Metastatic Non-small Cell Lung Cancer
Conditions
Brief summary
AC0010 is a novel, potent, small molecule irreversible tyrosine kinase inhibitor (TKI) that selectively targets mutant forms of the epidermal growth factor receptor (EGFR) while sparing wild-type (WT) EGFR. The purpose of the study is to evaluate the pharmacokinetic (PK) and safety profile of oral AC0010; to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of oral AC0010; to assess the safety and efficacy of AC0010 in previously treated mutant EGFR in NSCLC patients with EGFR T790M mutation.
Detailed description
Lung cancer remains the most common cancer worldwide with non-small cell lung cancer (NSCLC) accounting for 85% of cases. Molecularly targeted therapies have proven to be superior to chemotherapy for NSCLC patients whose tumors have mutations in EGFR. Recent studies have established tyrosine kinase inhibitors (TKIs) as the gold standard for treating EGFR-mutation-positive NCSLC. However, patients on TKIs eventually progress, and in approximately 50% of cases, progression is due to development of an additional mutation called T790M. AC0010 may provide an effective therapy for a patient population with few alternative treatment options. Pre-clinical data demonstrated that AC0010 inhibits T790M. It is anticipated that AC0010 may promote cell death in tumor cells with the T790M mutation, thus providing possible therapeutic benefit in patients who have developed T790M-mediated resistance to previous TKIs. This is a two-part, open-label study of oral AC0010 administered twice-daily in previously treated NSCLC patients who have documented evidence of an activating mutation in the EGFR gene and have failed treatment with an EGFR inhibitor such as erlotinib, gefitinib or afatinib. This study will include 2 parts: phase 1 : Dose-escalation Period with 28-day cycles; Optional Treatment Extension Period starting on Day 29 phase 2 : Evaluation of activity and safety in patients with the EGFR T790M mutation
Interventions
DRUGAC0010
Phase 1: AC0010 will be administered in escalating dosages in a period of 28-day cycles. Phase 2: AC0010 will be administered twice-daily at RP2D.
Sponsors
Guangdong Provincial People's Hospital
Acea Bio (Hangzhou) Co., Ltd.
Hangzhou ACEA Pharmaceutical Research Co., Ltd.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
- phase 1: 1. Patients of either gender, aged from 18 years older to 75. 2. Histologically or cytologically confirmed metastatic, or unresectable locally advanced, recurrent NSCLC. 3. At least one measurable disease by CT or MRI, according to RECIST Version 1.1. 4. Failed to the treatment of EGFRTKI with definite state of T790M, or harbored T790M mutation without the treatment of EGFRTKI. 5. Offer biopsy sample to central lab if failed or without the treatment of EGFRTKI. 6. Adequate hematological and physiological functions of heart, lung, liver, and kidney according to definitions given in Appendix D. 7. Any prior treatment (including chemotherapy, radiotherapy, biotherapy and other clinical medicine) must be completed over 28 days or 5 half-lives from the screening. 8. ECOG (Eastern Cooperative Oncology Group) performance status of 0 to 1. 9. NSCLC patients with asymptomatic brain metastasis or drug-controllable brain metastasis. 10. Life expectancy of at least 3 months. 11. Patients should cooperate with investigator to observe adverse events and efficacy. 12. Without other anticancer therapy. 13. Women without pregnancy or breastfeeding. 14. Adequate function of blood coagulation (INR≤1.5) 15. Signed consent on an Independent Ethics Committee-approved Informed Consent Form prior to any study-specific evaluation.
Exclusion criteria
- Phase 1: 1. No pathology confirmation. 2. HCV positive, active hepatitis B. 3. History of interstitial lung disease related to prior EGFR inhibitor therapy. 4. Positive to HIV antibody or other immunodeficiency disease or organ transplantation. 5. Residue toxicity related to prior therapies \> grade 1. 6. BUN or Cr \> 1.5 × upper limits of normal. 7. ALT or AST \> 2.5 × upper limits of normal, total bilirubin\> 1.5 × upper limits of normal. 8. Fever (temperature\>38℃ or any uncontrolled active infections. 9. Patients received high-dose glucocorticoid or any other immunosuppression within 1 month. 10. Any severe or uncontrolled disease, such as mental, neurologic, cardiovascular, respiratory diseases. 11. Patients with symptomatic and untreated brain metastasis. 12. Patients with organic heart disease, cardiac insufficiency, \>2 degree heart block, experienced myocardial infarction in 6 months. Abnormal PR, QT, QRS interval (defined as: 12 lead electrocardiogram QT interval correlated to Bazetts (QTcB)\>450ms (male) or \>470ms (female), PR\>240ms, QRS\>110ms). 13. Patients receiving medication known to prolong QT interval. 14. Past history of major surgery in 14 days prior to enrollment. 15. Pregnant or lactating women. 16. Any other reasons for the investigator to consider the patient should not participate in the study. Inclusion Criteria - Phase 2: 1. Patients of either gender, aged from 18 years older to 75. 2. Histologically or cytologically confirmed metastatic, or unresectable locally advanced, recurrent NSCLC. 3. At least one measurable disease by CT or MRI, according to RECIST Version 1.1. 4. Failed to the treatment of EGFR-TKI and harbored T790M mutation. 5. Offer biopsy sample to central lab if failed or without the treatment of EGFRTKI. 6. Patients failed the treatment of EGFR-TKI should be treated with only one kind of medicine. Patients with arbored T790M mutation should be treated with only one kind of medicine or never be treated. 7. Comply with the results of laboratory testing. 8. ECOG (Eastern Cooperative Oncology Group) performance status of 0 to 1 and no deterioration in 2 weeks. 9. Life expectancy of more than 12 weeks. 10. Patients should cooperate with investigator to observe adverse events and efficacy. 11. Women without pregnancy. 12. Signed consent on an Independent Ethics Committee-approved Informed Consent Form prior to any study-specific evaluation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| ORR(Objective Response Rate) | Every 6 weeks from time of first dose until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 11 months | To assess the overall objective response rate (ORR) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| PFS (Progression-free survival) | Every 6 weeks from time of first dose until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 11 months | To assess the progression-free survival (PFS) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC). |
| DCR (Disease control rate) | Every 6 weeks from time of first dose until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 11 months | To assess the disease control rate (DCR) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC). |
| DoR (Duration of Response) | Every 6 weeks from time of first dose until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 11 months | To assess the duration of response (DOR) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC). |
| EORTC QLQ-C30 and LC-13 questionnaire | From screening to the end of survival follow-up, which is assessed though study completion | To assess the safety of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC). |
| Adverse events | From screening to 30days after end of treatment, which is assessed through study completion | To assess the safety of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC). |
| OS (Overall survival) | Every 6 weeks from time of first dose until objective disease progression, then every 3 months until death of lost of follow-up, up to approximately 18 months | To assess the overall survival (OS) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC). |
Countries
China
Outcome results
None listed