Clinical Trials /

AZD9291 (Osimertinib) With or Without Bevacizumab as Initial Treatment for Patients With EGFR-Mutant Lung Cancer

NCT04181060

Description:

This phase III trial compares the effect of bevacizumab and AZD9291 (osimertinib) combination vs. osimertinib alone for the treatment of non-small cell lung cancer that has spread outside of the lungs (stage IIIB-IV) and has a change (mutation) in a gene called EGFR. The EGFR protein is involved in cell signaling pathways that control cell division and survival. Sometimes, mutations in the EGFR gene cause EGFR proteins to be made in higher than normal amounts on some types of cancer cells. This causes cancer cells to divide more rapidly. Osimertinib may stop the growth of tumor cells by blocking EGFR that is needed for cell growth in this type of cancer. Monoclonal antibodies, such as bevacizumab, may interfere with the ability of tumor cells to grow and spread. Giving osimertinib with bevacizumab may control cancer for longer and help patients live longer as compared to osimertinib alone.

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

Not yet recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: AZD9291 (Osimertinib) With or Without Bevacizumab as First-Treatment for Patients With EGFR-Mutant Lung Cancer
  • Official Title: Randomized Phase III Study of Combination AZD9291 (Osimertinib) and Bevacizumab Versus AZD9291 (Osimertinib) Alone as First-Line Treatment for Patients With Metastatic EGFR-Mutant Non-Small Cell Lung Cancer (NSCLC)

Clinical Trial IDs

  • ORG STUDY ID: NCI-2019-07941
  • SECONDARY ID: NCI-2019-07941
  • SECONDARY ID: EA5182
  • SECONDARY ID: EA5182
  • SECONDARY ID: U10CA180820
  • NCT ID: NCT04181060

Conditions

  • Advanced Lung Non-Squamous Non-Small Cell Carcinoma
  • Metastatic Lung Non-Squamous Non-Small Cell Carcinoma
  • Recurrent Lung Non-Squamous Non-Small Cell Carcinoma
  • Stage IIIB Lung Cancer AJCC v8
  • Stage IIIC Lung Cancer AJCC v8
  • Stage IV Lung Cancer AJCC v8
  • Stage IVA Lung Cancer AJCC v8
  • Stage IVB Lung Cancer AJCC v8

Interventions

DrugSynonymsArms
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 HD204, Bevacizumab Biosimilar HLX04, Bevacizumab Biosimilar IBI305, Bevacizumab Biosimilar LY01008, Bevacizumab Biosimilar MIL60, Bevacizumab Biosimilar QL 1101, Bevacizumab Biosimilar RPH-001, Bevacizumab Biosimilar SCT501, 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, Recombinant Humanized Anti-VEGF Monoclonal Antibody, rhuMab-VEGF, SCT501Arm B (osimertinib, bevacizumab)
OsimertinibAZD-9291, AZD9291, Mereletinib, TagrissoArm A (osimertinib)

Purpose

This phase III trial studies how well osimertinib with or without bevacizumab work for the treatment of EGFR-mutant stage IIIB-IV non-small cell lung cancer. Osimertinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as bevacizumab, may interfere with the ability of tumor cells to grow and spread. Giving osimertinib with bevacizumab may control cancer for longer and help patients live longer as compared to osimertinib alone.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To evaluate progression-free survival (PFS) of AZD9291 (osimertinib) and bevacizumab
      versus AZD9291 (osimertinib) alone as first-line treatment for patients with metastatic
      EGFR-mutant lung cancers.

      SECONDARY OBJECTIVES:

      I. To evaluate overall survival (OS). II. To evaluate overall response rate. III. To evaluate
      time to central nervous system (CNS) progression. IV. To evaluate safety/toxicity of the
      combination regimen.

      CORRELATIVE OBJECTIVES:

      I. To characterize mechanisms of resistance to AZD9291 (osimertinib) and AZD9291
      (osimertinib) with bevacizumab first-line therapy through post-progression circulating
      tumor-derived deoxyribonucleic acid (ctDNA).

      II. To assess for ctDNA clearance on study treatment and associate ctDNA clearance with
      clinical outcomes.

      OUTLINE: Patients are randomized to 1 of 2 arms.

      ARM A: Patients receive osimertinib orally (PO) once daily (QD) on days 1-21. Cycles repeat
      every 21 days in the absence of disease progression or unacceptable toxicity.

      ARM B: Patients receive osimertinib PO QD on days 1-21 and bevacizumab intravenously (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 every 3 months for 10 years.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (osimertinib)Active ComparatorPatients receive osimertinib PO QD on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  • Osimertinib
Arm B (osimertinib, bevacizumab)ExperimentalPatients receive osimertinib PO QD on days 1-21 and bevacizumab IV over 30-90 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  • Bevacizumab
  • Osimertinib

Eligibility Criteria

        Inclusion Criteria:

          -  Patient must have a pathologically-confirmed diagnosis of non-squamous, non-small cell
             lung cancer (NSCLC)

          -  Patient must have advanced disease, defined as - either stage IV disease, stage IIIB
             disease not amenable to definitive multi-modality therapy, or recurrent disease after
             a prior diagnosis of stage I-III disease. All staging is via the American Joint
             Committee on Cancer (AJCC)/International Association for the Study of Lung Cancer
             (IASLC) 8th edition staging criteria

          -  Patient must have somatic activating sensitizing mutation in EGFR (e.g. but not
             limited to Exon 19 deletion, L858R, G709X, G719X, exon 19 insertions, L861Q, S768I).
             Patients with non-sensitizing mutations in EGFR (EGFR exon 20 insertions) are not
             eligible. Test results originating from a Clinical Laboratory Improvement Act
             (CLIA)-certified or similarly accredited laboratory are acceptable; no specific assay
             is mandated. If there is any question as to whether an EGFR mutation is sensitizing,
             please contact the primary study team

          -  Patients that have received prior radiation therapy are eligible. Radiation
             (whole-brain radiotherapy [WBRT] or stereotactic radiation) must have been completed
             at least two weeks prior to study registration

          -  Patient must have measurable disease. Baseline measurements of sites of disease must
             be obtained within 4 weeks prior to study registration. If a potential target lesion
             is previously irradiated without subsequent growth and/or is radiated after the
             imaging from which baseline measurements are obtained, they cannot be included as
             target lesions, and additional target lesions are required to meet criteria for
             measurable disease

          -  Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0
             to 2

          -  All females of childbearing potential must have a blood test or urine study within 14
             days prior to registration to rule out pregnancy

          -  A female of childbearing potential is defined as any woman, regardless of sexual
             orientation or whether they have undergone tubal ligation, who meets the following
             criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy
             or bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea
             following cancer therapy does not rule out childbearing potential) for at least 24
             consecutive months (i.e., has had menses at any time in the preceding 24 consecutive
             months)

          -  Women of childbearing potential and sexually active males must not expect to conceive
             or father children by using accepted and effective method(s) of contraception or by
             abstaining from sexual intercourse for 2 weeks prior to the start of treatment, while
             on study treatment, and for

               -  6 weeks after the last dose of protocol treatment for female patients on the
                  AZD9291 (osimertinib) alone arm

               -  4 months after the last dose of protocol treatment for male patients on AZD9291
                  (osimertinib) alone arm

               -  6 months after the last dose of protocol treatment for all patients on AZD9291
                  (osimertinib) plus bevacizumab combination arm

          -  Leukocytes >= 3,000/mcL (obtained =< 14 days prior to registration)

          -  Absolute neutrophil count >= 1,500/mcL (obtained =< 14 days prior to registration)

          -  Platelets >= 100,000/mcL (obtained =< 14 days prior to registration)

          -  Hemoglobin >= 9 g/dL (obtained =< 14 days prior to registration)

          -  Total bilirubin and creatinine =< 1.5 x institutional upper limit of normal (ULN)
             (obtained =< 14 days prior to registration)

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 2.5 x institutional ULN (obtained =< 14 days prior to registration)

          -  Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
             therapy with undetectable viral load within 6 months are eligible for this trial

          -  For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral
             load must be undetectable on suppressive therapy, if indicated

          -  Patients with a history of hepatitis C virus (HCV) infection must have been treated
             and cured. For patients with HCV infection who are currently on treatment, they are
             eligible if they have an undetectable HCV viral load

          -  Patients with treated brain metastases are eligible if neurologically stable without
             glucocorticoid therapy after the stated washout period from radiation therapy (RT) or
             surgery provided the metastatic lesions are non-hemorrhagic

          -  Patients with untreated brain metastases or leptomeningeal disease are eligible if the
             treating physician determines that immediate CNS specific treatment is not required
             provided the metastatic lesions are non-hemorrhagic and are neurologically stable
             without glucocorticoid therapy

          -  Patients with a prior or concurrent malignancy whose natural history or treatment does
             not have the potential to interfere with the safety or efficacy assessment of the
             investigational regimen are eligible for this trial

          -  Patients with known history or current symptoms of cardiac disease, or history of
             treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac
             function using the New York Heart Association Functional Classification. To be
             eligible for this trial, patients should be class 2B or better

        Exclusion Criteria:

          -  Patient must not have received any prior treatment with an EGFR TKI or with an
             anti-VEGF agent

          -  Patient must not have any risk factors for anti-VEGF administration, specifically,
             hemoptysis, active cardiovascular disease, uncontrolled hypertension, significant
             proteinuria (screening urine dipstick > 3+) and tumor invading major blood vessels

          -  Women must not be pregnant or breast-feeding due to the potential harm to an unborn
             fetus and possible risk for adverse events in nursing infants with the treatment
             regimens being used
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression-free survival (PFS)
Time Frame:From randomization to documented disease progression per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or death from any cause, whichever occurs first, assessed up to 10 years
Safety Issue:
Description:Will be estimated using the Kaplan-Meier method, and Cox proportional hazards models will be used to estimate the treatment hazard ratios.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

December 5, 2019