Clinical Trials /

Alflutinib Mesylate Versus Gefitinib in Patients With Locally Advanced or Metastatic Non-small Cell Lung Cancer (FLAG)

NCT03787992

Description:

To assess the efficacy and safety of Alflutinib Mesylate versus Gefitinib in patients with locally advanced or Metastatic Non Small Cell Lung Cancer

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

Not yet recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Alflutinib Mesylate Versus Gefitinib in Patients With Locally Advanced or Metastatic Non-small Cell Lung Cancer (FLAGE)
  • Official Title: A Randomized, Double-blind, Positive-controlled, Multi-center Phase III Clinical Study of Evaluating Alflutinib Mesylate Versus Gefitinib as First-line Therapy in Patients With Locally Advanced or Metastatic Non-Small-Cell Lung Cancer (NSCLC) With EGFR-sensitive Mutations(Flage)

Clinical Trial IDs

  • ORG STUDY ID: 201801215
  • NCT ID: NCT03787992

Conditions

  • Locally Advanced or Metastatic EGFR Sensitising Mutation Positive Non-small Cell Lung Cancer

Interventions

DrugSynonymsArms
Alflutinib Mesylate (AST2818) 80mg//40 mg+ placeboAlflutinib Mesylate (AST2818) +placebo
Placebo Gefitinib 250 mgAlflutinib Mesylate (AST2818) +placebo
Gefitinib 250 mgGefitinib + placebo AST2818
Placebo AST2818 80mg//40 mgGefitinib + placebo AST2818

Purpose

To assess the efficacy and safety of Alflutinib Mesylate versus Gefitinib in patients with locally advanced or Metastatic Non Small Cell Lung Cancer

Detailed Description

      This is a Phase III, double-blind, randomised study assessing the efficacy and safety of
      Alflutinib Mesylate (AST2818) (80 mg orally, once daily) versus Gefitinib (250 mg orally,
      once daily] in patients with locally advanced or metastatic Non-small Cell Lung Cancer
      (NSCLC) that is known to be EGFR sensitising mutation (EGFRm) positive for first-line
      treatment with an EGFR-TKI.
    

Trial Arms

NameTypeDescriptionInterventions
Alflutinib Mesylate (AST2818) +placeboExperimentalAST2818 (80 mg or 40 mg orally, once daily) plus placebo Gefitinib (250 mg orally, once daily), in accordance with the randomization schedule
  • Alflutinib Mesylate (AST2818) 80mg//40 mg+ placebo
  • Placebo Gefitinib 250 mg
Gefitinib + placebo AST2818Active ComparatorGefitinib (250 mg orally, once daily) + placebo AST2818 (80 mg or 40 mg orally, once daily), in accordance with the randomisation schedule.
  • Gefitinib 250 mg
  • Placebo AST2818 80mg//40 mg

Eligibility Criteria

        Inclusion Criteria:

          1. Subjects must meet all the following criteria to be enrolled in this study: subjects
             will voluntarily participate and sign a written informed consent.

          2. Male or female, aged at least 18 years.

          3. ECOG performance status of 0 to 2. Life expectancy of at least 12 weeks.

          4. Patients had histologically or cytologically confirmed locally advanced or metastatic
             pancreatic adenocarcinoma not amenable to curative surgery or radiotherapy.

          5. The tumour harbours one of the 2 common EGFR mutations known to be associated with
             EGFR-TKI sensitivity (Ex19del, L858R).

          6. Tumour tissue sample in a quantity sufficient to allow for central analysis of EGFR
             mutation status.

          7. Patients must be treatment-naïve for locally advanced or metastatic NSCLC and eligible
             to receive first-line treatment with gefitinib or erlotinib as selected by the
             participating centre. Prior adjuvant and neo-adjuvant therapy is permitted
             (chemotherapy, radiotherapy, investigational agents) if the disease has no progression
             during one year.

          8. At least one measurable lesion by CT or MRI. The measureable lesion should receive no
             local treatments (i.e., radiotherapy) or not used for screening biopsies (If there is
             only one target lesion that must be biopsied, baseline tumor evaluation is required at
             least 14 days after screening biopsy) and can be accurately measured at baseline with
             the longest diameter greater than 10 mm at baseline (if it is a lymph node, short
             diameter greater than 15 mm is required). If the lesions located at the regions which
             were previously treated are confirmed to progress, they can be chosen as lesion
             according to RECIST Version 1.1

          9. Females who have fertility potential before menopause should have a pregnancy test in
             the time period of 7 days prior to start of dosing, should not be breast feeding and
             must have a negative pregnancy test (blood test or urinalysis) prior to start of
             dosing; Males and females of child-bearing age must take adequate contraceptive
             measures within 3 months after signing the informed consent of the study to the last
             drug treatment.

        Exclusion Criteria:

          1. Treatment with any of the following:

               -  Prior treatment with any systemic anti-cancer therapy for locally
                  advanced/metastatic NSCLC, such as standard chemotherapy, targeted therapy,
                  biological therapy, immune therapy and for the prior adjuvant / neo-adjuvant
                  therapy listed in the inclusion criteria VII

               -  Patients received other systemic anticancer therapies for advanced/metastatic
                  non-small cell lung cancer

               -  Patients who have received intrapleural perfusion therapy should be admitted to
                  the group unless the stabilization of hydrothorax is longer than 28 days

               -  Prior treatment with an EGFR-TKI

               -  Major surgery within 4 weeks of the first dose of study drug

               -  Radiotherapy treatment to more than 30% of the bone marrow or with a wide field
                  of radiation within 4 weeks of the first dose of study drug and local
                  radiotherapy or palliative radiotherapy for bone metastasis within 14 days before
                  first drug administration

               -  Patients receiving medications or herbal supplements known to be potent
                  inhibitors or inducers of cytochrome P450 (CYP) 3A4 within 7 days before first
                  drug administration and patients continuously taking these medications during
                  investigating period

               -  Patients taking traditional Chinese medicine and preparations whose therapeutic
                  goal is anti-tumors within 7 days before first drug administration; or
                  continuously taking these medications during investigating period

               -  Patients with any factors that increase the risk of QTc prolongation or risk of
                  Torsade ventricular tachycardia event who continuously take these medications
                  during investigating period.

               -  Before the first administration, the duration of discontinuation of other
                  clinical experimental drugs was less than 14 days

          2. Unrecovered toxic reaction due to anti-tumor therapy existed, with over 1 grade of
             CTCAE (except alopecia) or 2 grade if ever applied DDP curing related neuropathy; Bone
             marrow, liver and kidney organ function please refer to exclusion criteria 7.

          3. The tissue type is mixed type, that is, patients with lung adenocarcinoma mixed with
             lung squamous cell carcinoma.

          4. Patients with spinal cord compression, asymptomatic and stable brain metastases,
             except for those patients who have completion of the definitive therapy and steroids
             at least 28 days before investigation,or patients who received local radiotherapy for
             brain metastasis will be allowed in when the period of stabilization of brain
             metastases are at no shorter than 28 days.

          5. Patients with other malignant tumors or have a history of other malignant tumors,
             except for basal cell carcinoma of the skin, carcinoma in situ of the cervix and
             ductal carcinoma in situ of the breast.

          6. 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, history of gastrointestinal
             resection or surgery, uncured recurrent diarrhea, atrophic gastritis (the age of onset
             is less than 60 years old), stomach diseases, crohn's disease and ulcerative colitis
             that require long-term use of PPI antiacid drugs without cure.

          7. Patients of organ insufficiency in bone marrow, liver and kidney meet the following
             requirements (patients should receive no blood transfusion, blood product,
             hematopoietic stimulating factors, and albumin two weeks before blood sampling of
             admission ):

               -  Absolute neutrophil count < 1.5 x 109/L, Platelet count < 75 x109/L, Haemoglobin
                  < 90 g/L;

               -  Alanine aminotransferase/Aspartate aminotransferase > 2.5 times the upper limit
                  of normal (ULN) if no demonstrable liver metastases or > 5 times in the presence
                  of liver metastases;

               -  Total bilirubin > 1.5 times ULN, or >3 times ULN in the presence of definitive
                  Gilbert's syndrome (Unbound hyperbilirubinemia) or liver metastases;

               -  Creatinine >1.5 times ULN concurrent with creatinine clearance < 50 ml/min
                  (measured or calculated by Cockcroft and Gault equation);

               -  The international standardized ratio (INR) was > and 1.5, and the partial
                  activation time of prothrombin (APTT) was > 1.5 times ULN.

          8. Any condition meets the following cardiac standard:

               -  Mean resting corrected QT interval (QTc)>470 msec, obtained from 3 ECG, using the
                  screening clinic ECG machine-derived QTc value.

               -  Any clinically important abnormalities in rhythm, conduction, or morphology of
                  resting ECG, e.g., complete left bundle branch block, third-degree heart block,
                  second-degree heart block, PR interval >250 msec

               -  Any factors that increase the risk of QTc prolongation or risk of arrhythmic
                  events such as heart failure, hypokalaemia, 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.

               -  Echocardiographic examination: LVEF<50%

          9. Active infection with HBV, HCV, or HIV. All subjects will be screened for HBV, HCV, or
             Or HIV infection during the screening period:

               -  HBsAg positive, HBV DNA ≥1000cps/ml(or200IU/ml)

               -  Anti-HCV antibody was positive and HCV RNA was positive

               -  HIV antibody was positive

         10. Interstitial lung disease, drug - induced interstitial pulmonary disease, history of
             radiation pneumonia which required steroid treatment; acute or progressive pulmonary
             symptoms may occur at baseline or interstitial pulmonary disease may be identified
             that the researchers considered not suitable for trail

         11. Allergy to the study drug and/or its excipients is known or suspected

         12. Women during pregnancy or lactation

         13. Judgment by investigator that the patients should participate in the study if the
             patient is unlikely to comply with study procedure, restrictions, and requirements
             (for example, uncontrolled hypertension, uncontrolled diabetes, active bleeding
             constitution, etc.)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Median Progression Free Survival (PFS) (Months)
Time Frame:At baseline and every 6 weeks for the first 17 months and then every 12 weeks relative to randomisation until progression ( (approximately 12 months)
Safety Issue:
Description:Progression-free survival was defined as the time from randomization until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the participant withdrew from randomized therapy or received another anti-cancer therapy prior to progression and was used to assess the efficacy of single agent alflutinib compared with SoC EGFR-TKI therapy as measured by PFS.

Secondary Outcome Measures

Measure:Overall Survival (OS)- Number of Participants With an Event
Time Frame:From first dose to end of study or date of death from any cause, whichever comes first, assessed every 6 weeks (approximately 29 months)
Safety Issue:
Description:Overall survival was defined as the time from the date of randomisation until death from any cause and was used to further assess the efficacy of alflutinib compared with SoC EGFR-TKI therapy
Measure:Progression Free Survival (PFS) evaluated by investigator
Time Frame:At baseline and every 6 weeks for the first 17 months and then every 12 weeks relative to randomisation until progression (approximately 12 months)
Safety Issue:
Description:Progression-free survival was defined as the time from randomization until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the participant withdrew from randomized therapy or received another anti-cancer therapy prior to progression and was used to assess the efficacy of single agent alflutinib compared with SoC EGFR-TKI therapy as measured by PFS.
Measure:Objective Response Rate (ORR)
Time Frame:At baseline and every 6 weeks for the first 17 months and then every 12 weeks relative to randomisation until progression (approximately 12 months)
Safety Issue:
Description:ORR was defined as the number (%) of patients with measurable disease with at least 1 visit response of Complete response (CR) or Partial response (PR) and it was used to further assess the efficacy of alflutinib compared with SoC EGFR-TKI therapy
Measure:Duration of Response (DoR)
Time Frame:At baseline and every 6 weeks for the first 17 months and then every 12 weeks relative to randomisation until progression (approximately 12 months)
Safety Issue:
Description:Duration of response was defined as the time from the date of first documented response until the date of documented progression or death in the absence of disease progression and was used to further assess the efficacy of alflutinib compared with SoC EGFR-TKI therapy.
Measure:Depth of Response
Time Frame:At baseline and every 6 weeks for the first 17 months and then every 12 weeks relative to randomisation until progression (approximately 12 months)
Safety Issue:
Description:The Depth of response was defined as the relative change in the sum of the longest diameters of Response Evaluation Criteria in Solid Tumors (RECIST) Target lesions (TLs) at the nadir, in the absence of new lesions (NLs) or progression of Non-target lesions (NTLs), compared to baseline and was used to further assess the efficacy of alflutinib compared with SoC EGFR-TKI therapy
Measure:Change From Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life (QLQ) Questionnaires Lung Cancer 13 (QLQ-LC13)
Time Frame:Questionnaires completed at week 1, 4, 7, 9, 12, 15 , 18,21,27,33,39,45and51
Safety Issue:
Description:The EORTC QLQ-LC13 was a lung-cancer-specific module comprising 13 questions to assess lung cancer symptoms (cough, haemoptysis, dyspnoea, and site-specific pain [pain in chest, pain in arm or shoulder, and pain in other parts); treatment related side-effects (sore mouth, dysphagia, peripheral neuropathy, and alopecia); and pain medication. Except for a multi-item scale for dyspnoea, all were single items. An outcome variable consisting of a score from 0 to 100 was derived for each of the symptom scales/symptom items. Higher scores on the global health status/QoL and functioning scales indicated better health status/QoL and better function. Higher scores on the symptoms scales indicated greater symptom burden. The results of the analyses were presented in terms of a least squares mean together with its associated 95% profile likelihood CI
Measure:Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Items
Time Frame:Questionnaires completed at week 1, 4, 7, 9, 12, 15 , 18,21,27,33,39,45and51
Safety Issue:
Description:he EORTC QLQ-C30 cancer-specific questionnaire consisted of 30 questions, which were combined to produce 5 functional scales (Physical, Role, Cognitive, Emotional, Social); 3 symptom scales (Fatigue, Pain, Nausea/Vomiting); 6 individual items (dyspnoea, insomnia, appetite loss, constipation, diarrhoea, and financial difficulties); and a global measure of health status/QoL. An outcome variable consisting of a score from 0 to 100 was derived for each of the symptom scales/symptom items, the functional scales, and the global health status/QoL scale in the EORTC QLQ-C30. Higher scores on the global health status and functioning scales indicated better health status/function. Higher scores on the symptoms scales indicated greater symptom burden. The results of the analyses were presented in terms of a least squares mean together with its associated 95% profile likelihood CI.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Allist Pharmaceuticals, Inc.

Last Updated