A Phase 2 interventional study of AZD9291 in Non-Small Cell Lung Cancer With EGFR T790M Mutation, With Brain and/or Leptomeningeal Metastasis and Failed Tyrosine Kinase Inhibitors, sponsored by Samsung Medical Center. Status unknown at 1 site in Korea, Republic of. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2021-08-16.
Sponsored by Samsung Medical Center · Phase 2, Interventional, and Treatment
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.
Primary end points
Secondary end points
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.
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).
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.
Adequate organ function as evidenced by the following;
Exclusion Criteria:
1. Brain metastasis cohort (BM cohort) 2. Leptomeningeal metastasis cohort (LM cohort)
Drug: AZD9291
AZD9291 160mg per oral daily (1 cycle of 28 days)
Also known as: Osimertinib
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
Time frame: 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
Time frame: 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
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.
Time frame: December, 2019 (one-year follow-up from last patient -in)
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.
Time frame: December, 2019 (one-year follow-up from last patient -in)
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.
Time frame: December, 2019 (one-year follow-up from last patient -in)
Overall survival (OS)
OS is measured from the date of start of study to the date of death from any cause
Time frame: December, 2019 (one-year follow-up from last patient -in)
Adverse events (AEs)
Adverse events will be measured by the CTCAE scale, version 4.
Time frame: December, 2019 (one-year follow-up from last patient -in)
Exploratory analysis of EGFR mutation/T790M
Exploratory analysis of EGFR mutation/T790M in tissue, plasma or cerebrospinal fluid (CSF)
Time frame: December, 2019 (one-year follow-up from last patient -in)
Plan to share: No
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Samsung Medical Center