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A Phase III Trial Of Irinotecan /5-FU/ Leucovorin Or Oxaliplatin /5-FU / Leucovorin With And Without Cetuximab (C225) For Patients With Untreated Metastatic Adenocarcinoma Of The Colon or Rectum


Phase 3
18 Years
N/A
Not Enrolling
Both
Colorectal Cancer

Thank you

Trial Information

A Phase III Trial Of Irinotecan /5-FU/ Leucovorin Or Oxaliplatin /5-FU / Leucovorin With And Without Cetuximab (C225) For Patients With Untreated Metastatic Adenocarcinoma Of The Colon or Rectum


OBJECTIVES:

Primary

- Compare the survival rate of patients with previously untreated metastatic
adenocarcinoma of the colon or rectum treated with fluorouracil and leucovorin calcium
with oxaliplatin or irinotecan and with or without cetuximab.

Secondary

- Determine the level of epidermal growth factor receptor (EGFR) expression in patients
treated with these regimens.

- Determine whether expression of EGFR activity, markers of EGFR activity, and serum
levels of insulin-like growth factor-1, C-peptide, and insulin-like growth factor
binding protein 3 are independent predictors of response rate, time to tumor
progression, and survival of patients treated with these regimens.

- Correlate specific germline polymorphisms related to chemotherapy metabolism and
resistance with treatment-related toxicity, tumor response, time to tumor progression,
and survival of patients treated with these regimens.

- Correlate expression of putative prognostic markers in the tumor with tumor response,
time to tumor progression, and survival of patients treated with these regimens.

- Correlate diet, obesity, physical activity, and other lifestyle habits with
treatment-related toxicity, progression-free survival, and overall survival of patients
treated with these regimens.

OUTLINE: This is a randomized, open-label, multicenter study. Patients are stratified
according to prior adjuvant therapy (yes vs no) and prior pelvic radiotherapy (yes vs no).
Patients are randomized to 1 of 4 treatment arms.

- Arm I (FOLFIRI): Patients receive irinotecan IV over 90 minutes and leucovorin calcium
IV over 2 hours on days 1, 15, 29, and 43 and fluorouracil IV continuously over 46-48
hours beginning on days 1, 15, 29, and 43.

- Arm II (FOLFIRI and cetuximab): Patients receive FOLFIRI as in arm I and cetuximab IV
over 1-2 hours on days 1, 8, 15, 22, 29, 36, 43, and 50.

- Arm III (FOLFOX): Patients receive oxaliplatin IV over 2 hours and leucovorin calcium
IV over 2 hours on days 1, 15, 29, and 43 and fluorouracil IV continuously over 46-48
hours beginning on days 1, 15, 29, and 43.

- Arm IV (FOLFOX and cetuximab): Patients receive FOLFOX as in arm III and cetuximab IV
over 1-2 hours on days 1, 8, 15, 22, 29, 36, 43, and 50.

In all arms, courses repeat every 8 weeks in the absence of disease progression or
unacceptable toxicity.

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

PROJECTED ACCRUAL: Approximately 2,200 patients (550 per treatment arm) will be accrued for
this study within 4.6 years.

Inclusion Criteria


DISEASE CHARACTERISTICS:

- Histologically or cytologically confirmed metastatic colorectal adenocarcinoma

- Primary site of disease in the large bowel as determined endoscopically,
surgically, or radiologically

- Histologic or cytologic confirmation is not required for recurrent metastatic
disease in patients with prior colorectal cancer treated with surgery unless
either of the following criteria are met:

- More than 5 years have elapsed between the prior primary surgery and the
development of metastatic disease

- Primary cancer was stage I

- Tumor tissue available for epidermal growth factor receptor (EGFR) status analysis

- No pleural effusion or ascites that causes grade 2 or greater dyspnea

- No known CNS metastases or carcinomatous meningitis

PATIENT CHARACTERISTICS:

Age

- 18 and over

Performance status

- ECOG 0-1

Life expectancy

- Not specified

Hematopoietic

- Granulocyte count ≥ 1,500/mm^3

- Hemoglobin ≥ 9.0 g/dL (transfusion allowed)

- Platelet count ≥ 100,000/mm^3

Hepatic

- Bilirubin ≤ 1.5 mg/dL

- AST ≤ 5.0 times upper limit of normal (ULN)

- Albumin ≥ 2.5 g/dL

- No evidence of Gilbert's syndrome

Renal

- Creatinine ≤ 1.5 times ULN

Cardiovascular

- No unstable angina

- No congestive heart failure

- No prior myocardial infarction

- No prior stroke

- No other significant cardiac disease

- LVEF ≥ normal by echocardiogram or MUGA

Pulmonary

- No interstitial pneumonia or extensive and symptomatic interstitial fibrosis of the
lung

Neurologic

- No uncontrolled seizure disorder

- No Temporarily closed neurological disease

- No symptomatic sensory peripheral neuropathy grade 2 or greater

Other

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- No predisposing uncontrolled colonic or small bowel disorder as evidenced by > 3
watery or soft stools daily at baseline*

- No known sensitivity to chimerized or murine antibodies, cetuximab or other EGFR
inhibitors, or tyrosine kinase inhibitors

- No other malignancy within the past 5 years except adequately treated basal cell or
squamous cell skin cancer or carcinoma in situ of the cervix NOTE: *In patients
without a colostomy or ileostomy; patients with a colostomy or ileostomy are eligible
at the discretion of the investigator

PRIOR CONCURRENT THERAPY:

Biologic therapy

- No prior biologic therapy for metastatic colorectal cancer

- No prior chimerized or murine antibodies

- No prior cetuximab

- No concurrent prophylactic filgrastim (G-CSF) or sargramostim (GM-CSF)

Chemotherapy

- See Radiotherapy

- More than 12 months since prior chemotherapy

- No prior chemotherapy for metastatic colorectal cancer

- No prior irinotecan or oxaliplatin in the adjuvant or metastatic setting

- No more than 6 months or 4 courses of prior adjuvant chemotherapy

- No other concurrent chemotherapy

Endocrine therapy

- No prior endocrine therapy for metastatic colorectal cancer

- No concurrent hormonal therapy except the following:

- Steroids for adrenal failure

- Hormones administered for non-disease-related conditions (e.g., insulin for
diabetes)

- Intermittent use of dexamethasone as an antiemetic

Radiotherapy

- More than 4 weeks since prior radiotherapy

- No prior radiotherapy for metastatic colorectal cancer

- No prior radiotherapy to more than 25% of bone marrow

- Prior standard adjuvant chemoradiotherapy for rectal cancer allowed

- Prior adjuvant radiotherapy with radiosensitizing chemotherapy allowed

- No concurrent palliative radiotherapy except whole brain radiotherapy for documented
CNS disease

Surgery

- See Disease Characteristics

- More than 4 weeks since prior major surgery*

- More than 2 weeks since prior minor surgery* and recovered

- No prior surgery for metastatic colorectal cancer NOTE: *Insertion of a vascular
device is not considered major or minor surgery

Other

- At least 4 weeks since prior itraconazole or ketoconazole

- No other prior treatment for metastatic colorectal cancer

- No prior EGFR inhibitors

- No prior tyrosine kinase inhibitors

- No other concurrent investigational agents

- No concurrent agents to minimize neurotoxicity of oxaliplatin (e.g., carbamazepine,
magnesium, or calcium)

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Survival

Outcome Time Frame:

3 years

Safety Issue:

No

Principal Investigator

Alan P. Venook, MD

Investigator Role:

Study Chair

Investigator Affiliation:

University of California, San Francisco

Authority:

United States: Food and Drug Administration

Study ID:

CDR0000350016

NCT ID:

NCT00077233

Start Date:

December 2003

Completion Date:

June 2010

Related Keywords:

  • Colorectal Cancer
  • adenocarcinoma of the colon
  • adenocarcinoma of the rectum
  • recurrent colon cancer
  • recurrent rectal cancer
  • stage IV colon cancer
  • stage IV rectal cancer
  • Adenocarcinoma
  • Adenocarcinoma, Mucinous
  • Colorectal Neoplasms
  • Colonic Neoplasms

Name

Location

Memorial Sloan-Kettering Cancer CenterNew York, New York  10021
Walter Reed Army Medical CenterWashington, District of Columbia  20307-5000
University of Chicago Cancer Research CenterChicago, Illinois  60637
University of Minnesota Cancer CenterMinneapolis, Minnesota  55455
Duke Comprehensive Cancer CenterDurham, North Carolina  27710
CCOP - Kansas CityKansas City, Missouri  64131
CCOP - Southern Nevada Cancer Research FoundationLas Vegas, Nevada  89106
CCOP - Christiana Care Health ServicesWilmington, Delaware  19899
CCOP - Mount Sinai Medical CenterMiami Beach, Florida  33140
CCOP - North Shore University HospitalManhasset, New York  11030
CCOP - Southeast Cancer Control ConsortiumWinston-Salem, North Carolina  27104-4241
MBCCOP - Massey Cancer CenterRichmond, Virginia  23298-0037
CCOP - Illinois Oncology Research AssociationPeoria, Illinois  61602
Beth Israel Deaconess Medical CenterBoston, Massachusetts  02215
Comprehensive Cancer Center at Wake Forest UniversityWinston-Salem, North Carolina  27157-1082
Western Pennsylvania HospitalPittsburgh, Pennsylvania  15224
Martha Jefferson HospitalCharlottesville, Virginia  22901
MBCCOP - University of Illinois at ChicagoChicago, Illinois  60612
CCOP - EvanstonEvanston, Illinois  60201
CCOP - Northern Indiana CR ConsortiumSouth Bend, Indiana  46601
Holden Comprehensive Cancer Center at University of IowaIowa City, Iowa  52242-1002
UMASS Memorial Cancer Center - University CampusWorcester, Massachusetts  01605-2982
Ellis Fischel Cancer Center at University of Missouri - ColumbiaColumbia, Missouri  65203
Siteman Cancer Center at Barnes-Jewish HospitalSaint Louis, Missouri  63110
Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical CenterLebanon, New Hampshire  03756-0002
Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel HillChapel Hill, North Carolina  27599-7570
North Shore University HospitalManhasset, New York  11030
Veterans Affairs Medical Center - Chicago (Westside Hospital)Chicago, Illinois  60612
Naval Medical Center - San DiegoSan Diego, California  92134-3202
Veterans Affairs Medical Center - San FranciscoSan Francisco, California  94121
Baptist Hospital East - LouisvilleLouisville, Kentucky  40207
CCOP - Syracuse Hematology-Oncology Associates of Central New York, P.C.Syracuse, New York  13217
Veterans Affairs Medical Center - MinneapolisMinneapolis, Minnesota  55417
Veterans Affairs Medical Center - Columbia (Truman Memorial)Columbia, Missouri  65201
Veterans Affairs Medical Center - BuffaloBuffalo, New York  14215
Veterans Affairs Medical Center - SyracuseSyracuse, New York  13210
Veterans Affairs Medical Center - DurhamDurham, North Carolina  27705
Rebecca and John Moores UCSD Cancer CenterLa Jolla, California  92093-0658
Broward General Medical CenterFort Lauderdale, Florida  33316
Florida Hospital Cancer InstituteOrlando, Florida  32804
Dana-Farber/Harvard Cancer Center at Dana Farber Cancer InstituteBoston, Massachusetts  02115
Northeast Alabama Regional Medical CenterAnniston, Alabama  36207
Veterans Affairs Medical Center - San DiegoSan Diego, California  92161
UCSF Comprehensive Cancer CenterSan Francisco, California  94115
Veterans Affairs Medical Center - Washington, DCWashington, District of Columbia  20422
Louis A. Weiss Memorial HospitalChicago, Illinois  60640
West Suburban Center for Cancer CareRiver Forest, Illinois  60305
Fort Wayne Medical Oncology and Hematology, IncorporatedFort Wayne, Indiana  46885-5099
Veterans Affairs Medical Center - Las VegasLas Vegas, Nevada  89106
Cooper University HospitalCamden, New Jersey  08103
Queens Cancer Center of Queens HospitalJamaica, New York  11432
Veterans Affairs Medical Center - AshevilleAsheville, North Carolina  28805
Cape Fear Valley Health SystemFayetteville, North Carolina  28302-2000
FirstHealth Moore Regional HospitalPinehurst, North Carolina  28374
Lifespan: The Miriam HospitalProvidence, Rhode Island  02906
Veterans Affairs Medical Center - DallasDallas, Texas  75216
Virginia Oncology Associates - NorfolkNorfolk, Virginia  23502
St. Mary's Medical CenterHuntington, West Virginia  25701
Oklahoma University Medical CenterOklahoma City, Oklahoma  73104
Mount Sinai Medical CenterNew York, New York  10029
SUNY Upstate Medical University HospitalSyracuse, New York  13210
Vermont Cancer Center at University of VermontBurlington, Vermont  05405-0075
Lombardi Cancer Center at Georgetown University Medical CenterWashington, District of Columbia  20007
Greenebaum Cancer Center at University of Maryland Medical CenterBaltimore, Maryland  21201
UNMC Eppley Cancer Center at the University of Nebraska Medical CenterOmaha, Nebraska  68198-7680
New Hampshire Oncology-Hematology, PA - HooksettHooksett, New Hampshire  03106
NorthEast Oncology Associates - ConcordConcord, North Carolina  28025
Arthur G. James Cancer Hospital at Ohio State UniversityColumbus, Ohio  43210-1240
Oncology and Hematology Associates of Southwest Virginia, Incorporated - RoanokeRoanoke, Virginia  24014
Lakeland Cancer Care Center at Lakeland Hospital - St. JosephSaint Joseph, Michigan  49085
New York Weill Cornell Cancer Center at Cornell UniversityNew York, New York  10021
Zimmer Cancer Center at New Hanover Regional Medical CenterWilmington, North Carolina  28402-9025
Cedars-Sinai Comprehensive Cancer Center at Cedars-Sinai Medical CenterLos Angeles, California  90048
Simmons Cancer Center at University of Texas Southwestern Medical Center - DallasDallas, Texas  75390-9063
Memorial Regional Cancer Center at Memorial Regional HospitalHollywood, Florida  33021
Missouri Baptist Cancer CenterSt. Louis, Missouri  63131
Palm Beach Cancer InstituteWest Palm Beach, Florida  33401