Clinical Trials /

Osimertinib in Treating Patients With Stage IIIB-IV or Recurrent Non-small Cell Lung Cancer With EGFR Exon 20 Insertion Mutations

NCT03191149

Description:

This phase II trial studies how well osimertinib works in treating patients with non-small cell lung cancer with EGFR exon 20 insertion mutation that is stage IIIB-IV or has come back. Osimertinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

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

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Osimertinib in Treating Patients With Stage IIIB-IV or Recurrent Non-small Cell Lung Cancer With EGFR Exon 20 Insertion Mutations
  • Official Title: Phase II Study of AZD9291 (Osimertinib) in Advanced NSCLC Patients With Exon 20 Insertion Mutations in EGFR

Clinical Trial IDs

  • ORG STUDY ID: NCI-2017-01017
  • SECONDARY ID: NCI-2017-01017
  • SECONDARY ID: EA5162
  • SECONDARY ID: EA5162
  • SECONDARY ID: U10CA180820
  • NCT ID: NCT03191149

Conditions

  • Advanced Lung Carcinoma
  • EGFR Exon 20 Insertion Mutation
  • Recurrent Lung Non-Small Cell Carcinoma
  • Stage IIIB Lung Non-Small Cell Cancer AJCC v7
  • Stage IV Lung Non-Small Cell Cancer AJCC v7

Interventions

DrugSynonymsArms
OsimertinibAZD-9291, AZD9291, Mereletinib, TagrissoTreatment (osimertinib)

Purpose

This phase II trial studies how well osimertinib works in treating patients with non-small cell lung cancer with EGFR exon 20 insertion mutation that is stage IIIB-IV or has come back. Osimertinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To evaluate the best objective response rate of AZD9291 (osimertinib) among patients with
      EGFR exon 20 insertions.

      SECONDARY OBJECTIVES:

      I. To determine the safety profile of 160 mg once daily (QD) dose of AZD9291 (osimertinib) in
      patients with EGFR Exon 20 insertion mutations.

      II. To determine the progression-free survival. III. To determine the overall survival.

      TERTIARY OBJECTIVES:

      I. To characterize molecular markers of response to treatment in circulating tumor
      deoxyribonucleic acid (DNA).

      II. To evaluate biomarkers of response to treatment through retrospective analyses of
      pre-treatment tumor tissue.

      III. To identify resistance mechanisms to AZD9291 (osimertinib) through post-progression
      tumor biopsies and circulating tumor (ct)DNA.

      OUTLINE:

      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.

      After completion of study treatment, patients are followed up at 28 days and every 3 months
      for up to 5 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (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:

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

          -  Participants must have advanced disease - 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) 7th
             edition staging criteria

          -  An EGFR exon 20 insertion mutation must be detected in the tumor tissue; patients may
             be enrolled in the study based on an exon 20 insertion EGFR mutation detected by any
             Clinical Laboratory Improvement Act (CLIA)-certified tissue assay

               -  NOTE: Testing results are to be submitted via Medidata Rave and the study chair
                  or delegate will review the reports

          -  Patients must have measurable disease; baseline measurements and ALL sites of disease
             must be obtained within 4 weeks to registration

          -  Patients must have previously received at least one line of therapy for their advanced
             lung cancer; there are no restrictions on the maximum number of prior therapies
             allowed

          -  Participants may not have received any prior treatment with therapies targeting PDL1,
             PD1 or CTLA4

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 1

          -  Hemoglobin >= 9.0 g/L (within 4 weeks before registration)

          -  Leukocytes >= 3,000/mcL (within 4 weeks before registration)

          -  Absolute neutrophil count >= 1,500/mcL (within 4 weeks before registration)

          -  Platelets >= 100,000/mcL (within 4 weeks before registration)

          -  Total bilirubin < 1.5 x upper limit of normal (ULN) if no liver metastases or =< 3
             times ULN in the presence of documented Gilbert's syndrome (unconjugated
             hyperbilirubinemia) or liver metastases (within 4 weeks before registration)

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 3 x institutional upper limit of normal; for patients with known hepatic metastases
             AST and/or ALT =< 5 x ULN (within 4 weeks before registration)

          -  Creatinine =< 1.5 x institutional upper limit of normal (within 4 weeks before
             registration)

          -  Participants may not have clinically active or symptomatic interstitial lung disease
             or interstitial pneumonitis (i.e., affecting activities of daily living or requiring
             therapeutic intervention), or a history of clinically significant interstitial lung
             disease or radiation pneumonitis

          -  Participants may not have had radiation to the lung fields within four weeks (28 days)
             of starting treatment; for patients receiving palliative radiation to thoracic
             vertebrae, ribs or other sites where the radiation field includes the lungs, radiation
             must be completed at least two weeks before starting treatment; for all palliative
             radiation to all other sites, at least 7 days must have elapsed prior to starting to
             treatment; at least six months (180 days) must have elapsed from radiation given with
             curative intent

          -  Participants may not have clinically symptomatic brain metastases or leptomeningeal
             disease; patients may be on a stable dose of corticosteroids to control brain
             metastases if they have been on a stable dose for two weeks (14 days) prior to study
             treatment and are clinically asymptomatic

          -  Patients must have an echocardiogram (ECHO) or a nuclear study (multi-gated
             acquisition scan [MUGA] or first pass) within 4 weeks (28 days) prior to registration
             to treatment and must not have a left ventricular ejection fraction (LVEF) <
             institutional lower limit of normal (LLN); if the LLN is not defined at a site, the
             LVEF must be >= 50% for the patient to be eligible

          -  Participants may not have any of the following cardiac criteria:

               -  Mean resting corrected QT interval (QTc) >= 470 msec obtained from 3
                  electrocardiograms (ECGs) using the screening clinic ECG machine-derived QTc
                  value

               -  No history of QT prolongation associated with other medications that required
                  discontinuation of that medication

               -  Patient must not be receiving any concomitant medications that are known to be
                  associated with Torsades de Pointes

               -  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

               -  Symptomatic heart failure - New York Heart Association (NYHA) grade II-IV

          -  Participants may not have a second, clinically active, cancer; patients with second
             cancers which have been treated with curative intent and/or are currently inactive are
             allowed

          -  Participants may not be receiving any other investigational agents; patients
             previously treated with investigational agents must complete a washout period of at
             least two weeks or five half-lives, whichever is longer, before starting treatment

          -  Participants may not have 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

          -  Patients must have no history of hypersensitivity active or inactive excipients of
             AZD9291 (osimertinib) or drugs with a similar chemical structure or class to AZD9291
             (osimertinib)

          -  Patients must not currently be 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 week 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

          -  If medically feasible, patients taking regular medication, with the exception of
             potent inducers of CYP3A4, should be maintained on it throughout the study period;
             patients taking concomitant medications whose disposition is dependent upon breast
             cancer resistance protein (BCRP) and which have a narrow therapeutic index should be
             closely monitored for signs of changed tolerability as a result of increased exposure
             of the concomitant medication whilst receiving AZD9291 (osimertinib) NOTE: Use of St
             John's wort is a contra-indication for AZD9291 (osimertinib) use

          -  If applicable, it is recommended that the starting and maintenance dose of
             rosuvastatin (due to BCRP inhibition by AZD9291 [osimertinib]) should be as low as
             possible and should be guided by the statin label; monitoring of low-density
             lipoprotein (LDL) cholesterol levels is advised; if the subject experiences any
             potentially relevant adverse events suggestive of muscle toxicity including
             unexplained muscle pain, tenderness, or weakness, particularly if accompanied by
             malaise or fever, the statin should be stopped, creatine kinase (CK) levels should be
             checked, and any appropriate further management should be taken

          -  Subjects taking warfarin should be monitored regularly for changes in prothrombin time
             or international normalized ratio (INR)

          -  No 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, prior platinum-therapy-related neuropathy

          -  Patients with 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) are ineligible

          -  Women must not be pregnant or breast-feeding because AZD9291 (osimertinib) has been
             shown to cause fetal harm in animal models; all females of childbearing potential must
             have a blood test or urine study within 2 weeks prior to registration to rule out
             pregnancy; a female of childbearing potential is any woman, regardless of sexual
             orientation or whether they have undergone tubal ligation, who meets the following
             criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not
             been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses
             at any time in the preceding 24 consecutive months)

          -  Women of childbearing potential (WOCBP) and sexually active males must use an accepted
             and effective method of contraception while receiving protocol treatment or abstain
             from sexual intercourse for the duration of their participation in the study; WOCBP
             must use birth control for two weeks prior to the start of the treatment and continue
             for 6 weeks after the last dose of the study drug; sexually active male patients must
             use effective contraception from day 1 of treatment and continue for 4 months after
             the last dose of the study drug

          -  Other anticancer agents and investigational agents should not be given while the
             subject is on study treatment

          -  Supportive care and other medications that are considered necessary for the subject's
             wellbeing may be given at the discretion of the investigator

          -  A guidance regarding potential interactions with concomitant medications is provided
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Best objective response
Time Frame:Up to 5 years
Safety Issue:
Description:Will be evaluated via Response Evaluation Criteria in Solid Tumors 1.1 criteria. Categorical data, such as response rates (complete response + partial response), will be compared using Fisher's exact tests with a one-sided type I error rate of 10%; multivariable logistic regression modeling will be used to adjust for the effect of any covariates that are associated with these categorical outcomes. Any continuous outcomes will be analyzed using Wilcoxon rank sum test, and multivariable linear regression models may be used to adjust for multiple associations with outcome. Point estimates of all endpoints will be accompanied by the corresponding two-sided 80% confidence intervals. The method of Atkinson and Brown will be used for the estimation of the confidence interval for response.

Secondary Outcome Measures

Measure:Progression-free survival (PFS)
Time Frame:From registration to documented disease progression or death from any cause, whichever occurs first, assessed up to 5 years
Safety Issue:
Description:Will be estimated using the Kaplan-Meier method, and Cox proportional hazards models will be used to estimate hazard ratios. Comparisons of groups will be made using the logrank test and Cox modeling. Point estimates of all endpoints will be accompanied by the corresponding two-sided 80% confidence intervals. The method of Atkinson and Brown will be used for the estimation of the confidence interval for response.
Measure:Overall survival (OS)
Time Frame:From registration to death from any cause, assessed up to 5 years
Safety Issue:
Description:Will be estimated using the Kaplan-Meier method, and Cox proportional hazards models will be used to estimate hazard ratios. Comparisons of groups will be made using the logrank test and Cox modeling. Point estimates of all endpoints will be accompanied by the corresponding two-sided 80% confidence intervals. The method of Atkinson and Brown will be used for the estimation of the confidence interval for response.
Measure:Incidence of adverse events
Time Frame:Up to 5 years
Safety Issue:
Description:Will be graded according to Common Terminology Criteria for Adverse Events version 5.0. Categorical data, such as toxicity, will be compared using Fisher's exact tests with a one-sided type I error rate of 10%; multivariable logistic regression modeling will be used to adjust for the effect of any covariates that are associated with these categorical outcomes. Any continuous outcomes will be analyzed using Wilcoxon rank sum test, and multivariable linear regression models may be used to adjust for multiple associations with outcome. Point estimates of all endpoints will be accompanied by the corresponding two-sided 80% confidence intervals. The method of Atkinson and Brown will be used for the estimation of the confidence interval for response.

Details

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

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