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About
This phase II trial studies how well atezolizumab or atezolizumab plus bevacizumab works in treating patients with alveolar soft part sarcoma that has not been treated, has spread from where it started to other places in the body (advanced) and cannot be removed by surgery (unresectable). Atezolizumab works by unblocking the immune system, allowing the immune system cells to recognize and then attack tumor cells. Bevacizumab works by controlling the growth of new blood vessels. Giving atezolizumab alone or atezolizumab with bevacizumab may shrink the cancer.
Full description
PRIMARY OBJECTIVES:
I. Determine the objective response rate (ORR) using Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 of atezolizumab in patients with advanced alveolar soft part sarcoma (ASPS) in adult subjects >= 18 years and in pediatric/adolescent subjects >= 2 years.
II. Determine the ORR using RECIST v 1.1 of atezolizumab and bevacizumab in subjects >= 18 years old with advanced ASPS that has progressed on atezolizumab monotherapy.
SECONDARY OBJECTIVES:
I. Determine duration of response (DOR) to atezolizumab monotherapy or atezolizumab plus bevacizumab using RECIST v 1.1 and/or change in clinical symptoms.
II. Measure progression-free survival (PFS) time for patients receiving atezolizumab monotherapy or atezolizumab plus bevacizumab as determined by investigator using RECIST v 1.1.
III. Assess the number of activated CD8+ T cells infiltrating the tumor before and after treatment with atezolizumab monotherapy or atezolizumab plus bevacizumab, and correlate treatment-induced changes with clinical response.
IV. Measure and describe the atezolizumab pharmacokinetics (PK) and anti-drug antibodies (ADA) in patients ages 2-11 years old.
EXPLORATORY OBJECTIVES:
I. Compare RECIST v 1.1 vs immune RECIST (iRECIST) in patients with ASPS on atezolizumab and atezolizumab + bevacizumab.
II. Assess the post-progression response rate among patients who progress while on treatment holiday and then resume treatment.
III. Analyze the genomic and immune profiles of tumors expressing type 1 or type 2 ASPL-TFE3 fusions and correlate findings with response to atezolizumab or atezolizumab in combination with bevacizumab.
IV. Measure and describe the atezolizumab pharmacokinetics (PK) in patients >= 12 years old.
OUTLINE: Patients are assigned to 1 of 2 arms.
ARM I: Patients receive atezolizumab intravenously (IV) over 30-60 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients in arm I who do achieve disease progression may cross-over to arm II. Patients also undergo computed tomography (CT) imaging, and collection of blood and urine at baseline. (CLOSED TO ACCRUAL)
ARM II: Patients receive atezolizumab IV over 30-60 minutes and bevacizumab IV over 30-90 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT imaging, and collection of blood and urine at baseline.
After completion of study treatment, patients are followed up for 27-30 days. Patients who are progression-free at the end of a 2-year treatment holiday are followed every 6 months.
Enrollment
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Inclusion criteria
Patients must have histologically or cytologically confirmed alveolar soft part sarcoma that is not curable by surgery. Diagnosis of malignancy must be confirmed by the department of pathology at the institution where the patient is enrolled prior to patient enrollment. To be eligible for atezolizumab in combination with bevacizumab, the patient must have atezolizumab-refractory/resistant disease that has progressed (definitive clinical progression or confirmed progressive disease [iCPD]) on prior 10005 atezolizumab monotherapy
Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) by chest x-ray or as >= 10 mm (>= 1 cm) with computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam
Patients with newly diagnosed, unresectable, metastatic and measurable ASPS will also be eligible for atezolizumab monotherapy if they show clinical evidence of disease progression (including history and increasing physical symptoms); on-study documentation will include a physician's rationale that supports evidence of clinical disease progression (i.e., increasing tumor pain)
To be eligible for atezolizumab monotherapy, subjects must be >= 2 years of age. To be eligible for atezolizumab in combination with bevacizumab, subjects must be >= 18 years of age
Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky or Lansky >= 70%)
Life expectancy of greater than 3 months
Absolute neutrophil count >= 1,500/mcL
Platelets >= 100,000/mcL
Hemoglobin >= 8 g/dL
Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (however, patients with known Gilbert disease who have serum bilirubin level =< 3 x ULN may be enrolled)
Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 3 x ULN (AST and/or ALT =< 5 x ULN for patients with liver involvement)
Alkaline phosphatase =< 2.5 x ULN (=< 5 x ULN for patients with documented liver involvement or bone metastases)
Creatinine clearance for adult patients (>= 18 years of age): >= 30 mL/min/1.73 m^2 by Cockcroft-Gault; for pediatric patients (< 18 years of age), a serum creatinine based on age and gender as follows:
Administration of atezolizumab or bevacizumab may have an adverse effect on pregnancy and poses a risk to the human fetus, including embryo-lethality. Female patients of child-bearing potential and male patients must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 5 months (150 days) after the last dose of atezolizumab or 6 months (180 days) after the last dose of bevacizumab. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
Ability to understand and the willingness to sign a written informed consent document or a parent/guardian able to do the same
Willingness to provide biopsy samples for research purposes (patients >= 18 years of age only). At the principal investigator (PI's) discretion, archival tissue that was collected and preserved may be used in lieu of a baseline biopsy, provided no anti-cancer agents or immunotherapies were received since collection of the archival tissue
Patients who have received live attenuated vaccines within 30 days of the first dose of trial treatment are eligible at the discretion of the investigator. All seasonal influenza vaccines and vaccines intended to prevent SARS-CoV-2 and coronavirus disease 2019 (COVID-19) are allowed
For patients not receiving therapeutic anticoagulation: international normalized ratio (INR) or activated partial thromboplastin time (aPTT) =< 1.5 x ULN for bevacizumab patients
For patients receiving therapeutic anticoagulation: stable anticoagulant regimen for bevacizumab patients
Exclusion criteria
Any prior therapy must have been completed >= 4 weeks or, if known, >= 5 half-lives of the prior agent (whichever is shorter) prior to enrollment on protocol (minimum of 1 week between prior therapy and study enrollment), and the participant must have recovered to eligibility levels from prior toxicity. Note: For patients being treated on the atezolizumab plus bevacizumab arm, there is no washout requirement for prior anti-PD-1 or anti-PD-L1 agents.
Prior treatment with anti-PD-1 or anti-PD-L1 therapeutic antibody, or pathway-targeting agents
Patients who have received prior treatment with anti-CTLA-4 may be enrolled on the atezolizumab monotherapy arm, provided the following requirements and all other selection criteria are met:
Patients who have progressed on P10005 atezolizumab monotherapy may be eligible for the atezolizumab plus bevacizumab arm, provided the following requirements, and all other selection criteria, are met:
Treatment with any other investigational agent within 4 weeks (or within five half-lives of the investigational product, whichever is shorter) prior to cycle 1, day 1 (minimum of 1 week between prior therapy and study enrollment); patients must be >= 2 weeks since any investigational agent administered as part of a phase 0 study (also referred to as an "early phase I study" or "pre-phase I study" where a sub-therapeutic dose of drug is administered) at the coordinating center PI's discretion, and should have recovered to eligibility levels from any toxicities
Treatment with systemic immunostimulatory agents (including, but not limited to, interferon-alpha or interleukin-2 [aldesleukin]) within 6 weeks prior to cycle 1, day 1
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
Patients taking bisphosphonate therapy for symptomatic hypercalcemia; use of bisphosphonate therapy for other reasons (e.g., bone metastasis or osteoporosis) is allowed
Patients with known primary central nervous system (CNS) malignancy or symptomatic CNS metastases are excluded, with the following exceptions:
Patients with asymptomatic untreated CNS disease may be enrolled, provided all of the following criteria are met:
Patients with asymptomatic treated CNS metastases may be enrolled, provided all the criteria listed above are met as well as the following:
Known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies
History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies (i.e., antibodies with generic names ending in "ximab" or "zumab", respectively) or fusion proteins
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
Pregnant women are excluded from this study because atezolizumab is an investigational agent with the unknown potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with atezolizumab, breastfeeding should be discontinued if the mother is treated with atezolizumab
Human immunodeficiency virus (HIV)-positive patients may be on combination antiretroviral therapy but must have a CD4 count > 350 cells/mm^3 with an undetectable viral load
Patients on supraphysiologic doses of steroids or use of such within the previous six weeks
Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis; cirrhosis; fatty liver; and inherited liver disease.
History or risk 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
Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid replacement hormone may be eligible
Patients with controlled type 1 diabetes mellitus on a stable insulin regimen may be eligible
Patients with eczema, psoriasis, lichen simplex chronicus or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis would be excluded) are permitted provided that they meet the following conditions:
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; history of radiation pneumonitis in the radiation field (fibrosis) is permitted
Patients with active tuberculosis (TB) are excluded
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 intravenous (IV) antibiotics within 2 weeks prior to cycle 1, day 1; patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease) are eligible
Major surgical procedure within 28 days prior to cycle 1, day 1 or anticipation of need for a major surgical procedure during the course of the study. Note: Patients with a surgical procedure (excluding biopsy procedures) within 28 days prior to cycle 1 day 1, or any unhealed surgical wound, are not eligible for the atezolizumab + bevacizumab combination arm
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 and up to 5 months after the last dose of atezolizumab
Additional exclusion criteria include:
BEVACIZUMAB-SPECIFIC EXCLUSION CRITERIA
Age < 18 years
Prior disease progression on an immune checkpoint inhibitor plus tyrosine kinase inhibitor combination therapy
Major surgery within 6 weeks of enrollment. Procedures (e.g. port placement, endoscopy with intervention) within 7 days of enrollment (excluding biopsy procedures)
Chronic daily treatment with a non-steroidal anti-inflammatory drug (NSAID), clopidogrel, dypiridamole, or aspirin therapy > 81 mg/day. Treatment with any such agents within 7 days prior to cycle 1 day 1
2+ protein on urinalysis, followed by 24-hour protein of > 1 g
Patients with a history of bleeding varices within 1 year of enrollment
Thromboembolic event within 6 months of enrollment (including cerebrovascular accident [CVA] and myocardial infarction (MI)
Evidence of bleeding diathesis or significant coagulopathy (with or without current therapeutic anticoagulation)
International normalized ratio (INR) >= 1.5 (or > therapeutic range if patient is receiving warfarin). Partial thromboplastin time (PTT) >= 1.5 x ULN
History of hemoptysis (> 1/2 teaspoon of bright red blood per episode) within 1 month of enrollment
Serious, non-healing wound, active ulcer, or untreated bone fracture
Congestive heart failure, baseline left ventricular ejection fraction (LVEF) < 50%, transmural myocardial infarction, uncontrolled hypertension (defined as systolic blood pressure > 140 mmHg and/or diastolic blood pressure > 90 mmHg in patients >= 18 years of age), angina pectoris requiring medication, clinically significant valvular disease, high-risk arrhythmia within 12 months of enrollment. Prior history of hypertensive crisis or hypertensive encephalopathy
History of abdominal fistula or gastrointestinal perforation within 6 months prior to enrollment
History of allergic reactions attributed to compounds of similar chemical or biologic composition to bevacizumab
For patients not receiving therapeutic anticoagulation: INR or aPTT =< 1.5 x; for patients receiving therapeutic anticoagulation: stable anticoagulant regimen
Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent arterial thrombosis) within 6 months prior to randomization
Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to initiation of study treatment. Placement of a vascular access device should be at least 2 days prior to initiation of study treatment
Active infection requiring IV antibiotics at the time of initiation of study treatment
Current or recent (< 10 days prior to initiation of study treatment) use of aspirin (> 325 mg/day), or clopidogrel (> 75 mg/day)
Note: The use of full-dose oral or parenteral anticoagulants for therapeutic purpose is permitted as long as the INR and/or aPTT is within therapeutic limits (according to institution standards) within 7 days prior to initiation of study t
Primary purpose
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63 participants in 2 patient groups
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Data sourced from clinicaltrials.gov
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