Phase II Study of BEvacizumab in Combination with ATezolizumab in Patients with Untreated Melanoma Brain Metastases (BEAT-MBM).
The goal of this clinical research study is to learn if atezolizumab and bevacizumab can help to control the disease in patients with cancer that has spread to the brain.
Disease Group: Melanoma and other malignant neoplasms of skin
Treatment Agent: Atezolizumab,Bevacizumab
Treatment Location: Only at MDACC
Sponsor: MD Anderson Cancer Center
Primary 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 MRI of the brain. Secondary Safety and tolerability of bevacizumab + atezolizumab Overall response rates (intracranial + extracranial) using a modified version of iRANO and compared to modified RECIST v1.1 and Response Assessment in Neuro-oncology – Brain Metastases (RANO-BM) Duration of response intracranially and extracranially Progression-free survival Overall survival Immune modulation Changes in circulating cfDNA as determinants of response and markers of early progression Changes in relative apparent diffusion coefficient as measured by MRI as early predictor of response Changes in neurocognitive function and health-related quality of life Molecular and immunological changes demonstrated in extracranial lesions
IRB Review and Approval Date: 06/15/2017
Recruitment Status: Open
Projected Accrual: N/A
1) Signed Informed Consent Form (ICF)
2) Ability and willingness to comply with the requirements of the study protocol
3) Age >/= 18 years
4) Life expectancy > 12 weeks
5) 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 PO or equivalent
6) 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
7) 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 >/= 0.5cm, but </= 3cm as determined by contrast-enhanced MRI
8) 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.
9) Adequate hematologic and end organ function, defined by the following laboratory results obtained within 14 days prior to the first study treatment (Cycle 1, Day 1): a) Absolute neutrophil count (ANC) >/= 1500 cells/µ b) White blood cell (WBC) counts > 2500/µL c) Lymphocyte count >/= 500/µL d) Platelet count >/= 100,000/µL; e) Hemoglobin >/= 9.0 g/dL f) 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. g) AST and ALT </= 2.5 x ULN with the following exception: 1) Patients with documented liver metastases: AST and/or ALT </= 5 x ULN h) 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
10) (#9 CONTINUED) i) Serum creatinine </= 1.5 x ULN or creatinine clearance >/= 50 mL/min on the basis of the Cockcroft-Gault glomerular filtration rate estimation: 1) (140 - age) x (weight in kg) x (0.85 if female)/ 72 x (serum creatinine in mg/dL) j) Urine dipstick for proteinuria < 2+ unless a 24-hour urine protein >/= 1g of protein is demonstrated
11) 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
12) Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2
13) INR and aPTT </= 1.5 x ULN within 7 days prior to study enrollment
1) Symptomatic brain metastases requiring immediate local interventions
such as craniotomy or SRS
2) Patients who require immediate surgical or radiotherapy interventions
3) Increasing corticosteroid dose in 7 days prior to administration of first dose of study drug. a) Symptomatic patients who have stable or decreasing corticosteroid use in the past 7 days may be included
4) Patients with Leptomeningeal disease
5) 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)
6) 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
7) AEs from prior anticancer therapy that have not resolved to Grade </= 1 except for alopecia
8) Bisphosphonate therapy for symptomatic hypercalcemia a) Use of bisphosphonate therapy for other reasons (e.g., bone metastasis or osteoporosis) is allowed.
9) 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
10) Patients who are pregnant, lactating, or breastfeeding
11) Known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies
12) Inability to undergo MRI secondary to: a) Metal b) Claustrophobia c) Gadolinium Contrast allergy
13) Prior radiation therapy within the last 14 days
14) Inability to comply with study and follow-up procedures
15) 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, Sjögren’s syndrome, Bell’s palsy, Guillain-Barré 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)
16) (# 16 CONTINUED) Disease is well controlled at baseline and only requiring low potency topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, flucinolone 0.01%, desonide 0.05%, aclometasone 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)
17) 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.
18) 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
19) History of 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 RNA.
20) Active tuberculosis
21) 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
22) Signs or symptoms of infection within 2 weeks prior to Cycle 1, Day 1
23) 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.
24) 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.
25) 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.)
26) Life expectancy of less than 12 weeks
27) (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 (NCI CTCAE Grade 3 and 4)
28) (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
29) (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)
30) (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.
31) (Atezolizumab-Related Exclusion) History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
32) (Atezolizumab-Related Exclusion) Patients with prior allogeneic bone marrow transplantation or prior solid organ transplantation
33) (Bevacizumab-Related Exclusion) Inadequately controlled hypertension (defined as systolic blood pressure >150 mmHg and/or diastolic blood pressure > 100 mmHg)
34) (Bevacizumab-Related Exclusion) Prior history of hypertensive crisis or hypertensive encephalopathy
Criteria truncated, please contact Prinicipal Investigator's office for full criteria
Information and next steps
Melanoma and other malignant neoplasms of skin
Melanoma Medical Oncology
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