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NCT03257124 Clinical Trial

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

Failed Tyrosine Kinase Inhibitors Clinical Trial

Official title:
An Open Label, Multicenter, Phase II Study of AZD9291 in Non-small Cell Lung Cancer (NSCLC) Patients Harboring T790M Mutation Who Failed EGFR TKIs and With Brain and/or Leptomeningeal Metastasis

Clinical Trial Details — Status: Active, not recruiting

Administrative data
NCT number NCT03257124
Other study ID # 2016-09-058
Secondary ID
Status Active, not recruiting
Phase Phase 2
First received
Last updated
Start date May 8, 2017
Est. completion date December 31, 2021

Study information
Verified date August 2021
Source Samsung Medical Center
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial 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.

Description:

1. Primary end points - Overall response rate (ORR) in CNS -brain metastasis cohort - Overall survival - Leptomeningeal with or without brain metastasis cohort 2. Secondary end points - Whole body disease control rate (DCR) - Time to brain progression - Progression free survival (PFS) in BM cohort - Overall survival (OS) - Adverse events (AEs) - Exploratory analysis of EGFR mutation/T790M in tissue, plasma or cerebrospinal fluid (CSF) 3. Treatment AZD9291 160mg po daily (1 cycle of 28 days) 4. Total patient sample size Eligible patients will be divided into two cohorts, brain metastasis (BM) cohort and leptomeningeal metastasis (LM) with or without BM cohort. The two patient cohorts use different primary endpoints. 5. BM cohort For the BM cohort, the primary outcome is overall response (CR+PR). Let P denote the overall response rate of AZD9291. From some preliminary data of response in the brain or leptomeningeal seeding with AZD 9291 in phase II AURA and BLOOM study, we hypothesized that H0:P= 10% and H1:P =30%. The BM cohort uses Simon's optimal two-stage design as follows. Stage 1: Treat n1 = 18 patients. If r1 = 2 or fewer patients respond, stop the BM cohort concluding that the study therapy is inefficacious. Otherwise, proceed to Stage 2. Stage 2: Treat additional n2 = 17 patients. If r = 6 or fewer patients respond among the cumulative n1 + n2 = 35 patients, then conclude that the study therapy is inefficacious. Otherwise, accept the study therapy for further investigation. This design has 1-sided alpha = 5% for P0 = 10% and power = 90% for P1 = 30%. Considering about 10%, of attrition due to ineligibility and dropout, a total of 40 patients will be enrolled into the BM cohort. 6. LM ± BM cohort The primary outcome of the LM ± BM cohort is overall survival (OS). Let μ denote the median OS of AZD9291 in this cohort. Based on some preliminary results (we need a reference), we hypothesize that H0: μ=3 months vs. H1: μ=5 months. Assuming an exponential OS distribution under H0, the investigators will conduct the 1-sample log-rank test. In this cohort, the investigators expect an accrual rate of 30 patients per year and about 10% of attrition, and will have an additional follow-up of 6 months after completion of accrual. Under these assumptions, we need N=40 patients (D=29 deaths) for 90% of power by the 1-sample log-rank test with 1-sided alpha=5% (refer to Kwak and Jung 2013). The trial of this cohort is expected to take about 22 months (=16 months for patient accrual + 6 months for additional follow-up). 7. Statistical analysis plan The analysis is conducted separately for each cohort. OS, PFS, and time to brain progression will be summarized by Kaplan-Meier method. DCR and AEs will be summarized using contingency tables. Cohort specific analyses are conducted as follows. BM cohort Two-stage testing on ORR will be conducted as described in "Target number" section. If the final sample size is different from n1=18 or n1 + n2=35, then a 1-sided p-value will be calculated by Jung et al. (2006) and accept the experimental therapy if it is smaller than alpha = 5%. The ORR will be unbiasedly estimated by Jung and Kim (2004), and its confidence interval will be calculated by Jennison and Turnbull (1983). LM ± BM cohort The final analysis of this cohort will be conducted when D29 deaths are observed, which is expected to be about 22 months from the study open. The investigators will conduct a 1-sample log-rank test assuming the exponential OS distribution with a median of 3 months under H0.

Recruitment information / eligibility
Status Active, not recruiting
Enrollment 80
Est. completion date December 31, 2021
Est. primary completion date August 31, 2019
Accepts healthy volunteers No
Gender All
Age group 18 Years and older
Eligibility Inclusion Criteria: - 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 Exclusion Criteria: - 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

Study Design

Related Conditions & MeSH terms

Intervention

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

Locations
Country Name City State
Korea, Republic of Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine Seoul

Sponsors (1)
Lead Sponsor Collaborator
Samsung Medical Center

Country where clinical trial is conducted

Korea, Republic of, 

References & Publications (12)

Bonomi PD. Implications of key trials in advanced nonsmall cell lung cancer. Cancer. 2010 Mar 1;116(5):1155-64. doi: 10.1002/cncr.24815. Review. — View Citation

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. — View Citation

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. — View Citation

Jänne 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. — View Citation

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. — View Citation

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. — View Citation

Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y, Nishiwaki Y, Ohe Y, Yang JJ, Chewaskulyong B, Jiang H, Duffield EL, Watkins CL, Armour AA, Fukuoka M. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009 Sep 3;361(10):947-57. doi: 10.1056/NEJMoa0810699. Epub 2009 Aug 19. — View Citation

Mok TS. Personalized medicine in lung cancer: what we need to know. Nat Rev Clin Oncol. 2011 Aug 23;8(11):661-8. doi: 10.1038/nrclinonc.2011.126. Review. — View Citation

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. Epub 2005 Feb 22. — View Citation

Planchard D, Loriot Y, André 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. — View Citation

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. — View Citation

Wu YL, Zhou C, Cheng Y, Lu S, Chen GY, Huang C, Huang YS, Yan HH, Ren S, Liu Y, Yang JJ. Erlotinib as second-line treatment in patients with advanced non-small-cell lung cancer and asymptomatic brain metastases: a phase II study (CTONG-0803). Ann Oncol. 2013 Apr;24(4):993-9. doi: 10.1093/annonc/mds529. Epub 2012 Nov 4. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome
Type Measure Description Time frame Safety issue
Primary 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)
Primary 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 Whole body disease control rate (DCR) At least one visit response of CR (complete response), PR (partial response) or SD (stable disease) that is confirmed at least 4 weeks later by using RECIST 1.1 criteria. December, 2019 (one-year follow-up from last patient -in)
Secondary Time to brain progression Time to brain progression is measured from the date of start of study to the date of progression of BM or LM. December, 2019 (one-year follow-up from last patient -in)
Secondary Progression free survival (PFS) in BM cohort measured from the date of start of study to the date of disease progression or death from any cause. December, 2019 (one-year follow-up from last patient -in)
Secondary Overall survival (OS) OS is measured from the date of start of study to the date of death from any cause December, 2019 (one-year follow-up from last patient -in)
Secondary Adverse events (AEs) Adverse events will be measured by the CTCAE scale, version 4. December, 2019 (one-year follow-up from last patient -in)
Secondary Exploratory analysis of EGFR mutation/T790M Exploratory analysis of EGFR mutation/T790M in tissue, plasma or cerebrospinal fluid (CSF) December, 2019 (one-year follow-up from last patient -in)