Clinical trial NCT03137264: Resistance & Activating Mutations Diagnosed Among NSCLC Community Dwelling EGFR Mutation Positive Patients
Official title: An Open-Label, Non-randomized, Prospective Biomarker Study to Assess Analytic Concordance Between Non-invasive Testing and Tissue Testing for EGFR T790M Mutation Detection in Patients With Non-small Cell Lung Cancer
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Non-small Cell Lung Cancer
Keywords: T790M mutation
EGFR epidermal growth factor receptor
non-invasive testing
lung cancer
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
Collaborators: name: Medpace, Inc.
First posted: 2017-05-02
Enrollment: 44
Sex: ALL
Minimum age (years): 18
Maximum age (years): 130
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: The study population for this trial is non-small cell lung cancer patients who will come primarily from the community oncology practice setting.

Brief summary: The study is being done to determine if non-invasive testing (urine and plasma testing) is as effective as tissue testing in identifying epidermal growth factor receptor (EGFR) T790M mutation status. EGFR is a type of protein found on the surface of cells in the body. When this protein is mutated and becomes too active, it can lead to cancer growth. T790M is a mutation that develops in response to treatment of the EGFR mutation.

Participating patients will have tumor tissue (via cobas test), as well as 2 plasma samples (via cobas and Guardant360 tests) and 1 urine sample (via Trovera test), tested for EGFR T790M mutation status. If the results of the cobas tissue and/or plasma test show that a patient is T790M positive, they will be treated according to standard of care, which may include treatment with osimertinib. Osimertinib is approved for use in the United States for the treatment of EGFR T790M mutation-positive non-small cell lung cancer (NSCLC).

Detailed description: RADIANCE is an open-label, prospective biomarker study to assess analytic concordance between non-invasive testing (plasma and urine) and tissue testing for the EGFR T790M mutation. All patients will have tumor tissue (via cobas test) as well as 2 plasma samples (via cobas and Guardant360) and 1 urine sample (via Trovera) tested for the EGFR T790M mutation (Part 1). Patients who are confirmed T790M negative based on both cobas biomarker tests (tissue and plasma) will have completed the study. Patients who demonstrate T790M+ on cobas tissue and/or cobas plasma testing may choose to undergo treatment with osimertinib in consultation with their healthcare provider (no investigational product will be provided for this study) and will continue to Part 2. In case of insufficient samples for biomarker testing or invalid results from any of the 4 testing modalities, another sample may be acquired from the patient, if feasible, including the patient's decision to undergo a second biopsy. Failure of a patient to undergo a tissue, plasma, or urine sample collection for biomarker testing will result in their withdrawal from the study. If 1 or more samples are insufficient for testing or 1 or more of the test results are invalid, the patient may still qualify for the clinical outcomes part of the study (Part 2) as long as cobas tissue and/or cobas plasma test is T790M+ and the patient receives at least one dose of osimertinib.

During Part 2 Follow-Up Visits will occur according to standard of care, but at least every 12 weeks for the first 12 months of treatment. A Final Study Visit will occur at 18 months (Week 72 +/- 14 days) or upon early withdrawal.

Statistical methods Sample size: The sample size is such to provide enough statistical precision for the primary endpoint. A sample size of 400 patients with evaluable biomarker test results for analytic concordance has been selected in order to achieve a precision of no more than ±5% around the estimated concordance rate. If a 15% inflation factor is applied (\~70 patients) to this sample size to take into account those patients who may not be evaluable for concordance estimates, a total of approximately 470 patients will be enrolled.

The Full Analysis Sets will include the following:

Part 1: All patients in the study with cobas tissue, Guardant360 plasma, and Trovera urine test results.

Part 2: Patients who demonstrate T790M+ cobas tissue and/or cobas plasma testing and were treated with at least 1 dose of osimertinib (i.e., all patients in Part 2).

Safety analysis sets: The safety analysis sets will include the following:

Part 1: All patients in the study from the time of informed consent until completion of Part 1.

Part 2: Patients who demonstrate T790M+ cobas tissue and/or cobas plasms testing and were treated with at least 1 dose of osimertinib (i.e., all patients in Part 2).

The analyses of the data collected within this study will be descriptive only, with no formal statistical testing. Continuous variables will be summarized by the number of observations, mean, standard deviation, median, minimum, and maximum. Categorical variables will be summarized by frequency counts and percentages for each category. A Statistical Analysis Plan will be prepared and finalized prior to the first interim analysis, which will occur upon completion of the diagnostic analytic validity part of the study (Part 1). The concordance rate between non-invasive testing and cobas tissue testing will be presented as the point estimate together with the exact 95% confidence interval (CI) estimated using the Clopper-Pearson method. The ORR will be presented as the point estimate together with the exact 95% CI according to the Clopper-Pearson method. The duration of response (DoR) and progression-free survival (PFS) will be presented for all patients in Part 2, summarized using the Kaplan-Meier (K-M) method with associated K-M curves. The median DoR and PFS will be presented, as well as the rates at clinically relevant time points, together with the associated 95% CIs.

Eligibility criteria: Inclusion Criteria:

* Provision of informed consent prior to any study-specific procedures
* Females and males \>/= 18 years
* Primary diagnosis of NSCLC with evidence of disease progression during or following treatment with an EGFR tyrosine kinase inhibitor (diagnosis of NSCLC that is confirmed by cytology is acceptable)
* Willing to undergo tumor biopsy (e.g., excision, core biopsy, or endoscopic biopsy), preferably of a progressing lesion, and provide blood and urine for biomarker testing
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2

Exclusion Criteria:

* Involvement in the planning and/or conduct of the study
* Prior treatment with osimertinib or another T790M directed therapy
* Current participation in another clinical study with an investigational product or patients who plan to receive any treatment that is not FDA-approved for EGFR mutation positive NSCLC at any time during the course of this study
* Use of any chemotherapeutic agent within 1 week of tissue, plasma, and urine sample collection
* For women - currently pregnant or plan to become pregnant during the course of the study: pre-menopausal women of childbearing potential must have a urine or serum pregnancy test performed during the screening/enrollment period and prior to initiating anti-cancer treatment
* Judgment by the investigator that the patient should not participate in the study due to the patient being unlikely to comply with study procedures, restrictions, and requirements, such as in the case of severe or uncontrolled systemic disease.

Primary outcomes:
measure: The percentage of patients whose T790M results on Trovera urine AND Guardant360 plasma testing match their T790M results on cobas tissue testing.
timeFrame: Visit 1 (Day-21 to Day 0)
Secondary outcomes:
measure: Objective Response Rate (ORR)
timeFrame: Every 12 weeks for 12 months
measure: Duration of Response (DoR)
timeFrame: Every 12 weeks for the first 12 months, then at week 72
measure: Progression Free Survival (PFS)
timeFrame: Every 12 weeks for the first 12 months, then at Week 72
Other outcomes:
measure: Number of procedure-related adverse events and Serious Adverse Events (SAEs)
timeFrame: Up to 8 weeks after Visit 1
measure: Percentage of patients whose Trovera urine OR Guardant360 plasma T790M results are the same as their cobas tissue T790M results.
timeFrame: Visit 1 (Day -21 to Day 0)
measure: The presence of additional biomarkers from the blood and/or urine of NSCLC patients who have progressed during or following treatment with an EGFR tyrosine kinase inhibitor
timeFrame: Visit 1 (Day -21 to Day 0)
measure: Percentage of patients whose Trovera urine OR Guardant360 plasma EGFR mutation results are the same as their cobas tissue EGFR mutation results.
timeFrame: Visit 1 (Day -21 to Day 0)
measure: Physical Exam
timeFrame: Up to 8 weeks after Visit 1
measure: Vital signs
timeFrame: Up to 8 weeks after Visit 1
measure: ECG
timeFrame: Up to 8 weeks after Visit 1
measure: Number of Adverse Events, Serious Adverse Events, and Adverse Events of Special Interest
timeFrame: From the time of first dose of osimertinib through 30 days past the last dose of osimertinib or 30 days after Week 72, if osimertinib treatment remains ongoing at Week 72.
measure: Physical Exam
timeFrame: From the time of first dose of osimertinib through the date of last dose of osimertinib or at Week 72, whichever comes first.
measure: Vital signs
timeFrame: From the time of first dose of osimertinib through the date of last dose of osimertinib or at Week 72, whichever comes first.
measure: ECG
timeFrame: From the time of first dose of osimertinib through the date of last dose of osimertinib or at Week 72, whichever comes first.
Locations:
city: Anaheim
country: United States
facility: Research Site
state: California
city: Los Angeles
country: United States
facility: Research Site
state: California
city: Saint Helena
country: United States
facility: Research Site
state: California
city: Santa Rosa
country: United States
facility: Research Site
state: California
city: Deerfield Beach
country: United States
facility: Research Site
state: Florida
city: Fort Lauderdale
country: United States
facility: Research Site
state: Florida
city: Honolulu
country: United States
facility: Research Site
state: Hawaii
city: Boise
country: United States
facility: Research Site
state: Idaho
city: Chicago
country: United States
facility: Research Site
state: Illinois
city: Harvey
country: United States
facility: Research Site
state: Illinois
city: Annapolis
country: United States
facility: Research Site
state: Maryland
city: Southfield
country: United States
facility: Research Site
state: Michigan
city: Brick
country: United States
facility: Research Site
state: New Jersey
city: Farmington
country: United States
facility: Research Site
state: New Mexico
city: White Plains
country: United States
facility: Research Site
state: New York
city: Asheville
country: United States
facility: Research Site
state: North Carolina
city: Hendersonville
country: United States
facility: Research Site
state: North Carolina
city: Kettering
country: United States
facility: Research Site
state: Ohio
city: Seattle
country: United States
facility: Research Site
state: Washington
city: Seattle
country: United States
facility: Research Site
state: Washington
city: Edmonton
country: Canada
facility: Research Site
state: Alberta
city: Newmarket
country: Canada
facility: Research Site
state: Ontario
city: Montreal
country: Canada
facility: Research Site
state: Quebec
Study officials:
affiliation: AstraZeneca
name: Nabil Chehab, PhD
role: STUDY_DIRECTOR
References:
citation: Molina JR, Yang P, Cassivi SD, Schild SE, Adjei AA. Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc. 2008 May;83(5):584-94. doi: 10.4065/83.5.584.
citation: Morgillo F, Della Corte CM, Fasano M, Ciardiello F. Mechanisms of resistance to EGFR-targeted drugs: lung cancer. ESMO Open. 2016 May 11;1(3):e000060. doi: 10.1136/esmoopen-2016-000060. eCollection 2016.
citation: Sullivan I, Planchard D. Osimertinib in the treatment of patients with epidermal growth factor receptor T790M mutation-positive metastatic non-small cell lung cancer: clinical trial evidence and experience. Ther Adv Respir Dis. 2016 Dec;10(6):549-565. doi: 10.1177/1753465816670498. Epub 2016 Oct 26.
citation: Oxnard GR, Thress KS, Alden RS, Lawrance R, Paweletz CP, Cantarini M, Yang JC, Barrett JC, Janne PA. Association Between Plasma Genotyping and Outcomes of Treatment With Osimertinib (AZD9291) in Advanced Non-Small-Cell Lung Cancer. J Clin Oncol. 2016 Oct 1;34(28):3375-82. doi: 10.1200/JCO.2016.66.7162. Epub 2016 Jun 27.
citation: Thress KS, Brant R, Carr TH, Dearden S, Jenkins S, Brown H, Hammett T, Cantarini M, Barrett JC. EGFR mutation detection in ctDNA from NSCLC patient plasma: A cross-platform comparison of leading technologies to support the clinical development of AZD9291. Lung Cancer. 2015 Dec;90(3):509-15. doi: 10.1016/j.lungcan.2015.10.004. Epub 2015 Oct 9.
citation: Kawamura T, Kenmotsu H, Taira T, Omori S, Nakashima K, Wakuda K, Ono A, Naito T, Murakami H, Mori K, Nakajima T, Ohde Y, Endo M, Takahashi T. Rebiopsy for patients with non-small-cell lung cancer after epidermal growth factor receptor-tyrosine kinase inhibitor failure. Cancer Sci. 2016 Jul;107(7):1001-5. doi: 10.1111/cas.12963. Epub 2016 Jun 21.
citation: Lorenz J, Blum M. Complications of percutaneous chest biopsy. Semin Intervent Radiol. 2006 Jun;23(2):188-93. doi: 10.1055/s-2006-941449.
citation: Reckamp KL, Melnikova VO, Karlovich C, Sequist LV, Camidge DR, Wakelee H, Perol M, Oxnard GR, Kosco K, Croucher P, Samuelsz E, Vibat CR, Guerrero S, Geis J, Berz D, Mann E, Matheny S, Rolfe L, Raponi M, Erlander MG, Gadgeel S. A Highly Sensitive and Quantitative Test Platform for Detection of NSCLC EGFR Mutations in Urine and Plasma. J Thorac Oncol. 2016 Oct;11(10):1690-700. doi: 10.1016/j.jtho.2016.05.035. Epub 2016 Jul 25.
citation: Shyamala K, Girish HC, Murgod S. Risk of tumor cell seeding through biopsy and aspiration cytology. J Int Soc Prev Community Dent. 2014 Jan;4(1):5-11. doi: 10.4103/2231-0762.129446.
citation: Goss G, Tsai CM, Shepherd FA, Bazhenova L, Lee JS, Chang GC, Crino L, Satouchi M, Chu Q, Hida T, Han JY, Juan O, Dunphy F, Nishio M, Kang JH, Majem M, Mann H, Cantarini M, Ghiorghiu S, Mitsudomi T. Osimertinib for pretreated EGFR Thr790Met-positive advanced non-small-cell lung cancer (AURA2): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol. 2016 Dec;17(12):1643-1652. doi: 10.1016/S1470-2045(16)30508-3. Epub 2016 Oct 14.
citation: Soria JC, Wu YL, Nakagawa K, Kim SW, Yang JJ, Ahn MJ, Wang J, Yang JC, Lu Y, Atagi S, Ponce S, Lee DH, Liu Y, Yoh K, Zhou JY, Shi X, Webster A, Jiang H, Mok TS. Gefitinib plus chemotherapy versus placebo plus chemotherapy in EGFR-mutation-positive non-small-cell lung cancer after progression on first-line gefitinib (IMPRESS): a phase 3 randomised trial. Lancet Oncol. 2015 Aug;16(8):990-8. doi: 10.1016/S1470-2045(15)00121-7. Epub 2015 Jul 6.