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Phase II Study of Neoadjuvant Gemcitabine, Cisplatin and Bevacizumab in Stage IIIA (N2), Non-Squamous Cell Non-Small Cell Lung Cancer

Phase 2
18 Years
70 Years
Not Enrolling
NSCLC, Stage IIIA (N2)

Thank you

Trial Information

Phase II Study of Neoadjuvant Gemcitabine, Cisplatin and Bevacizumab in Stage IIIA (N2), Non-Squamous Cell Non-Small Cell Lung Cancer


- Stage IIIA-N2 is considered one of the most therapeutically challenging and
controversial subsets of lung cancer. This heterogenous group of patients have tumors
which range from minimal N2 (found incidentally during or after surgery) to
multi-station bulky N2 disease. The extent of mediastinal involvement has an inverse
correlation with survival.

- The 5-year survival ranges from 5-8% in patients with bulky N2 disease, to nearly 35%
in patients with single station, microscopic N2 involvement.

- Neo-adjuvant chemotherapy and chemo-radiotherapy have been shown to be superior to
surgery alone.

- Platinum-based induction chemotherapy in early and locally advanced non small cell lung
cancer (NSCLC) results in a radiological down-staging in at least 50% of patients, and
a pathological complete response rate of approximately 5%.

- Concurrent chemo-radiotherapy as an induction regimen increases the radiological and
pathological down-staging rate, but at the cost of increasing the morbidity and
mortality of a surgical intervention.

- Expectations have now turned towards a possible incremental effect of adding a targeted
biological agent to a standard induction treatment.

Primary Objectives:

- To determine the safety of neo-adjuvant Gemcitabine/Cisplatin and Bevacizumab in stage
IIIA-N2 non small cell lung cancer (NSCLC)

- To determine the pathological complete response rate

- To determine the resectability rate

- To determine the extent of surgery


- Histologically confirmed stage IIIA-N2 NSCLC (non-squamous)

- No previous chemotherapy, radiotherapy, surgery or biological therapy for lung cancer

- Adequate organ and bone marrow function


- Multi-center, international (United States Of America (USA)/Croatia), open labeled
phase II trial

- Following a Simon two-stage optimal design

Inclusion Criteria


- Histologically or cytologically documented non squamous cell non-small cell lung
cancer and confirmed by the pathological laboratories at participating centers.

- Patients must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded) as
greater than 20 mm with conventional techniques or as greater than 10 mm with spiral
computed tomography (CT) scan.

- Stage IIIA (N2) disease. All patients will require a baseline mediastinoscopy to
ensure histological proof of N2 disease.

- No prior treatment for lung cancer including chemotherapy, radiotherapy, surgery or
biological therapy.

- Age greater than or equal to 18 years (males or non-pregnant females).

- Life expectancy of greater than 3 months.

- Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (Karnofsky greater
than 60 percent).

- Adequate pulmonary and cardiovascular function to tolerate planned surgical

- Pulmonary Function criteria:

- Partial pressure of oxygen (paO2) greater than 65 mmHg, partial pressure of
carbon dioxide (paCO2) less than 45 mmHg on room air arterial blood gas

- Anticipated post-op forced expiratory volume 1 (FEV1) greater than or equal
to 40 percent predicted.

- Anticipated post-op carbon monoxide diffusing capacity (DLCO) greater than
or equal to 40 percent predicted.

- If anticipated post-op FEV1 or DLCO less than percent predicted, must have
volume of oxygen (VO2) greater than 15ml/kg on oxygen consumption study.

- Cardiac criteria:

- Left ventricular ejection fraction (LVEF) greater than 40 percent.

- No pulmonary hypertension or right ventricular (RV) dysfunction.

- No unstable angina.

- Serum Creatinine less than or equal to 1.5mg/dl

- Hemoglobin (baseline) greater than or equal to 10.0g/dl

- Absolute neutrophil count greater than or equal to 1,500/m^3 and platelets greater
than or equal to 100,000/m^3.

- aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) and
alanine aminotransferase (ALT)/ serum glutamic pyruvic transaminase (SGPT) less than
or equal to 2.5 times the upper limit of normal (ULN), total bilirubin less than or
equal to 1.5 times the ULN (In patients with evidence of Gilberts disease, elevated
bilirubin should not be related to tumor or other liver diseases and should be less
than or equal 2 times the upper limit of normal).

- The ability to understand and the willingness to sign a written informed consent
document and the ability to comply with the requirements of the protocol.

- Women of childbearing potential must have a negative pregnancy test and both men and
women must be willing to consent to using effective contraception while on treatment
and for at least 3 months thereafter.


- Squamous cell cancer or mixed tumors with small cell elements.

- Tumor of any histology in close proximity to a major vessel or cavitation. (Any tumor
abutting an interlobar, main pulmonary artery, vena cava or major vein will be

- History of hemoptysis (bright red blood of one-half teaspoon or more [greater than or
equal to 2.5 mL] unrelated to any diagnostic procedure. (Patients who have a history
of hemoptysis that occurred greater than 3 months prior to study entry and that is
assessed not to be related to tumor may be eligible).

- Patients with metastatic disease.

- History of uncontrolled or labile hypertension, defined as blood pressure greater
than 150/100mmHg (National Cancer Institute (NCI) Common Terminology Criteria for
Adverse Events (CTCAE) v.3.0 grade greater than or equal to 2), systolic blood
pressure greater than 180 mm Hg if diastolic blood pressure less than 90 mm Hg, or
diastolic blood pressure greater than 90 mm Hg, on at least 2 repeated determinations
on separate days within 3 months prior to study enrollment. Patients who have
medication controlled hypertension are eligible for the study.

- Any of the following within 6 months prior to study enrollment: myocardial
infarction, severe/unstable angina pectoris or uncontrolled angina pectoris,
coronary/peripheral artery bypass graft, New York Heart Association (NYHA) class III
or IV congestive heart failure, clinically significant peripheral vascular disease
(Grade II or greater).

- Psychiatric or neurologic illness that would limit compliance with study

- Patients with serious illness or medical condition.

- Active infection within 14 days before beginning treatment.

- Patients may not be receiving any other investigational agents.

- History of a malignancy in the last five years other than in situ carcinoma of the
cervix, or non-melanomatous skin cancers.

- Patients must not be on therapeutic anticoagulation or chronic daily treatment with
aspirin 325mg/day within 10 days prior to day 1 on study. Prophylactic
anticoagulation during perioperative period is acceptable. Full dose aspirin post
surgical resection is acceptable. Low dose aspirin 81mg/day and anticoagulation for
line protection are allowed in the perioperative period and the adjuvant setting.

- Women who are breast feeding.

- History of stroke or transient ischemic attack within 6 months.

- History of pulmonary embolism, deep venous thrombosis or other thrombo-embolic event
within 6 months prior to study.

- Patients with a history of severe hypersensitivity reaction to compounds of similar
chemical or biologic composition to cisplatin, gemcitabine, bevacizumab, etoposide or
other agents used in the study.

- History of a major surgical procedure, open biopsy, or a significant traumatic injury
within 35 days prior to commencing treatment, or the anticipation of the need for a
major surgical procedure during the course of the study prior to the predetermined
date of tumor excision. Fine needle aspirations, core biopsies or mediastinoscopies
within 7 days prior to commencing treatment.

- History of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess
or tracheo-esophageal fistula.

- Non-healing wound or ulcer

- Evidence of coagulopathic disorder or hemorrhagic diathesis. International normalized
ratio (INR) greater than 1.5.

- Patients with existing ototoxicity.

- Pregnancy (positive pregnancy test).

- Urine protein: creatinine ratio greater than or equal to 1.0 at screening.

- Patients known to be human immunodeficiency virus (HIV)-positive or have active
hepatitis B/C (due to possible interaction between chemotherapy and highly active
antiretroviral therapy (HAART) and antiviral medications used for treatment of active
hepatitis B/C).

- Serious illness that may preclude adherence to the protocol.

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Rate of Pathologic Complete Response

Outcome Description:

Complete response is defined as a disappearance of all target lesions and was assessed by the RECIST (Response Evaluation Criteria in Solid Tumors) criteria.

Outcome Time Frame:

25 weeks

Safety Issue:


Principal Investigator

Giuseppe Giaccone, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute, National Institutes of Health


United States: Federal Government

Study ID:




Start Date:

March 2009

Completion Date:

September 2011

Related Keywords:

  • Stage IIIA (N2)
  • Neoadjuvant
  • Stage IIIA (N2)
  • Cisplatin
  • Gemcitabine
  • Bevacizumab
  • Non-Small Cell Lung Cancer
  • Carcinoma, Non-Small-Cell Lung
  • Lung Neoplasms



National Institutes of Health Clinical Center, 9000 Rockville Pike Bethesda, Maryland  20892