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Avastin in Combination With Chemotherapy for RAS Mutant Unresectable Colorectal Liver-limited Metastases

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ClinicalTrials.gov Identifier: NCT01972490
Recruitment Status : Completed
First Posted : October 30, 2013
Last Update Posted : July 22, 2019
Sponsor:
Information provided by (Responsible Party):
Xu jianmin, Fudan University

Brief Summary:
In this study, the investigators assessed the effect of avastin in combination with chemotherapy in the treatment of RAS mutant-type, unresectable colorectal liver-limited metastases

Condition or disease Intervention/treatment Phase
Colorectal Neoplasms Drug: avastin+chemotherapy of mFOLFOX6 or FOLFIRI Drug: chemotherapy of mFOLFOX6 or FOLFIRI Phase 4

Detailed Description:
Patients will be eligible for inclusion if the patients have histologically confirmed colorectal adenocarcinoma with RAS mutant liver-confined metastases deemed non-resectable. Eligible patients will be randomly assigned to chemotherapy plus avastin (arm A) or chemotherapy alone (arm B). Treatment will continue until tumor response indicates suitability for surgery for liver metastases or until disease progression or unacceptable toxic effects. The primary endpoint is the conversion rate to radical resection for liver metastases,which will be assessed by local multidisciplinary team (includes more than three liver surgeons and one radiologist) with the use of contrast-enhanced CT or MRI after 4 cycles and then every other 2 cycles up to 12 cycles. To provide an objective assessment of changes in resectability, radiological images will be presented by a radiologist to more than 3 liver surgeons, who are blinded to the clinical data. Patients will be considered resectable if 50% or more of surgeons vote for radical resection of LM. For patients whose liver-metastases are assessed resectable, resection should be scheduled to be performed within 2~3 weeks of the last treatment cycle. Following resection, patients will be advised to continue the same therapeutic regimen until the treatments reach a sum of 12 cycles.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 240 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Study of Avastin in Combination With Chemotherapy for the First Line Treatment of RAS Mutant Unresectable Colorectal Liver-limited Metastases
Actual Study Start Date : June 2011
Actual Primary Completion Date : December 2017
Actual Study Completion Date : June 2019

Arm Intervention/treatment
Experimental: ARM A
patients received avastin in combination with chemotherapy
Drug: avastin+chemotherapy of mFOLFOX6 or FOLFIRI
Drug: avastin On day 1 of a 14 day treatment cycle, patients received a 2-hour infusion of avastin (5mg/kg) followed by chemotherapy of FOLFOX or FOLFIRI until progressive disease or unacceptable toxicity.

Drug: chemotherapy of mFOLFOX6 or FOLFIRI
mFOLFOX-6 (oxaliplatin, 85mg/m2 on day 1 infused during 2 hours;LV400mg/m2 on days 1 infused during 2 hours, followed by FU 400 mg/m2 intravenous bolus then 2400 mg/m2 continuous infusion for 46 hours of 2400 mg/m2) FOLFIRI(irinotecan 180mg/m2 on day 1 infused during 2 hours; fluorouracil in a bolus of 400 mg/m2 and then continuous infusion for 46 hours of 2400 mg/m2)

Active Comparator: ARM B
Patients received chemotherapy (mFOLFOX6 or FOLFIRI) alone
Drug: chemotherapy of mFOLFOX6 or FOLFIRI
mFOLFOX-6 (oxaliplatin, 85mg/m2 on day 1 infused during 2 hours;LV400mg/m2 on days 1 infused during 2 hours, followed by FU 400 mg/m2 intravenous bolus then 2400 mg/m2 continuous infusion for 46 hours of 2400 mg/m2) FOLFIRI(irinotecan 180mg/m2 on day 1 infused during 2 hours; fluorouracil in a bolus of 400 mg/m2 and then continuous infusion for 46 hours of 2400 mg/m2)




Primary Outcome Measures :
  1. the rate of patients converted to resection for liver metastases [ Time Frame: 3 years ]
    To explore whether avastin in combination with chemotherapy as treatment could improve the resection rate in patients with RAS mutant-type, unresectable colorectal liver-limited metastases compared with chemotherapy alone.


Secondary Outcome Measures :
  1. progression free survival [ Time Frame: 3 years ]
    PFS will be defined as the period from the first day of avastin treatment or chemotherapy to the date of disease progression (PD) or to death. Patients without PD who discontinued the study for any reason is censored at the last on-study tumor assessment date.or distant(i.e. metastasis) disease recurrence or death.

  2. overall survival [ Time Frame: 3 years ]
    OS will be calculated from randomization to death from any cause or the date of the last follow-up, at which point the data will be censored.

  3. tumor response [ Time Frame: 3 years ]


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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age ≥ 18 and ≤ 75 years;
  2. Primary tumour was histologically confirmed colorectal adenocarcinoma;
  3. Together with clinical or radiological evidence of first occurrence of non-resectable liver-only metastases
  4. With evidence of tumor RAS gene mutant status;
  5. With at least one measurable tumor.
  6. Performance status (ECOG) 0~1
  7. A life expectancy of ≥ 3 months
  8. Adequate hematological function: Neutrophils≥1.5 x109/l and platelet count≥100 x109/l; Hb ≥9g/dl (within 1 week prior to randomization)
  9. Adequate hepatic and renal function: Serum bilirubin≤1.5 x upper limit of normal (ULN), alkaline phosphatase ≤5x ULN, and serum transaminase (either AST or ALT) ≤ 5 x ULN(within 1 week prior to randomization);
  10. Written informed consent for participation in the trial.

Exclusion Criteria:

  1. Previous exposure to target therapy, chemotherapy, radiotherapy or intervention therapy for colorectal liver metastases.
  2. Known or suspected extrahepatic metastases.
  3. Patients with known hypersensitivity reactions to any of the components of the study treatments.
  4. Having previously participated in a study which included a possibility of being allocated to avastin therapy (whether or not the patient actually received avastin)
  5. Clinically relevant coronary artery disease or a history of a myocardial infarction within the last 12 months or left ventricular ejection fraction (LVEF) below the institutional range of normal
  6. Acute or sub-acute intestinal occlusion
  7. Pregnancy (absence confirmed by serum/urine β-HCG) or breast-feeding
  8. Other previous malignancy within 5 years, with exception of a history of a previous basal cell carcinoma of the skin or pre-invasive carcinoma of the cervix
  9. Known drug abuse/ alcohol abuse
  10. Legal incapacity or limited legal capacity
  11. Pre-existing peripheral neuropathy.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01972490


Locations
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China, Shanghai
Zhongshan Hospital, Fudan University
Shanghai, Shanghai, China, 200000
Sponsors and Collaborators
Xu jianmin

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Responsible Party: Xu jianmin, Jianmin Xu, PhD Fudan University, Fudan University
ClinicalTrials.gov Identifier: NCT01972490     History of Changes
Other Study ID Numbers: ACCMCLM
First Posted: October 30, 2013    Key Record Dates
Last Update Posted: July 22, 2019
Last Verified: July 2019

Keywords provided by Xu jianmin, Fudan University:
colorectal neoplasms
liver metastasis
chemotherapy
avastin

Additional relevant MeSH terms:
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Neoplasm Metastasis
Colorectal Neoplasms
Neoplasms
Neoplastic Processes
Pathologic Processes
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Bevacizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors