Clinical Trials /

Osimertinib, Surgery, and Radiation Therapy in Treating Patients With Stage IIIB or IV Non-small Cell Lung Cancer With EGFR Mutations

NCT03410043

Description:

This phase II trial studies how well osimertinib, surgery, and radiation therapy work in treating patients with stage IIIB or IV non-small cell lung cancer with EGFR mutations. Osimertinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving osimertinib, surgery, and radiation therapy may work better at treating non-small cell lung cancer with EGFR mutations.

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

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Osimertinib, Surgery, and Radiation Therapy in Treating Patients With Stage IIIB or IV Non-small Cell Lung Cancer With EGFR Mutations
  • Official Title: Randomized Phase II Trial of Local Consolidation Therapy (LCT) After Osimertinib for Patients With EGFR Mutant Metastatic Non-Small Cell Lung Cancer (NSCLC)

Clinical Trial IDs

  • ORG STUDY ID: 2017-0228
  • SECONDARY ID: NCI-2018-00937
  • SECONDARY ID: 2017-0228
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT03410043

Conditions

  • EGFR Exon 19 Deletion Mutation
  • EGFR NP_005219.2:p.L858R
  • EGFR NP_005219.2:p.T790M
  • Lung Non-Small Cell Carcinoma
  • Recurrent Lung Non-Small Cell Carcinoma
  • Stage IIIB Lung Cancer AJCC v8
  • Stage IV Lung Cancer AJCC v8
  • Stage IVA Lung Cancer AJCC v8
  • Stage IVB Lung Cancer AJCC v8

Interventions

DrugSynonymsArms
OsimertinibAZD-9291, AZD9291, Mereletinib, TagrissoGroup I (LCT)

Purpose

This phase II trial studies how well osimertinib, surgery, and radiation therapy work in treating patients with stage IIIB or IV non-small cell lung cancer with EGFR mutations. Osimertinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving osimertinib, surgery, and radiation therapy may work better at treating non-small cell lung cancer with EGFR mutations.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine whether, in patients with tyrosine kinase inhibitor (TKI) naive or TKI
      resistant (acquired T790M) metastatic EGFR mutant non-small cell lung cancer (NSCLC) who do
      not progress after 6-12 weeks of induction osimertinib, local consolidative therapy (LCT;
      radiotherapy +/- surgical resection) followed by osimertinib prolongs progression-free
      survival (PFS) compared with osimertinib alone.

      SECONDARY OBJECTIVES:

      I. To determine whether osimertinib plus LCT improves time to progression of non-irradiated
      lesions (TTP-NIL) and time to appearance of new metastases (TANM) compared with osimertinib
      alone.

      II. To determine whether osimertinib plus LCT improves the time to progression of target
      versus (vs.) non-target lesions compared with osimertinib alone.

      III. To determine whether osimertinib plus LCT improves progression-free survival compared
      with osimertinib alone in TKI naive EGFR (L8585R/exon 19 deletion) mutant metastatic NSCLC.

      IV. To determine whether osimertinib plus LCT improves progression-free survival compared
      with osimertinib alone in TKI resistant (acquired T790M) EGFR mutant NSCLC.

      V. To determine whether osimertinib plus LCT improves progression-free survival compared with
      osimertinib alone in the subgroup of patients with oligometastatic NSCLC (up to 3
      metastases).

      VI. To assess the safety and tolerability of osimertinib with and without LCT. VII. To
      determine whether osimertinib plus LCT improves overall survival (OS) compared with
      osimertinib alone.

      VIII. To determine if there is a difference in survival outcomes or toxicity by radiation
      treatment modality (protons vs. photons).

      EXPLORATORY OBJECTIVES:

      I. To explore the association of baseline genomic, proteomic and gene expression profiles
      (from tumor, germline deoxyribonucleic acid [DNA], and cell free [cf]DNA) with clinical
      benefit and in patients treated with osimertinib with or without LCT.

      II. To determine modulation of genomic, proteomic and gene expression tumor profiles by
      induction osimertinib.

      III. To explore osimertinib resistance mechanisms. IV. To determine the immunomodulatory
      effects of osimertinib plus LCT.

      OUTLINE: Patients are randomized to 1 of 2 groups.

      GROUP I (LCT): Patients receive osimertinib orally (PO) once daily (QD) for 6-12 weeks.
      Patients then undergo surgery and/or radiation therapy daily for 5 consecutive days every
      week for up to 8 weeks. Patients continue osimertinib during and after radiation therapy.
      Cycles repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

      GROUP II (NO LCT): Patients receive osimertinib PO QD. Cycles repeat every 4 weeks in the
      absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up within 30 days, then every 6
      months thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
Group I (LCT)ExperimentalPatients receive osimertinib PO QD for 6-12 weeks. Patients then undergo surgery and/or radiation therapy daily for 5 consecutive days every week for up to 8 weeks. Patients continue osimertinib during and after radiation therapy. Cycles repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
  • Osimertinib
Group II (no LCT)ExperimentalPatients receive osimertinib PO QD. Cycles repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
  • Osimertinib

Eligibility Criteria

        Inclusion Criteria:

          -  Histologically or cytologically confirmed non-small cell lung cancer

          -  Stage IIIB/IV or recurrent non-small cell lung cancer which is not amenable to
             curative intent therapy

          -  Patients must have one of the following:

               -  NSCLC which harbors EGFR exon 19 deletion or L858R mutation. This subset of
                  patients must be TKI naive; OR

               -  NSCLC which harbors an EGFR T790M mutation that was acquired following
                  progression on erlotinib, gefitinib or afatinib. This subset of patients must
                  have not received prior third generation TKI

               -  NOTE: EGFR mutation must be documented by a Clinical Laboratory Improvement
                  Amendments (CLIA) certified test

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

          -  Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1

          -  Candidate for local consolidation therapy to at least one site of disease

          -  Signed and dated written informed consent prior to admission to the study in
             accordance with International Council for Harmonization of Technical Requirements for
             Pharmaceuticals for Human Use (ICH)-Good Clinical Practice (GCP) guidelines and to the
             local legislation

          -  Ability to take pills by mouth

          -  Females of childbearing potential:

               -  Must not be breast feeding

               -  Must have a negative serum or urine pregnancy test

               -  Must agree to use adequate contraception for a minimum of two weeks prior to
                  receiving study medication until 3 months after discontinuation of the study
                  medication

                    -  NOTE: Acceptable methods of contraception include total and true sexual
                       abstinence, hormonal contraceptives that are not prone to drug-drug
                       interactions (IUS levonorgestrel intra uterine system [Mirena],
                       medroxyprogesterone injections [Depo-Provera]), copper-banded intra-uterine
                       devices, and vasectomized partner. All hormonal methods of contraception
                       should be used in combination with the use of a condom by their sexual male
                       partner. Females of childbearing potential are defined as those who are not
                       surgically sterile (i.e., bilateral tubal ligation, bilateral oophorectomy,
                       or complete hysterectomy) or postmenopausal (defined as 12 months with no
                       menses without an alternative medical cause)

          -  Women will be considered post-menopausal if they have been amenorrheic for the past 12
             months without an alternative medical cause. The following age-specific requirements
             must also apply:

               -  Women < 50 years old: they would be considered post-menopausal if they have been
                  amenorrheic for the past 12 months or more following cessation of exogenous
                  hormonal treatments. The levels of luteinizing hormone (LH) and
                  follicle-stimulating hormone (FSH) must also be in the post-menopausal range (as
                  per the institution)

               -  Women >= 50 years old: they would be considered post-menopausal if they have been
                  amenorrheic for the past 12 months or more following cessation of all exogenous
                  hormonal treatments, or have had radiation-induced oophorectomy with the last
                  menses > 1 year ago, or have had chemotherapy-induced menopause with > 1 year
                  interval since last menses, or have had surgical sterilization by either
                  bilateral oophorectomy or hysterectomy

          -  Non-sterilized males who are sexually active with a female partner of childbearing
             potential must use adequate contraception for the duration of the study and 3 month
             after the last dose of study medication. Adequate contraception methods include: birth
             control pills (e.g. combined oral contraceptive pill), barrier protection (e.g. condom
             plus spermicide, cervical/vault cap or intrauterine device), and abstinence. Patients
             should not father a child for 6 months after completion of the study medication.
             Patients should refrain from donating sperm from the start of dosing until 6 months
             after discontinuing the study medication. If male patients wish to father children
             they should be advised to arrange for freezing of sperm samples prior to the start of
             the study medication

          -  Life expectancy >= 12 weeks

          -  To be eligible for randomization, patients must:

               -  Meet all the inclusion criteria

               -  Have no progression of disease after 6-12 weeks of osimertinib per RECIST 1.1. To
                  assess for progressive disease patients must have the following imaging:

                    -  Either a positron emission tomography (PET)/computed tomography (CT) scan or
                       a CT scan of the chest/abdomen/pelvis (or CT chest)

                    -  A CT scan or a magnetic resonance imaging (MRI) of the brain

               -  Have target lesions (lesions that will be treated with LCT if the patient is
                  randomized to that arm). Patients that have a complete response (CR) to
                  front-line osimertinib (e.g. no visible disease to target) will continue to be
                  followed for progression on study but will not be randomized

        Exclusion Criteria:

          -  Previous treatment with osimertinib, or a 3rd generation EGFR TKI. NOTE: Patients who
             are receiving initial osimertinib (6-12 weeks) outside this study are not excluded

          -  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 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

          -  Patients with symptomatic central nervous system (CNS) metastases who are
             neurologically unstable

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

          -  Any evidence of severe or uncontrolled systemic diseases, including uncontrolled
             hypertension and active bleeding diatheses, which in the investigator's opinion makes
             it undesirable for the subject 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

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

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

          -  Patients with uncharacterized eye disorders

          -  Males and females of reproductive potential who are not using and effective method of
             birth control and females who are pregnant or breastfeeding or have a positive (urine
             or serum) pregnancy test prior to study entry

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

          -  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 requirement

          -  Absolute neutrophil count < 1,500/mcL

          -  Platelet < 100,000/mcL

          -  Hemoglobin < 9.0 g/dL

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

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             > 2.5 times ULN or > 5 times ULN if liver metastases are present

          -  Creatinine clearance < 50 mL/min/1.73 m^2 by Cockcroft-Gault equation

          -  Any of the following cardiac criteria:

               -  Mean resting corrected QT interval (corrected QT [QTc] using Fridericia's
                  formula) > 470 msec

               -  Any clinically important abnormalities in rhythm, conduction or morphology of
                  resting electrocardiogram (ECG) e.g., complete left bundle branch block, third
                  degree heart block, second degree heart block, PR interval > 250 msec

               -  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

          -  Patients will be excluded from randomization if they meet any of the following
             criteria:

               -  Any of the exclusion criteria

               -  Complete response to osimertinib or prior treatment to all visible lesions, such
                  that no lesion is amenable to LCT. Note that patients can receive palliative
                  radiation therapy prior to randomization to CNS lesions or those requiring urgent
                  treatment (e.g. for pain or bleeding), but are only eligible for the study if
                  they have one site amenable to further radiation therapy. In addition, these
                  lesions will be counted towards the total number of metastases, and will also be
                  counted as target lesions
      
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 the start date of osimertinib assessed up to 4 years
Safety Issue:
Description:Will be estimated using Kaplan-Meier method. The stratified log-rank test will be performed to test the difference in time-to-event distributions between treatment groups. Stratified Cox proportional hazards model will be utilized to include multiple covariates in the time-to-event analysis and to estimate hazard ratios.

Secondary Outcome Measures

Measure:Overall survival
Time Frame:From the treatment start date assessed up to 4 years
Safety Issue:
Description:Will be estimated using Kaplan-Meier method. The stratified log-rank test will be performed to test the difference in time-to-event distributions between treatment groups. Stratified Cox proportional hazards model will be utilized to include multiple covariates in the time-to-event analysis and to estimate hazard ratios.
Measure:Time to progression of target lesions
Time Frame:Up to 4 years
Safety Issue:
Description:Will be estimated using Kaplan-Meier method. The stratified log-rank test will be performed to test the difference in time-to-event distributions between treatment groups. Stratified Cox proportional hazards model will be utilized to include multiple covariates in the time-to-event analysis and to estimate hazard ratios.
Measure:Time to appearance of new metastases
Time Frame:Up to 4 years
Safety Issue:
Description:Will be estimated using Kaplan-Meier method. The stratified log-rank test will be performed to test the difference in time-to-event distributions between treatment groups. Stratified Cox proportional hazards model will be utilized to include multiple covariates in the time-to-event analysis and to estimate hazard ratios.
Measure:PFS in oligometastatic subgroup
Time Frame:Up to 4 years
Safety Issue:
Description:Will be estimated using Kaplan-Meier method. The stratified log-rank test will be performed to test the difference in time-to-event distributions between treatment groups. Stratified Cox proportional hazards model will be utilized to include multiple covariates in the time-to-event analysis and to estimate hazard ratios.
Measure:Incidence of adverse events
Time Frame:Up to 30 days post treatment
Safety Issue:
Description:Toxicity data related to the treatments will be summarized by frequency tables. The association between the types and severity of toxicity and the treatment groups will be evaluated.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

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