Study of AZD9291 in NSCLC Patients Harboring T790M Mutation Who Failed EGFR TKI and With Brain and/or LMS

NCT03257124 | Unknown Phase 2 DMC

• 1 other identifier: 2016-09-058
• Study Type: interventional
• Target: 80
• Locations: 1 country
• Sites: 1

Brief Summary

AZD9291 is an oral potent irreversible EGFR TKI selective for sensitizing EGFR mutation and T790M resistance mutation but sparing wild-type EGFR. Preclinical studies indicate that AZD9291 has significant exposure in the brain and activity against EGFR mutant brain metastasis. In addition, anti-tumor activities of AZD9291 in patients with advanced stage EGFR mutant NSCLC including patients with brain metastasis have been reported in an ongoing Phase I study. More recently, AZD9291 at a dose of 160mg also showed promising efficacy in heavily pre-treated patients with leptomeningeal disease from EGFR mutant NSCLC. Among 11 evaluable for response, 6 patients had LM imaging improvement and 3 out of 7 patients with abnormal neurological exam at baseline had symptomatic improvement. Compared to AZD9291, other 3rd generation EGFR TKIs, rociletinib or HM61713 has not been reported to be effective in most of CNS disease of NSCLC. Further, previous studies with AZD9291 showed anecdotal case series or undetermined for T790M mutation status, indicating more systematic study is warranted. Based on these data, the investigators are going to conduct phase II study of AZD9291 in NSCLC patients harboring T790M mutation who failed EGFR TKIs and brain and/or leptomeningeal metastasis.

Conditions

Non-Small Cell Lung Cancer With EGFR T790M Mutation; With Brain and/or Leptomeningeal Metastasis; Failed Tyrosine Kinase Inhibitors

Outcome Measures

Primary Outcomes (2)

• Overall response rate (ORR) in CNS -brain metastasis cohort

  At least one visit response of CR (complete response) or PR (partial response) that is confirmed at least 4 weeks later by using RECIST 1.1 criteria

  December, 2019 (one-year follow-up from last patient -in)

• Overall survival - Leptomeningeal with or without brain metastasis cohort

  From the date of study start to the date of all cause death

  From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months

Secondary Outcomes (6)

• Whole body disease control rate (DCR)

  December, 2019 (one-year follow-up from last patient -in)

• Time to brain progression

  December, 2019 (one-year follow-up from last patient -in)

• Progression free survival (PFS) in BM cohort

  December, 2019 (one-year follow-up from last patient -in)

• Overall survival (OS)

  December, 2019 (one-year follow-up from last patient -in)

• Adverse events (AEs)

  December, 2019 (one-year follow-up from last patient -in)

Study Arms (1)

AZD9291 in BM or LM cohort in T790M positive

EXPERIMENTAL

1. Brain metastasis cohort (BM cohort) 2. Leptomeningeal metastasis cohort (LM cohort)

Drug: AZD9291

Interventions

AZD9291 DRUG

AZD9291 160mg per oral daily (1 cycle of 28 days)

Also known as: Osimertinib

AZD9291 in BM or LM cohort in T790M positive

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• EGFR activating mutant NSCLC patients who failed EGFR TKIs (gefitinib, erlotinib, or afatinib) and develop CNS disease (BM and/or LM) with T790M mutation either tissue or plasma. For patients with intracranial progression, prior radiation therapy is not mandatory. Extracranial progression is allowed.
• Patients who failed to 3rd generation EGFR TKIs (AZD9291 (80mg), Rociletinib, HM61713) and develop CNS progression but stable extracranial disease
• Age ≥18 years
• ECOG performance status of 0 to 2
• For BM, at least one measurable intracranial lesion as ≥ 10mm in the longest diameter by magnetic resonance imaging (MRI)
• For LM, at least one site of CNS leptomeningeal disease that can be assessed by MRI
• Adequate organ function as evidenced by the following;
• Absolute neutrophil count \> 1.5 x 109/L;
• platelets \> 100 x 109/L;
• total bilirubin ≤1.5 UNL;
• AST and/or ALT \< 5 UNL;
• CCr ≥ 50mL/min.
• Female subjects must either be of non-reproductive potential
• Subject is willing and able to comply with the protocol
• Signed written informed consent

You may not qualify if:

• Radiotherapy with a wide field of radiation within 4 weeks or radiotherapy with a limited field of radiation for palliation within 1 week
• Any unresolved toxicities from prior therapy, greater than CTCAE grade 1
• Mean QT interval corrected for heart rate (QTc) ≥ 470 ms
• Uncontrolled systemic illness including uncontrolled hypertension, active bleeding, or active infection.
• Past medical history of interstitial lung disease, drug induced interstitial lung disease, radiation pneumonitis which required steroid treatment
• History of hypersensitivity to AZD9291
• Known intracranial haemorrahge which is unrelated to tumor Refractory nausea and vomiting

Sponsors & Collaborators

• Samsung Medical Center: lead

Study Sites (1)

Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine

Seoul, 135-710, South Korea

Location

Related Publications (13)

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• Lee SJ, Lee JI, Nam DH, Ahn YC, Han JH, Sun JM, Ahn JS, Park K, Ahn MJ. Leptomeningeal carcinomatosis in non-small-cell lung cancer patients: impact on survival and correlated prognostic factors. J Thorac Oncol. 2013 Feb;8(2):185-91. doi: 10.1097/JTO.0b013e3182773f21.

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• Lee E, Keam B, Kim DW, Kim TM, Lee SH, Chung DH, Heo DS. Erlotinib versus gefitinib for control of leptomeningeal carcinomatosis in non-small-cell lung cancer. J Thorac Oncol. 2013 Aug;8(8):1069-74. doi: 10.1097/JTO.0b013e318294c8e8.

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• Gow CH, Chien CR, Chang YL, Chiu YH, Kuo SH, Shih JY, Chang YC, Yu CJ, Yang CH, Yang PC. Radiotherapy in lung adenocarcinoma with brain metastases: effects of activating epidermal growth factor receptor mutations on clinical response. Clin Cancer Res. 2008 Jan 1;14(1):162-8. doi: 10.1158/1078-0432.CCR-07-1468.

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  PMID: 23129122 BACKGROUND

• Umemura S, Tsubouchi K, Yoshioka H, Hotta K, Takigawa N, Fujiwara K, Horita N, Segawa Y, Hamada N, Takata I, Yamane H, Kamei H, Kiura K, Tanimoto M. Clinical outcome in patients with leptomeningeal metastasis from non-small cell lung cancer: Okayama Lung Cancer Study Group. Lung Cancer. 2012 Jul;77(1):134-9. doi: 10.1016/j.lungcan.2012.03.002. Epub 2012 Apr 7.

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• Pao W, Miller VA, Politi KA, Riely GJ, Somwar R, Zakowski MF, Kris MG, Varmus H. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med. 2005 Mar;2(3):e73. doi: 10.1371/journal.pmed.0020073. Epub 2005 Feb 22.

  PMID: 15737014 BACKGROUND

• Planchard D, Loriot Y, Andre F, Gobert A, Auger N, Lacroix L, Soria JC. EGFR-independent mechanisms of acquired resistance to AZD9291 in EGFR T790M-positive NSCLC patients. Ann Oncol. 2015 Oct;26(10):2073-8. doi: 10.1093/annonc/mdv319. Epub 2015 Aug 12.

  PMID: 26269204 BACKGROUND

• Janne PA, Yang JC, Kim DW, Planchard D, Ohe Y, Ramalingam SS, Ahn MJ, Kim SW, Su WC, Horn L, Haggstrom D, Felip E, Kim JH, Frewer P, Cantarini M, Brown KH, Dickinson PA, Ghiorghiu S, Ranson M. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med. 2015 Apr 30;372(18):1689-99. doi: 10.1056/NEJMoa1411817.

  PMID: 25923549 BACKGROUND

• Cross DA, Ashton SE, Ghiorghiu S, Eberlein C, Nebhan CA, Spitzler PJ, Orme JP, Finlay MR, Ward RA, Mellor MJ, Hughes G, Rahi A, Jacobs VN, Red Brewer M, Ichihara E, Sun J, Jin H, Ballard P, Al-Kadhimi K, Rowlinson R, Klinowska T, Richmond GH, Cantarini M, Kim DW, Ranson MR, Pao W. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov. 2014 Sep;4(9):1046-61. doi: 10.1158/2159-8290.CD-14-0337. Epub 2014 Jun 3.

  PMID: 24893891 BACKGROUND

• Park S, Lee MH, Seong M, Kim ST, Kang JH, Cho BC, Lee KH, Cho EK, Sun JM, Lee SH, Ahn JS, Park K, Ahn MJ. A phase II, multicenter, two cohort study of 160 mg osimertinib in EGFR T790M-positive non-small-cell lung cancer patients with brain metastases or leptomeningeal disease who progressed on prior EGFR TKI therapy. Ann Oncol. 2020 Oct;31(10):1397-1404. doi: 10.1016/j.annonc.2020.06.017. Epub 2020 Jul 5.

  PMID: 32634610 DERIVED

MeSH Terms

Interventions

osimertinib

Study Officials

• Myung-Ju Ahn, Professor

  Samsung Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Model Details: 1. Brain Metastasis cohort (BM cohort) 2. Leptomeningeal Metastasis cohort (LM cohort)

Study Record Dates

• First Submitted: May 7, 2017
• First Posted: August 22, 2017
• Study Start: May 8, 2017
• Primary Completion: August 31, 2019
• Study Completion: December 31, 2021
• Last Updated: August 16, 2021

Record last verified: 2021-08

Data Sharing

• IPD Sharing: Will not share

Locations

KR (1)