Clinical Trials /

Study of Osimertinib and Stereotactic Ablative Radiation (SABR) in EGFR Mutant NSCLC

NCT03667820

Description:

This study evaluates the combination of two well-tolerated therapies, osimertinib and Stereotactic Ablative Radiation (SABR).

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

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study of Osimertinib and Stereotactic Ablative Radiation (SABR) in EGFR Mutant NSCLC
  • Official Title: Phase II Trial of Osimertinib in Combination With Stereotactic Ablative Radiation (SABR) in EGFR Mutant Advanced Non-Small Cell Lung Cancer (NSCLC)

Clinical Trial IDs

  • ORG STUDY ID: STU 122017-017
  • NCT ID: NCT03667820

Conditions

  • Non-small Cell Lung Cancer (NSCLC)

Interventions

DrugSynonymsArms
OsimertinibAZD9291, TAGRISSOOsimertinib

Purpose

This study evaluates the combination of two well-tolerated therapies, osimertinib and Stereotactic Ablative Radiation (SABR).

Detailed Description

      Patients with EGFR mutant non-small cell lung cancer will receive the current optimal therapy
      with osimertinib. After 8 weeks of targeted therapy, there will likely be some persisting
      lesions that would not have completely regressed. These persisting lesions would likely
      consist of cells that are less sensitive to targeted therapy. From the data summarized above
      [14], these persisting lesions are most to subsequently develop resistance and demonstrate
      progression.

      To delay the onset of clinical progression, lesions that persist after 8 weeks of osimertinib
      therapy and are amenable to stereotactic ablative radiation will be radiated. Osimertinib
      will be held for 3 days before the first dose of radiation and resumed 3 days after the last
      dose.

      After radiation, all patients will continue osimertinib therapy. If subsequently there is any
      evidence of progression, there will be an assessment of whether a repeat course of radiation
      is feasible. If it is feasible to repeat SABR to sites of progression, this will be performed
      and osimertinib resumed. If SABR is not possible, then a change in systemic therapy will be
      required.
    

Trial Arms

NameTypeDescriptionInterventions
OsimertinibExperimentalOsimertinib in combination with Stereotactic Ablative Radiation (SABR)
  • Osimertinib

Eligibility Criteria

        Inclusion Criteria

          -  Written informed consent

          -  Age > 18 years

          -  Advanced EGFR exon 19 or 21 mutant NSCLC, not amenable to curative surgery or
             radiotherapy. EGFR mutations may be demonstrated by standard, clinically accepted
             methods, including direct gene sequencing, PCR, and NextGen sequencing.

          -  World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) performance
             status 0-2.

          -  Patients must have a life expectancy ≥ 12 weeks.

          -  Females should be using adequate contraceptive measures, should not be breast feeding
             and must have a negative pregnancy test 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 LH and FSH levels in the post-menopausal range for the
                  institution

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

          -  Male patients should be willing to use barrier contraception.

          -  Patient is willing and able to comply with the protocol for the duration of the study
             including undergoing treatment and scheduled visits and examinations including follow
             up.

          -  At least one lesion, not previously irradiated, that can be accurately assessed at
             baseline with computed tomography (CT) or magnetic resonance imaging (MRI) and which
             is suitable for accurate repeated measurements.

          -  Adequate bone marrow reserve or organ function as demonstrated by any of the following
             laboratory values:

               -  Absolute neutrophil count >1.5 x 109/L

               -  Platelet count >100 x 109/L

               -  Haemoglobin >9.0 g/dL (transfusion is permitted to achieve Hgb ≥9.0 g/dL)

               -  Alanine aminotransferase <2.5 times the 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.

        Exclusion Criteria

          -  Involvement in the planning and/or conduct of the study (applies to both sponsor staff
             and/or staff at the study site).

          -  Previous treatment with osimertinib or any EGFR TKI.

          -  Previous treatment with immunotherapy or any check point inhibitors.

          -  Treatment with an investigational drug within five half-lives of the compound

          -  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) (Appendix A). 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 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.

          -  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 patient to participate in the trial or which would jeopardise
             compliance with the protocol, or active infection including hepatitis B, hepatitis C
             and human immunodeficiency virus (HIV). Screening for chronic conditions is not
             required.

          -  Patients with symptomatic CNS metastases who are neurologically unstable

          -  Past medical history of ILD, drug-induced ILD, radiation pneumonitis requiring steroid
             treatment, or any evidence of clinically active ILD

          -  Any of the following cardiac criteria:

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

               -  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

          -  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

          -  History of hypersensitivity to osimertinib (or drugs with a similar chemical structure
             or class to osimertinib) or any excipients of these agents

          -  Males and females of reproductive potential who are not using an 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

          -  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

        In addition, the following is considered a criterion for exclusion from the exploratory
        genetic research:

          -  Previous allogeneic bone marrow transplant.

          -  Non-leukocyte depleted whole blood transfusion within 120 days of the date of the
             genetic sample collection.
      
Maximum Eligible Age:99 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Determine efficacy of Osimertinib plus SABR in patients with EGFR mutant lung cancer measured by Progression-Free Survival (PFS)
Time Frame:Every 8 weeks from the time of first dose of study medication until subject death from any cause, assessed up to 150 weeks.
Safety Issue:
Description:Progression-Free Survival (PFS) as determined by RECIST 1.1 or death (in the absence of progression).

Secondary Outcome Measures

Measure:Determine the impact of Osimertinib plus SABR on survival
Time Frame:From time of first dose of study medication until subject death from any cause, up to 300 weeks.
Safety Issue:
Description:Overall survival defined as time from the date of initiation of Osimertinib until death of any cause.
Measure:Determine the impact of Osimertinib plus SABR on length of response
Time Frame:Every 8 weeks from time of first dose of study medication until disease progression or death from any cause, assessed up to 150 weeks.
Safety Issue:
Description:Duration of response (DoR) defined as the time from documentation of tumor response to disease progression.
Measure:Determine the impact of Osimertinib plus SABR on the length of time until next therapy needed
Time Frame:Every 8 Weeks from time of first dose of study medication until subsequent SABR, discontinuation, or disease progression, assessed up to 150 weeks.
Safety Issue:
Description:Time to subsequent SABR (2nd, 3rd, etc), initiation of new therapy, or death.
Measure:Determine the impact of Osimertinib plus SABR on tumor response
Time Frame:Every 8 weeks from time of first study medication dose until discontinuation or subject death from any cause, assessed up to 150 weeks.
Safety Issue:
Description:Objective response rate (ORR) defined as the proportion of patients with measurable disease who had a response after receiving at least one cycle of therapy.
Measure:Determine the impact of Osimertinib plus SABR on the duration of time while on Osimertinib
Time Frame:Every 8 weeks from time of first study medication dose until disease progression, discontinuation or subject death from any cause, up to 150 weeks.
Safety Issue:
Description:Impact defined as time from initiation of Osimertinib to evidence of disease progression by RECIST 1.1, unacceptable toxicity, withdrawal of consent, or discontinuation of the trial for any other reason.
Measure:Number and type of adverse events related to Osimertinib plus SABR as assessed by CTCAE v4.0
Time Frame:From time of first study medication dose through treatment period and including the follow-up period every 3 months following last dose of study medication, until subject death from any cause, up to 48 months.
Safety Issue:
Description:Defined as the risk to patients by using Osimertinib plus SABR and the degree to which overt adverse events of the Osimertinib plus SABR can be tolerated.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of Texas Southwestern Medical Center

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