Active Melanoma Brain Metastases
Conditions
Brief summary
The purpose of this study is to evaluate the effectiveness of the combination of vemurafenib with cobimetinib in patients with active melanoma brain metastases.
Interventions
DRUGCobimetinib
60mg once a day; will be taken on days 1-21 of each 28 day treatment cycle; will be taken in combination with Vemurafenib;
DRUGVemurafenib
960mg twice a day; 28 day treatment cycle; will be taken in combination with Cobimetinib;
Sponsors
Genentech, Inc.
Melissa Burgess, MD
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
* Signed informed consent * Histologically confirmed metastatic melanoma (Stage IV), carrying BRAF V600-mutation * Melanoma must be documented to contain a BRAFV600 mutation by a CLIA approved laboratory * At least one measurable intracranial target lesion for which all of the following criteria are met: 1. previously untreated or progressive according to RECIST 1.1 (equal to or greater than 20% increase in longest diameter on baseline scan) after previous local therapy (SRS and/or craniotomy) 2. immediate local therapy clinically not indicated or patient is not a suitable candidate to receive immediate local therapy (SRS and/or craniotomy) 3. largest diameter of ≥ 0.5cm but ≤ 4 cm as determined by contrast-enhanced MRI * Prior therapies for extracranial metastatic melanoma including chemo-, cytokine-, immuno-, biological- and vaccine-therapy will be allowed but prior BRAF or MEK not allowed * ECOG PS 0-2 * Life expectancy \>12 weeks * Age 18 years or older * Adequate bone marrow function as indicated by the following: 1. ANC \> 1500/µL 2. Platelets ≥ 100,000/µL 3. Hemoglobin \> 9 g/dL * Adequate renal function, as indicated by creatinine =/\< 1.5 x the upper limit of normal (ULN) * Adequate liver function, as indicated by bilirubin =/\< 1.5 x ULN * AST or ALT \< 3 x ULN (patients with documented liver metastases: AST and/or ALT =/\< 5 x ULN) * Able to swallow pills * Negative serum pregnancy test within 7 days prior to commencement of dosing in premenopausal women. Women of non-childbearing potential may be included without serum pregnancy test if they are either surgically sterile or have been postmenopausal for ≥ 1 year * Fertile men and women must use an effective method of contraception during treatment and for at least 6 months after completion of treatment as directed by their physician. Effective methods of contraception are defined as those which result in a low failure rate (i.e., less than 1% per year) when used consistently and correctly (for example implants, injectables, combined oral contraception or intra-uterine devices). At the discretion of the Investigator, acceptable methods of contraception may include total abstinence in cases where the lifestyle of the patient ensures compliance. (Periodic abstinence \[e.g., calendar, ovulation, symptothermal, post-ovulation methods\] and withdrawal are not acceptable methods of contraception.)
Exclusion criteria
* Active infection * Prior therapy with BRAFi and/or MEKi * Leptomeningeal disease * Symptomatic brain metastases requiring immediate local interventions such as craniotomy or SRS * Increasing corticosteroid dose in 7 days prior to administration of first dose of study drug. Symptomatic patients that have stable or decreasing corticosteroid use in the past 7 days will be allowed * Current use of therapeutic warfarin * Unresolved toxicity of National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (NCI v4.0) \[NCI, 2009\] Grade 2 or higher from previous anti-cancer therapy, except alopecia * Conditions that will interfere significantly with the absorption of drugs * Inability to undergo MRI secondary to metal, claustrophobia, Gadolinium Contrast allergy * Pregnant, lactating, or breast feeding women * Prior radiation therapy within the last 14 days * Concomitant malignancies or previous malignancies within the last 5 years, with the exception of adequately treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix * Unwillingness or inability to comply with study and follow-up procedures * The following foods/supplements are prohibited at least 7 days prior to initiation of and during study treatment: 1. St. John's wort or hyperforin 2. Grapefruit juice * History of or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment, Retinal Vein Occlusion (RVO), or neovascular macular degeneration * Uncontrolled glaucoma with intra-ocular pressures \> 21mmHg * Serum cholesterol ≥ Grade 2 * Hypertriglyceridemia ≥ Grade 2 * Hyperglycemia (fasting) ≥ Grade 2 * History of clinically significant cardiac dysfunction, including the following: 1. Current unstable angina 2. Current symptomatic congestive heart failure of NYHA class 2 or higher 3. History of congenital long QT syndrome or mean QTcF \> 450 msec at baseline or uncorrectable electrolyte abnormalities 4. Uncontrolled hypertension ≥ Grade 2 (patients with a history hypertension controlled with anti-hypertensives to ≤ Grade 1 are eligible) 5. Left ventricular ejection fraction (LVEF) below 50% 6. Uncontrolled Arrhythmias 7. Myocardial infarction, severe/unstable angina, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack within the previous 6 months
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Intracranial Response (OIRR) | Until disease progression, less than or equal to 5 years. | Change in overall size of the sum of diameters from baseline of up to 5 intracranial target lesions in response to study treatment, achieved by individual patients. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | Up to 5 years | Time (number of months) from first documented evidence of overall Complete Response (CR) or Partial Response (PR) until time of first documented disease progression or death due to any cause (for individual patients). Progression as defined by RECIST 1.1 (Response Evaluation Criteria In Solid Tumors) is 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 5mm. |
| Overall Survival (OS) | Up to 5 years | Number of months of survival for individual patients. |
| Duration of Response | Until disease progression, less than or equal to 5 years. | Change in relative apparent diffusion coefficient (rADC) as measured by MRI as early predictor of response value/result for each patient |
| Overall Response | Until disease progression, less than or equal to 5 years. | Response to study treatment achieved by individual patients as indicated by an overall change in size of the sum of diameters from baseline of up to 5 intracranial target lesions and up to 5 extracranial target lesions. |
| Early Markers of Progression in Peripheral Blood | Up to 5 years | — |
| Health-related Quality of Life as Measured by The Functional Assessment of Cancer Therapy (FACT) - Brain (FACT-Br) | Up to 5 years | The Functional Assessment of Cancer Therapy-Brain (FACT-Br) is used to measure general quality of life (QOL) that reflects symptoms or problems associated with brain malignancies across 5 scales. The brain subscale is usually used along with the core (general) questionnaire that includes 27 items. The measure yields information about total QOL, as well as information about the dimensions of physical well-being, social/family well-being, emotional well being, functional well-being, and disease-specific concerns. Patients rate all 5 items using a five-point Likert scale ranging from 0 not at all to 4 very much. Overall, higher ratings suggest higher QOL. Items are totaled to produce the following subscales, along with an overall QOL score: physical well-being (7 items); social/family well-being (7 items); emotional well-being (6 items); functional well-being (7 items); and concerns relevant to patients with brain tumors (23 items). Scoring range is 0-200. |
| Immune Modulation in Peripheral Blood | Up to 5 years | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cobimetinib in Combination With Vemurafenib Vemurafenib (960 mg twice a day) taken on Days 1 - 28 of each 28-day treatment cycle. Cobimetinib (60 mg once a day) taken on Days 1 - 21 of each 28-day treatment cycle. | 5 |
| Total | 5 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Did not receive study treatment | 1 |
Baseline characteristics
| Characteristic | Cobimetinib in Combination With Vemurafenib |
|---|---|
| Age, Customized Patient 1 | 26 years |
| Age, Customized Patient 2 | 65 years |
| Age, Customized Patient 3 | 31 years |
| Age, Customized Patient 4 | 33 years |
| Age, Customized Patient 5 | 63 years |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 4 / 4 |
| other Total, other adverse events | 4 / 4 |
| serious Total, serious adverse events | 4 / 4 |
Outcome results
Primary
Objective Intracranial Response (OIRR)
Change in overall size of the sum of diameters from baseline of up to 5 intracranial target lesions in response to study treatment, achieved by individual patients.
Time frame: Until disease progression, less than or equal to 5 years.
Population: Patients who received study treatment and were assessed by MRI every 8 weeks.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cobimetinib in Combination With Vemurafenib | Objective Intracranial Response (OIRR) | Patient #1 | -2.01 centimeters |
| Cobimetinib in Combination With Vemurafenib | Objective Intracranial Response (OIRR) | Patient #2 | -0.8 centimeters |
| Cobimetinib in Combination With Vemurafenib | Objective Intracranial Response (OIRR) | Patient #4 | -2.12 centimeters |
| Cobimetinib in Combination With Vemurafenib | Objective Intracranial Response (OIRR) | Patient #5 | 0.6 centimeters |
Secondary
Duration of Response
Change in relative apparent diffusion coefficient (rADC) as measured by MRI as early predictor of response value/result for each patient
Time frame: Until disease progression, less than or equal to 5 years.
Population: Patients for whom response duration data was obtainable in those that received MRI tumor assessments every 8 weeks.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cobimetinib in Combination With Vemurafenib | Duration of Response | Patient #1 | 1.6 months |
| Cobimetinib in Combination With Vemurafenib | Duration of Response | Patient #2 | 1.8 months |
| Cobimetinib in Combination With Vemurafenib | Duration of Response | Patient #4 | 2.1 months |
Secondary
Early Markers of Progression in Peripheral Blood
Time frame: Up to 5 years
Population: Zero participants were analyzed for this outcome.
Secondary
Health-related Quality of Life as Measured by The Functional Assessment of Cancer Therapy (FACT) - Brain (FACT-Br)
The Functional Assessment of Cancer Therapy-Brain (FACT-Br) is used to measure general quality of life (QOL) that reflects symptoms or problems associated with brain malignancies across 5 scales. The brain subscale is usually used along with the core (general) questionnaire that includes 27 items. The measure yields information about total QOL, as well as information about the dimensions of physical well-being, social/family well-being, emotional well being, functional well-being, and disease-specific concerns. Patients rate all 5 items using a five-point Likert scale ranging from 0 not at all to 4 very much. Overall, higher ratings suggest higher QOL. Items are totaled to produce the following subscales, along with an overall QOL score: physical well-being (7 items); social/family well-being (7 items); emotional well-being (6 items); functional well-being (7 items); and concerns relevant to patients with brain tumors (23 items). Scoring range is 0-200.
Time frame: Up to 5 years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cobimetinib in Combination With Vemurafenib | Health-related Quality of Life as Measured by The Functional Assessment of Cancer Therapy (FACT) - Brain (FACT-Br) | Patient #1 - Cycle 1 | 107 scores on a scale |
| Cobimetinib in Combination With Vemurafenib | Health-related Quality of Life as Measured by The Functional Assessment of Cancer Therapy (FACT) - Brain (FACT-Br) | Patient #1 - Cycle 2 | 84 scores on a scale |
| Cobimetinib in Combination With Vemurafenib | Health-related Quality of Life as Measured by The Functional Assessment of Cancer Therapy (FACT) - Brain (FACT-Br) | Patient #1 - Cycle 3 | 110 scores on a scale |
| Cobimetinib in Combination With Vemurafenib | Health-related Quality of Life as Measured by The Functional Assessment of Cancer Therapy (FACT) - Brain (FACT-Br) | Patient #1 - Cycle 4 | 97 scores on a scale |
| Cobimetinib in Combination With Vemurafenib | Health-related Quality of Life as Measured by The Functional Assessment of Cancer Therapy (FACT) - Brain (FACT-Br) | Patient #2 - Cycle 1 | 83 scores on a scale |
| Cobimetinib in Combination With Vemurafenib | Health-related Quality of Life as Measured by The Functional Assessment of Cancer Therapy (FACT) - Brain (FACT-Br) | Patient #2 - Cycle 2 | 91 scores on a scale |
| Cobimetinib in Combination With Vemurafenib | Health-related Quality of Life as Measured by The Functional Assessment of Cancer Therapy (FACT) - Brain (FACT-Br) | Patient #2 - Cycle 3 | 104 scores on a scale |
| Cobimetinib in Combination With Vemurafenib | Health-related Quality of Life as Measured by The Functional Assessment of Cancer Therapy (FACT) - Brain (FACT-Br) | Patient #2 - Cycle 4 | 95 scores on a scale |
| Cobimetinib in Combination With Vemurafenib | Health-related Quality of Life as Measured by The Functional Assessment of Cancer Therapy (FACT) - Brain (FACT-Br) | Patient #4 - Cycle 1 | 98 scores on a scale |
| Cobimetinib in Combination With Vemurafenib | Health-related Quality of Life as Measured by The Functional Assessment of Cancer Therapy (FACT) - Brain (FACT-Br) | Patient #4 - Cycle 2 | 97 scores on a scale |
| Cobimetinib in Combination With Vemurafenib | Health-related Quality of Life as Measured by The Functional Assessment of Cancer Therapy (FACT) - Brain (FACT-Br) | Patient #4 - Cycle 3 | 95 scores on a scale |
| Cobimetinib in Combination With Vemurafenib | Health-related Quality of Life as Measured by The Functional Assessment of Cancer Therapy (FACT) - Brain (FACT-Br) | Patient #4 - Cycle 4 | 101 scores on a scale |
| Cobimetinib in Combination With Vemurafenib | Health-related Quality of Life as Measured by The Functional Assessment of Cancer Therapy (FACT) - Brain (FACT-Br) | Patient #4 - Cycle 5 | 119 scores on a scale |
| Cobimetinib in Combination With Vemurafenib | Health-related Quality of Life as Measured by The Functional Assessment of Cancer Therapy (FACT) - Brain (FACT-Br) | Patient #4 - Cycle 6 | 98 scores on a scale |
| Cobimetinib in Combination With Vemurafenib | Health-related Quality of Life as Measured by The Functional Assessment of Cancer Therapy (FACT) - Brain (FACT-Br) | Patient #5 - Cycle 1 | 69 scores on a scale |
| Cobimetinib in Combination With Vemurafenib | Health-related Quality of Life as Measured by The Functional Assessment of Cancer Therapy (FACT) - Brain (FACT-Br) | Patient #5 - Cycle 2 | 103 scores on a scale |
| Cobimetinib in Combination With Vemurafenib | Health-related Quality of Life as Measured by The Functional Assessment of Cancer Therapy (FACT) - Brain (FACT-Br) | Patient #5 - Cycle 3 | 104 scores on a scale |
Secondary
Immune Modulation in Peripheral Blood
Time frame: Up to 5 years
Population: Data were not able to be collected and thus zero participants were analyzed for this outcome.
Secondary
Overall Response
Response to study treatment achieved by individual patients as indicated by an overall change in size of the sum of diameters from baseline of up to 5 intracranial target lesions and up to 5 extracranial target lesions.
Time frame: Until disease progression, less than or equal to 5 years.
Population: Patients who received study treatment and were assessed by MRI every 8 weeks.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cobimetinib in Combination With Vemurafenib | Overall Response | Patient #1 | -6.61 centimeters |
| Cobimetinib in Combination With Vemurafenib | Overall Response | Patient #2 | -5.3 centimeters |
| Cobimetinib in Combination With Vemurafenib | Overall Response | Patient #4 | -9.12 centimeters |
| Cobimetinib in Combination With Vemurafenib | Overall Response | Patient #5 | -0.4 centimeters |
Secondary
Overall Survival (OS)
Number of months of survival for individual patients.
Time frame: Up to 5 years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cobimetinib in Combination With Vemurafenib | Overall Survival (OS) | Patient #1 | 7.3 months |
| Cobimetinib in Combination With Vemurafenib | Overall Survival (OS) | Patient #2 | 4.2 months |
| Cobimetinib in Combination With Vemurafenib | Overall Survival (OS) | Patient #4 | 5.8 months |
| Cobimetinib in Combination With Vemurafenib | Overall Survival (OS) | Patient #5 | 5.4 months |
Secondary
Progression-free Survival (PFS)
Time (number of months) from first documented evidence of overall Complete Response (CR) or Partial Response (PR) until time of first documented disease progression or death due to any cause (for individual patients). Progression as defined by RECIST 1.1 (Response Evaluation Criteria In Solid Tumors) is 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 5mm.
Time frame: Up to 5 years
Population: Patients who received study treatment and were assessed by MRI every 8 weeks.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cobimetinib in Combination With Vemurafenib | Progression-free Survival (PFS) | Patient #1 | 3.7 months |
| Cobimetinib in Combination With Vemurafenib | Progression-free Survival (PFS) | Patient #2 | 3.7 months |
| Cobimetinib in Combination With Vemurafenib | Progression-free Survival (PFS) | Patient #4 | 5.8 months |
| Cobimetinib in Combination With Vemurafenib | Progression-free Survival (PFS) | Patient #5 | 1.7 months |