Safety, Tolerability, Pharmacokinetics and Anti-tumour Activity of Alflutinib in Advanced Non Small Cell Lung Cancer

Study Overview
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Brief Summary
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Alflutinib Mesylate Tablets is a Epidermal Growth Factor Receptor (EGFR) mutation selective Tyrosine Kinase Inhibitor which can efficient suppress the EGFR T790M drug-resistant mutation tumor cell in Xenograft mouse model. This study aims at local advanced or metastatic non-small cell lung cancer patients with T790M drug-resistant mutation.

Detailed Description
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This is a Phase I study, to evaluate the safety, tolerability, pharmacokinetics and anti-tumor activity of AST2818 in patients with advanced non-small cell lung cancer who progressed on prior therapy with an epidermal growth factor receptor tyrosine kinase inhibitor agent. The tolerability of AST2818 20 mg/day - 240 mg/day in 14 subjects was observed. 7-days observation period for a single dose and 21-days observation period for multiple doses.

Official Title
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Safety, Tolerability, Pharmacokinetics and Anti-tumour Activity of Alflutinib in Patients With Advanced Non Small Cell Lung Cancer Who Progressed on Prior Therapy With an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Agent

Conditions
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NSCLC

Intervention / Treatment
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* Drug: Alflutinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients of either gender, aged from 18 years older to 65. Histologically or cytologically confirmed metastatic, or unresectable locally advanced, recurrent NSCLC. Radiological documentation of disease progression while on a previous continuous treatment with an EGFR TKI e.g. gefitinib or erlotinib or Afatinib, or Icotinib (Third EGFR TKI are not included). In addition other lines of therapy may have been given. Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including at least one of G719X, exon 19 deletion, L858R, L861Q mutation) Documented evidence of definitely EGFR T790M+ state in the tumor tissue after disease progression on the most recent treatment regimen (irrespective of whether this is EGFR TKI or chemotherapy). ECOG performance status of 0 to 2. Life expectancy of at least 12 weeks. At least one measurable disease by CT or PET-CT or MRI, according to RECIST Version 1.1. Organ function must meet the following requirements： Absolute neutrophil count >= 1.5 x 109/L, Platelet count >= 75 x 109/L, Haemoglobin >= 90 g/L； Alanine aminotransferase/Aspartate aminotransferase <= 2.5 times the upper limit of normal if no demonstrable liver metastases or <= 5 times in the presence of liver metastases； Total bilirubin <= 1.5 times ULN if no liver metastases or <= 3 times ULN in the presence of liver metastases or liver metastases； Creatinine <=1.5 times ULN concurrent with creatinine clearance >= 50 ml/min (measured or calculated by Cockcroft and Gault equation); Females should not be in lactation period and must have a negative pregnancy test prior to start of dosing; During the whole treatment,all patients should be in the entire 3 months during and after the treatment, repeated barrier precautions Signed consent on an Independent Ethics Committee-approved Informed Consent Form prior to any study-specific evaluation. Exclusion Criteria: Any cytotoxic chemotherapy from a previous treatment regimen or clinical study within 21 days，Any Target cancer drug from a previous treatment regimen or clinical study within 14 days, or less than approximately 5x half-life of the first dose of study treatment； The third EGFR-TKI from a previous treatment regimen or clinical study (ie, AZD9291, CO-1686, HM61713, ASP8273, EGF816, avitinib, Taking (or cannot stop taking 1 week before the first dose receiving) strong inhibitor of CYP3A4 or antitumor herb. Unrecovered toxic reaction due to former therapy existed, with over 1 grade of CTCAE (except alopecia) or 2 grade if ever applied DDP curing related neuropathy. Spinal compression, or brain metastasis exhibiting symptoms but untreated (except those exhibit no symptom with stable condition and do not apply corticosteroids for 4 weeks before the trail initiating) Any evidence showing severe or inadequate controlled systemic disease. For example patients with inadequate controlled hypertension considered not suitable for the trail or would affect the compliance towards the protocol, with active hemorrhagic tendency, with active infection such as HBV (HBV-DNA≥1000cps/ml), with HCV, with HIV et al (except for HBV carrier those the researcher considered meet the criterion). Any condition affecting the drug taking, or significantly affecting the absorption or the pharmacokinetic parameters, include any kind of uncontrollable nausea or vomit, chronic gastroenteropathy, disability in swallowing, and history of gastrointestinal resection or surgery. Any condition meet the following cardiac standard: ECG show a QTc>470 msec under resting state (Repeat in 48 hours when a first abnormal discovered, take mean of the two measurements). All kinds of abnormal in cardiac rhythm, conduction and resting ECG profile with clinical significance, for example complete left bundle branch block, 2 or 3 grade of conduction block and a PR interval>250 msec. Any possible factors increasing the risk of QTc extending or leading to arrhythmia, such as heart failure, hypokalemia, congenital long QT syndrome, any first degree relative suffered from long QT syndrome or undertook unexplained sudden death before 40 years old, or taking any drug leading to a longer QTc. Any history of interstitial lung disease, drug induced interstitial lung disease, radiation pneumonia require steroid therapy or active interstitial lung disease with clinical evidence during recruiting. Patients with other factors the researchers considered not suitable for the trail (for example, patients those who not willing to follow the procedure, limitation or requirements, who once experienced bone marrow allotransplantation, who have other kinds of malignant tumor coexisted or who showed allergic to the active ingredients or inactive adjuvant of the investigational drug, as well as drugs with similar chemical structure or in the same class). Confirmed mutation of EGFR 20 exon insertion at anytime after the first diagnosis.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Alflutinib<br>patients take Alflutinib orally once per day at different dose | Drug: Alflutinib<br> <br> * Other names: AST2818;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and Severity of Treatment-Emergent Adverse Events | Assessed by number and severity of adverse events as recorded on the case report form, vital signs, laboratory variables, physical examination, electrocardiogram, ophthalmic examinations, RECIST1.1, and NCI CTCAE v4.03 | Adverse events will be collected from baseline until 28 days after the last dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Plasma Concentration [Cmax] of single dose Alflutinib and 2 metabolites | Collect plasma concentrations of Alflutinib and 2 metabolites following single dose at designated time points of Day 1 to figure out Cmax. | Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose) | 
| Peak Plasma Time [tmax] of single dose Alflutinib and 2 metabolites | Collect plasma concentrations of Alflutinib and 2 metabolites following single dose at designated time points of Day 1 to figure out tmax. | Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose) | 
| Area under the plasma concentration versus time curve (AUC) of single dose Alflutinib and 2 metabolites | Collect plasma concentrations of Alflutinib and 2 metabolites following single dose at designated time points of Day1 to figure out AUC. | Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose) | 
| Terminal rate constant of single dose Alflutinib and 2 metabolites | Collect plasma concentrations of Alflutinib and 2 metabolites following single dose at designated time points of Day 1 to figure out terminal rate constant. | Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose) | 
| Clearance of single dose Alflutinib and 2 metabolites | Collect plasma concentrations of Alflutinib and 2 metabolites following single dose at designated time points of Day 1 to figure out clearance. | Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose) | 
| Half life of single dose Alflutinib and 2 metabolites | Collect plasma concentrations of Alflutinib and 2 metabolites following single dose at designated time points of Day 1 to figure out half life. | Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose) | 
| Volume of distribution of single dose Alflutinib and 2 metabolites | Collect plasma concentrations of Alflutinib and 2 metabolites following single dose at designated time points of Day 1 to figure out volume of distribution. | Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose) | 
| Mean resistance time of single dose Alflutinib and 2 metabolites | Collect plasma concentrations of Alflutinib and 2 metabolites following single dose at designated time points of Day 1 to figure out mean resistance time. | Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose) | 
| Steady state Cmax of multiple doses Alflutinib and 2 metabolites | Cmax of Alflutinib and 2 metabolites at steady state following multiple doses. | Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8, 15. Cycle 2 D1- pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose) | 
| Steady state tmax of multiple doses Alflutinib and 2 metabolites | tmax of Alflutinib and 2 metabolites at steady state following multiple doses. | Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8, 15. Cycle 2 D1- pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose) | 
| Steady state Cmin (Minimum Plasma Concentration) of multiple doses Alflutinib and 2 metabolites | Cmin of Alflutinib and 2 metabolites at steady state following multiple doses. | Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8, 15. Cycle 2 D1- pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose) | 
| Steady state AUC of multiple doses Alflutinib and 2 metabolites | AUC of Alflutinib and 2 metabolites at steady state following multiple doses. | Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8, 15. Cycle 2 D1- pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose) | 
| Steady state clearance of multiple doses Alflutinib and 2 metabolites | Clearance of Alflutinib and 2 metabolites at steady state following multiple doses. | Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8, 15. Cycle 2 D1- pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose) | 
| Accumulation ratio of multiple doses Alflutinib and 2 metabolites | Accumulation ratio of Alflutinib and 2 metabolites following multiple doses. | Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8, 15. Cycle 2 D1- pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose) | 
| Time dependency of multiple doses Alflutinib and 2 metabolites | Time dependency of Alflutinib and 2 metabolites following multiple doses. | Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8, 15. Cycle 2 D1- pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose) | 
| Objective response rate of Alflutinib | Evaluation of objective response rate assessed by RECIST 1.1 | CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression or withdrawal from study, expected average 6 months | 
| Duration of response of Alflutinib | Duration of response assessed by RECIST 1.1 | CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression or withdrawal from study, expected average 6 months | 
| Progression free survival of Alflutinib | Progression of tumor was assessed by RECIST 1.1 thereby to evaluate progression free survival | CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression or withdrawal from study, expected average 6 months | 
| Disease progression rate of Alflutinib | Progression of tumor was assessed by RECIST 1.1 thereby to evaluate disease progression rate | CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression or withdrawal from study, expected average 6 months | 
| Clinical benefit rate of Alflutinib | Clinical benefit rate was calculated by adding up complete remission, partial remission and stabilization of disease assessed by RECIST 1.1 | CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression or withdrawal from study, expected average 6 months |