Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Published Results
Related Publications
Trial Contact Information
Registry Information

Alternate Title

Combination Chemotherapy With or Without Bevacizumab in Treating Patients With Advanced, Metastatic, or Recurrent Non-Small Cell Lung Cancer

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase III, Phase II	Treatment	Closed	18 and over	NCI	ECOG-4599 CALGB-E4599, E4599, NCT00021060

Special Category: CTSU trial

Objectives

1. Compare the toxicity of paclitaxel and carboplatin with or without bevacizumab in patients with advanced, metastatic, or recurrent non-squamous cell non-small cell lung cancer.
2. Compare the survival of patients treated with these regimens.
3. Compare the response rates and time to progression in patients treated with these regimens.

Entry Criteria

Disease Characteristics:

• Histologically or cytologically confirmed non-small cell lung cancer (NSCLC)
  • Stage IIIB with malignant pleural effusion, stage IV, or recurrent
  • Measurable or nonmeasurable disease



• No squamous cell NSCLC



• No known CNS metastases by head CT scan or MRI within the past 4 weeks

Prior/Concurrent Therapy:

Biologic therapy:

• At least 3 weeks since prior immunotherapy and recovered

Chemotherapy:

• No prior systemic chemotherapy

Endocrine therapy:

• At least 3 weeks since prior hormonal therapy and recovered

Radiotherapy:

• At least 3 weeks since prior radiotherapy and recovered

Surgery:

• At least 3 weeks since prior major surgery

Other:

• No concurrent therapeutic anticoagulation
• No concurrent chronic daily aspirin (greater than 325 mg/day)
• No concurrent non-steroidal anti-inflammatory agents known to inhibit platelet function (arm II only)
• No concurrent dipyridamole, ticlopidine, clopidogrel, and/or cilostazol

Patient Characteristics:

Age:

• 18 and over

Performance status:

• ECOG 0-1

Life expectancy:

• Not specified

Hematopoietic:

• Absolute neutrophil count at least 1,500/mm³
• Platelet count at least 100,000/mm³
• No prior thrombotic or hemorrhagic disorders

Hepatic:

• Bilirubin no greater than 1.5 mg/dL
• Transaminases no greater than 5 times upper limit of normal (ULN)
• PTT normal
• INR no greater than 1.5

Renal:

• Creatinine no greater than 1.5 times ULN
• Urine protein less than 1+ (i.e., trace or 0 by dipstick or urinalysis)

  OR

• 24-hour urine protein less than 500 mg

Cardiovascular:

• No symptomatic congestive heart failure
• No unstable angina pectoris
• No cardiac arrhythmia
• Concurrent hypertension allowed provided well-controlled on a stable regimen of anti-hypertensive therapy

Pulmonary:

• No history of gross hemoptysis (½ teaspoon of bright red blood or more)

Other:

• No ongoing or active infection
• No serious non-healing wound ulcer
• No bone fracture
• No psychiatric illness or social situation that would preclude study compliance
• No other concurrent comorbidities that would preclude study participation
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception

Expected Enrollment

A total of 842 patients will be accrued for this study.

Outline

This is a randomized study. Patients are stratified according to measurable disease (yes vs no), prior radiotherapy (yes vs no), weight loss (less than 5% vs 5% or more), and disease stage (IIIB vs IV vs recurrent). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive paclitaxel IV over 3 hours followed by carboplatin IV over 15-30 minutes on day 1.



• Arm II: Patients receive paclitaxel and carboplatin as in arm I followed by bevacizumab IV over 30-90 minutes on day 1.

Treatment in both arms repeats every 3 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity.

After completion of 6 courses, patients in arm II with stable or responding disease continue to receive bevacizumab only. Treatment repeats every 3 weeks in the absence of disease progression or unacceptable toxicity.

Patients are followed every 3 months for 2 years and then every 6 months for 3 years.

Dowlati A, Gray R, Sandler AB, et al.: Cell adhesion molecules, vascular endothelial growth factor, and basic fibroblast growth factor in patients with non-small cell lung cancer treated with chemotherapy with or without bevacizumab--an Eastern Cooperative Oncology Group Study. Clin Cancer Res 14 (5): 1407-12, 2008.[PUBMED Abstract]

Ramalingam SS, Dahlberg SE, Langer CJ, et al.: Outcomes for elderly, advanced-stage non small-cell lung cancer patients treated with bevacizumab in combination with carboplatin and paclitaxel: analysis of Eastern Cooperative Oncology Group Trial 4599. J Clin Oncol 26 (1): 60-5, 2008.[PUBMED Abstract]

Somer RA, Sherman E, Langer CJ: Restrictive eligibility limits access to newer therapies in non-small-cell lung cancer: the implications of Eastern Cooperative Oncology Group 4599. Clin Lung Cancer 9 (2): 102-5, 2008.[PUBMED Abstract]

Cohen MH, Gootenberg J, Keegan P, et al.: FDA drug approval summary: bevacizumab (Avastin) plus Carboplatin and Paclitaxel as first-line treatment of advanced/metastatic recurrent nonsquamous non-small cell lung cancer. Oncologist 12 (6): 713-8, 2007.[PUBMED Abstract]

Ramalingam SS, Dahlberg SE, Langer CJ, et al.: Outcomes for elderly advanced stage non-small cell lung cancer (NSCLC) patients (pts) treated with bevacizumab (B) in combination with carboplatin (C) and paclitaxel (P): analysis of Eastern Cooperative Oncology Group (ECOG) 4599 study. [Abstract] J Clin Oncol 25 (Suppl 18): A-7535, 393s, 2007.

Brahmer JR, Gray R, Schiller JH, et al.: ECOG 4599 phase III trial of carboplatin and paclitaxel ±bevacizumab: subset analysis of survival by gender. [Abstract] J Clin Oncol 24 (Suppl 18): A-7036, 373s, 2006.

Dowlati A, Gray R, Johnson DH, et al.: Prospective correlative assessment of biomarkers in E4599 randomized phase II/III trial of carboplatin and paclitaxel ± bevacizumab in advanced non-small cell lung cancer (NSCLC). [Abstract] J Clin Oncol 24 (Suppl 18): A-7027, 370s, 2006.

Sandler AB, Johnson DH, Brahmer J, et al.: Retrospective study of clinical and radiographic risk factors associated with early onset, severe pulmonary hemorrhage in bevacizumab-treated patients with advanced non-small cell lung cancer (NSCLC). [Abstract] J Clin Oncol 24 (Suppl 18): A-7068, 381s, 2006.

Sandler A, Gray R, Perry MC, et al.: Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355 (24): 2542-50, 2006.[PUBMED Abstract]

Sandler AB, Gray R, Brahmer J, et al.: Randomized phase II/III trial of paclitaxel (P) plus carboplatin (C) with or without bevacizumab (NSC # 704865) in patients with advanced non-squamous non-small cell lung cancer (NSCLC): an Eastern Cooperative Oncology Group (ECOG) Trial - E4599. [Abstract] J Clin Oncol 23 (Suppl 16): A-LBA4, 2s, 2005.

Tyagi P: Bevacizumab, when added to paclitaxel/carboplatin, prolongs survival in previously untreated patients with advanced non-small-cell lung cancer: preliminary results from the ECOG 4599 trial. Clin Lung Cancer 6 (5): 276-8, 2005.[PUBMED Abstract]

Sandler A: Bevacizumab in non small cell lung cancer. Clin Cancer Res 13 (15): 4613s-6s, 2007.

Dornbusch D, Allegra C, Willey J, et al.: How do U.S. medical oncologists learn and apply new clinical trials information from press releases in nonmedical media? A case study based on ECOG 4599. Oncologist 11 (1): 31-8, 2006.[PUBMED Abstract]

Gray R, Giantonio BJ, O'Dwyer PJ, et al.: The safety of adding angiogenesis inhibition into treatment for colorectal, breast, and lung cancer: the Eastern Cooperative Oncology Group's (ECOG) experience with bevacizumab (anti-VEGF). [Abstract] Proceedings of the American Society of Clinical Oncology 22: A-825, 2003.

Trial Contact Information

Trial Lead Organizations

Eastern Cooperative Oncology Group

Alan Sandler, MD, Protocol chair		Ph: 615-343-4070; 800-811-8480 Email: alan.sandler@vanderbilt.edu

Cancer and Leukemia Group B

Michael Perry, MD, Protocol chair		Ph: 573-882-4979 Email: perrym@health.missouri.edu

Registry Information
Official Title		Randomized Phase II/III Trial of Paclitaxel plus Carboplatin With or Without Bevacizumab (NSC #704865) in Patients with Advanced Nonsquamous NSCLC
Trial Start Date		2001-07-19
Registered in ClinicalTrials.gov		NCT00021060
Date Submitted to PDQ		2001-05-15
Information Last Verified		2004-05-25
NCI Grant/Contract Number		CA21115