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Exploring the Theragnostic Value of Osimertinib in EGFR-mutated Lung Cancer (THEROS)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03810066
Recruitment Status : Recruiting
First Posted : January 18, 2019
Last Update Posted : July 17, 2019
Information provided by (Responsible Party):
Martin Schuler, Prof. Dr. med., Universität Duisburg-Essen

Tracking Information
First Submitted Date  ICMJE January 10, 2019
First Posted Date  ICMJE January 18, 2019
Last Update Posted Date July 17, 2019
Actual Study Start Date  ICMJE June 3, 2019
Estimated Primary Completion Date December 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 17, 2019)
Rate of metabolic responses [ Time Frame: 28 days ]
Rate of metabolic responses as detected by FDG-PET before end of cycle 1. One cycle is defined as 28 days continuous treatment.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Exploring the Theragnostic Value of Osimertinib in EGFR-mutated Lung Cancer (THEROS)
Official Title  ICMJE Exploring the Theragnostic Value of Osimertinib in EGFR-mutated Lung Cancer (THEROS) - A Multicentric Phase II Study in Patients With TKI-resistant EGFR-mutated Lung Cancer Exhibiting Early Metabolic Response to Osimertinib
Brief Summary

This is a single arm, open label, multicentric proof-of-concept, phase II study in patients with EGFR-mutated non-small-cell lung cancer (NSCLC) with acquired TKI resistance who are "unknown" for EGFR T790M status due to non-informative or unfeasible tumor rebiopsy, and a negative finding for EGFR T790M in a standard plasma genotyping assay. All patients will receive osimertinib as continuous oral treatment for one cycle (28 days). Patients who demonstrate a metabolic response by FDG-PET scanning (to be conducted between day 15 and day 28 of cycle 1) will continue treatment until clinical or radiological progression. Osimertinib treatment will be terminated in patients not experiencing a metabolic response.

Primary objective:

To study the rate of early metabolic responses to osimertinib in patients with EGFR-mutated NSCLC and acquired TKI resistance who are "unknown" for EGFR T790M status due to non-informative or unfeasible tumor rebiopsy, and a negative finding for EGFR T790M in a standard plasma genotyping assay.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • EGFR T790M
Intervention  ICMJE Drug: Osimertinib
All patients will be treated with osimertinib 80 mg/d for one cycle (28 days).
Study Arms  ICMJE Experimental: Osimertinib
Intervention: Drug: Osimertinib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 17, 2019)
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2022
Estimated Primary Completion Date December 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Provision of informed consent prior to any study specific procedures
  2. Patients (male/female) must be > 18 years of age.
  3. EGFR-mutated NSCLC not amenable to curative treatment (surgery, curative radiochemotherapy).
  4. Acquired resistance to a first- or second-generation EGFR-TKI (e.g. afatinib, erlotinib, gefitinib) following initial benefit (defined as objective response, or stable disease for at least 3 months)
  5. No tumor rebiopsy available or absence of an informative result for EGFR T790M mutation status by a SoC molecular pathology test (e.g. Sanger sequencing, PCRbased genotyping, deep sequencing) of a rebiopsy of a progressive tumor lesion
  6. Negative finding from EGFR T790M mutation testing in plasma-derived DNA using a SoC assay (e.g. Roche Cobas)
  7. At least one tumor lesion with significant FDG uptake as determined by PET/CT scanning prior to study treatment
  8. Consent to the research use of donated biological samples.
  9. World Health Organization (WHO) performance status 0-2.
  10. Patients must have a life expectancy ≥ 12 weeks.
  11. 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 childbearing potential, which will be repeated on a monthly basis, 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
  12. Male patients should be willing to use barrier contraception (see Restrictions, Section 3.6).
  13. 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.

Exclusion Criteria:

  1. EGFR-mutated NSCLC and demonstration of the T790M resistance mutation by standard assay technology in tumor-derived or plasma-derived DNA
  2. Absence of a tumor lesion with significant FDG uptake at PET/CT scanning prior to study treatment
  3. Involvement in the planning and/or conduct of the study (applies to both sponsor staff and/or staff at the study site)
  4. Previous treatment with osimertinib or any experimental or approved mutationspecific EGFR-TKI with clinical activity against the EGFR T790M resistance mutation
  5. Treatment with an investigational drug within one week or five drug half-lives (whichever is longer) of the compound (3 weeks for antibodies)
  6. 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 - Guidance regarding Potential Interactions With Concomitant Medications). All patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects on CYP3A4. A list for drug interaction potential is found in section of the osimertinib IB.
  7. 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 chemotherapy related neuropathy.
  8. 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.
  9. Patients with symptomatic CNS metastases who are neurologically unstable
  10. Past medical history of ILD, drug-induced ILD, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active ILD
  11. Fasting blood glucose levels above 150 mg/dl (precluding informative FDGPET/ CT scanning)
  12. Inadequate 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 <90 g/L 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 hyperbilirubinaemia) or liver metastases 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.

  13. Any of the following cardiac criteria:

    1. Mean resting corrected QT interval (QTc using Fredericia's formula) > 470 msec obtained from the screening clinic ECG machine-derived QTc value
    2. 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)
    3. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, electrolyte abnormalities (including serum/plasma potassium level below lower level of normal), 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
  14. 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
  15. History of hypersensitivity to osimertinib (or drugs with a similar chemical structure or class to osimertinib) or any excipients of these agents
  16. 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
  17. 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Martin Schuler, Prof. Dr. med. +49-201-723 2000
Listed Location Countries  ICMJE Germany
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT03810066
Other Study ID Numbers  ICMJE THEROS
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Martin Schuler, Prof. Dr. med., Universität Duisburg-Essen
Study Sponsor  ICMJE Martin Schuler, Prof. Dr. med.
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Universität Duisburg-Essen
Verification Date April 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP