Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

Combination Chemotherapy and Bevacizumab With or Without Erlotinib in Treating Patients With Metastatic Colorectal Cancer That Cannot Be Removed By Surgery

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase III Treatment Active 18 to 80 Other, Pharmaceutical / Industry GERCOR-C04-2 EU-20565, GERCOR-OPTIMOX3-TARCEVA, ROCHE-GERCOR-C04-2, NCT00265824, GERCOR-DREAM- C04-2

Objectives

Primary

1. Compare the efficacy of oxaliplatin, leucovorin calcium, and fluorouracil (modified FOLFOX) or oxaliplatin and capecitabine (XELOX) in combination with bevacizumab with vs without erlotinib, in terms of progression-free or overall survival, in patients with unresectable metastatic colorectal cancer.

Secondary

1. Compare the duration of disease control and overall survival of patients treated with these regimens.
2. Compare the tolerability of these regimens in these patients.
3. Compare the quality of life of patients treated with these regimens.
4. Compare the occurrence of secondary surgery in patients treated with these regimens.
5. Compare the chemotherapy-free intervals and response rates in patients treated with these regimens.

Entry Criteria

Disease Characteristics:

• Histologically proven metastatic adenocarcinoma of colon or rectum
  • Documented inoperable disease (i.e., not suitable for complete carcinological surgical resection)



• Measurable lesion as assessed by CT scan or MRI in at least one dimension (longest diameter to be recorded) ≥ 20 mm with conventional CT scan or ≥ 10 mm with spiral CT scan



• No history or evidence upon physical examination of CNS disease (e.g., non-irradiated CNS metastasis, seizure not controlled with standard medical therapy, or history of stroke) unless adequately treated



• No exclusive bone metastasis



• No symptomatic ascites or pleural effusion not evacuated prior to entry into the study

Prior/Concurrent Therapy:

• No previous chemotherapy and/or immunotherapy for metastatic disease
  • More than 6 months since prior adjuvant chemotherapy (2 years if oxaliplatin or irinotecan was received as adjuvant therapy)
• No prior palliative chemotherapy and/or immunotherapy for metastatic disease
• More than 28 days since prior major surgical procedure or open biopsy
• More than 10 days since prior use of full-dose oral or parenteral anticoagulants for therapeutic purposes
• No concurrent full-dose oral or parenteral anticoagulants for therapeutic purposes
• No concurrent chronic, daily treatment with aspirin (> 325 mg/day)
• No other concurrent antitumor treatment
• No participation in another clinical trial with any investigational drug within 30 days prior to randomization or during study participation
• No other concurrent agents known to have anticancer activity
• No concurrent radiotherapy
• No concurrent treatments that could cause an interstitial pulmonary syndrome (e.g., thoracic radiotherapy, beta blockers, nonsteroidal anti-inflammatory drugs, or bleomycin)

Patient Characteristics:

• ECOG performance status 0-2
• WBC ≥ 1,500/mm³
• Platelets ≥ 100,000/mm³
• Hemoglobin > 9 g/dL (may be transfused to maintain or exceed this level)
• INR ≤ 1.5
• PPT < 1.5 times upper limit of normal (ULN)
• Creatinine < 1.5 mg/dL
• Creatinine clearance > 30 mL/min
• Proteinuria < 2+ by dipstick OR ≤ 1 g of protein on 24-hr urine collection
• Bilirubin < 1.5 times ULN
• Alkaline phosphatase < 3 times ULN
• No peripheral sensory neuropathy
• Negative pregnancy test
• Fertile patients must use effective means of contraception (oral contraceptives, intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal jelly, or surgically sterilization)
• No significant traumatic injury within the past 28 days
• Fully healed wounds
• No total or partial bowel obstruction
• No uncontrolled hypercalcemia
• No other concomitant or previous malignancy, except adequately treated in situ carcinoma of the uterine cervix or basal or squamous cell carcinoma of the skin or cancer in complete remission for < 5 years
• No peripheral neuropathy ≥ grade 1
• No other serious nonmalignant disease
• No pre-existing lung disease (in particular chronic obstructive lung disease, pleural effusion, lymphangitis carcinomatosis, or interstitial syndrome)
• No clinically significant (i.e. active) cardiovascular disease including any the following:
  • Cerebrovascular accidents in the past 6 months
  • Myocardial infarction in the past year
  • Unstable angina
  • New York Heart Association grade II or greater congestive heart failure
  • Serious cardiac arrhythmia requiring medication
  • Uncontrolled hypertension
• No evidence of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates use of an investigational drug
• Not at high risk of treatment complications
• No evidence of bleeding diathesis or coagulopathy
• No serious, non-healing wound, ulcer, or bone fracture
• No known allergy to any excipients of study drugs
• No significant ophthalmologic abnormality, especially severe dry eye syndrome, keratoconjunctivitis sicca, Sjögren's syndrome, severe exposure keratitis or any other disorder likely to increase the risk of corneal epithelial lesions (the use of contact lenses is not recommended during the study)

Expected Enrollment

A total of 640 patients will be accrued for this study.

Outcomes

Progression-free survival

Duration of disease control
Overall survival
Response rates
Chemotherapy-free interval
Salvage surgery rates
Tolerability as measured by NCI CTCAE v3.0
Quality of life as measured by Functional Assessment of Cancer Therapy Neurotoxicity Module v4.0 and European Quality of Life questionnaire (EQ-5D) scale at baseline, courses 4 and 6, and every 2 months thereafter
Pharmacogenetics and pharmacoeconomics

Outline

This is a randomized, multicenter study. Patients are stratified according to ECOG performance status (0-1 vs 2), number of metastatic sites involved (1 vs > 1), age (18-50 years vs 51-75 years vs 76-80 years), prior adjuvant chemotherapy (yes vs no), and baseline alkaline phosphatase (normal vs elevated). Patients are randomized to 1 of 4 treatment arms.

• Arm I (modified FOLFOX with bevacizumab): Patients receive oxaliplatin IV over 2 hours and leucovorin calcium IV over 2 hours on day 1 and fluorouracil IV continuously over 46 hours beginning on day 2. Patients also receive bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 2 weeks for 6 courses in the absence of disease progression or unacceptable toxicity. Patients with stable or responding disease then receive additional bevacizumab IV over 30-90 minutes on day 1 and oral erlotinib once daily on days 1-21. Treatment with bevacizumab and erlotinib repeats every 3 weeks in the absence of disease progression or unacceptable toxicity. Patients with a subsequent relapse may restart treatment with modified FOLFOX and bevacizumab as before at the discretion of the principal investigator.



• Arm II (modified FOLFOX with bevacizumab and erlotinib): Patients receive oxaliplatin, leucovorin calcium, fluorouracil, and bevacizumab as in arm I. Patients also receive oral erlotinib once daily on days 1-14. Treatment repeats every 2 weeks for 6 courses in the absence of disease progression or unacceptable toxicity. Patients with stable or responding disease then receive additional bevacizumab IV over 30-90 minutes on day 1 and oral erlotinib once daily on days 1-21. Treatment with bevacizumab and erlotinib repeats every 3 weeks in the absence of disease progression or unacceptable toxicity. Patients with a subsequent relapse may restart treatment with modified FOLFOX, bevacizumab, and erlotinib as before at the discretion of the principal investigator.



• Arm III (XELOX with bevacizumab): Patients receive oxaliplatin IV over 2 hours on day 1, oral capecitabine twice daily on days 1-7, and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 2 weeks for 6 courses in the absence of disease progression or unacceptable toxicity. Patients with stable or responding disease then receive additional bevacizumab alone IV over 30-90 minutes on day 1 and oral erlotinib once daily on days 1-21. Treatment with bevacizumab and erlotinib repeats every 3 weeks in the absence of disease progression or unacceptable toxicity. Patients with a subsequent relapse may restart treatment with XELOX and bevacizumab as before at the discretion of the principal investigator.



• Arm IV (XELOX with bevacizumab and erlotinib): Patients receive oxaliplatin, capecitabine, and bevacizumab as in arm III. Patients also receive oral erlotinib once daily on days 1-14. Treatment repeats every 2 weeks for 6 courses in the absence of disease progression or unacceptable toxicity. Patients with stable or responding disease then receive additional bevacizumab IV over 30-90 minutes on day 1 and oral erlotinib once daily on days 1-21. Treatment with bevacizumab and erlotinib repeats every 3 weeks in the absence of disease progression or unacceptable toxicity. Patients with a subsequent relapse may restart treatment with XELOX, bevacizumab, and erlotinib as before at the discretion of the principal investigator.

Quality of life is assessed at baseline, 8 weeks, 12 weeks, and then every 2 months thereafter.

After completion of study treatment, patients are followed periodically for 2 years.

Trial Contact Information

Trial Lead Organizations

GERCOR Groupe Cooperateur Multidisciplinaire en Oncologie

Aimery de Gramont, MD, Protocol co-chair		Ph: 33-1-49-282-336 Email: aimery.de-gramont@sat.ap-hop-paris.fr
Christophe Tournigand, Protocol chair		Ph: 33-1-4928-2329 Email: christophe.tournigand@sat.ap-hop-paris.fr

France
	Avignon
	Institut Sainte Catherine
		Laurent Mineur, MD	Ph:  33-4-9027-6397
	Dijon
	Hopital Drevon
		Michel Flesch, MD	Ph:  33-3-8036-4822
	Le Mans
	Clinique Victor Hugo
		Gerard Ganem, MD	Ph:  33-2-4339-1300
	Libourne
	Hopital Robert Boulin
		Dominique Auby	Ph:  33-5-5755-3552
			Email: dominique.auby@cheibourne.aquisante.fr
	Lyon
	Clinique Saint Jean
		Gerard Lledo	Ph:  33-4-7878-1051
	Montfermeil
	Centre Hospitalier Intercommunal Le Raincy - Montfermeil
		Mostefa Bennamoun, MD	Ph:  33-1-41-70-80-00
	Paris
	Hopital Europeen Georges Pompidou
		Bruno Landi, MD	Ph:  33-1-5609-3555
			Email: bruno.landi@egp.aphp.fr
	Hopital Saint Antoine
		Christophe Tournigand	Ph:  33-1-4928-2329
			Email: christophe.tournigand@sat.ap-hop-paris.fr
	Hopital Tenon
		Thierry Andre, MD	Ph:  33-1-6177-0708
			Email: thierry.andre@tnn.ap-hop-paris.fr
	Reims
	Polyclinique De Courlancy
		Philippe Colin, MD	Ph:  33-3-2684-0284
			Email: colin.courlancy@wanadoo.fr
	Senlis
	C.H. Senlis
		Elisabeth Carola, MD	Ph:  33-3-4421-7026
	Suresnes
	Hopital Foch
		May Mabro, MD	Ph:  33-1-4625-2168
			Email: m.mabro@hopital-foch.org
	Toulouse
	Institut Claudius Regaud
		Jean-Pierre Delord, MD, PhD	Ph:  33-5-6142-4114
			Email: delord.jean-pierre@claudiusregaud.fr

Registry Information
Official Title		Phase III Study of an Optimized Chemotherapy + Avastin Strategy ± Tarceva in Metastatic Colorectal Cancer
Trial Start Date		2005-05-12
Registered in ClinicalTrials.gov		NCT00265824
Date Submitted to PDQ		2005-09-14
Information Last Verified		2007-05-08