Clinical trial NCT02228369: Oral Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors, AZD3759 or AZD9291, in Patients Who Have Advanced Non-Small Cell Lung Cancer
Official title: A Phase I, Open-label, Multicentre Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Anti-Tumour Activity of AZD3759 or AZD9291 in Patients With EGFR Mutation Positive Advanced Stage Non Small Cell Lung Cancer (NSCLC)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: EGFR Mutation Positive Advanced Non Small Cell Lung Cancer
Keywords: Non Small Cell Lung Cancer, EGFR, Tyrosine kinase inhibitor,EGFR mutation positive, Brain Metastasis, Leptomeningeal Metastasis
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2014-08-29
Enrollment: 108
Sex: ALL
Minimum age (years): 18
Maximum age (years): 130
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is the first time in patient study to assess the safety, tolerability and preliminary efficacy of AZD3759 in patients with advanced Non Small Cell Lung Cancer (NSCLC) In this study, patients with Leptomeningeal Metastasis and Brain Metastasis may also be enrolled to assess the anti-tumour efficacy, safety, pharmacokinetics and potential biological activity of AZD9291

Detailed description: A Phase I, Open-Label, Multicentre Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Anti-Tumour Activity of AZD3759 or AZD9291 in Patients with EGFR Mutation Positive Advanced Stage Non Small Cell Lung Cancer (NSCLC) who failed standard treatment and developed brain or leptomeningeal diseases

Eligibility criteria: Inclusion Criteria:

1. Obtained written informed consent
2. Male or female aged at least 18 years. Aged at least 20 if Japanese.
3. Histologically or cytologically confirmed diagnosis of NSCLC with single activating EGFR mutations (L858R or Exon19Del).
4. Eastern Cooperative Oncology Group performance status of 0 to1. For LM patients, 0 to 2 is acceptable.
5. In Part A, prior treatment with at least one line of a single agent EGFR TKI and at least 1 line of chemotherapy.
6. In Part B-BM expansion, patients must have not received any EGFR TKI and have asymptomatic brain metastasis, either found during screening process which does not require local treatment in the opinion of the investigator or local treatment has been given (surgery or radiation), patient must be stable without corticosteroid and/or anti-convulsants treatment for at least 2 weeks before study enrollment. For Part B-LM expansion, patients who received previous EGFR TKI treatment must have stable extracranial disease;EGFR TKI treatment naïve patients can also be enrolled into AZD9291 cohorts, or AZD3759 cohorts if efficacy signal seen in Part A and agreed by Safety Review Committee.
7. For patients with neither LM nor measurable BM: At least one measurable extracranial lesion. For patients with measurable BM but without LM: at least one measurable intracranial lesion
8. For patients with LM: Confirmed diagnosis of LM by positive CSF cytology.
9. Male patients should be willing to use barrier contraception, i.e., condoms, until 3 months after last study drug is taken.
10. Females should agree to use adequate contraceptive measures, should not be breast feeding and must have a negative pregnancy test prior to start of dosing if of child-bearing potential or must have evidence of non-child-bearing potential
11. In Part B-AZD9291 LM expansion (sub-cohort of T790M+ LM patients), patients must have central confirmation of T790M+ mutation status from a sample taken after documented progression on the last treatment administered prior to enrolling in the study. Patients must have received prior therapy with an EGFR TKI and may also have received additional lines of treatment. Stable extracranial disease is not required.

Exclusion Criteria:

1. For patients with LM and/or BM, CNS complications that require urgent neurosurgical intervention
2. For patient with LM, inability to undergo collection of CSF
3. Treatment with an EGFR TKI (e.g., erlotinib or gefitinib) within 8 days or approximately 5 x half-life, whichever is the longer, of the first dose of study treatment.
4. Any cytotoxic chemotherapy,or other anticancer drugs for the treatment of advanced NSCLC from a previous treatment regimen within 14 days of the first dose of study treatment
5. Radiotherapy with a wide field of radiation within 4 weeks or radiotherapy with a limited field of radiation for palliation within 1 week of the first dose of study treatment with the exception of patients receiving radiation to more than 30% of the bone marrow which must be completed within 4 weeks of the first dose of study treatment.
6. Patients currently receiving (or unable to stop use at least 1 week prior to receiving the first dose of AZD3759/AZD9291) medications or herbal supplements known to be potent inhibitors or inducers of cytochrome P450 3A4/5 and potential inhibitors of cytochrome P450 2C8 (for patients to be enrolled into AZD9291 cohorts only).
7. Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease.
8. Known intracranial haemorrhage which is unrelated to tumour
9. Refractory nausea and vomiting if not controlled by supportive therapy, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of AZD3759/AZD9291
10. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses
11. Inadequate bone marrow reserve or organ function
12. Clinically significant ECG abnormalities or any factors that increase the risk of corrected QT interval prolongation or risk of arrhythmic events
13. Prior history of whole brain radiotherapy (only applicable for AZD3759 BM expansion)

Primary outcomes:
measure: Safety and Tolerability (The number of patients with each AE by system organ class, preferred term and CTCAE grade)
timeFrame: From Informed consent until the end of the follow-up period which is defined as 28 days (+7 days) after study treatment is discontinued.
Secondary outcomes:
measure: Plasma concentration of AZD3759 and metabolite and pharmacokinetics parameters after single dose of AZD3759(Cmax, tmax, terminal rate constant, half life, AUC, clearance, volume of distribution, mean residence time)
timeFrame: Cycle 0 Day 1 to 3 in Part A patients.
measure: Plasma,urine,cerebrospinal fluid concentration of AZD3759 and metabolite and pharmacokinetics parameters after multiple dosing(Cmax,ss, tmax,ss, Cmin,ss, AUCss, CLss/F).
timeFrame: Blood samples: Cycle 1 Day 8 and Cycle 3 Day 1 in all patients. Urine samples: 0-12h at Cycle 1 Day 8 in Part A. CSF samples: pre-dose of Cycle 1 Day 8 in BM; Pre-dose of Cycle 1 Day 8 and Cycle 3 Day 1 in LM
measure: Plasma,urine, cerebrospinal fluid concentration of AZD3759 and metabolite and pharmacokinetics parameters after multiple dosing (extent of accumulation, renal clearance, time dependency of pharmacokinetics and amount of drug excreted)
timeFrame: Blood samples: Cycle 1 Day 8 and Cycle 3 Day 1 in all patients. Urine samples: 0-12h at Cycle 1 Day 8 in Part A patients. CSF samples: pre-dose of Cycle 1 Day 8 and Cycle 3 Day 1 in Part B patients .
measure: Plasma, cerebrospinal fluid concentration of AZD9291 and metabolite and pharmacokinetics parameters after multiple dose of AZD9291(Cmax,ss, tmax,ss, Cmin,ss, AUCss, CLss/F).
timeFrame: Blood samples: Cycle 1 Day 1, 8, 15 and Cycle 2 Day 1. Cerebrospinal fluid samples: pre-dose of Cycle 2 Day 1 and pre-dose of Cycle 3 Day 1.
measure: Plasma, cerebrospinal fluid concentration of AZD9291 and metabolites and pharmacokinetics parameters after multiple dosing (extent of accumulation, renal clearance, time dependency of pharmacokinetics and amount of drug excreted)
timeFrame: Blood samples: Cycle 1 Day 1, 8, 15 and Cycle 2 Day 1. Cerebrospinal fluid samples: pre-dose of Cycle 2 Day 1 and pre-dose of Cycle 3 Day 1.
measure: Overall survival follow up for all expansion patients
timeFrame: Every 6 weeks after the 28- day safety follow-up visit
measure: 4b-hydroxy cholesterol in Part B patients with BM
timeFrame: pre-dose of Cycle 0 Day 1 and Cycle 1 Day 15
measure: The effect of food on the pharmacokinetics of a single dose of AZD3759 in plasma
timeFrame: Cycle 0 Day 1 to Day 4 in Part B patients with BM
measure: Cerebrospinal fluid response rate for patients with LM and/or BM
timeFrame: Screening and every 6 weeks (relative to first dose of multiple dosing) until progression, expected average 6 months
measure: Changes from baseline in central nervous system symptoms (analyzed from QLQ-BN20) in patients with LM treated with AZD3759 /AZD9291
timeFrame: Screening, Day 1 of every 3-week cycle and treatment discontinuation, expected average 6 months.
measure: Changes from baseline in neurological exam in patients with LM treated with AZD3759 /AZD9291
timeFrame: Screening, Day 1 of every 3-week cycle and treatment discontinuation, expected average 6 months.
measure: Measurement of Objective Response Rate (ORR)
timeFrame: Screening within 28days of treatments start and then every 6 weeks ± 1week(relative to first dose of multiple dosing) until objective disease progression or withdrawal from study,expected average 6 months.
measure: Measurement of Disease Control Rate (DCR)
timeFrame: Screening within 28days of treatments start and then every 6 weeks ± 1week(relative to first dose of multiple dosing) until objective disease progression or withdrawal from study,expected average 6 months.
measure: Measurement of Response Rate (RR)
timeFrame: Screening within 28days of treatments start and then every 6 weeks ± 1week(relative to first dose of multiple dosing) until objective disease progression or withdrawal from study,expected average 6 months.
measure: Measurement of Progression Free Survival (PFS)
timeFrame: Screening within 28days of treatments start and then every 6 weeks ± 1week(relative to first dose of multiple dosing) until objective disease progression or withdrawal from study,expected average 6 months.
measure: Best Leptomeningeal Metastasis (LM) assessment for AZD9291 LM patients
timeFrame: Screening within 28days
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Research Site
state: California
city: Santa Monica
country: United States
facility: Research Site
state: California
city: Camperdown
country: Australia
facility: Research Site
city: Heidelberg
country: Australia
facility: Research Site
city: Seongnam-si
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Taipei
country: Taiwan
facility: Research Site
Study officials:
affiliation: Building 2, 199 Liangjing Road, Zhangjiang Hi-tech Park, Shanghai 201203, China
name: Pamela Yang, M.D. PhD
role: STUDY_DIRECTOR
References:
citation: Yang JCH, Kim SW, Kim DW, Lee JS, Cho BC, Ahn JS, Lee DH, Kim TM, Goldman JW, Natale RB, Brown AP, Collins B, Chmielecki J, Vishwanathan K, Mendoza-Naranjo A, Ahn MJ. Osimertinib in Patients With Epidermal Growth Factor Receptor Mutation-Positive Non-Small-Cell Lung Cancer and Leptomeningeal Metastases: The BLOOM Study. J Clin Oncol. 2020 Feb 20;38(6):538-547. doi: 10.1200/JCO.19.00457. Epub 2019 Dec 6.
citation: Ahn MJ, Kim DW, Cho BC, Kim SW, Lee JS, Ahn JS, Kim TM, Lin CC, Kim HR, John T, Kao S, Goldman JW, Su WC, Natale R, Rabbie S, Harrop B, Overend P, Yang Z, Yang JC. Activity and safety of AZD3759 in EGFR-mutant non-small-cell lung cancer with CNS metastases (BLOOM): a phase 1, open-label, dose-escalation and dose-expansion study. Lancet Respir Med. 2017 Nov;5(11):891-902. doi: 10.1016/S2213-2600(17)30378-8. Epub 2017 Oct 19.