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

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.

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.

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.