This study is NOT currently recruiting participants.
Number
17-C-0074
Sponsoring Institute
National Cancer Institute (NCI)
Recruitment Detail
Type: No longer recruiting/follow-up only Gender: Male & Female Min Age: 2 Years Max Age: N/A
Referral Letter Required
No
Population Exclusion(s)
None
Keywords
Bevacizumab; Immunotherapy; Pharmacodynamics; Pediatric; Checkpoint Inhibitor
Recruitment Keyword(s)
Condition(s)
Alveolar Soft Part Sarcoma
Investigational Drug(s)
Atezolizumab Bevacizumab
Investigational Device(s)
Intervention(s)
Drug: Atezolizumab Drug: Bevacizumab
Supporting Site
National Cancer Institute
Sometimes the cancer advanced alveolar soft part sarcoma (ASPS) cannot be helped with surgery or other treatment. The drug atezolizumab unblocks the immune system. This allows immune cells to recognize and attack tumor cells. The drug could shrink cancer but could also have side effects. Researchers want to study if the drug will shrink a tumor in people with advanced ASPS.
Objective:
To test good and bad effects of the drug atezolizumab.
Eligibility:
People at least 6 years old with ASPS that cannot be cured with surgery
Design:
Participants will be screened with heart and pregnancy tests. Some may have scans or other tests.
At the study start, participants will have:
-Medical history
-Physical exam
-Heart, blood, and pregnancy tests
-Scan to measure tumor
-Optional tumor sample taken
Each study cycle is 21 days.
In cycle 1:
-On day 1, participants will have blood tests. They will get the study drug in a vein for about 1 hour. They will be observed for a few hours after.
-On days 8 and 15, participants will have blood tests.
In other cycles:
-On day 1, participants will get the study drug in a vein for about 1 hour.
-On days 1 and 15, participants will have blood tests.
Some participants will have a tumor sample taken in cycle 3.
Participants will have tumor scans at the end of cycle 3 and then every 2 cycles.
Participants can stay in the study as long as their cancer does not get worse.
Participants will be observed for 30 days after stopping the study drug.
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ELIGIBILITY 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 iCPD) on prior P10005 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 nonnodal lesions and short axis for nodal lesions) as >=20 mm (>=2 cm) by chest x-ray or as >=10 mm (>=1 cm) with CT scan, MRI, or calipers by clinical exam. Note: Once the primary endpoint of the trial has been met, pediatric patients may enroll with evaluable non-measurable disease and will not be required to have measurable disease. Evaluable non-measurable disease is that which is not measurable by RECIST1.1 but can be evaluated by imaging (e.g., CT, bone scan, or ultrasound) or other methods. -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 greater than or equal to 2 years of age. To be eligible for atezolizumab in combination with bevacizumab, subjects must be greater than or equal to 18 years of age. -ECOG performance status less than or equal to 2 (Karnofsky or Lansky greater than or equal to 70%,). -Life expectancy of greater than 3 months. -Patients must have normal organ and marrow function as defined below: --absolute neutrophil count: greater than or equal to 1,500/mcL --platelets: greater than or equal to 100,000/mcL --hemoglobin: greater than or equal to 8 g/dL --total bilirubin: less than or equal to 1.5 times institutional upper limit of normal (ULN) (however, patients with known Gilbert disease who have serum bilirubin level greater than or equal to 3 times ULN may be enrolled) --AST(SGOT)/ALT(SGPT) less than or equal to 3 times ULN (AST and/or ALT less than or equal to 5 times ULN for patients with liver involvement) --alkaline phosphatase less than or equal to 2.5 times ULN (less than or equal to 5 times ULN for patients with documented liver involvement or bone metastases). For adult patients greater than or equal to 18 years of age. --creatinine clearance for adult patients (greater than or equal to 18 years of age): greater than or equal to 30 mL/min/1.73 m(2) by Cockcroft-Gault: (140 - age) times (weight in kg) times (0.85 if female)/72 times (serum creatinine in mg/dL) For pediatric patients (less than 18 years of age), a serum creatinine based on age and gender as follows: Serum Creatinine for Age/Gender Age: 2 to less than 6 years; Maximum Serum Creatinine (mg/dL): Male-0.8, Female-0.8 Age: 6 to less than 10 years; Maximum Serum Creatinine (mg/dL): Male-1, Female-1 Age: 10 to less than 13 years; Maximum Serum Creatinine (mg/dL): Male-1.2, Female-1.2 Age: 13 to less than 16 years; Maximum Serum Creatinine (mg/dL): Male-1.5, Female-1.4 Age: 16 to less than 18 years; Maximum Serum Creatinine (mg/dL): Male-1.7, Female-1.4 The threshold creatinine values in this table were derived from the Schwartz formula for estimating GFR, utilizing child length and stature data published by the CDC. -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 greater than or equal to 18 years of age only). At the 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: INR or aPTT 1.5 (SqrRoot) ULN for bevacizumab patients. -For patients receiving therapeutic anticoagulation: stable anticoagulant regimen for bevacizumab patients. EXCLUSION CRITERIA: -Any prior therapy must have been completed (Bullet)4 weeks or, if known, greater than or equal to 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. Patients should be at least 6 weeks out from nitrosoureas and mitomycin C. Prior definitive radiation should have been completed greater than or equal to 4 weeks or palliative radiation should have been completed >2 weeks prior to study enrollment or crossover and all associated toxicities resolved to eligibility levels (patients on study may be eligible for palliative radiotherapy to non-targeted lesions after 2 cycles of therapy at the PI s discretion). Patients who have had prior monoclonal antibody therapy must have completed that therapy greater than or equal to 6 weeks (or 3 half-lives of the antibody, whichever is shorter) prior to enrollment on protocol (minimum of 1 week between prior therapy and study enrollment). A patient who has received a cumulative dose of greater than or equal to 350 mg/m2 of anthracycline (regardless of cardioprotectant) may only be enrolledif their ejection fraction measured by an echocardiogram is within normal institutional limits. -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: ---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) -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: --No prior disease progression on an immune checkpoint inhibitor plus tyrosine kinase inhibitor combination therapy --Any prior toxicities have resolved to eligibility levels --No contraindications -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 greater than or equal to 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- 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 who have received acute, low dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled. --The use of inhaled corticosteroids and systemic mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension or adrenocortical insufficiency is allowed. -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: ---Evaluable or measurable disease outside the CNS ---No metastases to brain stem, midbrain, pons, medulla, or cerebellum ---No history of intracranial hemorrhage or spinal cord hemorrhage ---No ongoing requirement for dexamethasone for CNS disease; patients on a stable dose of anticonvulsants are permitted. ---No neurosurgical resection or brain biopsy within 28 days prior to Cycle 1, Day 1 --Patients with asymptomatic treated CNS metastases may be enrolled, provided all the criteria listed above are met as well as the following: ---Radiographic demonstration of improvement upon the completion of CNS-directed therapy and no evidence of interim progression between the completion of CNS-directed therapy and radiographic screening for the current study ---No stereotactic radiation or whole-brain radiation within 28 days prior to Cycle 1, Day 1 ---Screening CNS radiographic study greater than or equal to 4 weeks from completion of radiotherapy and greater than or equal to 2 weeks from discontinuation of corticosteroids -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. -HIV-positive patients may be on combination antiretroviral therapy but must have a CD4 count >350 cells/mm3 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. --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. --Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA. -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, Sj(SqrRoot)(Delta)gren s syndrome, Bell s palsy, Guillain-Barr(SqrRoot)(Copyright) syndrome, multiple sclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis. --Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid C-0074 24 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: ---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%, 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) -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 described in Section 9.3) 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. --Influenza vaccination should be given during influenza season only (approximately October to March). Patients must not receive live, attenuated influenza vaccine within 4 weeks prior to Cycle 1, Day 1 or at any time during the study. -Bevacizumab-Specific Exclusion Criteria: The following exclusion criteria, in addition to those in Section 3.2, apply to the atezolizumab +bevacizumab combination arm: -Age <18 years. -Prior disease progression on an immune checkpoint inhibitor plus tyrosine kinase inhibitor combination therapy. -Major surgery within 6 weeks of enrollment. Minor procedures (e.g. port placement, endoscopy with intervention) within 28 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 ration (INR) greater than or equal to 1.5 (or >therapeutic range if patient is receiving warfarin). PTT greater than or equal to 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 LVEF <50%, transmural myocardial infarction, uncontrolled hypertension (defined as systolic blood pressure > 140 mmHg and/or diastolic blood pressure > 90 mmHg in patients greater than or equal to 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 (SqrRoot) -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 treatment and the patient has been on a stable dose of anticoagulants for (Bullet) 2 weeks prior to initiation of study treatment. Prophylactic use of anticoagulants is allowed. However, the use of direct oral anticoagulant therapies such as dabigatran (Pradaxa o) and rivaroxaban (Xarelto o) is not recommended due to bleeding risk.
-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 iCPD) on prior P10005 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 nonnodal lesions and short axis for nodal lesions) as >=20 mm (>=2 cm) by chest x-ray or as >=10 mm (>=1 cm) with CT scan, MRI, or calipers by clinical exam.
Note: Once the primary endpoint of the trial has been met, pediatric patients may enroll with evaluable non-measurable disease and will not be required to have measurable disease. Evaluable non-measurable disease is that which is not measurable by RECIST1.1 but can be evaluated by imaging (e.g., CT, bone scan, or ultrasound) or other methods.
-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 greater than or equal to 2 years of age. To be eligible for atezolizumab in combination with bevacizumab, subjects must be greater than or equal to 18 years of age.
-ECOG performance status less than or equal to 2 (Karnofsky or Lansky greater than or equal to 70%,).
-Life expectancy of greater than 3 months.
-Patients must have normal organ and marrow function as defined below:
--absolute neutrophil count: greater than or equal to 1,500/mcL
--platelets: greater than or equal to 100,000/mcL
--hemoglobin: greater than or equal to 8 g/dL
--total bilirubin: less than or equal to 1.5 times institutional upper limit of normal (ULN) (however, patients with known Gilbert disease who have serum bilirubin level greater than or equal to 3 times ULN may be enrolled)
--AST(SGOT)/ALT(SGPT) less than or equal to 3 times ULN (AST and/or ALT less than or equal to 5 times ULN for patients with liver involvement)
--alkaline phosphatase less than or equal to 2.5 times ULN (less than or equal to 5 times ULN for patients with documented liver involvement or bone metastases). For adult patients greater than or equal to 18 years of age.
--creatinine clearance for adult patients (greater than or equal to 18 years of age): greater than or equal to 30 mL/min/1.73 m(2) by Cockcroft-Gault: (140 - age) times (weight in kg) times (0.85 if female)/72 times (serum creatinine in mg/dL)
For pediatric patients (less than 18 years of age), a serum creatinine based on age and gender as follows:
Serum Creatinine for Age/Gender
Age: 2 to less than 6 years; Maximum Serum Creatinine (mg/dL): Male-0.8, Female-0.8
Age: 6 to less than 10 years; Maximum Serum Creatinine (mg/dL): Male-1, Female-1
Age: 10 to less than 13 years; Maximum Serum Creatinine (mg/dL): Male-1.2, Female-1.2
Age: 13 to less than 16 years; Maximum Serum Creatinine (mg/dL): Male-1.5, Female-1.4
Age: 16 to less than 18 years; Maximum Serum Creatinine (mg/dL): Male-1.7, Female-1.4
The threshold creatinine values in this table were derived from the Schwartz formula for estimating GFR, utilizing child length
and stature data published by the CDC.
-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 greater than or equal to 18 years of age only). At the 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: INR or aPTT 1.5 (SqrRoot) ULN for bevacizumab patients.
-For patients receiving therapeutic anticoagulation: stable anticoagulant regimen for bevacizumab patients.
EXCLUSION CRITERIA:
-Any prior therapy must have been completed (Bullet)4 weeks or, if known, greater than or equal to 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.
Patients should be at least 6 weeks out from nitrosoureas and mitomycin C. Prior definitive radiation should have been completed greater than or equal to 4 weeks or palliative radiation should have been completed >2 weeks prior to study enrollment or crossover and all associated toxicities resolved to eligibility levels (patients on study may be eligible for palliative radiotherapy to non-targeted lesions after 2 cycles of therapy at the PI s discretion). Patients who have had prior monoclonal antibody therapy must have completed that therapy greater than or equal to 6 weeks (or 3 half-lives of the antibody, whichever is shorter) prior to enrollment on protocol (minimum of 1 week between prior therapy and study enrollment). A patient who has received a cumulative dose of greater than or equal to 350 mg/m2 of anthracycline (regardless of cardioprotectant) may only be enrolledif their ejection fraction measured by an echocardiogram is within normal institutional limits.
-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:
---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)
-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:
--No prior disease progression on an immune checkpoint inhibitor plus tyrosine kinase inhibitor combination therapy
--Any prior toxicities have resolved to eligibility levels
--No contraindications
-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 greater than or equal to 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- 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 who have received acute, low dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled.
--The use of inhaled corticosteroids and systemic mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension or adrenocortical insufficiency is allowed.
-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:
---Evaluable or measurable disease outside the CNS
---No metastases to brain stem, midbrain, pons, medulla, or cerebellum
---No history of intracranial hemorrhage or spinal cord hemorrhage
---No ongoing requirement for dexamethasone for CNS disease; patients on a stable dose of anticonvulsants are permitted.
---No neurosurgical resection or brain biopsy within 28 days prior to Cycle 1, Day 1
--Patients with asymptomatic treated CNS metastases may be enrolled, provided all the criteria listed above are met as well as the following:
---Radiographic demonstration of improvement upon the completion of CNS-directed therapy and no evidence of interim progression between the completion of CNS-directed therapy and radiographic screening for the current study
---No stereotactic radiation or whole-brain radiation within 28 days prior to Cycle 1, Day 1
---Screening CNS radiographic study greater than or equal to 4 weeks from completion of radiotherapy and greater than or equal to 2 weeks from discontinuation of corticosteroids
-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.
-HIV-positive patients may be on combination antiretroviral therapy but must have a CD4 count >350 cells/mm3 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.
--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.
--Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.
-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, Sj(SqrRoot)(Delta)gren s
syndrome, Bell s palsy, Guillain-Barr(SqrRoot)(Copyright) syndrome, multiple sclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis.
--Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid C-0074 24
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:
---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%, 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)
-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 described in Section 9.3) 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.
--Influenza vaccination should be given during influenza season only (approximately October to March). Patients must not receive live, attenuated influenza vaccine within 4 weeks prior to Cycle 1, Day 1 or at any time during the study.
-Bevacizumab-Specific Exclusion Criteria:
The following exclusion criteria, in addition to those in Section 3.2, apply to the atezolizumab +bevacizumab combination arm:
-Age <18 years.
-Prior disease progression on an immune checkpoint inhibitor plus tyrosine kinase inhibitor combination therapy.
-Major surgery within 6 weeks of enrollment. Minor procedures (e.g. port placement, endoscopy with intervention) within 28 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 ration (INR) greater than or equal to 1.5 (or >therapeutic range if patient is receiving warfarin). PTT greater than or equal to 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 LVEF <50%, transmural myocardial infarction, uncontrolled hypertension (defined as systolic blood pressure > 140 mmHg and/or diastolic blood pressure > 90 mmHg in patients greater than or equal to 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 (SqrRoot)
-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 treatment and the patient has been on a stable dose of anticoagulants for (Bullet) 2 weeks prior to initiation of study treatment. Prophylactic use of anticoagulants is allowed. However, the use of direct oral anticoagulant therapies such as dabigatran (Pradaxa o) and rivaroxaban (Xarelto o) is not recommended due to bleeding risk.
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