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Safety, Pharmacokinetic and Preliminary Efficacy Study of AC0010 in Patients With EGFR T790M Positive NSCLC

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ClinicalTrials.gov Identifier: NCT02330367
Recruitment Status : Active, not recruiting
First Posted : January 1, 2015
Last Update Posted : February 19, 2019
Sponsor:
Collaborators:
Guangdong Provincial People's Hospital
Acea Bio (Hangzhou) Co., Ltd.
Information provided by (Responsible Party):
Hangzhou ACEA Pharmaceutical Research Co., Ltd.

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.

Condition or disease Intervention/treatment Phase
Metastatic Non-small Cell Lung Cancer Drug: AC0010 Phase 1

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:

Stage 1 : Dose-escalation Period with 28-day cycles; Optional Treatment Extension Period starting on Day 29

Stage 2 : Evaluation of activity and safety in patients with the EGFR T790M mutation


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 368 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Safety, Tolerability, Pharmacokinetics and Anti-tumour Activity of AC0010 in Patients With EGFR T790M Positive Advanced Non Small Cell Lung Cancer Who Progressed on Prior Therapy With EGFR TKIs
Actual Study Start Date : January 2015
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : December 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lung Cancer

Arm Intervention/treatment
Experimental: AC0010
Oral AC0010 monotherapy
Drug: AC0010

Stage 1: AC0010 will be administered in escalating dosages in a period of 28-day cycles.

Stage 2: AC0010 will be administered twice-daily at RP2D.

Other Name: AC0010MA




Primary Outcome Measures :
  1. ORR(Objective Response Rate) [ Time Frame: 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 Outcome Measures :
  1. DoR (Duration of Response) [ Time Frame: 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).

  2. PFS (Progression-free survival) [ Time Frame: 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).

  3. DCR (Disease control rate) [ Time Frame: 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).

  4. OS (Overall survival) [ Time Frame: 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).

  5. EORTC QLQ-C30 and LC-13 questionnaire [ Time Frame: 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).

  6. Adverse events [ Time Frame: 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).



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria - Stage 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 - Stage 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 - Stage 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.

Exclusion Criteria - Stage 2:

  1. Acute and chronic hepatitis C, active hepatitis B (including positive HBsAg and/or HBeAg; HBcAb and/or positive HBeAb and positive HBV DNA), hepatitis E Virus IgM antibody positive.
  2. History of interstitial lung disease related to prior EGFR inhibitor therapy.
  3. Positive to HIV antibody or other immunodeficiency disease or organ transplantation.
  4. Fever (temperature>38℃ or any uncontrolled active infections.
  5. Patients received high-dose glucocorticoid or any other immunosuppression within 1 month.
  6. Any severe or uncontrolled disease, such as mental, neurologic, cardiovascular, respiratory diseases.
  7. ECG showed abnormal rhythm, conduction and form, such as complete left bundle branch block, >2 degree heart block, PR interval >250ms, experienced myocardial infarction in 6 months. Risks leading to prolonged QT interval or arrhythmia, such as heart failure, hypokalemia, congenital long QT, long QT family history or sudden death under 40 years old in first degree relatives (12 lead electrocardiogram QT interval correlated to Bazetts (QTcB) > 450ms.
  8. Prior history of malignancies other than NSCLC (except cured malignancy such as removed basal-cell carcinoma and carcinoma in situ) within 5 years.
  9. Patients with CNS metastasis (except asymptomatic CNS metastasis with stable radiography in 4 weeks and no long-term use of corticosteroid. CNS metastasis focuses ≤2, maximum diameter of focus <10mm)
  10. Radiation field covered more than 30% bone marrow within 4 weeks of enrollment.
  11. Lab test of 1ml plasma prove treatment of AZD9291.
  12. Patients already received treatment of this research or quite the treatment of this research. Patients treated with 3rd generation of EGFR-TKI (AZD9291, AC0010, BPI-15086, CO-1686, HM61713).
  13. Past history of major surgery in 14 days prior to enrollment.
  14. Pregnant or lactating women.
  15. Patients with uncontrolled pleural effusion and/or pericardial effusion.
  16. Any other reasons for the investigator to consider the patient should not participate in the study

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02330367


Locations
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China, Beijing
307 Hospital of PLA
Beijing, Beijing, China, 100000
Beijing Cancer Hospital
Beijing, Beijing, China, 100000
Cancer Hospital Chinese Academy of Medical Sciences
Beijing, Beijing, China, 100000
Chinese PLA General Hospital
Beijing, Beijing, China, 100000
Peking Union Medical College Hospital
Beijing, Beijing, China, 100000
China, Fujian
Fujian Medical University Union Hospital
Fuzhou, Fujian, China, 350000
China, Guangdong
Sun Yat-sen University Cancer Center
Guangzhou, Guangdong, China, 510000
Guangdong Provincial People's Hospital
Guangzhou, Guangdong, China
China, Hunan
Hunan Cancer Hospital
Changsha, Hunan, China, 410000
China, Jiangsu
Jiangsu Cancer Hospital
Nanjing, Jiangsu, China, 210000
Jiangsu Province Hospital
Nanjing, Jiangsu, China, 210000
Nanjing General Hospital of Nanjing Military Command
Nanjing, Jiangsu, China, 210000
China, Jilin
Jilin Cancer Hospital
Chang Chun, Jilin, China, 130000
China, Shanghai
Shanghai Chest Hospital
Shanghai, Shanghai, China, 200000
China, Sichuan
West China Hospital,Sichuan University
Chendu, Sichuan, China, 610000
China, Zhejiang
The First Affiliated Hospital, Zhejiang University
Hangzhou, Zhejiang, China, 310000
The Second Affiliated Hospital of Zhejiang University School of Medicine
Hanzhou, Zhejiang, China, 310000
Sponsors and Collaborators
Hangzhou ACEA Pharmaceutical Research Co., Ltd.
Guangdong Provincial People's Hospital
Acea Bio (Hangzhou) Co., Ltd.
Investigators
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Principal Investigator: Yilong Wu, MD. Guangdong Provincial People's Hospital

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Hangzhou ACEA Pharmaceutical Research Co., Ltd.
ClinicalTrials.gov Identifier: NCT02330367     History of Changes
Other Study ID Numbers: AC201410AVTN02.
First Posted: January 1, 2015    Key Record Dates
Last Update Posted: February 19, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Additional relevant MeSH terms:
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Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms