Clinical Trials /

Testing Atezolizumab and Bevacizumab in People With Advanced Alveolar Soft Part Sarcoma

NCT03141684

Description:

This phase II trial studies how well atezolizumab 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 your immune system, allowing your immune system cells to recognize and then attack your tumor cells. Bevacizumab works by controlling the growth of new blood vessels. Giving atezolizumab and bevacizumab may shrink the cancer.

Related Conditions:
  • Alveolar Soft Part Sarcoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Testing Atezolizumab and Bevacizumab in People With Advanced Alveolar Soft Part Sarcoma
  • Official Title: A Phase 2 Study of Anti-PD-L1 Antibody (Atezolizumab) in Alveolar Soft Part Sarcoma

Clinical Trial IDs

  • ORG STUDY ID: NCI-2016-01040
  • SECONDARY ID: NCI-2016-01040
  • SECONDARY ID: CC 17-C-0074
  • SECONDARY ID: 17-C-0074
  • SECONDARY ID: 17-C-007
  • SECONDARY ID: 10005
  • SECONDARY ID: 10005
  • SECONDARY ID: ZIABC011078
  • NCT ID: NCT03141684
  • NCT ALIAS: NCT03233698

Conditions

  • Metastatic Alveolar Soft Part Sarcoma
  • Unresectable Alveolar Soft Part Sarcoma

Interventions

DrugSynonymsArms
AtezolizumabMPDL 3280A, MPDL 328OA, MPDL-3280A, MPDL3280A, MPDL328OA, RG7446, RO5541267, TecentriqArm I (atezolizumab)
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 GB-222, Bevacizumab Biosimilar HD204, Bevacizumab Biosimilar HLX04, Bevacizumab Biosimilar IBI305, Bevacizumab Biosimilar LY01008, Bevacizumab Biosimilar MIL60, Bevacizumab Biosimilar Mvasi, Bevacizumab Biosimilar QL 1101, Bevacizumab Biosimilar RPH-001, Bevacizumab Biosimilar SCT501, Bevacizumab Biosimilar Zirabev, Bevacizumab-awwb, Bevacizumab-bvzr, 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, Mvasi, Recombinant Humanized Anti-VEGF Monoclonal Antibody, rhuMab-VEGF, SCT501, ZirabevArm II (atezolizumab, bevacizumab)

Purpose

This phase II trial studies how well atezolizumab 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 your immune system, allowing your immune system cells to recognize and then attack your tumor cells. Bevacizumab works by controlling the growth of new blood vessels. Giving atezolizumab and bevacizumab may shrink the cancer.

Detailed Description

      PRIMARY OBJECTIVE:

      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.

      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.

      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.

      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.

      After completion of study treatment, patients are followed up for 27-30 days.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (atezolizumab)ExperimentalPatients receive atezolizumab IV over 30-60 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  • Atezolizumab
Arm II (atezolizumab, bevacizumab)ExperimentalPatients 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.
  • Atezolizumab
  • Bevacizumab

Eligibility Criteria

        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 iCPD) on, or within 3 months of, 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
             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 at the
             National Cancer Institute (NCI) clinical center (>= 14 years of age at other
             participating sites). 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:

               -  Age 2 to < 6 years, maximum serum creatinine (mg/dL) male 0.8, female 0.8;

               -  Age 6 to < 10 years, maximum serum creatinine (mg/dL) male 1, female 1;

               -  Age 10 to < 13 years, maximum serum creatinine (mg/dL) male 1.2, female 1.2;

               -  Age 13 to < 16 years, maximum serum creatinine (mg/dL) male 1.5, female 1.4;

               -  Age 16 to < 18 years, maximum serum creatinine (mg/dL) male 1.7, female 1.4

          -  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)

        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. Patients should be at least 6 weeks out from
             nitrosoureas and mitomycin C. Prior definitive radiation should have been completed >=
             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 principal investigator [PI]'s discretion). Patients
             who have had prior monoclonal antibody therapy must have completed that therapy >= 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 > 350 mg/m^2 of anthracycline (regardless of
             cardioprotectant) may only be enrolled if 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
                       Common Terminology Criteria for Adverse Events [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 >=
             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 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 >= 4 weeks from completion of radiotherapy
                       and >= 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

          -  Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
             therapy are ineligible; patients must also 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.

               -  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 ribonucleic acid (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, 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 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; 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

               -  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

          -  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)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:2 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response rate
Time Frame:Up to 4 weeks after the last dose of study treatment
Safety Issue:
Description:Will be evaluated using Response Evaluation Criteria in Solid Tumors version 1.1. If at least 3 responses (at least 12.5%) are observed among the 24 evaluable patients, this regimen would be considered worthy of further testing in this disease.

Secondary Outcome Measures

Measure:Duration of response
Time Frame:Baseline until disease progression, death, loss to follow-up, initiation of another anti-cancer treatment, withdrawal of consent, or study, assessed up to 4 weeks after the last dose of study treatment
Safety Issue:
Description:Will be assessed using Response Evaluation Criteria in Solid Tumors version 1.1. Exploratory evaluations will be performed, with results reported with appropriate caveats about the exploratory nature of the analysis, and without formal adjustment for multiple comparisons.
Measure:Progression free survival
Time Frame:Baseline until disease progression, death, loss to follow-up, initiation of another anti-cancer treatment, withdrawal of consent, or study, assessed up to 4 weeks after the last dose of study treatment
Safety Issue:
Description:Will be evaluated using Response Evaluation Criteria in Solid Tumors version 1.1. Exploratory evaluations will be performed, with results reported with appropriate caveats about the exploratory nature of the analysis, and without formal adjustment for multiple comparisons.
Measure:Immune biomarkers in paired biopsies
Time Frame:Up to 4 weeks after the last dose of study treatment
Safety Issue:
Description:Response will be correlated with expression of potential immune biomarkers in paired biopsies. Exploratory evaluations will be performed, with results reported with appropriate caveats about the exploratory nature of the analysis, and without formal adjustment for multiple comparisons.
Measure:Immune-related response
Time Frame:Up to 4 weeks after the last dose of study treatment
Safety Issue:
Description:Will be evaluated by immune Response Evaluation Criteria in Solid Tumors. Response evaluated with immune Response Evaluation Criteria in Solid Tumors version 1.1 will be compared to immune Response Evaluation Criteria in Solid Tumors. Exploratory evaluations will be performed, with results reported with appropriate caveats about the exploratory nature of the analysis, and without formal adjustment for multiple comparisons.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

March 17, 2021