Malignant Melanoma
Conditions
Brief summary
This is an open-label, non-comparative, multicenter, expanded access study of RO5185426 in patients who have received prior systemic therapy for metastatic melanoma and who have no other satisfactory treatment options.
Interventions
DRUGRO5185426
Sponsors
Hoffmann-La Roche
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
16 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed metastatic melanoma with documented BRAF V600E mutation, determined by the cobas BRAF V600 mutation test * Patients with either measurable or non-measurable disease * Adequate recovery from most recent systemic or local treatment for metastatic melanoma * Adequate organ function * For women of childbearing potential, agreement to the use of two acceptable methods of contraception, including one barrier method, during the study and for 6 months after discontinuation of RO5185426 * For men with female partners of childbearing potential, agreement to use a latex condom, and to advise their female partner to use an additional method of contraception during the study and for 6 months after discontinuation of RO5185426 * Negative serum or urine pregnancy test within 7 days of commencement of treatment in premenopausal women. Women who are either surgically sterile or have been post-menopausal for at least 1 year are eligible to participate in this study * Agreement not to donate blood or blood products during the study and for at least 6 months after discontinuation of RO5185426; for male patients, agreement not to donate sperm during the study and for at least 6 months after discontinuation of RO5185426
Exclusion criteria
* Pregnant or breast-feeding * Concurrent anti-tumor therapy * Uncontrolled medical illness * History of congenital prolonged QT syndrome or patients with a mean QTc interval greater than 470 milliseconds at baseline, or ongoing grade 2 or greater cardiac arrhythmia
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Any Adverse Event, Adverse Events With Severity, Adverse Events Leading to Discontinuation | Up to 1 year | An Adverse Event (AE) is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. AEs will be graded according to the 'National Cancer Institute Common Terminology Criteria for Adverse Events' (NCI CTCAE, v4.0). However Laboratory data will be summarized by grade using the NCI CTCAE, v4.0 toxicity grade. |
| Number of Participants With Any Serious Adverse Event, Death and Cause of Death | Up to 1 year | Serious Adverse Event (SAEs) is defined as those events that were fatal or immediately life-threatening, and those events that resulted in hospitalization; prolonged an existing hospitalization; resulted in disability; or was a congenital anomaly. Number of participants who died and the cause of death are also recorded. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Best Overall Response (Confirmed) | Up to 1 year | The best overall response (confirmed) is the best response recorded from the start of the treatment until disease progression/recurrence which was confirmed. Participants were assessed for best overall response by investigator as per RECIST v1.1. |
| Number of Participants With Best Overall Response (Unconfirmed) | Up to 1 year | The best overall response (unconfirmed) is the best response recorded from the start of the treatment until disease progression/recurrence which was unconfirmed. Participants were assessed for best overall response by investigator as per 'Response Evaluation Criteria in Solid Tumors' (RECIST v1.1). |
| Mean Time to Complete Response/Partial Response | Up to 1 year | Mean time to Complete Response (CR)/Partial Response(PR) (confirmed or unconfirmed was assessed). Participants were assessed for best overall response by investigator as per RECIST v1.1. |
| Number of Participants With Best Overall Response (Confirmed) by ECOG Performance | Up to 1 year | The best overall response recorded from the start of the treatment until disease progression/recurrence which was confirmed in patients with Eastern Cooperative Oncology Group (ECOG) performance status 2 or 3/0 or 1. Following are ECOG grades. 0: Fully active, perform all pre-disease activities without restriction. 1: Restricted in physically strenuous activity but ambulatory, carry out work of a light or sedentary nature. 2: Ambulatory, capable of selfcare, unable to carry out any work activities, up and about more than (\>) 50% of waking hours. 3: Capable of limited selfcare, confined to bed or chair \>50% of waking hours. 4: Completely disabled, not capable of any selfcare, totally confined to bed or chair. 5: Dead. Participants were assessed for best overall response by investigator as per RECIST v1.1. The 'n' is number of participants with ECOG performance status in each criteria. |
| Number of Participants With Best Overall Response (Unconfirmed) by ECOG Performance | Up to 1 year | The best overall response recorded from the start of the treatment until disease progression/recurrence which was unconfirmed in patients with Eastern Cooperative Oncology Group (ECOG) performance status 2 or 3/0 or 1. Following are ECOG grades. 0: Fully active, perform all pre-disease activities without restriction. 1: Restricted in physically strenuous activity but ambulatory, carry out work of a light or sedentary nature. 2: Ambulatory, capable of selfcare, unable to carry out any work activities, up and about more than (\>) 50% of waking hours. 3: Capable of limited selfcare, confined to bed or chair \>50% of waking hours. 4: Completely disabled, not capable of any selfcare, totally confined to bed or chair. 5: Dead. This endpoint was tumor response category according to investigator assessment per RECIST v1.1 for efficacy assessment. The 'n' is number of participants with ECOG performance status in each criteria. |
Countries
United States
Participant flow
Recruitment details
The study was conducted in 29 study sites in the United States (US). The study period was from 10 December 2010 to 24 October 2011.
Pre-assignment details
Overall, 745 participants were screened during the study, of which 374 were enrolled to receive study treatment; the main reason for screen failure was negative cobas test, consent withdrawal, BRAF test not performed, patient died or progressed, and other unspecified reasons. Of 374 participants, 3 did not receive treatment after enrollment.
Participants by arm
| Arm | Count |
|---|---|
| Overall Trial Participants received vemurafenib 960 mg orally two times a day for up to one year. Participants were treated until disease progression, unmanageable toxicity most probably attributable to vemurafenib, withdrawal of consent, and study termination by the sponsor. | 371 |
| Total | 371 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 8 |
| Overall Study | Death | 26 |
| Overall Study | Lost to Follow-up | 7 |
| Overall Study | Other reason | 3 |
| Overall Study | Progression of Disease | 50 |
| Overall Study | Refused Treatment | 1 |
| Overall Study | Sponsor Decision | 259 |
| Overall Study | Withdrawal of Consent | 20 |
Baseline characteristics
| Characteristic | Overall Trial |
|---|---|
| Age, Continuous | 53.5 years STANDARD_DEVIATION 13.8 |
| Age, Customized Adolescents (12-17 year) | 1 participants |
| Age, Customized From 18 - 64 years | 289 participants |
| Age, Customized From 65 - 84 years | 79 participants |
| Age, Customized Over 85 years | 2 participants |
| Sex: Female, Male Female | 142 Participants |
| Sex: Female, Male Male | 229 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 308 / 371 |
| serious Total, serious adverse events | 83 / 371 |
Outcome results
Primary
Number of Participants With Any Adverse Event, Adverse Events With Severity, Adverse Events Leading to Discontinuation
An Adverse Event (AE) is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. AEs will be graded according to the 'National Cancer Institute Common Terminology Criteria for Adverse Events' (NCI CTCAE, v4.0). However Laboratory data will be summarized by grade using the NCI CTCAE, v4.0 toxicity grade.
Time frame: Up to 1 year
Population: The safety population was defined as participants who received at least one dose, or a partial dose, of vemurafenib.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Overall Trial | Number of Participants With Any Adverse Event, Adverse Events With Severity, Adverse Events Leading to Discontinuation | Any AE | 346 participants |
| Overall Trial | Number of Participants With Any Adverse Event, Adverse Events With Severity, Adverse Events Leading to Discontinuation | Grade 3 AEs | 115 participants |
| Overall Trial | Number of Participants With Any Adverse Event, Adverse Events With Severity, Adverse Events Leading to Discontinuation | Grade 4 AEs | 15 participants |
| Overall Trial | Number of Participants With Any Adverse Event, Adverse Events With Severity, Adverse Events Leading to Discontinuation | Grade 5 AEs | 7 participants |
| Overall Trial | Number of Participants With Any Adverse Event, Adverse Events With Severity, Adverse Events Leading to Discontinuation | AEs leading to discontinuation | 9 participants |
Primary
Number of Participants With Any Serious Adverse Event, Death and Cause of Death
Serious Adverse Event (SAEs) is defined as those events that were fatal or immediately life-threatening, and those events that resulted in hospitalization; prolonged an existing hospitalization; resulted in disability; or was a congenital anomaly. Number of participants who died and the cause of death are also recorded.
Time frame: Up to 1 year
Population: The safety population was defined as participants who received at least one dose, or a partial dose, of vemurafenib.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Overall Trial | Number of Participants With Any Serious Adverse Event, Death and Cause of Death | Any SAEs | 83 participants |
| Overall Trial | Number of Participants With Any Serious Adverse Event, Death and Cause of Death | All Deaths | 43 participants |
| Overall Trial | Number of Participants With Any Serious Adverse Event, Death and Cause of Death | Death due to progression of disease | 22 participants |
| Overall Trial | Number of Participants With Any Serious Adverse Event, Death and Cause of Death | Death due to adverse event | 8 participants |
| Overall Trial | Number of Participants With Any Serious Adverse Event, Death and Cause of Death | Deaths which are not related to study drug | 6 participants |
| Overall Trial | Number of Participants With Any Serious Adverse Event, Death and Cause of Death | Deaths which are related to study drug | 2 participants |
Secondary
Mean Time to Complete Response/Partial Response
Mean time to Complete Response (CR)/Partial Response(PR) (confirmed or unconfirmed was assessed). Participants were assessed for best overall response by investigator as per RECIST v1.1.
Time frame: Up to 1 year
Population: The efficacy population was defined as treated participants who had measurable disease at baseline and at least one post-baseline tumor assessment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Overall Trial | Mean Time to Complete Response/Partial Response | Mean time to confirmed CR or PR | 1.8 Months | Standard Deviation 0.3 |
| Overall Trial | Mean Time to Complete Response/Partial Response | Mean time to unconfirmed CR or PR | 2.0 Months | Standard Deviation 0.7 |
Secondary
Number of Participants With Best Overall Response (Confirmed)
The best overall response (confirmed) is the best response recorded from the start of the treatment until disease progression/recurrence which was confirmed. Participants were assessed for best overall response by investigator as per RECIST v1.1.
Time frame: Up to 1 year
Population: The efficacy population was defined as treated participants who had measurable disease at baseline and at least one post-baseline tumor assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Overall Trial | Number of Participants With Best Overall Response (Confirmed) | 26 Participants |
Secondary
Number of Participants With Best Overall Response (Confirmed) by ECOG Performance
The best overall response recorded from the start of the treatment until disease progression/recurrence which was confirmed in patients with Eastern Cooperative Oncology Group (ECOG) performance status 2 or 3/0 or 1. Following are ECOG grades. 0: Fully active, perform all pre-disease activities without restriction. 1: Restricted in physically strenuous activity but ambulatory, carry out work of a light or sedentary nature. 2: Ambulatory, capable of selfcare, unable to carry out any work activities, up and about more than (\>) 50% of waking hours. 3: Capable of limited selfcare, confined to bed or chair \>50% of waking hours. 4: Completely disabled, not capable of any selfcare, totally confined to bed or chair. 5: Dead. Participants were assessed for best overall response by investigator as per RECIST v1.1. The 'n' is number of participants with ECOG performance status in each criteria.
Time frame: Up to 1 year
Population: The efficacy population was defined as treated participants who had measurable disease at baseline and at least one post-baseline tumor assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Overall Trial | Number of Participants With Best Overall Response (Confirmed) by ECOG Performance | ECOG performance status 2 or 3); n= 31 | 1 Participants |
| Overall Trial | Number of Participants With Best Overall Response (Confirmed) by ECOG Performance | ECOG performance status 0 or 1); n= 210 | 25 Participants |
Secondary
Number of Participants With Best Overall Response (Unconfirmed)
The best overall response (unconfirmed) is the best response recorded from the start of the treatment until disease progression/recurrence which was unconfirmed. Participants were assessed for best overall response by investigator as per 'Response Evaluation Criteria in Solid Tumors' (RECIST v1.1).
Time frame: Up to 1 year
Population: The efficacy population was defined as treated participants who had measurable disease at baseline and at least one post-baseline tumor assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Overall Trial | Number of Participants With Best Overall Response (Unconfirmed) | 129 participants |
Secondary
Number of Participants With Best Overall Response (Unconfirmed) by ECOG Performance
The best overall response recorded from the start of the treatment until disease progression/recurrence which was unconfirmed in patients with Eastern Cooperative Oncology Group (ECOG) performance status 2 or 3/0 or 1. Following are ECOG grades. 0: Fully active, perform all pre-disease activities without restriction. 1: Restricted in physically strenuous activity but ambulatory, carry out work of a light or sedentary nature. 2: Ambulatory, capable of selfcare, unable to carry out any work activities, up and about more than (\>) 50% of waking hours. 3: Capable of limited selfcare, confined to bed or chair \>50% of waking hours. 4: Completely disabled, not capable of any selfcare, totally confined to bed or chair. 5: Dead. This endpoint was tumor response category according to investigator assessment per RECIST v1.1 for efficacy assessment. The 'n' is number of participants with ECOG performance status in each criteria.
Time frame: Up to 1 year
Population: The efficacy population was defined as treated patients who had measurable disease at baseline and at least one post-baseline tumor assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Overall Trial | Number of Participants With Best Overall Response (Unconfirmed) by ECOG Performance | ECOG performance status 2 or 3; n=31 | 13 Participants |
| Overall Trial | Number of Participants With Best Overall Response (Unconfirmed) by ECOG Performance | ECOG performance status 0 or 1; n=210 | 116 Participants |