Malignant Melanoma
Conditions
Brief summary
This is an open-label, multicenter, single-agent, phase II study of continuous oral Zelboraf (vemurafenib) in participants with locally-advanced, unresectable, stage IIIc or metastatic melanoma and activating exon 15 BRAF mutations other than V600E.
Interventions
DRUGVemurafenib
Vemurafenib 960 mg BID
Sponsors
Genentech, Inc.
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
* Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2 * Histologically-confirmed metastatic melanoma (unresectable Stage IIIc or IV) with an activating BRAF mutation other than V600E, as detected by DNA sequencing of exon 15 performed at a centralized laboratory * Measurable disease (as defined by RECIST, v1.1) * Adequate recovery from most recent systemic or local treatment for cancer * Adequate organ function within 28 days prior to initiation of treatment * 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 vemurafenib * 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 vemurafenib * Negative serum 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 vemurafenib; for male participants, agreement not to donate sperm during the study and for at least 6 months after discontinuation of vemurafenib * Signed informed consent form (prior to study entry and before performing any study-related procedures)
Exclusion criteria
* Invasive malignancy other than melanoma at the time of enrollment and within 2 years prior to first study drug administration, except for adequately treated (with curative intent) basal or squamous cell carcinoma, in situ carcinoma of the cervix, in situ ductal adenocarcinoma of the breast, in situ prostate cancer, or limited stage bladder cancer or other cancers from which the patient has been disease-free for at least 2 years * Pregnant or breast-feeding * Inability to swallow pills * Concurrent anti-tumor therapy (e.g., chemotherapy, other targeted therapy, radiation therapy, including participation in an experimental drug study) * Radiation therapy \</= 1 week prior to first administration of vemurafenib and stereotactic radiotherapy \</= 1 day prior to first administration of vemurafenib * Prior treatment with a BRAF or MEK inhibitor * Either a concurrent condition (including medical illness, such as active infection requiring treatment with IV antibiotics or the presence of laboratory abnormalities) or history of a prior condition that places the patient at unacceptable risk if he/she were treated with the study drug or confounds the ability to interpret data from the study * History of congenital long QT syndrome or a corrected QT (QTc) interval \> 450 ms at baseline * Ongoing cardiac dysrhythmia \>/= Grade 2 * Unwillingness to practice effective birth control * Inability to comply with other requirements of the protocol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Best Objective Response Rate (BORR) | Up to 42 months | BORR was assessed by the investigators according to the Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. BORR was defined as the number of participants whose best overall response was a complete response (CR) or partial response (PR). CR was defined as complete disappearance of all target lesions and non-target disease. PR was defined as a \>/=30% decrease under baseline of the sum of diameters of all target lesions. BORR was summarized along with the associated exact 95% confidence interval (CI) using the method of Clopper-Pearson. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response | From date of earliest qualifying response up to date of disease progression or death (up to 42 months) | In participants with a confirmed CR or PR, duration of response was defined as the time interval between the date of the earliest qualifying response and the date of progressive disease (PD) or death due to any cause. CR was defined as complete disappearance of all target lesions and non-target disease. PR was defined as a \>/=30% decrease under baseline of the sum of diameters of all target lesions. PD was defined as a 20% increase in the sum of the longest diameter of target lesions or the appearance of new lesions and increase of at least 5 mm in the sum of diameters of target lesions. Duration of response was summarized using Kaplan-Meier method. |
| Progression-free Survival (PFS) | From start of treatment up to first documentation of disease progression or death (up to 42 months) | PFS was assessed by the investigators according to RECIST v1.1 and defined as the time interval between the date of the first treatment dose and the date of disease progression or death due to any cause, whichever occurred first. PD was defined as a 20% increase in the sum of the longest diameter of target lesions or the appearance of new lesions and increase of at least 5 mm in the sum of diameters of target lesions. PFS was summarized using Kaplan-Meier method. |
| Overall Survival (OS) | Date of first treatment to date of death due to any cause (up to 42 months) | OS was defined as the time from the date of first treatment to the date of death due to any cause. OS was summarized using Kaplan-Meier method. |
| Time to BORR | From start of treatment up to first documentation of confirmed CR or PR (up to 42 months) | In participants with a confirmed CR or PR, time to BORR was defined as the interval between the date of first treatment and the date of first documentation of confirmed CR or PR (whichever occurred first). BORR was assessed by the investigators according to RECIST v1.1. CR was defined as complete disappearance of all target lesions and non-target disease. PR was defined as a \>/=30% decrease under baseline of the sum of diameters of all target lesions. Participants without confirmed CR or PR were censored at the date of last tumor assessment. The time to response was summarized using univariate statistics. |
| Percentage of Participants With 12-Month Survival | Baseline to Month 12 | — |
| Number of Participants With an Adverse Event (AE) | Up to 42 months | An AE was defined as any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. |
| Percentage of Participants With 6-Month Survival | Baseline to Month 6 | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Vemurafenib Participants with untreated or previously treated locally advanced, unresectable, Stage IIIc or metastatic melanoma who have an activating exon 15 BRAF mutation other than V600E received vemurafenib 960 mg orally BID until disease progression. | 31 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 11 |
| Overall Study | Reason not specified | 9 |
| Overall Study | Started new anti-melanoma therapy | 1 |
| Overall Study | Withdrawal of Consent | 5 |
Baseline characteristics
| Characteristic | Vemurafenib |
|---|---|
| Age, Continuous | 60.0 years STANDARD_DEVIATION 11.39 |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 30 / 31 |
| serious Total, serious adverse events | 13 / 31 |
Outcome results
Primary
Best Objective Response Rate (BORR)
BORR was assessed by the investigators according to the Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. BORR was defined as the number of participants whose best overall response was a complete response (CR) or partial response (PR). CR was defined as complete disappearance of all target lesions and non-target disease. PR was defined as a \>/=30% decrease under baseline of the sum of diameters of all target lesions. BORR was summarized along with the associated exact 95% confidence interval (CI) using the method of Clopper-Pearson.
Time frame: Up to 42 months
Population: ITT population defined as all enrolled participants who received any amount of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vemurafenib | Best Objective Response Rate (BORR) | 22.6 percentage of participants |
Secondary
Duration of Response
In participants with a confirmed CR or PR, duration of response was defined as the time interval between the date of the earliest qualifying response and the date of progressive disease (PD) or death due to any cause. CR was defined as complete disappearance of all target lesions and non-target disease. PR was defined as a \>/=30% decrease under baseline of the sum of diameters of all target lesions. PD was defined as a 20% increase in the sum of the longest diameter of target lesions or the appearance of new lesions and increase of at least 5 mm in the sum of diameters of target lesions. Duration of response was summarized using Kaplan-Meier method.
Time frame: From date of earliest qualifying response up to date of disease progression or death (up to 42 months)
Population: ITT population defined as all enrolled participants who received any amount of study drug. Participants with a confirmed CR or PR were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vemurafenib | Duration of Response | 10.7 months |
Secondary
Number of Participants With an Adverse Event (AE)
An AE was defined as any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution.
Time frame: Up to 42 months
Population: Safety population defined as all enrolled participants who received any amount of vemurafenib on study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vemurafenib | Number of Participants With an Adverse Event (AE) | 30 participants |
Secondary
Overall Survival (OS)
OS was defined as the time from the date of first treatment to the date of death due to any cause. OS was summarized using Kaplan-Meier method.
Time frame: Date of first treatment to date of death due to any cause (up to 42 months)
Population: ITT population defined as all enrolled participants who received any amount of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vemurafenib | Overall Survival (OS) | NA months |
Secondary
Percentage of Participants With 12-Month Survival
Time frame: Baseline to Month 12
Population: ITT population defined as all enrolled participants who received any amount of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vemurafenib | Percentage of Participants With 12-Month Survival | 61.6 percentage of participants |
Secondary
Percentage of Participants With 6-Month Survival
Time frame: Baseline to Month 6
Population: ITT population defined as all enrolled participants who received any amount of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vemurafenib | Percentage of Participants With 6-Month Survival | 82.4 percentage of participants |
Secondary
Progression-free Survival (PFS)
PFS was assessed by the investigators according to RECIST v1.1 and defined as the time interval between the date of the first treatment dose and the date of disease progression or death due to any cause, whichever occurred first. PD was defined as a 20% increase in the sum of the longest diameter of target lesions or the appearance of new lesions and increase of at least 5 mm in the sum of diameters of target lesions. PFS was summarized using Kaplan-Meier method.
Time frame: From start of treatment up to first documentation of disease progression or death (up to 42 months)
Population: ITT population defined as all enrolled participants who received any amount of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vemurafenib | Progression-free Survival (PFS) | 5.5 months |
Secondary
Time to BORR
In participants with a confirmed CR or PR, time to BORR was defined as the interval between the date of first treatment and the date of first documentation of confirmed CR or PR (whichever occurred first). BORR was assessed by the investigators according to RECIST v1.1. CR was defined as complete disappearance of all target lesions and non-target disease. PR was defined as a \>/=30% decrease under baseline of the sum of diameters of all target lesions. Participants without confirmed CR or PR were censored at the date of last tumor assessment. The time to response was summarized using univariate statistics.
Time frame: From start of treatment up to first documentation of confirmed CR or PR (up to 42 months)
Population: ITT population defined as all enrolled participants who received any amount of study drug. Participants with a confirmed CR or PR were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vemurafenib | Time to BORR | 1.7 months |