Clinical Trials /

Osimertinib With or Without Bevacizumab in Treating Patients With EGFR Positive Non-small Cell Lung Cancer and Brain Metastases

NCT02971501

Description:

This phase II trial studies how well osimertinib with or without bevacizumab works in treating patients with EGFR positive non-small cell lung cancer that has spread to the brain (brain metastases). Osimertinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Bevacizumab may stop or slow non-small cell lung cancer by blocking the growth of new blood vessels necessary for tumor growth. Giving osimertinib with or without bevacizumab may work better in treating patients with non-small cell lung cancer.

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

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Osimertinib With or Without Bevacizumab in Treating Patients With EGFR Positive Non-small Cell Lung Cancer and Brain Metastases
  • Official Title: A Phase II Trial of AZD9291 (Osimertinib) With or Without Bevacizumab in Patients With EGFR Mutation Positive NSCLC and Brain Metastases

Clinical Trial IDs

  • ORG STUDY ID: NCI-2016-01733
  • SECONDARY ID: NCI-2016-01733
  • SECONDARY ID: 2000021123
  • SECONDARY ID: 10042
  • SECONDARY ID: 10042
  • SECONDARY ID: 10042
  • SECONDARY ID: UM1CA186689
  • NCT ID: NCT02971501

Conditions

  • EGFR Activating Mutation
  • EGFR Exon 19 Deletion Mutation
  • EGFR NP_005219.2:p.L858R
  • Lung Carcinoma Metastatic in the Brain
  • Lung Non-Small Cell Carcinoma

Interventions

DrugSynonymsArms
BevacizumabAnti-VEGF, Anti-VEGF Humanized Monoclonal Antibody, Anti-VEGF rhuMAb, Avastin, Bevacizumab Biosimilar BEVZ92, Bevacizumab Biosimilar BI 695502, Bevacizumab Biosimilar CBT 124, Bevacizumab Biosimilar FKB238, Bevacizumab Biosimilar HD204, Bevacizumab Biosimilar HLX04, Bevacizumab Biosimilar IBI305, Bevacizumab Biosimilar LY01008, Bevacizumab Biosimilar MIL60, Bevacizumab Biosimilar QL 1101, Bevacizumab Biosimilar SCT501, 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 I (osimertinib, bevacizumab)
OsimertinibAZD-9291, AZD9291, Mereletinib, TagrissoArm I (osimertinib, bevacizumab)

Purpose

This phase II trial studies how well osimertinib with or without bevacizumab works in treating patients with EGFR positive non-small cell lung cancer that has spread to the brain. Osimertinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as bevacizumab, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Giving osimertinib with or without bevacizumab may work better in treating patients with non-small cell lung cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the progression-free survival with AZD9291 (osimertinib) plus bevacizumab
      compared to AZD9291 (osimertinib) alone.

      SECONDARY OBJECTIVES:

      I. To assess the safety and tolerability of the combination of AZD9291 (osimertinib) and
      bevacizumab.

      II. To evaluate the time to progression in the central nervous system (CNS) with AZD9291
      (osimertinib) plus bevacizumab versus single-agent osimertinib.

      III. To determine the overall response rate and the intracranial response rate to the
      combination versus single agent.

      IV. To assess the overall survival in patients receiving AZD9291 (osimertinib) plus
      bevacizumab compared to AZD9291 (osimertinib) alone.

      TRANSLATIONAL OBJECTIVES:

      I. To investigate mechanisms of sensitivity and resistance to combination AZD9291
      (osimertinib) plus bevacizumab versus AZD9291 (osimertinib) by molecularly characterizing
      tumor samples including T790M status.

      II. To assess whether circulating tumor deoxyribonucleic acid (DNA) in plasma can be used as
      an indicator of sensitivity and resistance to treatment.

      III. To determine whether an angiogenic signature using a multiplex panel array is associated
      with benefit from the combination of AZD9291 (osimertinib) plus bevacizumab.

      IV. To investigate angiogenesis, immune and signaling pathway markers in tumor samples to
      determine biomarkers predictive of benefit from combination therapy.

      OUTLINE: Patients are randomized to 1 of 2 arms.

      ARM I: Patients receive osimertinib orally (PO) once daily (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.

      ARM II: Patients receive osimertinib PO QD on days 1-21. Cycles repeat every 21 days in the
      absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up for a minimum of 4 weeks.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (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
Arm II (osimertinib)ExperimentalPatients receive osimertinib PO QD on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  • Osimertinib

Eligibility Criteria

        Inclusion Criteria:

          -  Non-small cell lung cancer (NSCLC) with an activating EGFR mutation (exon 19 deletion,
             L858R point mutation, or any other mutation known to be associated with EGFR TKI
             sensitivity); presence of an activating EGFR mutation may be documented in tumor
             tissue or by plasma testing if performed in a Clinical Laboratory Improvement Act
             (CLIA)-certified laboratory

          -  No prior treatment with an EGFR TKI; patient may have received prior chemotherapy for
             early-stage or advanced disease but this is not required; prior immunotherapy is not
             allowed

          -  Patients must have at least one measurable CNS lesion that is asymptomatic, untreated,
             and does not require local therapy at the time of enrollment; measurable CNS disease
             is defined as a brain metastasis that can be accurately measured in at least one
             dimension (longest diameter to be recorded) as >= 5 mm (>= 0.5 cm) with brain magnetic
             resonance imaging (MRI); if the lesion is 5-10 mm in size and is the only measurable
             disease, MRI imaging must be performed with 1.5 mm slice thickness or less; a history
             of previously treated brain metastases is allowed, however any lesion present at the
             time of whole brain radiotherapy or included in the stereotactic radiotherapy field
             (or within 2 mm of the treated lesion) will NOT be considered "untreated" unless it is
             new or documented to have progressed unequivocally since treatment

          -  Patients are not required to have measurable systemic (i.e. non-CNS) disease; if
             present, measurable systemic disease must be able to 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) with conventional techniques or as >= 10
             mm (>= 1 cm) with spiral computed tomography (CT) scan, MRI, or calipers by clinical
             exam

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2

          -  Life expectancy of greater than 3 months

          -  The use of anti-convulsants is allowed, as long as the patient is on a stable dose
             with no seizure activity for at least 2 weeks prior to initiating trial therapy

          -  Female subjects should be using highly effective contraceptive measures, and must have
             a negative pregnancy test and not be breast-feeding prior to start of dosing if of
             child- bearing potential or must have evidence of non-child-bearing potential by
             fulfilling one of the following criteria at screening:

               -  Post-menopausal defined as aged more than 50 years and amenorrheic for at least
                  12 months following cessation of all exogenous hormonal treatments

               -  Women under 50 years old would be consider postmenopausal if they have been
                  amenorrheic for 12 months or more following cessation of exogenous hormonal
                  treatments and with luteinizing hormone (LH) and follicle stimulating hormone
                  (FSH) levels in the post-menopausal range for the institution

               -  Documentation of irreversible surgical sterilization by hysterectomy, bilateral
                  oophorectomy or bilateral salpingectomy but not tubal ligation

          -  Fertile men should be willing to use barrier contraception during and for 4 months
             after AZD9291 (osimertinib), and fertile women must agree to use adequate
             contraceptive measures during and for 6 weeks after AZD9291 (osimertinib); fertile men
             and women must agree to use adequate contraceptive measures during study therapy and
             for at least 6 months after the completion of bevacizumab therapy; should a woman
             become pregnant or suspect she is pregnant while she or her partner is participating
             in this study, the patient should inform the treating physician immediately

          -  Ability to understand and the willingness to sign a written informed consent document

        Exclusion Criteria:

          -  Symptomatic brain metastases or symptomatic leptomeningeal disease; asymptomatic
             leptomeningeal disease is allowed

          -  Patients with brain metastases for whom complete surgical resection is clinically
             appropriate

          -  Prior treatment with any EGFR TKI

          -  Prior treatment with agents targeting the VEGF pathway, including bevacizumab

          -  The use of corticosteroids to control cerebral edema or treat neurologic symptoms will
             not be allowed, and patients who previously required corticosteroids for symptom
             control must be off steroids for at least 3 days without recurrence of symptoms prior
             to starting trial therapy; corticosteroids for other indications is allowed

          -  Patients may not be receiving any other investigational agents and may not have
             participated in a study of an investigational agent or using an investigational device
             within five half-lives of the compound or 3 months, whichever is greater

          -  Any unresolved toxicities from prior therapy greater than Common Terminology Criteria
             for Adverse Events (CTCAE) grade 1 at the time of starting study treatment with the
             exception of alopecia and grade 2 platinum-therapy related neuropathy

          -  Concurrent, active malignancies in addition to that being studied (other than
             cutaneous squamous cell carcinoma or basal cell carcinoma)

          -  Any contraindication to MRI (i.e. patients with pacemakers or other metal implanted
             medical devices)

          -  Past medical history of interstitial lung disease, drug-induced interstitial lung
             disease, radiation pneumonitis which required steroid treatment, or any evidence of
             clinically active interstitial lung disease

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to AZD9291 (osimertinib) or bevacizumab

          -  Urine protein should be screened by urine analysis; if protein is 2+ or higher,
             24-hour urine protein should be obtained; patients with 24-hour urine protein >= 1000
             mg are excluded

          -  Serious or non-healing wound, ulcer or bone fracture

          -  History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess
             within 6 months prior to day 1

          -  Invasive procedures defined as follows:

               -  Major surgical procedure, open biopsy or significant traumatic injury within 28
                  days prior to day 1 therapy

               -  Anticipation of need for major surgical procedures during the course of the study

               -  Core biopsy within 7 days prior to day 1 (D1) therapy

          -  Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or
             recent peripheral arterial thrombosis) within 6 months prior to day 1

          -  Patients with clinically significant cardiovascular disease are excluded

               -  Inadequately controlled hypertension (HTN) (systolic blood pressure [SBP] > 160
                  mmHg and/or diastolic blood pressure [DBP] > 90 mmHg despite antihypertensive
                  medication)

               -  History of cerebrovascular accident (CVA) within 6 months (see additional
                  requirement for adjuvant protocols)

               -  Myocardial infarction or unstable angina within 6 months (see additional
                  requirement for adjuvant protocols)

               -  New York Heart Association grade II or greater congestive heart failure

               -  Serious and inadequately controlled cardiac arrhythmia

               -  Significant vascular disease (e.g. aortic aneurysm, history of aortic dissection)

               -  Clinically significant peripheral vascular disease

          -  Any of the following cardiac criteria:

               -  Mean resting corrected QT interval (Fridericia's correction formula [QTcF]) > 470
                  ms obtained from 3 electrocardiograms (ECGs), using the screening clinic ECG
                  machine derived corrected QT (QTc) value

               -  Any clinically important abnormalities in rhythm, conduction or morphology of
                  resting ECG (e.g., complete left bundle branch block, third degree heart block,
                  second degree heart block)

               -  Any factors that increase the risk of QTc prolongation or risk of arrhythmic
                  events such as heart failure, hypokalemia, congenital long QT syndrome, family
                  history of long QT syndrome or unexplained sudden death under 40 years of age in
                  first degree relatives or any concomitant medication known to prolong the QT
                  interval

          -  Evidence of bleeding diathesis or coagulopathy (including clinically significant
             hemoptysis)

          -  Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to
             swallow the formulated product or previous significant bowel resection that would
             preclude adequate absorption of AZD9291 (osimertinib)

          -  Patients with known hypersensitivity to Chinese hamster ovary cell products or other
             recombinant human antibodies

          -  Patients currently receiving (or unable to stop use prior to receiving the first dose
             of study treatment) medications or herbal supplements known to be potent inducers of
             CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any
             medications, herbal supplements and/or ingestion of foods with known inducer effects
             on CYP3A4

          -  Any evidence of severe or uncontrolled systemic diseases, including, but not limited
             to, uncontrolled hypertension, symptomatic congestive heart failure, unstable angina
             pectoris, cardiac arrhythmia, or psychiatric illness/social situations which in the
             investigator's opinion makes it undesirable for the patient to participate in the
             trial or which would jeopardize compliance with the protocol, or active infection
             including hepatitis B, hepatitis C and human immunodeficiency virus (HIV); screening
             for chronic conditions is not required

          -  History of hypersensitivity active or inactive excipients of AZD9291 (osimertinib) or
             drugs with a similar chemical structure or class to AZD9291 (osimertinib)

          -  Absolute neutrophil count < 1.5 x 10^9/L

          -  Platelet count < 100 x 10^9/L

          -  Hemoglobin < 90 g/L

          -  Alanine aminotransferase > 2.5 times upper limit of normal (ULN) if no demonstrable
             liver metastases or > 5 times ULN in the presence of liver metastases; aspartate
             aminotransferase > 2.5 times ULN if no demonstrable liver metastases or > 5 times ULN
             in the presence of liver metastases

          -  Total bilirubin > 1.5 times ULN if no liver metastases or > 3 times ULN in the
             presence of documented Gilbert's syndrome (unconjugated hyperbilirubinemia) or liver
             metastases

          -  Serum creatinine > 1.5 times ULN concurrent with creatinine clearance < 50 mL/min
             (measured or calculated by Cockcroft and Gault equation)—confirmation of creatinine
             clearance is only required when creatinine is > 1.5 times ULN

          -  Judgment by the investigator that the patient should not participate in the study if
             the patient is unlikely to comply with study procedures, restrictions and requirements
      
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 start of treatment to time of progression (in CNS or non-CNS disease) or death, whichever occurs first, assessed up to 2 years
Safety Issue:
Description:The two study arms will be compared for PFS with Kaplan-Meier estimates and log-rank tests. The Rothman confidence interval (CI), and the simultaneous confidence bands will be reported. In addition, the possible risk factors will be compared for survival with log-rank test. For multivariate analysis, the proportional hazards Cox model will be applied to investigate potential prognostic factors, such as age and stage of disease of the PFS data. The adjusted p-values of the hazard ratios and the adjusted 95% confidence interval will be reported.

Secondary Outcome Measures

Measure:Overall survival (OS)
Time Frame:From start of treatment to death, assessed up to 2 years
Safety Issue:
Description:The two study arms will be compared for OS with Kaplan-Meier estimates and log-rank tests. The Rothman CI, and the simultaneous confidence bands will be reported. In addition, the possible risk factors will be compared for survival with log-rank test. For multivariate analysis, the proportional hazards Cox model will be applied to investigate potential prognostic factors, such as age and stage of disease of the OS data. The adjusted p-values of the hazard ratios and the adjusted 95% confidence interval will be reported.
Measure:OS rate
Time Frame:At 12 months
Safety Issue:
Description:The two study arms will be compared for OS with Kaplan-Meier estimates and log-rank tests. The Rothman CI, and the simultaneous confidence bands will be reported. In addition, the possible risk factors will be compared for survival with log-rank test. For multivariate analysis, the proportional hazards Cox model will be applied to investigate potential prognostic factors, such as age and stage of disease of the OS data. The adjusted p-values of the hazard ratios and the adjusted 95% confidence interval will be reported.
Measure:Incidence of adverse events
Time Frame:Up to 2 years
Safety Issue:
Description:Assessed by Common Terminology Criteria for Adverse Events. Adverse medical events will be tabulated. National Cancer Institute toxicity grade 1 to grade 4 laboratory abnormalities will be listed.
Measure:Overall response rate
Time Frame:Up to 2 years
Safety Issue:
Description:Will be estimated using the 95% confidence CI based on Wilson's method. The Wilcoxon rank sum test and Fisher's exact test will be applied to study the association between the response status and the continuous and categorical variables respectively.
Measure:Intracranial response rate
Time Frame:Up to 2 years
Safety Issue:
Description:Will be estimated using the 95% confidence CI based on Wilson's method. The Wilcoxon rank sum test and Fisher's exact test will be applied to study the association between the response status and the continuous and categorical variables respectively.
Measure:Time to intracranial progression
Time Frame:Up to 2 years
Safety Issue:
Description:Will be assessed by Response Assessment in Neuro-Oncology Brain Metastases.
Measure:Brain metastasis response rate
Time Frame:Up to 2 years
Safety Issue:
Description:
Measure:Time to central nervous system (CNS) progression
Time Frame:From start of treatment to time of progression in the CNS, assessed up to 2 years
Safety Issue:
Description:
Measure:Intracranial response
Time Frame:Up to 2 years
Safety Issue:
Description:Assessed by Response Assessment in Neuro-Oncology Criteria-Glioblastoma Multiforme. Will be estimated using the 95% confidence interval CI based on Wilson's method. The Wilcoxon rank sum test and Fisher's exact test will be applied to study the association between the response status and the continuous and categorical variables respectively. The generalized non-linear model and logistic regression will be applied for multivariable data analysis. The adjusted p-value and 95% CI of the odds ratios will be reported.
Measure:Objective response defined as a complete or partial response
Time Frame:Up to 2 years
Safety Issue:
Description:Will be determined by investigator assessment using Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1.

Details

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

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