Clinical Trials /

Bevacizumab and Atezolizumab With or Without Cobimetinib in Treating Patients With Untreated Melanoma Brain Metastases

NCT03175432

Description:

This phase II trial studies how well bevacizumab and atezolizumab with or without cobimetinib work in treating patients with untreated melanoma that has spread to the brain (brain metastases). Monoclonal antibodies, such as bevacizumab and atezolizumab, may interfere with the ability of tumor cells to grow and spread. Cobimetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known if giving bevacizumab and atezolizumab with or without cobimetinib will work better in treating patients with melanoma brain metastases.

Related Conditions:
  • Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Bevacizumab and Atezolizumab With or Without Cobimetinib in Treating Patients With Untreated Melanoma Brain Metastases
  • Official Title: Phase II Study of BEvacizumab (Avastin) in Combination With Atezolizumab or Atezolizumab (Tencentriq) and Cobimetinib (Cotellic) in Patients With Untreated Melanoma Brain Metastases (TACo-BEAT-MBM)

Clinical Trial IDs

  • ORG STUDY ID: 2016-0866
  • SECONDARY ID: NCI-2018-01188
  • SECONDARY ID: 2016-0866
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT03175432

Conditions

  • BRAF V600 Wild Type
  • Clinical Stage IV Cutaneous Melanoma AJCC v8
  • Intracranial Melanoma
  • Metastatic Malignant Neoplasm in the Brain
  • Metastatic Melanoma
  • Pathologic Stage IV Cutaneous Melanoma AJCC v8
  • Refractory Melanoma

Interventions

DrugSynonymsArms
AtezolizumabMPDL 3280A, MPDL 328OA, MPDL-3280A, MPDL3280A, MPDL328OA, RG7446, RO5541267, TecentriqArm I (atezolizumab, bevacizumab)
BevacizumabAnti-VEGF, Anti-VEGF Humanized Monoclonal Antibody, Anti-VEGF rhuMAb, Avastin, Bevacizumab awwb, Bevacizumab Biosimilar BEVZ92, Bevacizumab Biosimilar BI 695502, Bevacizumab Biosimilar CBT 124, Bevacizumab Biosimilar CT-P16, Bevacizumab Biosimilar FKB238, Bevacizumab Biosimilar HD204, Bevacizumab Biosimilar HLX04, Bevacizumab Biosimilar IBI305, Bevacizumab Biosimilar LY01008, Bevacizumab Biosimilar MIL60, Bevacizumab Biosimilar QL 1101, Bevacizumab Biosimilar RPH-001, Bevacizumab Biosimilar SCT501, BP102, BP102 Biosimilar, HD204, Immunoglobulin G1 (Human-Mouse Monoclonal rhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal rhuMab-VEGF Light Chain, Dimer, Recombinant Humanized Anti-VEGF Monoclonal Antibody, rhuMab-VEGF, SCT501Arm I (atezolizumab, bevacizumab)
CobimetinibCotellic, GDC-0973, MEK Inhibitor GDC-0973, XL518Arm II (atezolizumab, bevacizumab, cobimetinib)

Purpose

This phase II trial studies how well bevacizumab and atezolizumab with or without cobimetinib work in treating patients with untreated melanoma that has spread to the brain (brain metastases). Monoclonal antibodies, such as bevacizumab and atezolizumab, may interfere with the ability of tumor cells to grow and spread. Cobimetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known if giving bevacizumab and atezolizumab with or without cobimetinib will work better in treating patients with melanoma brain metastases.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the objective intracranial response rate of the combination of bevacizumab
      and atezolizumab in patients with active melanoma brain metastases (MBM) as measured by a
      modified immunotherapy Response Assessment in Neuro-oncology (iRANO) criteria measured by
      magnetic resonance imaging (MRI) of the brain.

      II. To assess the safety, tolerability, and preliminary efficacy of the triplet combination
      of atezolizumab (Tencentriq), bevacizumab (Avastin), and cobimetinib (Cotellic). (TACo)

      SECONDARY OBJECTIVES:

      I. Safety and tolerability of bevacizumab + atezolizumab. II. Safety and tolerability of the
      combination of atezolizumab + bevacizumab + cobimetinib in patients with BRAFV600 wild-type
      metastatic melanoma to the brain who've experienced prior progression on anti-PD1.

      III. Overall response rates (intracranial + extracranial) using a modified version of iRANO
      and compared to modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
      and Response Assessment in Neuro-oncology - Brain Metastases (RANO-BM).

      IV. Duration of response intracranially and extracranially. V. Progression-free survival. VI.
      Overall survival. VII. Immune modulation. VIII. Changes in circulating cell free
      deoxyribonucleic acid (cfDNA) as determinants of response and markers of early progression.

      IX. Changes in relative apparent diffusion coefficient as measured by MRI as early predictor
      of response.

      X. Changes in neurocognitive function and health-related quality of life. XI. Molecular and
      immunological changes demonstrated in extracranial lesions.

      OUTLINE: Patients are assigned to 1 of 2 arms.

      ARM I: Patients receive atezolizumab intravenously (IV) over 30-60 minutes and bevacizumab IV
      over 30-90 minutes on day 1. Cycles repeat every 14 days in the absence of disease
      progression or unacceptable toxicity.

      ARM II: Patients receive atezolizumab IV over 30-60 minutes and bevacizumab IV over 30-90
      minutes on day 1. Cycles with atezolizumab and bevacizumab repeat every 14 days in the
      absence of disease progression or unacceptable toxicity. Patients also receive cobimetinib
      orally (PO) thrice daily (TID) on days 1-21. Cycles with cobimetinib repeat every 28 days in
      the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 90 days and then every 3
      months thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (atezolizumab, bevacizumab)ExperimentalParticipants receive atezolizumab IV over 30-60 minutes and bevacizumab IV over 30-90 minutes on day 1. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity.
  • Atezolizumab
  • Bevacizumab
Arm II (atezolizumab, bevacizumab, cobimetinib)ExperimentalPatients receive atezolizumab IV over 30-60 minutes and bevacizumab IV over 30-90 minutes on day 1. Cycles with atezolizumab and bevacizumab repeat every 14 days in the absence of disease progression or unacceptable toxicity. Patients also receive cobimetinib PO TID on days 1-21. Cycles with cobimetinib repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Atezolizumab
  • Bevacizumab
  • Cobimetinib

Eligibility Criteria

        Inclusion Criteria:

          -  Signed informed consent form (ICF)

          -  Ability and willingness to comply with the requirements of the study protocol

          -  Life expectancy > 12 weeks

          -  Asymptomatic off steroids for at least 10 days except patients: a) who have mild
             symptoms from intracranial disease that do not affect their performance status; or b)
             who are asymptomatic, but require steroids for control of symptoms on a maximum dose
             of dexamethasone 4mg/day orally (PO) or equivalent

          -  Prior therapies for extracranial metastatic melanoma including chemotherapy,
             BRAFi/MEKi, cytokine or vaccine therapy as long as it did not include PD-1/PD-L1.
             Note: Patients who are PD-1 refractory are allowed to enroll into the TACo arm if
             BRAFV600 wild-type is confirmed.

          -  At least one measurable intracranial target lesion for which all of the following
             criteria are met: a) Previously untreated or progressive after previous local therapy
             b) Immediate local therapy clinically not indicated or patient is not a suitable
             candidate to receive immediate local therapy c) Largest diameter of >= 0.5 cm, but =<
             3 cm as determined by contrast-enhanced MRI

          -  Representative formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin
             blocks (blocks are preferred) or at least 4 unstained slides, with an associated
             pathology report, for central testing of tumor PD-L1 expression a) Tumor tissue should
             be of good quality based on total and viable tumor content. Fine needle aspiration,
             brushing, cell pellet from pleural effusion, bone metastases, and lavage samples are
             not acceptable. For core-needle biopsy specimens, at least three cores should be
             submitted for evaluation. b) Patients who do not have tissue specimens meeting
             eligibility requirements may undergo a biopsy during the screening period. Acceptable
             samples include core needle biopsies for deep tumor tissue (minimum of three cores) or
             excisional, incisional, punch, or forceps biopsies for cutaneous, subcutaneous, or
             mucosal lesions. c) Tumor tissue from bone metastases is not evaluable for PD-L1
             expression and is therefore not acceptable

          -  Histologically or cytologically confirmed BRAFV600 wild-type melanoma through archival
             or newly obtained tissue.(only patients who are PD-1 refractory who will enroll onto
             the TACo arm)

          -  Obtained within 14 days prior to the first study treatment (cycle 1, day 1): Absolute
             neutrophil count (ANC) >= 1500 cells/u

          -  Obtained within 14 days prior to the first study treatment (cycle 1, day 1): White
             blood cell (WBC) counts > 2500/uL

          -  Obtained within 14 days prior to the first study treatment (cycle 1, day 1):
             Lymphocyte count >= 500/uL

          -  Obtained within 14 days prior to the first study treatment (cycle 1, day 1): Platelet
             count >= 100,000/uL

          -  Obtained within 14 days prior to the first study treatment (cycle 1, day 1):
             Hemoglobin >= 9.0 g/dL

          -  Obtained within 14 days prior to the first study treatment (cycle 1, day 1): Total
             bilirubin =< 1.5 x upper limit of normal (ULN) with the following exception: 1)
             patients with known Gilbert disease who have serum bilirubin level =< 3 x ULN may be
             enrolled

          -  Obtained within 14 days prior to the first study treatment (cycle 1, day 1): Aspartate
             aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN with the
             following exception: 1) patients with documented liver metastases: AST and/or ALT =< 5
             x ULN

          -  Obtained within 14 days prior to the first study treatment (cycle 1, day 1): Alkaline
             phosphatase =< 2.5 x ULN with the following exception: 1) =< 5 x ULN in patients with
             documented liver metastases =< 7 x ULN in patients with documented bone metastases

          -  Obtained within 14 days prior to the first study treatment (cycle 1, day 1): Serum
             creatinine =< 1.5 x ULN or creatinine clearance >= 50 mL/min on the basis of the
             Cockcroft-Gault glomerular filtration rate estimation

          -  Obtained within 14 days prior to the first study treatment (cycle 1, day 1): Urine
             dipstick for proteinuria < 2+ unless a 24-hour urine protein =< 1 g of protein is
             demonstrated

          -  For female patients of childbearing potential and male patients with partners of
             childbearing potential, agreement (by patient and/or partner) to use highly effective
             form(s) of contraception (i.e., one that results in a low failure rate [< 1% per year]
             when used consistently and correctly) and to continue its use for at least 12 months
             after the last dose of atezolizumab

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2

          -  International normalized ratio (INR) and activated partial thromboplastin time (aPTT)
             =< 1.5 x ULN within 7 days prior to study enrollment

        Exclusion Criteria:

          -  Symptomatic brain metastases requiring immediate local interventions such as
             craniotomy or stereotactic radiosurgery (SRS)

          -  Patients who require immediate surgical or radiotherapy interventions

          -  Increasing corticosteroid dose in 7 days prior to administration of first dose of
             study drug. Symptomatic patients who have stable or decreasing corticosteroid use in
             the past 7 days may be included

          -  Patients with leptomeningeal disease

          -  Any approved anticancer therapy, including chemotherapy and hormonal therapy within 3
             weeks prior to initiation of study treatment; however, the following are allowed: a)
             Hormone-replacement therapy or oral contraceptives b) Herbal therapy > 1 week prior to
             cycle 1, day 1 (herbal therapy intended as anticancer therapy must be discontinued at
             least 1 week prior to cycle 1, day 1)

          -  Current, recent (within 3 weeks of the first infusion of this study), or planned
             participation in an experimental drug study other than a Genentech-sponsored
             bevacizumab cancer study

          -  Adverse events (AEs) from prior anticancer therapy that have not resolved to grade =<
             1 except for alopecia

          -  Bisphosphonate therapy for symptomatic hypercalcemia a) Use of bisphosphonate therapy
             for other reasons (e.g., bone metastasis or osteoporosis) is allowed

          -  Known clinically significant liver disease, including active viral, alcoholic, or
             other hepatitis; cirrhosis; fatty liver; and inherited liver disease. Patients with
             acute leukemias, accelerated/blast phase chronic myelogenous leukemia, chronic
             lymphocytic leukemia, Burkitt lymphoma, plasma cell leukemia, or non-secretory myeloma

          -  Patients who are pregnant, lactating, or breastfeeding

          -  Known hypersensitivity to Chinese hamster ovary cell products or other recombinant
             human antibodies

          -  Inability to undergo MRI secondary to: a) metal b) claustrophobia c) gadolinium
             contrast allergy

          -  Prior radiation therapy within the last 14 days

          -  Inability to comply with study and follow-up procedures

          -  History of autoimmune disease, including but not limited to systemic lupus
             erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis
             associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's
             syndrome, Bell's palsy, Guillain-Barre syndrome, multiple sclerosis, autoimmune
             thyroid disease, vasculitis, or glomerulonephritis a) Patients with a history of
             autoimmune hypothyroidism on a stable dose of thyroid replacement hormone may be
             eligible. b) Patients with controlled Type 1 diabetes mellitus on a stable insulin
             regimen may be eligible. c) Patients with eczema, psoriasis, lichen simplex chronicus
             of vitiligo with dermatologic manifestations only (e.g., patients with psoriatic
             arthritis would be excluded) are permitted provided that they meet the following
             conditions: Patients with psoriasis must have a baseline ophthalmologic exam to rule
             out ocular manifestations; rash must cover less than 10% of body surface area (BSA)

          -  Disease is well controlled at baseline and only requiring low potency topical steroids
             (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, fluocinolone 0.01%, desonide
             0.05%, alclometasone dipropionate 0.05%) No acute exacerbations of underlying
             condition within the last 12 months (not requiring psoralen plus ultraviolet A
             radiation [PUVA], methotrexate, retinoids, biologic agents, oral calcineurin
             inhibitors; high potency or oral steroids)

          -  History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced),
             organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing
             pneumonia, etc.), or evidence of active pneumonitis on screening chest computed
             tomography (CT) scan a) history of radiation pneumonitis in the radiation field
             (fibrosis) is permitted

          -  Any other diseases, metabolic dysfunction, physical examination finding, or clinical
             laboratory finding giving reasonable suspicion of a disease or condition that
             contraindicates the use of an investigational drug or that may affect the
             interpretation of the results or render the patient at high risk from treatment
             complications

          -  History of human immunodeficiency virus (HIV) infection or active hepatitis B (chronic
             or acute) or hepatitis C infection; a) Patients with past or resolved hepatitis B
             infection (defined as having a negative hepatitis B surface antigen [HBsAg] test and a
             positive anti-HBc [antibody to hepatitis B core antigen] antibody test) are eligible;
             b) Patients positive for hepatitis C virus (HCV) antibody are eligible only if
             polymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA)

          -  Active tuberculosis

          -  Severe infections within 4 weeks prior to cycle 1, day 1, including but not limited to
             hospitalization for complications of infection, bacteremia, or severe pneumonia

          -  Signs or symptoms of infection within 2 weeks prior to cycle 1, day 1

          -  Received oral or IV antibiotics within 2 weeks prior to cycle 1, day 1 a) Patients
             receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection
             or chronic obstructive pulmonary disease) are eligible

          -  Administration of a live, attenuated vaccine within 4 weeks before cycle 1, day 1 or
             anticipation that such a live, attenuated vaccine will be required during the study a)
             Influenza vaccination should be given during influenza season only (approximately
             October to March). Patients must not receive live, attenuated influenza vaccine (e.g.,
             FluMist) within 4 weeks prior to cycle 1, day 1 or at any time during the study

          -  Malignancies other than the disease under study within 5 years prior to cycle 1, day
             1, with the exception of those with a negligible risk of metastasis or death and with
             expected curative outcome (such as adequately treated carcinoma in situ of the cervix,
             basal or squamous cell skin cancer, localized prostate cancer treated surgically with
             curative intent, or ductal carcinoma in situ treated surgically with curative intent)
             or undergoing active surveillance per standard-of-care management (e.g., chronic
             lymphocytic leukemia Rai Stage 0, prostate cancer with Gleason score =< 6, and
             prostate-specific antigen [PSA] =< 10 mg/mL, etc.)

          -  Known hypersensitivity to any component of bevacizumab, atezolizumab, or cobimetinib

          -  Life expectancy of less than 12 weeks

          -  (Atezolizumab-related exclusion) Prior treatment with anti-PD-1, or anti-PD-L1
             therapeutic antibody or pathway targeting agents a) Patients who have received prior
             treatment with anti-CTLA-4 may be enrolled, provided the following requirements are
             met: Minimum of 12 weeks from the first dose of anti-CTLA-4 and > 6 weeks from the
             last dose. No history of severe immune-related adverse effects from anti-CTLA 4
             (National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events
             [CTCAE] Grade 3 and 4)

          -  (Atezolizumab-related exclusion) Treatment with systemic immunostimulatory agents
             (including but not limited to interferon [IFN]-(alpha) or interleukin [IL]-2) within 6
             weeks or five half-lives of the drug (whichever is shorter) prior to cycle 1, day 1

          -  (Atezolizumab-related exclusion) Treatment with investigational agent within 4 weeks
             prior to cycle 1, day 1 (or within five half lives of the investigational product,
             whichever is longer)

          -  (Atezolizumab-Related Exclusion) Treatment with systemic immunosuppressive medications
             (including but not limited to prednisone, cyclophosphamide, azathioprine,
             methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) within 2
             weeks prior to cycle 1, day 1 a) Patients who have received acute, low dose, systemic
             immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) may
             be enrolled. b) The use of inhaled corticosteroids and mineralocorticoids (e.g.,
             fludrocortisone) for patients with orthostatic hypotension or adrenocortical
             insufficiency is allowed

          -  (Atezolizumab-related exclusion) History of severe allergic, anaphylactic, or other
             hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins

          -  (Atezolizumab-related exclusion) Patients with prior allogeneic bone marrow
             transplantation or prior solid organ transplantation

          -  (Bevacizumab-related exclusion) Inadequately controlled hypertension (defined as
             systolic blood pressure > 150 mmHg and/or diastolic blood pressure > 100 mmHg)

          -  (Bevacizumab-related exclusion) Prior history of hypertensive crisis or hypertensive
             encephalopathy

          -  (Bevacizumab-related exclusion) Clinically significant (i.e. active) cardiovascular
             disease, for example cerebrovascular accidents =< 6 months prior to study enrolment,
             myocardial infarction =< 6 months prior to study enrollment, unstable angina, grade II
             or greater congestive heart failure, or serious cardiac arrhythmia uncontrolled by
             medication or potentially interfering with protocol treatment

          -  (Bevacizumab-related exclusion) History or evidence upon physical/neurological
             examination of central nervous system (CNS) disease (e.g. seizures) unrelated to
             cancer unless adequately treated with standard medical therapy

          -  (Bevacizumab-related exclusion) Significant vascular disease (e.g., aortic aneurysm,
             requiring surgical repair or recent peripheral arterial thrombosis) within 6 months
             prior of study enrollment

          -  (Bevacizumab-related exclusion) Any previous venous thromboembolism > NCI CTCAE grade
             3

          -  (Bevacizumab-related exclusion) History of hemoptysis (>= 1/2 teaspoon of bright red
             blood per episode) within 1 month of study enrollment for any tumor type

          -  (Bevacizumab-related exclusion) Evidence of bleeding diathesis or significant
             coagulopathy (in the absence of therapeutic anticoagulation)

          -  (Bevacizumab-related exclusion) Current or recent (within 10 days of study enrolment)
             use of aspirin (> 325 mg/day), clopidogrel (> 75 mg/day), or current or recent (within
             10 days prior to first dose of bevacizumab) use of therapeutic oral or parenteral
             anticoagulants or thrombolytic agents for therapeutic purposes Note: The use of
             full-dose oral or parenteral anticoagulants is NOT permitted for at least two weeks at
             the time of study enrollment. Prophylactic use of anticoagulants is NOT allowed

          -  (Bevacizumab-related exclusion) Surgical procedure (including open biopsy, surgical
             resection, wound revision, or any othe
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective intracranial response rate (OIRR) as measured by the modified immunotherapy Response Assessment in Neuro-Oncology (iRANO) criteria
Time Frame:Up to 3 years
Safety Issue:
Description:Each response rate measure will be summarized using frequencies and percentages overall and by cohort. In addition, 90% exact confidence intervals will be presented for each response rate measure, for all patients and by cohort.

Secondary Outcome Measures

Measure:Incidence of adverse events graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (Arm I)
Time Frame:Up to 3 years
Safety Issue:
Description:
Measure:Incidence of adverse events graded according to CTCAE version 4.0 (Arm II)
Time Frame:Up to 3 years
Safety Issue:
Description:The safety and tolerability of the combination of atezolizumab, bevacizumab, cobimetinib in patients with BRAFV600 wild-type metastatic melanoma to the brain who've experienced prior progression on anti-PD1 will be assessed.
Measure:Overall response rates (intracranial + extracranial) using modified version of iRANO and compared to modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and Response Assessment in Neuro-oncology - Brain Metastases (RANO-BM)
Time Frame:Up to 3 years
Safety Issue:
Description:Each response rate measure will be summarized using frequencies and percentages overall and by cohort. In addition, 90% exact confidence intervals will be presented for each response rate measure, for all patients and by cohort. Associations between response and clinical measures of interest (e.g., changes in circulating cell free deoxyribonucleic acid [cfDNA]) will be determined by logistic regression models.
Measure:Duration of response (DOR)
Time Frame:From date of first response to date of disease progression, assessed up to 3 years
Safety Issue:
Description:Duration of response is defined as the duration of time from date of first response to date of disease progression. DOR will be assessed using the Kaplan-Meier method overall and by cohort.
Measure:Progression-free survival
Time Frame:From treatment start date to date of disease progression or death, assessed up to 3 years
Safety Issue:
Description:PFS is defined as the duration from treatment start date to date of disease progression or death. PFS will be assessed using the Kaplan-Meier method overall and by cohort.
Measure:Overall survival (OS)
Time Frame:From treatment start date to death, assessed up to 3 years
Safety Issue:
Description:Overall survival is defined as the time from treatment start date to death. OS will be assessed using the Kaplan-Meier method overall and by cohort.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

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