Clinical Trials /

Atezolizumab Versus Atezolizumab Plus Bevacizumab as First Line in NSCLC Patients (BEAT)

NCT03896074

Description:

phase II controlled randomized study comparing atezolizumab as single agent to the combination of atezolizumab and bevacizumab in patients with chemonaive metastatic NSCLC with PD-L1 expression. All NSCLC patients with tumor tissue available for biomarker assessment and candidate for first-line therapy are considered eligible for the study. After evaluation of all inclusion and exclusion criteria and after informed consent signature all eligible patients will be randomized to atezolizumab (Arm A) or to the combination of atezolizumab and bevacizumab (Arm B). Disease assessment will be performed every 6 weeks.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Atezolizumab Versus Atezolizumab Plus Bevacizumab as First Line in NSCLC Patients (BEAT)
  • Official Title: Phase II Randomized Trial Comparing Atezolizumab Versus Atezolizumab Plus Bevacizumab as First-line Treatment in PD-L1+ Advanced Metastatic Non-small-cell Lung Cancer Patients

Clinical Trial IDs

  • ORG STUDY ID: FoRT 05- BEAT
  • NCT ID: NCT03896074

Conditions

  • Non-small-cell Lung Cancer Patients

Interventions

DrugSynonymsArms
AtezolizumabAtezolizumab
BevacizumabAtezolizumab plus bevacizumab

Purpose

phase II controlled randomized study comparing atezolizumab as single agent to the combination of atezolizumab and bevacizumab in patients with chemonaive metastatic NSCLC with PD-L1 expression. All NSCLC patients with tumor tissue available for biomarker assessment and candidate for first-line therapy are considered eligible for the study. After evaluation of all inclusion and exclusion criteria and after informed consent signature all eligible patients will be randomized to atezolizumab (Arm A) or to the combination of atezolizumab and bevacizumab (Arm B). Disease assessment will be performed every 6 weeks.

Detailed Description

      This is a phase II controlled randomized study comparing atezolizumab as single agent to the
      combination of atezolizumab and bevacizumab in patients with chemonaive metastatic NSCLC with
      PD-L1 expression.

      A total of maximum of 206 patients will be enrolled in the study. Patients will be treated
      with atezolizumab (1200 mg) every 3 weeks (6-week cycles) or the combination of atezolizumab
      (1200 mg) every 3 weeks (6-week cycles) plus bevacizumab (15 mg/kg) every 3 weeks until
      disease progression, unacceptable toxicity or patient refusal. Disease evaluation, along with
      various assessments, will be made every 3 weeks and every 6 weeks and follow-up every 3
      months. Toxicities will be evaluated throughout the study period. A follow-up of 12 months is
      planned for each patient from the end of treatment .The study will be performed in
      approximately 20 centers across Italy.
    

Trial Arms

NameTypeDescriptionInterventions
AtezolizumabExperimentalPatients allocated to Arm A will be treated with atezolizumab administered intravenously at 1200 mg every 3 weeks given until disease progression, toxicity or patient refusal
  • Atezolizumab
Atezolizumab plus bevacizumabExperimentalPatients in the Arm B will receive atezolizumab administered intravenously at 1200 mg every 3 weeks plus bevacizumab intravenously at 15 mg/kg every 3 weeks given until disease progression, toxicity or patient refusal
  • Atezolizumab
  • Bevacizumab

Eligibility Criteria

        Inclusion Criteria:

          1. Histologically confirmed diagnosis of stage IV non-squamous NSCLC with no evidence of
             EGFR sensitizing mutations or ALK or ROS1 rearrangements.

          2. Availability of tumor tissue.

          3. Evidence of PD-L1 expression evaluated with immunohistochemistry (≥1%).

          4. No previous chemotherapy. Patients who have received prior neo-adjuvant, adjuvant
             chemotherapy, radiotherapy or chemoradiotherapy with curative intent for
             non-metastatic disease must have experienced a treatment-free interval of at least 6
             months from randomization since the last dose of chemotherapy and/or radiotherapy.

          5. ECOG performance status 0-1.

          6. Life expectancy > 3 months

          7. Age ≥18 years.

          8. Measurable disease, as defined by RECIST v1.1.

          9. Adequate hematologic and organ function, defined by the following laboratory results
             obtained within 28 days prior to randomization:

               -  ANC ≥ 1500 cells/μL without granulocyte colony-stimulating factor support

               -  Platelet count ≥ 100,000/μL without transfusion

               -  Hemoglobin ≥ 9.0 g/dL Patients may be transfused to meet this criterion

               -  AST, ALT, and alkaline phosphatase ≤ 2.5 × ULN, with the following exceptions:

               -  Patients with documented liver metastases: AST and/or ALT ≤ 5 × ULN

               -  Patients with documented liver or bone metastases: alkaline phosphatase ≤ 5 ×
                  ULN.

               -  Serum bilirubin ≤ 1.25 × ULN

               -  Patients with known Gilbert disease who have serum bilirubin level ≤ 3 mg/dL may
                  be enrolled

               -  Calculated creatinine clearance (CRCL) ≥ 45 mL/min or calculated CRCL must be ≥
                  60 mL/min

         10. Patient compliance to trial procedures.

         11. Written informed consent.

        Exclusion Criteria:

          1. No tumor tissue available.

          2. PD-L1 expression < 1 % or PD-L1 expression unknown or not assessable

          3. Patient positive for EGFR mutations or ALK or ROS1 rearrangements.

          4. Patients with squamous histology or with specific contraindication to bevacizumab
             therapy.

          5. Previous chemotherapy. Adjuvant or neoadjuvant chemotherapy is considered a line of
             therapy if completed less than 6 months before evidence of disease relapse.

          6. Concomitant radiotherapy or chemotherapy.

          7. Previous therapy with any checkpoint inhibitor.

          8. Pregnancy or lactating women who are pregnant, lactating, or intending to become
             pregnant during the study.

          9. Symptomatic brain metastases; asymptomatic brain metastases are accepted if no steroid
             therapy is required and if pretreated.

         10. Spinal cord compression not definitively treated with surgery and/or radiation or
             previously diagnosed and treated spinal cord compression without evidence that disease
             has been clinically stable for > 2 weeks prior to randomization.

         11. Leptomeningeal disease.

         12. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent
             drainage procedures (once monthly or more frequently). Patients with indwelling
             catheters (e.g., PleurX) are allowed.

         13. Uncontrolled or symptomatic hypercalcemia (> 1.5 mmol/L ionized calcium or Ca > 12
             mg/dL or corrected serum calcium >ULN). Patients who are receiving denosumab prior to
             randomization must be willing and eligible to receive a bisphosphonate instead while
             on study.

         14. Malignancies other than NSCLC within 5 years prior to randomization, with the
             exception of those with a negligible risk of metastasis or death (e.g., expected
             5-year OS> 90%) treated 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, ductal carcinoma in situ
             treated surgically with curative intent)

         15. History of severe allergic, anaphylactic, or other hypersensitivity reactions to
             chimeric or humanized antibodies or fusion proteins

         16. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster
             ovary cells or any component of the Atezolizumab formulation

         17. History of autoimmune disease, including but not limited to myasthenia gravis,
             myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis,
             psoriatic arthritis, inflammatory bowel disease, vascular thrombosis associated with
             antiphospholipid syndrome, Wegener granulomatosis, Sjögren's syndrome, Guillain-Barré
             syndrome, multiple sclerosis, vasculitis, or glomerulonephritis. Patients with: 1)
             history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement
             hormone, 2) controlled Type I diabetes mellitus who are receiving a stable dose of
             insulin regimen and 3) eczema, psoriasis, lichen simplex chronicus of vitiligo with
             dermatologic manifestations only in less than 10% of body surface area, well
             controlled at baseline and only requiring low potency topical steroids are eligible
             for this study.

         18. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis
             obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active
             pneumonitis on screening chest CT scan. History of radiation pneumonitis in the
             radiation field (fibrosis) is permitted.

         19. Positive test for HIV

         20. Patients with active hepatitis B (chronic or acute; defined as having a positive
             hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C. Patients with
             past hepatitis B virus (HBV) infection or resolved HBV infection (defined as the
             presence of hepatitis B core antibody [HBc Ab] and absence of HBsAg) are eligible. HBV
             DNA must be obtained in these patients prior to randomization. Patients positive for
             hepatitis C virus (HCV) antibody are eligible only if PCR is negative for HCV RNA.

         21. Active tuberculosis

         22. Severe infections within 4 weeks prior to randomization, including but not limited to
             hospitalization for complications of infection, bacteremia, or severe pneumonia
             received therapeutic oral or IV antibiotics within 2 weeks prior to randomization.
             Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract
             infection or to prevent chronic obstructive pulmonary disease exacerbation) are
             eligible.

         23. Significant cardiovascular disease, such as New York Heart Association cardiac disease
             (Class II or greater), myocardial infarction within 3 months prior to randomization,
             unstable arrhythmias, or unstable angina. Patients with known coronary artery disease,
             congestive heart failure not meeting the above criteria, or left ventricular ejection
             fraction < 50% must be on a stable medical regimen that is optimized in the opinion of
             the treating physician, in consultation with a cardiologist if appropriate.

         24. Major surgical procedure other than for diagnosis within 28 days prior to
             randomization or anticipation of need for a major surgical procedure during the course
             of the study

         25. Prior allogeneic bone marrow transplantation or solid organ transplant

         26. Administration of a live, attenuated vaccine within 4 weeks before randomization or
             anticipation that such a live attenuated vaccine will be required during the study

         27. 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

         28. Any approved anti-cancer therapy, including chemotherapy, or hormonal therapy within 3
             weeks prior to initiation of study treatment; the following exceptions are allowed:
             Hormone-replacement therapy or oral contraceptives, TKIs approved for treatment of
             NSCLC discontinued > 7 days prior to randomization; the baseline scan must be obtained
             after discontinuation of prior TKIs.

         29. Treatment with any other investigational agent or participation in another clinical
             trial with therapeutic intent within 28 days prior to randomization

         30. Prior treatment with CD137 agonists or immune checkpoint blockade therapies,
             anti−PD-1, and anti−PD-L1 therapeutic antibodies. Patients who have had prior
             anti−CTLA-4 treatment may be enrolled, provided the following requirements are met:
             Minimum of 6 weeks from the last dose of anti−CTLA-4; No history of severe
             immune-mediated adverse effects from anti−CTLA-4 (NCI CTCAE Grade 3 and 4)

         31. Treatment with systemic immunostimulatory agents (including but not limited to IFNs,
             IL-2) within 6 weeks or five half-lives of the drug, wichever is shorter, prior to
             randomization. Prior treatment with cancer vaccines is allowed.

         32. 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 randomization.

         33. Patients who have received acute, low-dose, systemic immunosuppressant medications
             (e.g., a one-time dose of dexamethasone for nausea) may be enrolled in the study after
             discussion with and approval by the Medical Monitor.

         34. Patients with history of allergic reaction to IV contrast requiring steroid
             pre-treatment should have baseline and subsequent tumor assessments done by MRI. The
             use of inhaled corticosteroids for chronic obstructive pulmonary disease,
             mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension,
             and low-dose supplemental corticosteroids for adrenocortical insufficiency are
             allowed.

         35. Inadequately controlled hypertension (defined as systolic blood pressure > 150 mmHg
             and/or diastolic blood pressure > 100 mmHg) Anti-hypertensive therapy to achieve these
             parameters is allowable.

         36. Prior history of hypertensive crisis or hypertensive encephalopathy

         37. Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or
             recentperipheral arterial thrombosis) within 6 months prior to randomization

         38. History of hemoptysis (≥ one-half teaspoon of bright red blood per episode) within 1
             month prior to randomization; Evidence of bleeding diathesis or coagulopathy (in the
             absence of therapeutic anticoagulation).

         39. Current or recent (within 10 days of randomization) use of aspirin (> 325 mg/day) or
             treatment with dipyramidole, ticlopidine, clopidogrel, and clostazol

         40. Current use of full-dose oral or parenteral anticoagulants or thrombolytic agents for
             therapeutic purposes that has not been stable for > 2 weeks prior to randomization.
             The use of full-dose oral or parenteral anticoagulants is permitted as long as the INR
             or aPTT is within therapeutic limits (according to the medical standard of the
             enrolling institution) and the patient has been on a stable dose of anticoagulants for
             at least 2 weeks prior to randomization.

         41. Prophylactic anticoagulation for the patency of venous access devices is allowed,
             provided the activity of the agent results in an INR< 1.5 ×ULN and aPTT is within
             normal limits within 14 days prior to randomization.

         42. Prophylactic use of low-molecular-weight heparin (i.e., enoxaparin 40 mg/day) is
             permitted.

         43. Core biopsy or other minor surgical procedure, excluding placement of a vascular
             access device, within 7 days prior to the first dose of bevacizumab

         44. History of abdominal or tracheosphageal fistula or gastrointestinal perforation within
             6 months prior to randomization; Clinical signs of gastrointestinal obstruction or
             requirement for routine parenteral hydration, parenteral nutrition, or tube feeding;
             Evidence of abdominal free air not explained by paracentesis or recent surgical
             procedure.

         45. Serious, non-healing wound, active ulcer, or untreated bone fracture

         46. Proteinuria, as demonstrated by urine dipstick or > 1.0 g of protein in a 24-hour
             urine collection. All patients with ≥ 2+ protein on dipstick urinalysis at baseline
             must undergo a 24-hour urine collection and must demonstrate ≤ 1 g of protein in 24
             hours.

         47. Known sensitivity to any component of bevacizumab
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall Survival (OS)
Time Frame:18 months
Safety Issue:
Description:Overall Survival (OS) rate at 18 months in patients treated with atezolizumab alone versus atezolizumab-bevacizumab combination

Secondary Outcome Measures

Measure:Response rate (complete + partial responses)
Time Frame:Up to 24 months
Safety Issue:
Description:Response rate will be evaluated by investigators according to RECIST criteria version 1.1. Partial and complete responses will be confirmed following RECIST criteria 1.1.
Measure:Progression-free survival
Time Frame:Up to 24 months
Safety Issue:
Description:Progression free survival (PFS) will be calculated from the date of randomization to the first documented evidence of progressive disease or death due to any cause (whichever occurs first).
Measure:Overall survival according to presence of bone and/ or hepatic metastases
Time Frame:Up to 24 months
Safety Issue:
Description:Overall response rate (ORR) is defined as the number of subjects with a best overall response (BOR) of CR or PR divided by the number of randomized subjects for each treatment group.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Fondazione Ricerca Traslazionale

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