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)
Overview
- Phase
- Phase 2
- Intervention
- Quality-of-Life Assessment
- Conditions
- BRAF V600 Wild Type
- Sponsor
- M.D. Anderson Cancer Center
- Enrollment
- 29
- Locations
- 1
- Primary Endpoint
- Safety, tolerability, and efficacy of atezolizumab, bevacizumab, and cobimetinib (Arm II)
- Status
- Active, not recruiting
- Last Updated
- 17 days ago
Overview
Brief Summary
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Signed informed consent form (ICF)
- •Age \>/= 18 years
- •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-L
- •Note: Patients who are PD-1 refractory are allowed to enroll into the TACo arm if BRAFV600 wild-type is confirmed. Patients that are known to have BRAFV600 mutation must have received prior BRAFi/MEKi prior to enrolling on TACo. Patients that have received prior BRAF/MEKi have to have received their last dose of BRAF/MEKi \> 3 months prior to being treated on this study.
- •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)
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
Arms & Interventions
Arm I (atezolizumab, bevacizumab)
Participants 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.
Intervention: Quality-of-Life Assessment
Arm I (atezolizumab, bevacizumab)
Participants 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.
Intervention: Atezolizumab
Arm II (atezolizumab, bevacizumab, cobimetinib)
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 PO TID on days 1-21. Cycles with cobimetinib repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Quality-of-Life Assessment
Arm II (atezolizumab, bevacizumab, cobimetinib)
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 PO TID on days 1-21. Cycles with cobimetinib repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Bevacizumab
Arm I (atezolizumab, bevacizumab)
Participants 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.
Intervention: Bevacizumab
Arm II (atezolizumab, bevacizumab, cobimetinib)
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 PO TID on days 1-21. Cycles with cobimetinib repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Atezolizumab
Arm II (atezolizumab, bevacizumab, cobimetinib)
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 PO TID on days 1-21. Cycles with cobimetinib repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Cobimetinib
Outcomes
Primary Outcomes
Safety, tolerability, and efficacy of atezolizumab, bevacizumab, and cobimetinib (Arm II)
Time Frame: Up to 3 years
Safety assessments will consist of monitoring and reporting adverse events (AEs) and serious adverse events (SAEs) that are considered related to atezolizumab. Bevacizumab and cobimetinib, all events of death, and any study-specific issue of concern summaries of AEs and SAEs with respect to incidence, severity, and causality will be provided for all patients and by cohort. In addition, discontinuation due to AEs, SAEs and deaths will be summarized. Patients will also be evaluated for dose-limiting toxicities through the first cycle.
Objective intracranial response rate (OIRR) as measured by the modified immunotherapy Response Assessment in Neuro-Oncology (iRANO) criteria
Time Frame: Up to 3 years
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 Outcomes
- Incidence of adverse events graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (Arm I)(Up to 3 years)
- 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)(Up to 3 years)
- Progression-free survival(From treatment start date to date of disease progression or death, assessed up to 3 years)
- Incidence of adverse events graded according to CTCAE version 4.0 (Arm II)(Up to 3 years)
- Duration of response (DOR)(From date of first response to date of disease progression, assessed up to 3 years)
- Overall survival (OS)(From treatment start date to death, assessed up to 3 years)