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

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ClinicalTrials.gov Identifier: NCT03896074
Recruitment Status : Not yet recruiting
First Posted : March 29, 2019
Last Update Posted : March 29, 2019
Sponsor:
Information provided by (Responsible Party):
Fondazione Ricerca Traslazionale

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Non-small-cell Lung Cancer Patients Drug: Atezolizumab Drug: Bevacizumab Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 206 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Estimated Study Start Date : May 2019
Estimated Primary Completion Date : May 2022
Estimated Study Completion Date : April 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Atezolizumab
Patients 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
Drug: Atezolizumab
Atezolizumab administered intravenously at 1200 mg every 3 weeks

Experimental: Atezolizumab plus bevacizumab
Patients 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
Drug: Atezolizumab
Atezolizumab administered intravenously at 1200 mg every 3 weeks

Drug: Bevacizumab
Bevacizumab intravenously at 15 mg/kg every 3 weeks




Primary Outcome Measures :
  1. Overall Survival (OS) [ Time Frame: 18 months ]
    Overall Survival (OS) rate at 18 months in patients treated with atezolizumab alone versus atezolizumab-bevacizumab combination


Secondary Outcome Measures :
  1. Response rate (complete + partial responses) [ Time Frame: Up to 24 months ]
    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.

  2. Progression-free survival [ Time Frame: Up to 24 months ]
    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).

  3. Overall survival according to presence of bone and/ or hepatic metastases [ Time Frame: Up to 24 months ]
    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.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03896074


Contacts
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Contact: Federico Cappuzzo 0544285206 f.cappuzzo@gmail.com
Contact: Lorenza Landi 0544285206 landi.lorenza@gmail.com

Locations
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Italy
AOU Ospedali Riuniti "Umberto I- G.M.Lancisi-G.Salesi" Not yet recruiting
Ancona, Italy, 60020
Contact: Rossana Berardi    715965715    r.berardi@univpm.it   
IRCCS Oncologico Istituto Tumori "Giovanni Paolo II" Not yet recruiting
Bari, Italy, 70124
Contact: Domenico Galetta    0805555442    galetta@oncologico.bari.it   
P.O. Antonio Perrino Not yet recruiting
Brindisi, Italy, 72100
Contact: Saverio Cinieri    0831/537218    saverio.cinieri@ieo.it   
A.O. Per l' emergenza Cannizzaro Not yet recruiting
Catania, Italy, 95126
Contact: Giuseppe Luigi Banna    0957262082    gbanna@yahoo.com   
Irccs S.R.L. Irst Not yet recruiting
Meldola, Italy, 47014
Contact: Angelo Delmonte    0543-739100    angelo.delmonte@irst.emr.it   
AO Papardo Not yet recruiting
Messina, Italy, 98158
Contact: Vincenzo Adamo    0903996150    vadamo@unime.it   
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Not yet recruiting
Milano, Italy, 20122
Contact: Francesco Grossi    02 5503 2556    francesco.grossi@policlinico.mi.it   
Istituto Nazionale Tumori di Napoli IRCCS Pascale Not yet recruiting
Napoli, Italy, 80131
Contact: Alessandro Morabito    0815903631    a.morabito@istitutotumori.na.it   
Ospedale Sacro Cuore- Don Calabria Not yet recruiting
Negrar, Italy, 37024
Contact: Stefania Gori    045/60133801    stefania.gori@sacrocuore.it   
AOU S. Luigi Orbassano Not yet recruiting
Orbassano, Italy, 10043
Contact: Silvia Novello    0119026978    silvia.novello@unito.it   
IRCCS ISTITUTO Oncologico Veneto Not yet recruiting
Padova, Italy, 35128
Contact: Laura Bonanno    +390498215931    laura.bonanno@iov.veneto.it   
Arcispedale Santa Maria Nuova Not yet recruiting
Reggio Emilia, Italy, 42100
Contact: Francesca Zanelli    0522-296632    francesca.zanelli@ausl.re.it   
Azienda Ospedaliera San Camillo-Forlanini Not yet recruiting
Roma, Italy, 00152
Contact: Maria Rita Migliorino    0658704670    ritamigliorino@tiscali.it   
IRCCS Ospedale Casa Sollievo della Sofferenza Not yet recruiting
San Giovanni Rotondo, Italy, 71013
Contact: Antonio Rossi    0882410716    arossi_it@yahoo.it   
ASST Sette Laghi Not yet recruiting
Varese, Italy, 21100
Contact: Alessandro Tuzi    0332278558    alessandro.tuzi@asst-settelaghi.it   
AUOI di Verona- Borgo Trento Not yet recruiting
Verona, Italy, 37126
Contact: Sara Pilotto    0458123876    sara.pilotto.85@gmail.com   
Sponsors and Collaborators
Fondazione Ricerca Traslazionale

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Responsible Party: Fondazione Ricerca Traslazionale
ClinicalTrials.gov Identifier: NCT03896074     History of Changes
Other Study ID Numbers: FoRT 05- BEAT
First Posted: March 29, 2019    Key Record Dates
Last Update Posted: March 29, 2019
Last Verified: March 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Bevacizumab
Atezolizumab
Antibodies, Monoclonal
Antineoplastic Agents, Immunological
Antineoplastic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Immunologic Factors