Clinical Trials /

Compare Bevacizumab in Combination With Erlotinib Versus Erlotinib Alone in NSCLC Patients Activating EGFR Mutations

NCT02759614

Description:

This is a randomized, open-label, controlled, multicenter, Phase III study. Patients will be randomly assigned to treatment group (1:1) through a dynamic randomization process with use of the following stratification factors: sex (female/male), disease stage (stage IIIb vs. stage IV vs. recurrence), and EGFR gene mutation (exon 19 deletion vs. exon 21 L858R).

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

Active, not recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Compare Bevacizumab in Combination With Erlotinib Versus Erlotinib Alone in NSCLC Patients Activating EGFR Mutations
  • Official Title: Randomized, Open-label, Controlled Multicenter Study to Compare Bevacizumab in Combination With Erlotinib Versus Erlotinib Alone in Chinese NSCLC Patients Harbouring Activating EGFR Mutations(Artemis)

Clinical Trial IDs

  • ORG STUDY ID: CTONG1509
  • NCT ID: NCT02759614

Conditions

  • NSCLC

Interventions

DrugSynonymsArms
BevacizumabAvastinBevacizumab and Erlotinib
ErlotinibTarcevaBevacizumab and Erlotinib

Purpose

This is a randomized, open-label, controlled, multicenter, Phase III study. Patients will be randomly assigned to treatment group (1:1) through a dynamic randomization process with use of the following stratification factors: sex (female/male), disease stage (stage IIIb vs. stage IV vs. recurrence), and EGFR gene mutation (exon 19 deletion vs. exon 21 L858R).

Detailed Description

      This is a randomized, open-label, controlled, multicenter, Phase III study. Patients will be
      randomly assigned to treatment group (1:1) through a dynamic randomization process with use
      of the following stratification factors: sex (female/male), disease stage (stage IIIb vs.
      stage IV vs. recurrence), and EGFR gene mutation (exon 19 deletion vs. exon 21 L858R).

      An independent review committee (IRC) will be used to determine the response based study
      endpoints. IRC membership and procedures will be detailed in an IRC charter.

      A data safety monitoring board (DSMB) will be used in this study. DSMB is an independent body
      and will be responsible for reviewing safety data of the study. DSMB membership and
      procedures will be detailed in a separate DSMB document.

      Information regarding the nature and the duration of subsequent treatment will be collected.
    

Trial Arms

NameTypeDescriptionInterventions
Bevacizumab and ErlotinibExperimentalBevacizumab 15 mg/kg shall be intravenous infusion on day 1 once every 3 weeks, Erlotinib 150 mg tablets shall be administered orally every day at least one hour before or two hours after the ingestion of food.
  • Bevacizumab
  • Erlotinib
ErlotinibActive ComparatorErlotinib 150 mg tablets shall be administered orally every day at least one hour before or two hours after the ingestion of food.
  • Erlotinib

Eligibility Criteria

        Inclusion Criteria:

        Patients must meet the following criteria for study entry:

          1. Signed Informed Consent Form.

          2. Age≥18 years.

          3. Able to comply with the study protocol, in the investigator's judgment.

          4. Histologically or cytologically documented inoperable, locally advanced (Stage IIIb
             who are not amenable for combined modality treatment), metastatic (Stage IV) or
             recurrent non-squamous NSCLC. Diagnoses of non-squamous NSCLC based on sputum cytology
             alone are not acceptable.

          5. An exon 19 deletion mutation or exon 21 L858R mutation has been found in
             high-sensitivity EGFR mutation tests by PCR using tumor tissue centrally confirmed.
             Direct sequencing is not accepted.

          6. Eastern Cooperative Oncology Group performance status 0-1.

          7. Life expectancy≥12 weeks.

          8. Previous systemic cytotoxic chemotherapy for locally advanced, metastatic or recurrent
             disease has not been performed. Subjects who have undergone intracavity administration
             with an antineoplastic agent during pleurodesis are not permitted. For patients who
             have undergone pre- or postoperative adjuvant chemotherapy, at least 6 months have
             elapsed since the final administration date.

          9. Patients who have undergone radiotherapy may be enrolled if they meet the following
             conditions:

               -  The patient has no history of radiotherapy for lesions in lung fields within 28
                  days before the randomization.

               -  For radiotherapy outside the chest region, at least 28 days have elapsed by the
                  time of randomization since the final irradiation date. (if the radiotherapy
                  given as palliation to bone metastases within 2 weeks, the patient should
                  recovery from all toxicities)

         10. Measurable disease at baseline. At least one lesion is present that can be measured in
             accordance with the criteria in Response Evaluation Criteria in Solid Tumors (RECIST)
             Version 1.1. However, sites treated by radiotherapy should not be considered
             measurable.

         11. Adequate haematological function:

               -  Absolute neutrophil count (ANC)≥1.5×109/L AND

               -  Platelet count≥100×109/L AND

               -  Haemoglobin≥9 g/dL (may be transfused to maintain or exceed this level)

         12. Adequate liver function.

               -  Total bilirubin<1.5×upper limit of normal (ULN) AND

               -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT)<2.5×ULN in
                  patients without liver metastases; <5×ULN in patients with liver metastases

         13. Adequate renal function

               -  Serum creatinine≤1.5×ULN or calculated creatinine clearance≧45mL/min AND

               -  Urine dipstick for proteinuria<2+. Patients discovered to have ≥2+ proteinuria on
                  dipstick urinalysis at baseline should undergo a 24-hour urine collection and
                  must demonstrate≤1 g of protein in 24 hours.

         14. International normalised ratio (INR)≤1.5 and partial prothrombin time (PTT or
             aPTT)≤1.5×ULN within 7 days prior to randomization.

         15. For women who are not postmenopausal (≥12 months of non-therapy-induced amenorrhea) or
             surgically sterile (absence of ovaries and/or uterus): agreement to remain abstinent
             or use single or combined contraceptive methods that result in a failure rate of < 1%
             per year during the treatment period and for at least 6 months after the last dose of
             study drug.

         16. For men: agreement to remain abstinent or use a condom plus an additional
             contraceptive method that together result in a failure rate of < 1% per year during
             the treatment period and for at least 6 months after the last dose of study drug and
             agreement to refrain from donating sperm during this same period.

        Exclusion Criteria:

        Patients who meet any of the following criteria will be excluded from study entry:

          1. Mixed adenosquamous carcinomas with predominantly squamous component.

          2. A positive result for the exon 20 T790M mutation from any high-sensitivity EGFR
             mutation test such as digital PCR using tumor tissue or cells.

          3. Evidence of CNS metastases, except for the patients without any symptom or the
             patients with symptom but have stable disease for at least 28 days after treatment of
             CNS metastases.

          4. History of haemoptysis, defined as > 2.5 ml of red blood per event within 3 months
             prior to randomization.

          5. Evidence of tumour invading major blood vessels on imaging. The investigator or the
             local radiologist must exclude evidence of tumour that is fully contiguous with,
             surrounding, or extending into the lumen of a major blood vessel (e.g., pulmonary
             artery or superior vena cava).

          6. Major surgery (including open biopsy) or significant traumatic injury within 28 days
             prior to randomization or anticipation of the need for major surgery during study
             treatment.

          7. Core biopsy or other minor surgical procedure, excluding placement of a vascular
             access device are excluded within 7 days prior to initiation of study treatment.
             Placement of a vascular access device should be at least 2 days prior to initiation of
             study treatment.

          8. Current or recent (within 10 days of first dose of bevacizumab) use of aspirin (325
             mg/day) or other nonsteroidal anti-inflammatory agents known to inhibit platelet
             function.

          9. Current or recent (within 10 days of first dose of bevacizumab) use of full-dose oral
             or parenteral anticoagulants or thrombolytic agent for therapeutic purposes.
             Prophylactic use of anticoagulants is allowed.

         10. History or evidence of inherited bleeding diathesis or coagulopathy that increases the
             risk of bleeding.

         11. Uncontrolled hypertension (blood pressures: systolic>150 mmHg and/or diastolic >100
             mmHg).

         12. Prior history of hypertensive crisis or hypertensive encephalopathy.

         13. Clinically significant (i.e., active) cardiovascular disease, including but not
             limited to cerebral vascular accident (CVA) or (transient ischemic attack) TIA (≤6
             months before randomization), myocardial infarction (≤6 months before randomization),
             unstable angina, congestive heart failure New York Heart Association Class≥II, or
             serious cardiac arrhythmia requiring medication during the study and that might
             interfere with regularity of the study treatment or not controlled by medication.

         14. Significant vascular disease (including but not limited to aortic aneurysm requiring
             surgical repair or recent arterial thrombosis) within 6 months prior to randomization.

         15. Non-healing wound, active peptic ulcer, or bone fracture.

         16. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess
             within 6 months of enrollment.

         17. Pregnant or lactating, or intending to become pregnant during the study.

         18. Treatment with any other investigational agent or participation in another clinical
             trial within 28 days prior to randomization.

         19. Known hypersensitivity to bevacizumab and Chinese hamster ovary cell products or other
             recombinant human or humanised antibodies or erlotinib or any of its excipients.

         20. Evidence of ongoing or active infection requiring IV antibiotics; any other disease,
             neurological, or metabolic dysfunction; physical examination finding or laboratory
             finding giving reasonable suspicion of a disease or condition that contraindicates the
             use of an investigational drug or puts the patient at high risk for treatment-related
             complications.

         21. Patients diagnosed with a tracheo-oesophageal fistula.

         22. Prior chemotherapy or treatment with another systemic anti-cancer agent (e.g.,
             monoclonal antibody, tyrosine kinase inhibitors, EGFR inhibitors, VEGF receptor
             inhibitors) for the treatment of the patient's current stage of disease (Stage IIIB
             not amenable for combined modality treatment, Stage IV or postoperative recurrent
             disease). NOTE:

             i. Previous adjuvant or neo-adjuvant treatment for non-metastatic disease is permitted
             if completed ≥ 6 months before randomization.

         23. Lack of physical integrity of the upper gastrointestinal tract, or malabsorption
             syndrome, or inability to take oral medication, or have active gastroduodenal ulcer
             disease.

         24. Any inflammatory changes of the surface of the eye (e.g.: severe dry eye syndrome,
             keratoconjunctivitis, keratitis etc.) or any other disorder likely to increase the
             risk of corneal epithelial lesions. The use of contact lenses is not recommended
             during the study. The decision to continue to wear contact lenses should be discussed
             with the patient's treating oncologist and the ophthalmologist.

         25. Patients with pre-existing Interstitial Lung Disease or pulmonary fibrosis.

         26. Malignancies other than NSCLC within 5 years prior to randomization, except for
             adequately treated carcinoma in situ of the cervix, basal or squamous cell skin
             cancer, localized prostate cancer treated surgically with curative intent, ductal
             carcinoma in situ treated surgically with curative intent.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression-free survival (PFS) by IRC
Time Frame:The primary PFS analysis will be performed when approximately 224 PFS events (disease progression or death, whichever occurs first) have occurred, which is estimated to occur at approximately 18 months after enrollment of the last patient.
Safety Issue:
Description:To evaluate the efficacy of bevacizumab combined with erlotinib compared with erlotinib alone in patients with NSCLC harbouring activating EGFR mutations, as measured by independent review committee assessed progression-free survival using RECIST v1.1

Secondary Outcome Measures

Measure:Progression-free survival (PFS) by investigator using RECIST v1.1
Time Frame:The primary PFS analysis will be performed when approximately 224 PFS events (disease progression or death, whichever occurs first) have occurred, which is estimated to occur at approximately 18 months after enrollment of the last patient.
Safety Issue:
Description:To evaluate the efficacy of bevacizumab combined with erlotinib compared with erlotinib alone in patients with NSCLC harbouring activating EGFR mutations, as measured by investigators assessed progression-free survival using RECIST v1.1
Measure:Objective response rate (ORR) by IRC using RECIST v1.1
Time Frame:baseline overall tumor assessment can be performed up to 28 days prior to randomization. Post-baseline assessment will be performed every six weeks until 1st disease progression, through study completion, an average of 2 years.
Safety Issue:
Description:To evaluate the efficacy of bevacizumab combined with erlotinib compared with erlotinib alone in patients with NSCLC harbouring activating EGFR mutations, as measured by independent review committee assessed objective response rate using RECIST v1.1
Measure:Objective response rate (ORR) by investigator using RECIST v1.1
Time Frame:baseline overall tumor assessment can be performed up to 28 days prior to randomization. Post-baseline assessment will be performed every six weeks until 1st disease progression, through study completion, an average of 2 years.
Safety Issue:
Description:To evaluate the efficacy of bevacizumab combined with erlotinib compared with erlotinib alone in patients with NSCLC harbouring activating EGFR mutations, as measured by investigators assessed objective response rate using RECIST v1.1
Measure:Disease control rate (DCR) by IRC using RECIST v1.1
Time Frame:That is expected to be approximately 57 months.
Safety Issue:
Description:Disease control rate (DCR) will be analyzed using similar method as objective response rate.
Measure:Disease control rate (DCR) by investigator using RECIST v1.1
Time Frame:That is expected to be approximately 57 months.
Safety Issue:
Description:Disease control rate (DCR) will be analyzed using similar method as objective response rate.
Measure:Duration of response(DOR) by IRC using RECIST v1.1
Time Frame:That is expected to be approximately 57 months.
Safety Issue:
Description:Duration of response(DOR) will be analyzed using similar method as objective response rate.
Measure:Duration of response(DOR) by investigator using RECIST v1.1
Time Frame:That is expected to be approximately 57 months.
Safety Issue:
Description:Duration of response(DOR) will be analyzed using similar method as objective response rate.
Measure:Overall survival(OS)
Time Frame:That is expected to be approximately 57 months.
Safety Issue:
Description:To evaluate the efficacy of bevacizumab combined with erlotinib compared with erlotinib alone in patients with NSCLC harbouring activating EGFR mutations, as measured by investigators assessed overall survival .

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Guangdong Association of Clinical Trials

Last Updated

June 5, 2017