Clinical Trials /

Bevacizumab and Erlotinib in Lung Cancer With Brain Metastases, a Phase II Trial

NCT02655536

Description:

This is an open-label, randomized, multicenter phase II study conducting in 3 medical centers in Asia. Patients will receive erlotinib in combination with bevacizumab or erlotinib alone. This study will enroll EGFR-mutant NSCLC patients who have asymptomatic brain metastases. The primary objective is to compare the systemic progression-free survival (PFS) to bevacizumab plus erlotinib versus erlotinib alone in patients with EGFR mutant NSCLC who have asymptomatic brain metastases.

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

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Bevacizumab and Erlotinib in Lung Cancer With Brain Metastases, a Phase II Trial
  • Official Title: A Phase II, Open Label, Multicenter Study of Bevacizumab in Combination With Erlotinib Versus Erlotinib Alone in Patients With EGFR Mutant Non-small Cell Lung Cancer Who Have Brain Metastases

Clinical Trial IDs

  • ORG STUDY ID: 201510073MIPB
  • NCT ID: NCT02655536

Conditions

  • Carcinoma, Non-Small-Cell Lung
  • Brain Neoplasms

Interventions

DrugSynonymsArms
Bevacizumab plus erlotinibavastin plus tarcevabevacizumab plus erlotinib
Erlotinibtarcevaerlotinib

Purpose

This is an open-label, randomized, multicenter phase II study conducting in 3 medical centers in Asia. Patients will receive erlotinib in combination with bevacizumab or erlotinib alone. This study will enroll EGFR-mutant NSCLC patients who have asymptomatic brain metastases. The primary objective is to compare the systemic progression-free survival (PFS) to bevacizumab plus erlotinib versus erlotinib alone in patients with EGFR mutant NSCLC who have asymptomatic brain metastases.

Detailed Description

      This is an open-label, randomized, multicenter phase II study conducting in 3 medical centers
      in Asia. Patients will receive erlotinib in combination with bevacizumab or erlotinib alone.
      This study will enroll EGFR-mutant NSCLC patients who have asymptomatic brain metastases.

      The primary objective is to compare the systemic progression-free survival (PFS) to
      bevacizumab plus erlotinib versus erlotinib alone in patients with EGFR mutant NSCLC who have
      asymptomatic brain metastases.

      Patients will be randomized, at a 1:1 ratio, into bevacizumab plus erlotinib group or
      erlotinib alone group. Compute tomography (CT) or MRI scans will be performed every 6 weeks
      in the first 12 months since start of investigational drugs, and then performed every 12
      weeks. Patients will be followed until documented progression at brain and/or extra-cranial
      lesions. Patients with intracranial progression only are allowed to continue investigational
      drugs until a second progression of either intracranial progression or extracranial
      progression, developed, and the time-to extracranial progression will be determined. In
      patients with EGFR mutant advanced NSCLC who had brain metastases, it was reported that PFS
      to erlotinib or gefitinib was 6.6 months(Park et al., 2012). In the current study, it is
      assumed that the median PFS, both intracranial and extracranial included, is 7 months for
      erlotinib group alone and is 12.3 months for bevacizumab plus erlotinib group (hazard ratio
      0.57) (Seto et al., 2014). 109 patients will be required for analysis in this randomized
      phase II study. Patients will be stratified according to the EGFR L858R mutation and the EGFR
      exon 19 deletion mutation.
    

Trial Arms

NameTypeDescriptionInterventions
bevacizumab plus erlotinibExperimentalbevacizumab 15mg/kg every 3 weeks plus erlotinib 150mg per day
  • Bevacizumab plus erlotinib
erlotinibActive Comparatorerlotinib 150mg per day
  • Erlotinib

Eligibility Criteria

        Inclusion Criteria:

          -  Pathologically confirmed, stage IV (AJCC 7th Edition) non-small cell lung cancer.

          -  A tumor harboring an EGFR mutation known to be associated with erlotinib sensitivity
             (exon 19 deletion and L858R)

          -  Documented brain metastases.

          -  At least one measure brain lesion and one extracranial lesion

          -  No emergent operation or radiotherapy is indicated. Patients who have received
             operation for brain tumor may be enrolled if they have recovered from the operation
             and there are measurable brain lesions after operation.

          -  No prior exposure to EGFR inhibitors or anti-angiogenesis therapy including
             bevacizumab.

          -  No prior systemic anti-cancer therapy for advanced NSCLC is allowed. -Previous
             adjuvant or neo-adjuvant treatment for non-metastatic disease is permitted if
             completed ≥ 6 months before the start of study treatment.

          -  Written informed consent obtained prior to any screening procedures.

             ≥20 years of age.

          -  Must have discontinued any previous anti-cancer and investigational therapy for at
             least 28 days, major operation for at least 28 days with full healing of surgical
             wounds, or radiotherapy for at least 14 days before study treatment administration,
             and must have recovered to grade 1 from the adverse effects of such treatment before
             starting study treatment.

          -  Life expectancy ≥ 3 months.

          -  ECOG performance status: 0-1.

          -  Female patients of child-bearing potential should have a negative pregnancy test.

          -  Required baseline laboratory status:

        Hemoglobin>9g/dL Platelet count≥100x109/L Absolute neutrophil count (ANC)≥1.5x109/L without
        growth factor support Total bilirubin>1.5x upper limit of normal (ULN) AST/SGOT and/or
        ALT/SGPT>2.5x ULN Serum creatinine clearance >50 ml/min, by either Cockcroft-Gault formula
        or by 24-hour urine collection analysis

        -Willing and able to comply with scheduled visits, treatment plan and laboratory tests.

        Exclusion Criteria:

          -  Squamous cell carcinoma

          -  Unable or unwilling to swallow tablet once daily.

          -  allergy to erlotinib and/or bevacizumab

          -  Previous treatment of EGFR inhibitors or anti-angiogenesis therapies.

          -  History of gross hemoptysis (defined as bright red blood of at least 1/2 teaspoon or
             2.5 mL per episode) within 3 months prior to randomization unless definitively treated
             with surgery or radiation

          -  Symptomatic CNS metastases which are neurologically unstable or requiring increasing
             doses of steroids to control the CNS condition.

          -  CNS bleeding; history or clinical evidence of CNS stroke (hemorrhagic or thrombotic)
             within the last 6 months

          -  Chronic daily use of aspirin (>325 mg/day) or other full-dose NSAIDs with anti
             platelet activity. Treatment with other antiplatelet agents (e.g., dipyridamole,
             ticlopidine, clopidogrel, and/or cilostazol) is permitted.

          -  Other baseline laboratory values Uncontrolled hypercalcemia (>11.5 mg/dL) Urinary
             protein to creatinine ratio >1 (spot urine) Serum creatinine >2.0 ULN

          -  Radiation therapy within 2 weeks prior to the first dose of study drug. Any persistent
             side effect of prior radiotherapy must be resolved to grade 1 prior to the first dose
             of study treatment.

          -  Any unresolved toxicity from previous anticancer therapy > Grade 1.

          -  Currently receiving any prohibited medications including vitamins supplements, and
             herbal supplements.

          -  Unable to undergo an MRI or contrast CT procedures.

          -  Active HBV or HCV infection, HBV carrier can be enrolled if HBV DNA titer is low under
             antiviral treatment.

          -  Known history of HIV seropositivity. HIV testing is not required as part of this
             study.

          -  Undergone a bone marrow or solid organ transplant.

          -  Another malignancy diagnosed or treated within 5 years, except carcinoma in situ or
             skin cancer.

          -  Major surgery within 4 weeks prior to initiating study treatment, excluding the
             placement of vascular access.

          -  Cardiac conditions as

               1. Uncontrolled hypertension (BP ≥150/95 mmHg despite medical therapy).

               2. myocardial infarction

               3. unstable symptomatic arrhythmia requiring medication (patients with chronic
                  atrial arrhythmia, i.e., atrial fibrillation or paroxysmal supraventricular
                  tachycardia are eligible)

               4. Symptomatic heart failure (NYHA grade II-IV)

               5. Clinically significant peripheral vascular disease, abdominal fistula,
                  gastrointestinal perforation, or intra abdominal abscess

               6. Uncontrolled angina (Canadian Cardiovascular Society grade II-IV despite medical
                  therapy)

          -  Past medical history of interstitial lung disease, drug-induced interstitial disease,
             radiation pneumonitis which required steroid treatment, pre-existing idiopathic
             pulmonary fibrosis or any evidence of clinically active interstitial lung disease.

          -  Pregnant or lactating women, where pregnancy is defined as the state of a female after
             conception and until the termination of gestation, confirmed by a positive hCG
             laboratory test (>5mIU/mL).

          -  Women of child-bearing potential, defined as all women physically capable of becoming
             pregnant, unless they are using highly effective methods of contraception during
             dosing and for at least 6 months after stopping study drug. Highly effective
             contraception methods include:

        Male or female sterilization or

        Combination of any two of the following:

        Use oral, injected or implanted hormonal methods of contraception. Placement of an
        intrauterine device (IUD) or intrauterine system (IUS). Barrier methods of contraception:
        condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal
        foam/gel/film/cream/vaginal suppository).

          -  Women are considered post-menopausal and not of child baring potential if they have
             had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile
             (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral
             oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago.
             In the case of oophorectomy alone, only when the reproductive status of the woman has
             been confirmed by follow up hormone level assessment is she considered not of child
             bearing potential.

          -  Sexually active males must use a condom during intercourse while taking the drug and
             for 6 more months after stopping study drug and should not father a child in this
             period. A condom is required to be used also by vasectomized men in order to prevent
             delivery of the drug via seminal fluid.

          -  Any other condition that would, in the Investigator's judgment, contraindicate
             patient's participation in the clinical study due to safety concerns or compliance
             with clinical study procedures, e.g. infection/inflammation, intestinal obstruction,
             unable to swallow medication, social/psychological issues, etc.
      
Maximum Eligible Age:99 Years
Minimum Eligible Age:20 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression-free survival
Time Frame:The PFS will be evaluated per RECIST 1.1 criteria every 6 weeks for the first 12 months and then every 12 weeks up to 36 months.
Safety Issue:
Description:The PFS will be evaluated from date of randomization until the date of documented progression or the date of death from any cause, whichever came first.

Secondary Outcome Measures

Measure:overall survival
Time Frame:The survival will be assessed from date of randomization until the date of death from any cause. The survival will be assessed every 3 weeks up to 36 months.
Safety Issue:
Description:
Measure:overall response rate
Time Frame:The response rate will be evaluated per RECIST 1.1 criteria every 6 weeks for the first 12 months and then every 12 weeks up to 36 months.
Safety Issue:
Description:The response rate will be evaluated from date of randomization until the date of documented progression or the date of death from any cause, whichever came first.
Measure:Time-to-central nervous system (CNS) progression
Time Frame:Time-to-central nervous system(CNS) progression will be evaluated per RECIST 1.1 criteria every 6 weeks for the first 12 months and then every 12 weeks up to 36 months.
Safety Issue:
Description:The Time-to- CNS progression will be evaluated from date of randomization until the date of documented CNS progression.
Measure:Time to extra-CNS progression
Time Frame:Time to extra-CNS progression will be evaluated per RECIST 1.1 criteria every 6 weeks for the first 12 months and then every 12 weeks up to 36 months.
Safety Issue:
Description:The Time-to-extra-CNS progression will be evaluated from date of randomization until the date of documented extra-CNS progression.
Measure:The PFS-2 in patients in patients with CNS progression only
Time Frame:The PFS-2 will be evaluated per RECIST 1.1 criteria every 6 weeks for the first 12 months and then every 12 weeks up to 36 months.
Safety Issue:
Description:The PFS-2 will be evaluated from date of randomization until the date of second documented progression or the date of death from any cause, whichever came first.
Measure:Time to neurological symptom progression
Time Frame:Time to neurological symptom progression will be evaluated every 3 weeks up to 36 months.
Safety Issue:
Description:Time to neurological symptom will be assessed from date of randomization until the dated of documented progression of neurological symptom.
Measure:Number of participants with treatment-related adverse events as assessed by CTCAE version 4.03
Time Frame:Treatment-related adverse events will be evaluated from date of randomization until 30 days after discontinuation of the trial. It will be evaluated every 3 weeks up to 36 months.
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Taiwan University Hospital

Last Updated

September 20, 2016