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)

AstraZeneca1 site in 1 country108 target enrollmentNovember 5, 2014

ConditionsEGFR Mutation Positive Advanced Non Small Cell Lung Cancer

InterventionsAZD3759 AZD9291

DrugsAZD3759 AZD9291

Overview

Phase: Phase 1
Intervention: AZD3759
Conditions: EGFR Mutation Positive Advanced Non Small Cell Lung Cancer
Sponsor: AstraZeneca
Enrollment: 108
Locations: 1
Primary Endpoint: Safety and Tolerability (The number of patients with each AE by system organ class, preferred term and CTCAE grade)
Status: Completed
Last Updated: 5 years ago

Overview Investigators Eligibility Criteria Arms & Interventions Outcomes Sites Similar Trials

Overview

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

Registry

clinicaltrials.gov

Start Date

November 5, 2014

End Date

October 28, 2020

Last Updated

5 years ago

Study Type

Interventional

Study Design

Parallel

Sex

All

Investigators

Sponsor

AstraZeneca

Responsible Party

Sponsor

Eligibility Criteria

Inclusion Criteria

•Obtained written informed consent
•Male or female aged at least 18 years. Aged at least 20 if Japanese.
•Histologically or cytologically confirmed diagnosis of NSCLC with single activating EGFR mutations (L858R or Exon19Del).
•Eastern Cooperative Oncology Group performance status of 0 to
•For LM patients, 0 to 2 is acceptable.
•In Part A, prior treatment with at least one line of a single agent EGFR TKI and at least 1 line of chemotherapy.
•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.
•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
•For patients with LM: Confirmed diagnosis of LM by positive CSF cytology.
•Male patients should be willing to use barrier contraception, i.e., condoms, until 3 months after last study drug is taken.

Exclusion Criteria

•For patients with LM and/or BM, CNS complications that require urgent neurosurgical intervention
•For patient with LM, inability to undergo collection of CSF
•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.
•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
•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.
•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).
•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.
•Known intracranial haemorrhage which is unrelated to tumour
•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
•Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses

Arms & Interventions

Daily dose of AZD3759

Daily oral dose of AZD3759

Intervention: AZD3759

Daily Dose of AZD9291

Daily oral dose of AZD9291

Intervention: AZD9291

Outcomes

Primary Outcomes

Safety and Tolerability (The number of patients with each AE by system organ class, preferred term and CTCAE grade)

Time Frame: From Informed consent until the end of the follow-up period which is defined as 28 days (+7 days) after study treatment is discontinued.

Adverse events will be collected from Informed consent until the end of the follow-up period which is defined as 28 days (+7 days) after study treatment is discontinued.Physical exam (screening, single dosing day, Day 1 of every 3-week cycle of multiple dosing and treatment discontinuation). ECG and vital signs (screening, Day 1 and 2 of Cycle 0 for AZD3759 cohorts, Day 8 of Cycle 1 for AZD3759 cohorts, Day 1 of every 3-week cycle, treatment discontinuation, and if occurrence of any cardiac adverse event). Lab variables (screening, first dosing day, Day 1, 8 and 15 of multiple dosing, Day 1 of every 3-week cycle and treatment discontinuation). Eye exam (at screening and study drug discontinuation and upon occurrence of any visual AE). Echocardiogram or multigated radionuclide angiography (at screening,whenever necessary as clinically indicated throughout the study for AZD3759 cohorts.

Secondary Outcomes

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)(Cycle 0 Day 1 to 3 in Part A patients.)
Plasma,urine,cerebrospinal fluid concentration of AZD3759 and metabolite and pharmacokinetics parameters after multiple dosing(Cmax,ss, tmax,ss, Cmin,ss, AUCss, CLss/F).(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)
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)(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 .)
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).(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.)
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)(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.)
Overall survival follow up for all expansion patients(Every 6 weeks after the 28- day safety follow-up visit)
4b-hydroxy cholesterol in Part B patients with BM(pre-dose of Cycle 0 Day 1 and Cycle 1 Day 15)
The effect of food on the pharmacokinetics of a single dose of AZD3759 in plasma(Cycle 0 Day 1 to Day 4 in Part B patients with BM)
Cerebrospinal fluid response rate for patients with LM and/or BM(Screening and every 6 weeks (relative to first dose of multiple dosing) until progression, expected average 6 months)
Changes from baseline in central nervous system symptoms (analyzed from QLQ-BN20) in patients with LM treated with AZD3759 /AZD9291(Screening, Day 1 of every 3-week cycle and treatment discontinuation, expected average 6 months.)
Changes from baseline in neurological exam in patients with LM treated with AZD3759 /AZD9291(Screening, Day 1 of every 3-week cycle and treatment discontinuation, expected average 6 months.)
Measurement of Objective Response Rate (ORR)(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.)
Measurement of Disease Control Rate (DCR)(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.)
Measurement of Response Rate (RR)(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.)
Measurement of Progression Free Survival (PFS)(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.)
Best Leptomeningeal Metastasis (LM) assessment for AZD9291 LM patients(Screening within 28days)