Clinical Trials /

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

NCT02330367

Description:

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.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: AC201410AVTN02(v1.8)
  • NCT ID: NCT02330367

Conditions

  • Metastatic Non-small Cell Lung Cancer

Interventions

DrugSynonymsArms
AC0010AC0010MAAC0010

Purpose

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:

      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
    

Trial Arms

NameTypeDescriptionInterventions
AC0010ExperimentalOral AC0010 monotherapy
  • AC0010

Eligibility 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
      
Maximum Eligible Age:75 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description: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

Measure: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
Safety Issue:
Description:To assess the duration of response (DOR) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).
Measure: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
Safety Issue:
Description:To assess the progression-free survival (PFS) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).
Measure: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
Safety Issue:
Description:To assess the disease control rate (DCR) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).
Measure: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
Safety Issue:
Description:To assess the overall survival (OS) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).
Measure:EORTC QLQ-C30 and LC-13 questionnaire
Time Frame:From screening to the end of survival follow-up, which is assessed though study completion
Safety Issue:
Description:To assess the safety of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).
Measure:Safety
Time Frame:From screening to 30days after end of treatment, which is assessed through study completion
Safety Issue:
Description:To assess the safety of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Hangzhou ACEA Pharmaceutical Research Co.,Ltd.

Last Updated

September 29, 2017