Resistance & Activating Mutations Diagnosed Among NSCLC Community Dwelling EGFR Mutation Positive Patients

Non-small Cell Lung Cancer Clinical Trial

— RADIANCE  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03137264
• Other study ID #: D5160L00032
• Status: Completed
• Start date: October 24, 2017
• Est. completion date: November 10, 2018

Study information

• Verified date: November 2019
• Source: AstraZeneca
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 44
• Est. completion date: November 10, 2018
• Est. primary completion date: November 10, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 130 Years

Eligibility

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.

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Lung Neoplasms
• Non-small Cell Lung Cancer

Intervention

Drug:
• Other
Patients who are T790M positive via cobas plasma and/or cobas tissue testing during Part 1 will be treated per standard of care during Part 2, which may include osimertinib.

Locations

Country	Name	City	State
Canada	Research Site	Edmonton	Alberta
Canada	Research Site	Montreal	Quebec
Canada	Research Site	Newmarket	Ontario
United States	Research Site	Anaheim	California
United States	Research Site	Annapolis	Maryland
United States	Research Site	Asheville	North Carolina
United States	Research Site	Boise	Idaho
United States	Research Site	Brick	New Jersey
United States	Research Site	Chicago	Illinois
United States	Research Site	Deerfield Beach	Florida
United States	Research Site	Farmington	New Mexico
United States	Research Site	Fort Lauderdale	Florida
United States	Research Site	Harvey	Illinois
United States	Research Site	Hendersonville	North Carolina
United States	Research Site	Honolulu	Hawaii
United States	Research Site	Kettering	Ohio
United States	Research Site	Los Angeles	California
United States	Research Site	Saint Helena	California
United States	Research Site	Santa Rosa	California
United States	Research Site	Seattle	Washington
United States	Research Site	Seattle	Washington
United States	Research Site	Southfield	Michigan
United States	Research Site	White Plains	New York

Sponsors (2)

Lead Sponsor	Collaborator
AstraZeneca	Medpace, Inc.

Countries where clinical trial is conducted

United States,  Canada, 

References & Publications (11)

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. — View 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. — View 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. — View 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. Review. — View 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. eCollection 2016. Review. — View Citation

Oxnard GR, Thress KS, Alden RS, Lawrance R, Paweletz CP, Cantarini M, Yang JC, Barrett JC, Jänne 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. — View 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. — View 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. Review. — View 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. — View 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. Epub 2016 Oct 26. Review. — View 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. — View Citation

* Note: There are 11 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Number of procedure-related adverse events and Serious Adverse Events (SAEs)	To evaluate safety and tolerability of study procedures.	Up to 8 weeks after Visit 1
Other	Percentage of patients whose Trovera urine OR Guardant360 plasma T790M results are the same as their cobas tissue T790M results.	The overall percent agreement will be estimate as analytic concordance between cobas tissue and Guardant360 plasma, and cobas tissue and Trovera urine testing in identifying T790M status. The positive percent agreement will be estimated as the percentage of cobas tissue positive patients who are also Guardant360 plasma positive and cobas tissue positive patients who are Trovera urine positive. The negative percent agreement will be estimated as the percentage of cobas tissue negative patients who are also Guardant360 plasma negative and cobas tissue negative patients who are Trovera urine negative.	Visit 1 (Day -21 to Day 0)
Other	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	Biomarker results will be assessed and may be compared to T790M status and/or clinical response.	Visit 1 (Day -21 to Day 0)
Other	Percentage of patients whose Trovera urine OR Guardant360 plasma EGFR mutation results are the same as their cobas tissue EGFR mutation results.	The overall percent agreement will be estimated as analytic concordance between Guardany360 plasma and Trovera urine testing versus cobas tissue testing in identifying the status of specified EGFR mutations. The positive percent agreement will be estimated as the percentage of cobas tissue positive patients who are also Guardant360 plasma and/or Trovera urine positive. The negative percent agreement will be estimated as the percentage of cobas tissue negative patients who are also Guardant360 plasma and Trovera urine negative.	Visit 1 (Day -21 to Day 0)
Other	Physical Exam	Changes in physical exams from baseline	Up to 8 weeks after Visit 1
Other	Vital signs	Changes in vital signs from baseline	Up to 8 weeks after Visit 1
Other	ECG	Changes in ECGs from baseline.	Up to 8 weeks after Visit 1
Other	Number of Adverse Events, Serious Adverse Events, and Adverse Events of Special Interest	To evaluate the safety and tolerability of osimertinib.	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.
Other	Physical Exam	To evaluate the safety and tolerability of osimertinib.	From the time of first dose of osimertinib through the date of last dose of osimertinib or at Week 72, whichever comes first.
Other	Vital signs	To evaluate the safety and tolerability of osimertinib	From the time of first dose of osimertinib through the date of last dose of osimertinib or at Week 72, whichever comes first.
Other	ECG	To evaluate the safety and tolerability of osimertinib	From the time of first dose of osimertinib through the date of last dose of osimertinib or at Week 72, whichever comes first.
Primary	The percentage of patients whose T790M results on Trovera urine AND Guardant360 plasma testing match their T790M results on cobas tissue testing.	The Overall Percent Agreement will be estimated as analytic concordance between Guardant360 plasma and Trovera urine testing versus cobas tissue testing in identifying T790M status (positive or negative). The Positive Percent Agreement will be estimated as the percentage of cobas tissue positive patients who are also Guardant360 plasma and/or Trovera urine positive. The Negative Percent Agreement will be estimated as the percentage of cobas tissue negative patients who are also Guardant360 plasma and Trovera urine negative.	Visit 1 (Day-21 to Day 0)
Secondary	Objective Response Rate (ORR)	The number of patients achieving a confirmed partial response or complete response per RECIST 1.1 from treatment with osimertinib.	Every 12 weeks for 12 months
Secondary	Duration of Response (DoR)	The time from first documented tumor response defined by RECIST 1.1 from osimertinib treatment until the date of documented progression or death from any cause.	Every 12 weeks for the first 12 months, then at week 72
Secondary	Progression Free Survival (PFS)	Defined as the time from date of first dose of osimertinib until the date of disease progression by RECIST 1.1 or death by any cause.	Every 12 weeks for the first 12 months, then at Week 72

External Links

•   Link
•   Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 2013. Accessed on 18 January 2017.
•   redacted synopsis