Baseline in Subject-reported Quality of Life (QoL) Assessed by Functional Assessment Cancer Therapy - Melanoma Subscale Score (FACT-M MS) | Month 1 | -2.46 Score on a scale | Standard Deviation 5.488 |
| Dabrafenib+Trametinib | Change From Baseline in Subject-reported Quality of Life (QoL) Assessed by Functional Assessment Cancer Therapy - Melanoma Subscale Score (FACT-M MS) | Month 2 | -2.42 Score on a scale | Standard Deviation 4.892 |
| Dabrafenib+Trametinib | Change From Baseline in Subject-reported Quality of Life (QoL) Assessed by Functional Assessment Cancer Therapy - Melanoma Subscale Score (FACT-M MS) | Month 4 | -2.34 Score on a scale | Standard Deviation 5.297 |
| Dabrafenib+Trametinib | Change From Baseline in Subject-reported Quality of Life (QoL) Assessed by Functional Assessment Cancer Therapy - Melanoma Subscale Score (FACT-M MS) | Month 5 | -2.03 Score on a scale | Standard Deviation 5.278 |
| Dabrafenib+Trametinib | Change From Baseline in Subject-reported Quality of Life (QoL) Assessed by Functional Assessment Cancer Therapy - Melanoma Subscale Score (FACT-M MS) | Month 6 | -2.19 Score on a scale | Standard Deviation 5.494 |
| Dabrafenib+Trametinib | Change From Baseline in Subject-reported Quality of Life (QoL) Assessed by Functional Assessment Cancer Therapy - Melanoma Subscale Score (FACT-M MS) | Month 9 | -2.06 Score on a scale | Standard Deviation 5.534 |
| Dabrafenib+Trametinib | Change From Baseline in Subject-reported Quality of Life (QoL) Assessed by Functional Assessment Cancer Therapy - Melanoma Subscale Score (FACT-M MS) | Month 10 | -2.15 Score on a scale | Standard Deviation 5.743 |
| Dabrafenib+Trametinib | Change From Baseline in Subject-reported Quality of Life (QoL) Assessed by Functional Assessment Cancer Therapy - Melanoma Subscale Score (FACT-M MS) | Month 11 | -2.05 Score on a scale | Standard Deviation 5.578 |
| Dabrafenib+Trametinib | Change From Baseline in Subject-reported Quality of Life (QoL) Assessed by Functional Assessment Cancer Therapy - Melanoma Subscale Score (FACT-M MS) | Month 12 | -1.96 Score on a scale | Standard Deviation 5.757 |
| Dabrafenib+Trametinib | Change From Baseline in Subject-reported Quality of Life (QoL) Assessed by Functional Assessment Cancer Therapy - Melanoma Subscale Score (FACT-M MS) | Follow-up Month 3 | 2.43 Score on a scale | Standard Deviation 4.685 |
| Dabrafenib+Trametinib | Change From Baseline in Subject-reported Quality of Life (QoL) Assessed by Functional Assessment Cancer Therapy - Melanoma Subscale Score (FACT-M MS) | Follow-up Month 6 | -0.33 Score on a scale | Standard Deviation 4.915 |
| Dabrafenib+Trametinib | Change From Baseline in Subject-reported Quality of Life (QoL) Assessed by Functional Assessment Cancer Therapy - Melanoma Subscale Score (FACT-M MS) | Follow-up Month 12 | -1.71 Score on a scale | Standard Deviation 5.671 |
| Dabrafenib+Trametinib | Change From Baseline in Subject-reported Quality of Life (QoL) Assessed by Functional Assessment Cancer Therapy - Melanoma Subscale Score (FACT-M MS) | Follow-up Month 15 | -0.60 Score on a scale | Standard Deviation 6.018 |
| Dabrafenib+Trametinib | Change From Baseline in Subject-reported Quality of Life (QoL) Assessed by Functional Assessment Cancer Therapy - Melanoma Subscale Score (FACT-M MS) | Follow-up Month 18 | -0.09 Score on a scale | Standard Deviation 4.948 |
| Dabrafenib+Trametinib | Change From Baseline in Subject-reported Quality of Life (QoL) Assessed by Functional Assessment Cancer Therapy - Melanoma Subscale Score (FACT-M MS) | Follow-up Month 24 | -0.75 Score on a scale | Standard Deviation 5.406 |
Secondary
Overall Survival (OS) Rate
OS is defined as the time from date of the first dose of study medication to date of death due to any cause, whichever comes first. If a patient was not known to have died, then OS rate is the estimated probability that a patient will remain event-free up to the specified time point. OS rate was obtained from the Kaplan-Meier survival estimates. OS was censored at the last contact date when the patient was known to be alive (on or before the cut-off date).
Time frame: At 12 and 24 months
Population: All subjects who received at least one dose of any study treatment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dabrafenib+Trametinib | Overall Survival (OS) Rate | 12 months | 99.1 Percent probability |
| Dabrafenib+Trametinib | Overall Survival (OS) Rate | 24 months | 92.6 Percent probability |
Secondary
Percentage of Participants Who Permanently Discontinued Treatment Due to Any Adverse Event (AE)
Percentage of participants who permanently discontinued treatment due to any AE during treatment. An AE is any untoward medical occurrence (e.g., any unfavorable and unintended sign, symptom or disease) in a subject or clinical investigation subject after providing written informed consent for participation in the study.
Time frame: Baseline up to 12 months
Population: All subjects who received at least one dose of any study treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dabrafenib+Trametinib | Percentage of Participants Who Permanently Discontinued Treatment Due to Any Adverse Event (AE) | 87 Participants |
Secondary
Percentage of Participants Who Required Management of Pyrexia
Percentage of patients who experienced pyrexia and required intervention including hospitalizations, concomitant medications, and study treatment modifications (dose reductions, permanent discontinuations and/or interruptions) due to pyrexia. Pyrexia is defined as fever ≥ 38 °C
Time frame: Baseline up to 12 months
Population: All subjects who received at least one dose of any study treatment
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dabrafenib+Trametinib | Percentage of Participants Who Required Management of Pyrexia | Permanent discontinuation of dabrafenib and trametinib (both drugs together) due to pyrexia | 13 Participants |
| Dabrafenib+Trametinib | Percentage of Participants Who Required Management of Pyrexia | Reduction of dabrafenib and trametinib (both drugs together) due to pyrexia | 29 Participants |
| Dabrafenib+Trametinib | Percentage of Participants Who Required Management of Pyrexia | Interruption of dabrafenib and trametinib (both drugs together) due to pyrexia | 339 Participants |
| Dabrafenib+Trametinib | Percentage of Participants Who Required Management of Pyrexia | Hospitalizations due to pyrexia | 24 Participants |
| Dabrafenib+Trametinib | Percentage of Participants Who Required Management of Pyrexia | Concomitant medications due to pyrexia | 210 Participants |
Secondary
Relapse Free Survival (RFS) Rate
RFS is defined as the time from the date of first dose of the study treatment to the date of the first documented disease recurrence or death due to any cause whichever comes first. Treatment emergent malignancies other than second melanomas were not considered as events. RFS rate is the estimated percent probability that a patient will remain event-free up to the specified time point. RFS rate was obtained from the Kaplan-Meier survival estimates. RFS was censored if no RFS event was observed before the first to occur between: (i) the analysis cut-off date, and (ii) the date when a new anti-cancer therapy is started. The censoring date was the date of the last adequate tumor assessment prior to data cut-off date/start of new anti-cancer therapy date.
Time frame: At 12 and 24 months
Population: All subjects who received at least one dose of any study treatment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dabrafenib+Trametinib | Relapse Free Survival (RFS) Rate | 12 months | 91.7 Percent probability |
| Dabrafenib+Trametinib | Relapse Free Survival (RFS) Rate | 24 months | 57.5 Percent probability |
Post Hoc
All Collected Deaths
On-treatment deaths were collected from date of first administration of study treatment to 30 days after date of last administration of any study treatment (dabrafenib or trametinib). Post-treatment follow-up deaths were collected after the on-treatment period. All deaths refer to the sum of on-treatment and post-treatment follow-up deaths
Time frame: On-treatment: from first study treatment to 30 days after last dose of study treatment, up to 13 months. Post-treatment: From day 31 after last study treatment up to approximately 39 months
Population: All subjects who received at least one dose of any study treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dabrafenib+Trametinib | All Collected Deaths | On-treatment deaths | 1 Participants |
| Dabrafenib+Trametinib | All Collected Deaths | Post-treatment follow-up deaths | 47 Participants |
| Dabrafenib+Trametinib | All Collected Deaths | All deaths | 48 Participants |