Clinical Trials /

Phase II Study of Cobimetinib in Combination With Vemurafenib in Active Melanoma Brain Metastases

NCT02230306

Description:

The purpose of this study is to evaluate the effectiveness of the combination of vemurafenib with cobimetinib in patients with active melanoma brain metastases.

Related Conditions:
  • Melanoma
Recruiting Status:

Terminated

Phase:

Phase 2

Trial Eligibility

Document

Title

    <li>Brief Title: Phase II Study of Cobimetinib in Combination With Vemurafenib in Active Melanoma Brain Metastasesli><li>Official Title: Phase II Study of Cobimetinib in Combination With Vemurafenib in Active Melanoma Brain Metastasesli>

Clinical Trial IDs

    <li>ORG STUDY ID: 13-123li><li>SECONDARY ID: ML29155li><li>NCT ID: NCT02230306li>

Conditions

    <li>Active Melanoma Brain Metastasesli>

Interventions

<td>Cobimetinibtd><td/><td>Cobimetinib in Combination with Vemurafenibtd><td>Vemurafenibtd><td>Zelboraftd><td>Cobimetinib in Combination with Vemurafenibtd>
DrugSynonymsArms

Purpose

The purpose of this study is to evaluate the effectiveness of the combination of vemurafenib with cobimetinib in patients with active melanoma brain metastases.

Trial Arms

<td>Cobimetinib in Combination with Vemurafenibtd><td>Experimentaltd><td>Vemurafenib (960 mg twice a day) will be taken on Days 1 - 28 of each 28-day treatment cycle. The first dose of vemurafenib should be taken in the morning, and the second dose should be taken in the evening. Vemurafenib can be taken with or without a meal and should be taken with a glass of water. Cobimetinib (60 mg once a day) will be taken on Days 1 - 21 of each 28-day treatment cycle. The cobimetinib tablet should be taken at approximately the same time each day in the morning with the vemurafenib dose, but no later than 4 hours after the scheduled time. Cobimetinib can be taken with or without a meal and should never be chewed, cut, or crushed and should be taken with a glass of water.td><td>
    <li>Cobimetinibli><li>Vemurafenibli>
td>
NameTypeDescriptionInterventions

Eligibility Criteria

        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
      
<td>Maximum Eligible Age:td><td>N/Atd><td>Minimum Eligible Age:td><td>18 Yearstd><td>Eligible Gender:td><td>Alltd><td>Healthy Volunteers:td><td>Notd>

Primary Outcome Measures

<td>Measure:td><td>Objective Intracranial Response (OIRR)td><td>Time Frame:td><td>Until disease progression, less than or equal to 5 years.td><td>Safety Issue:td><td/><td>Description:td><td>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.td>

Secondary Outcome Measures

<td>Measure:td><td>Overall Responsetd><td>Time Frame:td><td>Until disease progression, less than or equal to 5 years.td><td>Safety Issue:td><td/><td>Description:td><td>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.td>
<td>Measure:td><td>Progression-free Survival (PFS)td><td>Time Frame:td><td>Up to 5 yearstd><td>Safety Issue:td><td/><td>Description:td><td>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.td>
<td>Measure:td><td>Overall Survival (OS)td><td>Time Frame:td><td>Up to 5 yearstd><td>Safety Issue:td><td/><td>Description:td><td>Number of months of survival for individual patients.td>
<td>Measure:td><td>Duration of Responsetd><td>Time Frame:td><td>Until disease progression, less than or equal to 5 years.td><td>Safety Issue:td><td/><td>Description:td><td>Change in relative apparent diffusion coefficient (rADC) as measured by MRI as early predictor of response value/result for each patienttd>
<td>Measure:td><td>Immune Modulation in Peripheral Bloodtd><td>Time Frame:td><td>Up to 5 yearstd><td>Safety Issue:td><td/><td>Description:td><td/>
<td>Measure:td><td>Early Markers of Progression in Peripheral Bloodtd><td>Time Frame:td><td>Up to 5 yearstd><td>Safety Issue:td><td/><td>Description:td><td/>
<td>Measure:td><td>Health-related Quality of Life as Measured by The Functional Assessment of Cancer Therapy (FACT) - Brain (FACT-Br)td><td>Time Frame:td><td>Up to 5 yearstd><td>Safety Issue:td><td/><td>Description:td><td>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.td>

Details

<td>Phase:td><td>Phase 2td><td>Primary Purpose:td><td>Interventionaltd><td>Overall Status:td><td>Terminatedtd><td>Lead Sponsor:td><td>Melissa Burgess, MDtd>

Last Updated

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