Clinical trial NCT00640081: Combination Chemotherapy and Cetuximab as First-Line Therapy in Treating Patients With Advanced and/or Metastatic Colorectal Cancer
Official title: A Two-arm Phase II Randomised Trial of Intermittent Chemotherapy Plus Continuous Cetuximab and of Intermittent Chemotherapy Plus Intermittent Cetuximab in First Line Treatment of Patients With K-ras-normal (Wild-type) Metastatic Colorectal Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Colorectal Cancer
Keywords: adenocarcinoma of the colon
stage IV colon cancer
adenocarcinoma of the rectum
stage IV rectal cancer
stage III colon cancer
stage III rectal cancer
recurrent colon cancer
recurrent rectal cancer
Lead sponsor: Medical Research Council
Sponsor class: OTHER_GOV
First posted: 2008-03-20
Enrollment: 169
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as cetuximab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. It is not yet known whether giving combination chemotherapy together with intermittent cetuximab is more effective than combination chemotherapy given together with continuous cetuximab in treating colorectal cancer.

PURPOSE: This randomized phase II trial is studying giving combination chemotherapy together with intermittent cetuximab to see how well it works compared to combination chemotherapy given together with continuous cetuximab as first-line therapy in treating patients with advanced or metastatic colorectal cancer.

Detailed description: OBJECTIVES:

Primary

* To compare the activity, in terms of failure-free survival, of patients with K-ras-normal (wild type) advanced and/or metastatic colorectal cancer treated with intermittent combination chemotherapy comprising oxaliplatin, leucovorin calcium, and fluorouracil (OxMdG) or oxaliplatin and capecitabine (XELOX) and intermittent vs continuous cetuximab as first-line therapy.
* To compare the safety and feasibility of these regimens in these patients.

Secondary

* To compare the safety of cetuximab reintroduction, in terms of frequency of grade 3-4 allergic reactions in these patients.
* To compare improvement in disease control (i.e., complete response plus partial response plus stable disease) at 24 weeks in patients treated with these regimens.
* To compare overall and progression-free survival of patients treated with these regimens.
* To compare response rates at 12, 24, and 36 weeks in patients treated with these regimens.
* To compare toxicity of these regimens in these patients.

OUTLINE: This is a multicenter study. Patients are randomised to 1 of 2 treatment arms.

* Arm I (intermittent chemotherapy and intermittent cetuximab): Patients receive 1 of the following combination chemotherapy and cetuximab regimens:

  * OxMdG: Patients receive oxaliplatin IV over 2 hours and leucovorin calcium IV over 2 hours on day 1 and fluorouracil IV continuously over 46 hours on days 1 and 2. Patients also receive cetuximab IV over 1-2 hours on days 1 and 8. Treatment repeats every 14 days for up to 6 courses (12 weeks) in the absence of disease progression or unacceptable toxicity.
  * XELOX (for patients with line-related problems): Patients receive oxaliplatin IV over 2 hours on day 1 and oral capecitabine twice daily on days 1-15 (28 doses). Patients also receive cetuximab IV over 1-2 hours on days 1, 8, and 15. Treatment repeats every 21 days for up to 4 courses (12 weeks) in the absence of disease progression or unacceptable toxicity.

After completion of 12 weeks of study therapy, patients with disease progression are removed from study. Patients with stable or responding disease stop treatment with OxMdG or XELOX and cetuximab and undergo clinical evaluation at least every 6 weeks until disease progression or clinical deterioration. Upon evidence of disease progression or clinical deterioration, patients restart treatment with OxMdG or XELOX and cetuximab as before and continue to alternate 12 weeks of treatment with treatment breaks in the absence of disease progression or unacceptable toxicity. Patients with disease progression during study therapy stop treatment and proceed to second-line therapy or best supportive care.

* Arm II (intermittent chemotherapy and continuous cetuximab): Patients receive OxMdG or XELOX and cetuximab for 12 weeks as in arm I. Patients with disease progression after 12 weeks of study therapy are removed from study. Patients with stable or responding disease\* after 12 weeks of study therapy stop treatment with OxMdG or XELOX and continue treatment with cetuximab weekly as monotherapy in the absence of disease progression or unacceptable toxicity. Patients undergo clinical evaluation as in arm I. Upon progression, patients restart treatment with OxMdG or XELOX and continue cetuximab, as before, alternating 12 weeks of combined OxMdG or XELOX and cetuximab therapy with cetuximab monotherapy. Patients with disease progression during study therapy stop treatment and proceed to second-line therapy as in arm I.

Previously collected tumor tissue samples are obtained at baseline and analyzed by IHC for EGFR status of tumor.

After completion of study treatment, patients are followed every 12 weeks.

Peer Reviewed and Funded or Endorsed by Cancer Research UK.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Diagnosis of colorectal adenocarcinoma, defined by 1 of the following:

  * Prior or current histologically confirmed primary adenocarcinoma of colon or rectum with clinical or radiological evidence of advanced and/or metastatic disease
  * Histologically and cytologically confirmed metastatic adenocarcinoma with clinical and/or radiological evidence of colorectal primary tumor
* Unidimensionally measurable disease by RECIST criteria
* Inoperable metastatic or locoregional disease

  * Potentially resectable liver metastases allowed provided the following criteria are met:

    * Fewer than 4 unilobar liver metastases, each \< 4 cm in size and without major vascular involvement
    * No combination chemotherapy allowed prior to the planned resection of operable liver metastases
* No confirmed K-ras mutation of tumor after screening
* No brain metastases

PATIENT CHARACTERISTICS:

* WHO performance status 0-2
* Must be considered fit to undergo combination chemotherapy
* ANC ≥ 1,500/mm³
* Platelet count ≥ 100,000/mm³
* Serum bilirubin ≤ 1.25 times upper limit of normal (ULN)
* Alkaline phosphatase ≤ 5 times ULN
* AST or ALT ≤ 2.5 times ULN
* Creatinine clearance ≥ 50mL/min OR glomerular filtration rate ≥ 50 mL/min
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception
* No severe uncontrolled concurrent medical illness (including poorly controlled angina or myocardial infarction within the past 12 weeks) likely to interfere with protocol treatments
* No psychiatric or neurological condition that would preclude study compliance with oral medication or giving informed consent
* No partial or complete bowel obstruction
* No preexisting neuropathy \> grade 1
* No prior or current malignant disease which, in the judgement of the treating investigator, is likely to interfere with COIN-B treatment or assessment of response
* No patients with known hypersensitivity reactions to any of the components of the study treatments
* No proven dihydropyrimidine dehydrogenase deficiency (DPD) or personal or family history of DPD

PRIOR CONCURRENT THERAPY:

* See Disease Characteristics
* No prior systemic palliative chemotherapy for metastatic disease
* No prior oxaliplatin
* More than 1 month since prior adjuvant chemotherapy comprising fluorouracil (with or without leucovorin calcium), capecitabine, or irinotecan hydrochloride
* More than 1 month since prior chemoradiotherapy comprising fluorouracil (with or without leucovorin calcium) or capecitabine for rectal cancer
* No ongoing requirement for contraindicated concurrent medication
* No concurrent enrollment in any type of study other than observational studies

Primary outcomes:
measure: Failure-free survival at 10 months
timeFrame: 10 months
Secondary outcomes:
measure: Safety of cetuximab reintroduction, in terms of risk of grade 3-4 allergic reactions
timeFrame: 12, 24 and 36 weeks
measure: Proportion of patients achieving disease control (complete response plus partial response plus stable disease) at 24 weeks
timeFrame: 24 weeks
measure: Overall survival
timeFrame: at 12, 24 and 36 weeks
measure: Progression-free survival
timeFrame: at 12, 24 and 36 weeks
measure: Response rates
timeFrame: at 12, 24 and 36 weeks
measure: Toxicity of each treatment regimen by NCI CTCAE v3.0
timeFrame: at 12, 24 and 36 weeks
Other outcomes:
Locations:
city: Nicosia
country: Cyprus
facility: Bank of Cyprus Oncology Centre
city: Bradford
country: United Kingdom
facility: Bradford Royal Infirmary
state: England
city: Cheltenham
country: United Kingdom
facility: Gloucestershire Oncology Centre at Cheltenham General Hospital
state: England
city: Colchester
country: United Kingdom
facility: Essex County Hospital
state: England
city: Dorchester
country: United Kingdom
facility: Dorset County Hospital
state: England
city: Guildford
country: United Kingdom
facility: St. Luke's Cancer Centre at Royal Surrey County Hospital
state: England
city: London
country: United Kingdom
facility: Hammersmith Hospital
state: England
city: London
country: United Kingdom
facility: St. Mary's Hospital
state: England
city: Oxford
country: United Kingdom
facility: Churchill Hospital
state: England
city: Peterborough
country: United Kingdom
facility: Peterborough Hospitals Trust
state: England
city: Stoke-On-Trent
country: United Kingdom
facility: University Hospital of North Staffordshire
state: England
city: Swansea
country: United Kingdom
facility: Singleton Hospital
state: Wales
city: Bath
country: United Kingdom
facility: Royal United Hospital
city: Bournemouth
country: United Kingdom
facility: Royal Bournemouth Hospital
city: Cambridge
country: United Kingdom
facility: Addenbrookes Hospital
city: Dartford
country: United Kingdom
facility: Darent Valley Hospital
city: Hereford
country: United Kingdom
facility: Hereford County Hospital
city: London
country: United Kingdom
facility: Charing Cross Hospital
city: London
country: United Kingdom
facility: Guys and St Thomas' hospitals
city: Poole
country: United Kingdom
facility: Dorset Cancer Centre, Poole Hospital
city: Sheffield
country: United Kingdom
facility: Weston Park
city: Southport
country: United Kingdom
facility: Southport and Ormskirk
city: St Helens
country: United Kingdom
facility: St Helens and Whiston hospitals
city: Warrington
country: United Kingdom
facility: Warrington and Halton Hospitals
city: Worcester
country: United Kingdom
facility: Worcestershire Royal Hospital
Study officials:
affiliation: Hammersmith Hospitals NHS Trust
name: Harpreet S. Wasan
role: PRINCIPAL_INVESTIGATOR
References: