Safety, Tolerability, Pharmacokinetics and Anti-tumour Activity of ASK120067 in Locally Advanced and Metastatic Non Small Cell Lung Cancer

Study Overview
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Brief Summary
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ASK120067 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.

Official Title
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A Phase I/II Study to Assess the Safety,Tolerability, Pharmacokinetics and Anti-tumour Activity of ASK120067 in Patients With Locally Advanced or Metastatic T790M Mutation-positive Non-Small Cell Lung Cancer Who Have Progressed Following Prior Therapy With an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Agent

Conditions
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Locally Advanced or Metastatic NSCLC

Intervention / Treatment
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* Drug: ASK120067


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients of either gender, aged from 18 years older to 70. Histologically or cytologically confirmed metastatic, or unresectable locally advanced, recurrent NSCLC 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) 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 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) At least one lesion, not previously irradiated and not chosen for fresh biopsy during the study screening period, that can be accurately measured at baseline as ≥ 10mm in the longest diameter (except lymph nodes which must have short access ≥ 15mm) with computerised tomography (CT) or magnetic resonance imaging (MRI) which is suitable for accurate repeated measurements. ECOG performance status of 0 to 2. Life expectancy of at least 12 weeks 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. Male patients were to be willing to use barrier contraception, ie, condoms and avoid sperm donation within 6 months Signed consent on an Independent Ethics Committee-approved Informed Consent Form prior to any study-specific evaluation Exclusion Criteria: Any Target cancer drug from a previous treatment regimen or clinical study within 8 days, or less than approximately 5x half-life of the first dose of study treatment Any cytotoxic chemotherapy, investigational agents or other anticancer drugs （including traditional Chinese medicine）from a previous treatment regimen or clinical study within 14 days of the first dose of study treatment The third EGFR-TKI from a previous treatment regimen or clinical study (ie, AZD9291, CO-1686, HM61713, avitinib,BPI-15086,BPI-7711,Alflutinib,Almonertinib) Major surgery within 4 weeks of the first dose of study treatment Radiotherapy with a wide field of radiation or bone marrow radiotherapy is more than 30% within 4 weeks of the first dose of study treatment Taking (or cannot stop taking 1 week before the first dose receiving) strong inhibitor of CYP3A4 With the exception of alopecia and grade 2 or higher, prior platinum-therapy related neuropathy, any unresolved toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE) grade 2 at the time of starting study treatment 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 or active hemorrhagic tendency considered not suitable for the trail or would affect the compliance towards the protocol Active infection such as HBV (HBV-DNA≥1000cps/ml), HCV, HIV, syphilis et al . 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: Mean resting corrected QT interval (QTc) > 470 msec obtained from 3 ECG. 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 prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval. left ventricular ejection fraction (LVEF) within 40%. 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 Hyperglycemia that cannot be stably controlled by drugs (fasting blood glucose is greater than or equal to 7.0mmol/L) Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values: Absolute neutrophil count < 1.5 x 109/L. Platelet count < 100 x 109/L. Haemoglobin < 90 g/L. Alanine aminotransferase> 2.5 times the upper limit of normal (ULN) if no demonstrable liver metastases or > 5 times ULN in the presence of liver metastases. Aspartate aminotransferase > 2.5 times ULN if no demonstrable liver metastases or > 5 times ULN in the presence of liver metastases. Total bilirubin > 1.5 times ULN if no liver metastases or > 3 times ULN in the presence of documented Gilbert's Syndrome (unconjugated hyperbilirubinaemia) or liver metastases Creatinine >1.5 times ULN concurrent with creatinine clearance < 50 ml/min (measured or calculated by Cockcroft and Gault equation); confirmation of creatinine clearance is only required when creatinine is > 1.5 times ULN. History of hypersensitivity to active or inactive excipients of ASK120067 or drugs with a similar chemical structure or class to ASK120067 Women who were breastfeeding and pregnant Any other cancer, within 5 years prior to screening with the exception of adequately treated cervical carcinoma in situ, or adequately treated basal or squamous cell carcinoma of the skin, or papillary thyroid cancer Judgment by the investigator that any serious or uncontrolled eye disease may increase the safety risk of the patient . Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: ASK120067<br>patients take ASK120067 orally once per day at different dose | Drug: ASK120067<br>* patients take ASK120067 orally once per day at 40,80,160,240,320,480mg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate | 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,date of death or withdrawal from study,whichever came first, assessed up to approximately 2 years. | 

Secondary 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 and NCI CTCAE v4.03 | Adverse events will be collected from baseline until 28 days after the last dose | 
| Progression free survival | 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,date of death or withdrawal from study,whichever came first, assessed up to approximately 2 years. | 
| Duration of response | 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,date of death or withdrawal from study,whichever came first, assessed up to approximately 2 years. | 
| Disease control rate | Evaluation of Disease control rate assessed by RECIST 1.1 | CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression,date of death or withdrawal from study,whichever came first, assessed up to approximately 2 years. | 
| Overall survival | defined as the time from date of first dose until date of death due to any cause | Time from treatment start to the time of death due to any cause or withdrawal from study,whichever came first, assessed up to approximately 2 years. | 
| Maximum Plasma Concentration [Cmax] of single dose ASK120067 | Collect plasma concentrations of ASK120067 and 1 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, 1, 2, 3, 4, 5,6, 8, 10, 24, 48, 72 ,96,144 hours post dose) | 
| Peak Plasma Time [tmax] of single dose ASK120067 | Collect plasma concentrations of ASK120067 and 1 metabolite 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, 1, 2, 3, 4, 5,6, 8, 10, 24, 48, 72 ,96,144 hours post dose) | 
| Area under the plasma concentration versus time curve (AUC) of single dose ASK120067 | Collect plasma concentrations of ASK120067 and 1 metabolite 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, 1, 2, 3, 4, 5,6, 8, 10, 24, 48, 72 ,96,144 hours post dose) | 
| Terminal rate constant of single dose single dose ASK120067 | Collect plasma concentrations of ASK120067 and 1 metabolite 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, 1, 2, 3, 4, 5,6, 8, 10, 24, 48, 72 ,96,144 hours post dose) | 
| Clearance of single dose ASK120067 | Collect plasma concentrations of ASK120067 and 1 metabolite 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, 1, 2, 3, 4, 5,6, 8, 10, 24, 48, 72 ,96,144 hours post dose) | 
| Half life of single dose ASK120067 | Collect plasma concentrations of ASK120067 and 1 metabolite 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, 1, 2, 3, 4, 5,6, 8, 10, 24, 48, 72 ,96,144 hours post dose) | 
| Volume of distribution of single dose ASK120067 | Collect plasma concentrations of f ASK120067 and 1 metabolite 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, 1, 2, 3, 4, 5,6, 8, 10, 24, 48, 72 ,96,144 hours post dose) | 
| Mean resistance time of single dose ASK120067 | Collect plasma concentrations of ASK120067 and 1 metabolite 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, 1, 2, 3, 4, 5,6, 8, 10, 24, 48, 72 ,96,144 hours post dose) | 
| Steady state Cmax of multiple doses ASK120067 | Cmax of ASK120067 and 1 metabolite 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 8, 10,12,15,18,22. Cycle 1 D28- pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24 hours post dose) | 
| Steady state tmax of multiple doses ASK120067 | Tmax of ASK120067 and 1 metabolite 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 8, 10,12,15,18,22. Cycle 1 D28- pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24 hours post dose) | 
| Steady state Cmin (Minimum Plasma Concentration) of multiple doses ASK120067 | Cmin of ASK120067 and 1 metabolite 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 Day8, 10,12,15,18,22. Cycle 1 D28- pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24 hours post dose) | 
| Steady state AUC of multiple doses ASK120067 | AUC of ASK120067 and 1 metabolite 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 8, 10,12,15,18,22. Cycle 1 D28- pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24 hours post dose) | 
| Steady state clearance of multiple doses ASK120067 | Clearance of ASK120067 and 1 metabolite 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 8, 10,12,15,18,22. Cycle 1 D28- pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24 hours post dose) | 
| Accumulation ratio of multiple doses ASK120067 | Accumulation ratio of ASK120067 and 1 metabolite 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 8, 10,12,15,18,22. Cycle 1 D28- pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24 hours post dose) | 
| Time dependency of multiple doses ASK120067 | Time dependency of ASK120067 and 1 metabolite 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 8, 10,12,15,18,22. Cycle 1 D28- pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24 hours post dose) |