Safety, Pharmacokinetic and Preliminary Efficacy Study of AC0010MA in Advanced Non Small Cell Lung Cancer

Study Overview
=================
Brief Summary
-----------------
AC0010MA is a new, irreversible, Epidermal Growth Factor Receptor (EGFR) mutation selective Tyrosine Kinase Inhibitor. Aim at local advanced or metastatic non-small cell lung cancer patients with EGFR mutation or T790M drug-resistant mutation. The molecular mechanism: by irreversible combining the EGFR-RTKs ATP binding site of cell, selectively suppress the activities of EGFR tyrosine kinase phosphorylation, block the signal transduction pathway of EGFR and inhibit the function of ras/raf/MAPK downstream, thus block the tumor cell growth by EGFR induction, and promotes apoptosis. AC0010MA Maleate Capsules has three characters: 1. Irreversible binding to EGFR; 2. Effectively suppresses the tumor cell with EGFR mutant while has no suppression to EGFR wild-type cell; 3. Efficient suppress the tumor cell with EGFR T790M drug-resistant mutation.

Official Title
-----------------
A Phase I, Multicenter, Open-Label Safety, Pharmacokinetic and Preliminary Efficacy Study of Wild-type Sparing EGFR Inhibitor, AC0010MA, in Adult Patients With Previously Treated EGFRmut and Acquired T790M Mutation Non-Small Cell Lung Cancer (NSCLC)

Conditions
-----------------
Non Small Cell Lung Cancer

Intervention / Treatment
-----------------
* Drug: AC0010MA


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Is male or female, aged 18 years or older at the time of consent; preferably non-Asian. Has histologically or cytologically confirmed metastatic, or unresectable locally advanced, recurrent NSCLC. Has at least one measurable disease by computed tomography (CT) or magnetic resonance imaging (MRI), according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1. Has documented evidence of an activating EGFR mutation in the tumor tissue determined by either sequencing or PCR-based technique (Part 1). For Part 1 only: subjects with a positive T790M mutation are preferred, but not required. Confirmation of T790M mutation status will be determined from an archived tumor tissue sample or fresh tumor tissue sample obtained via biopsy if archived tissue is not available. In Part 2, subjects must have a confirmed, positive T790M EGFR mutation (acquired T790M EGFR mutation or de novo T790M EGFR mutation). Has a life expectancy of at least 3 months. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Has adequate hematological and physiological functions. Has documented disease progression while receiving at least 30 days of treatment with a currently approved EGFR tyrosine kinase inhibitor (TKI) (e.g., erlotinib, gefitinib or afatinib) with intervening treatment after most recent EGFR TKI therapy (not required for de novo T790M EGFR mutation). Signed and dated written informed consent obtained prior to any study-specific evaluation. Exclusion Criteria: Has a history of interstitial lung disease related to prior EGFR inhibitor therapy. Has an EGFR TKI- related toxicity that has NOT resolved to Grade 1 or less. Is test positive for hepatitis C virus (HCV), hepatitis B virus (HBV) or human immunodeficiency virus (HIV) antibody. Has received the prohibited therapy (e.g., concurrent anti-cancer therapy including but not limited to: chemotherapy, radiation, hormonal, or immunotherapy) ≤14 days prior to first planned dose of AC0010MA. Received prior treatment with AZD9291 (osimertinib) or CO1686 (rociletinib) and experienced disease progression. Is a female subject who is pregnant or breastfeeding. Female subjects (if of child bearing potential) and male subjects (with a partner of child bearing potential) must use medically acceptable methods of birth control before study entry, for the duration of the study, and for at least 6 months after the last intake of study drug. Has a serious or unstable concomitant systemic disorder incompatible with the clinical study (e.g., substance abuse, uncontrolled psychiatric condition, uncontrolled intercurrent illness including active infection, arterial thrombosis, or symptomatic pulmonary embolism). Has any other reason(s) for the investigator to consider that the subject should not participate in the study. Is receiving treatment with medication(s) that are known to be strong inhibitors or inducers of CYP3A4/5.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: single dose per day (QD)<br>Phase I Arm 1: AC0010MA orally taking once daily, starting from 100 mg per day. | Drug: AC0010MA<br>* Following Phase I, a protocol amendment will be submitted to the IND to specify the selected dose and dose justification to be used in Phase II.<br>|
| Experimental: two doses per day (BID)<br>Phase I Arm 2: AC0010MA orally taking twice daily, starting from 200 mg per day (100 mg BID). Arm 2 will be initiated once the drug plasma t1/2 is 10 hours or below in the first dose cohort (100 mg QD). | Drug: AC0010MA<br>* Following Phase I, a protocol amendment will be submitted to the IND to specify the selected dose and dose justification to be used in Phase II.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability, and the maximum tolerated dose (MTD) of AC0010MA determined by incidence of dose limiting toxicity (DLT) | To determine the safety and tolerability and to establish the maximum tolerated dose (MTD) of AC0010MA by incidence of dose limiting toxicity (DLT), defined as Grade 3 or 4 adverse events (AEs) and clinical lab abnormalities occurring within the first 28 days of treatment. | Within the first 28 days of treatment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of tumor response and duration of response of AC0010MA ((objective response rate, ORR) | To characterize tumor response (objective response rate, ORR) and duration of response of AC0010MA as a criterion for further development of AC0010MA in this patient population. | within the time frame of every 8 weeks (2 cycles) for up to 3 years | 
| Maximum plasma concentration (Cmax) of AC0010MA | To evaluate pharmacokinetic parameter of AC0010MA | Blood samples will be collected at pre-treatment, and at 0.5, 1, 2, 3, 4, 6, 8, 12, and 24h post-treatment on Days 1, 8, and 28 in the first treatment cycle (QD and BID) in Phase I | 
| Time to Cmax | To evaluate pharmacokinetic parameter of AC0010MA | Blood samples will be collected at pre-treatment, and at 0.5, 1, 2, 3, 4, 6, 8, 12, and 24h post-treatment on Days 1, 8, and 28 in the first treatment cycle (QD and BID) in Phase I | 
| Terminal half-life (t1/2) | To evaluate pharmacokinetic parameter of AC0010MA | Blood samples will be collected at pre-treatment, and at 0.5, 1, 2, 3, 4, 6, 8, 12, and 24h post-treatment on Days 1, 8, and 28 in the first treatment cycle (QD and BID) in Phase I | 
| Area under the plasma concentration-time curve | To evaluate pharmacokinetic parameter of AC0010MA | Blood samples will be collected at pre-treatment, and at 0.5, 1, 2, 3, 4, 6, 8, 12, and 24h post-treatment on Days 1, 8, and 28 in the first treatment cycle (QD and BID) in Phase I | 
| Volume of distribution (V/F) | To evaluate pharmacokinetic parameter of AC0010MA | Blood samples will be collected at pre-treatment, and at 0.5, 1, 2, 3, 4, 6, 8, 12, and 24h post-treatment on Days 1, 8, and 28 in the first treatment cycle (QD and BID) in Phase I | 
| Plasma Concentration (CL/F) | To evaluate pharmacokinetic parameter of AC0010MA | Blood samples will be collected at pre-treatment, and at 0.5, 1, 2, 3, 4, 6, 8, 12, and 24h post-treatment on Days 1, 8, and 28 in the first treatment cycle (QD and BID) in Phase I |