Hepatic Arterial Chemotherapy With Raltitrexed and Oxaliplatin Versus Standard Chemotherapy in Unresectable Liver Metastases From Colorectal Cancer After Conventional Chemotherapy Failure

NCT01348412 | Completed Phase 2 DMC

• 1 other identifier: 0329-1ghfr09
• Study Type: interventional
• Target: 31
• Locations: 1 country
• Sites: 1

Brief Summary

Standard treatment of metastatic colorectal cancers relies on fluoropyrimidines, irinotecan alone or in association with fluoropyrimidines, oxaliplatin in association with fluoropyrimidines, bevacizumab and anti EGFR antibodies. After failure of classical regimen the national reference frame on the basis of phase II study proposes an association of fluoropyrimidine and mitomycin. These treatments give response rates of 10-20% with progression free survivals from 2 to 3 months. Hepatic intra-arterial chemotherapy is logical in the case of isolated hepatic metastases nonaccessible to curative resection: 1) hepatic metastases are vascularized by hepatic arterial system in contrast to nontumoral hepatic parenchyma; 2) arterial perfusion of oxaliplatin leads to a strong extraction by the liver during the first passage, a high intra-tumoral concentration and a low systemic concentration. So oxaliplatin is a drug of choice for arterial treatment but combination with fluoropyrimidines is impossible because of need for prolonged perfusion. Floxuridin is not available in France. Raltitrexed, a definitive inhibitor of the thymidylate synthase, does not require a prolonged perfusion and could be a good substitute.In a previous pilot study we demonstrated the feasibility, safety and efficacy of combination of raltitrexed and oxaliplatin arterial perfusion. Now we propose a phase II randomized clinical trial to evaluate the efficacy of hepatic arterial infusion of raltitrexed and oxaliplatin association versus standard chemotherapy for patients with metastases of colorectal origin restricted to the liver after failure of conventional chemotherapy.

Conditions

Colorectal Cancer; Liver Metastases

Keywords

non resectable metastases; liver of colic or rectal origin; after failure of the conventional treatments

Outcome Measures

Primary Outcomes (1)

• progression-free survival

  for each patient after the 6 months of treatment

Secondary Outcomes (6)

• Estimate the parameters of tumor perfusion using arterial CT Scan data

  for each patient of experimental arm every 9 weeks after the six months of treatment or until progression

• Estimate the rate of objective response according to the criteria of CHOI and RECIST

  for each patient every 9 weeks during the 6 months of treatment or until progression

• Estimate the overall survival which will be compared with the median of overall survival in other studies published in the literature

  after all data completion after the end of all patient follow-up (december 2013-anticipated)

• Estimate the rate of secondary resectable hepatic metastases

  after all data completion after the end of all patient follow-up (december 2013-anticipated)

• Estimate the tolerance of the treatment (NCI-CTCAE version 4.0)

  For each patient every 21 days during the six months of treatment and for one year of follow up or until progression

Study Arms (2)

ARM A

EXPERIMENTAL

Hepatic artery infusion through an implanted arterial catheter of the combination of raltitrexed (3 mg/m ²) and oxaliplatin (100 mg/m ²) every 21 days.

Drug: oxaliplatin; Drug: raltitrexed

ARM B

ACTIVE COMPARATOR

Intravenous standard chemotherapy.

Drug: other intravenous chemotherapy drugs

Interventions

oxaliplatin DRUG

130 mg/m²Every 21 days

ARM A

raltitrexed DRUG

3 mg/m² with a maximum of 6 mg every 21 days

ARM A

other intravenous chemotherapy drugs DRUG

ARM B

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Informed consent signature by the patient-
• Cover by an health insurance
• Age between 18 and 75 years
• Age between 76 et 80 years if patient WHO Status 0
• WHO status of 0 or 1
• Estimated Life expectancy \> 3 months
• Hepatic metastases of colorectal cancer confirmed on CT Scan without extra-hepatic metastasis (the presence of asymptomatic primary tumor is tolerated)
• TEP-Scan without fixation outside the liver and the primary tumor
• Histological proven colorectal cancer obtained from primary tumor or the hepatic metastases
• Metastases not accessible to curative hepatectomy (impossible R0 surgery or leaving less than 30 % of residual liver), or requiring a complex, very wide hepatectomy (5 segments or more) and\\or risky procedure (RPC Class II)- - Presence of hepatic lesion \> 10 mm on CTScan or hepatic MRI
• Failure or arrest of a previous chemotherapy because of intolerance to oxaliplatin, irinotecan, a fluoropyrimidine and/or target therapies (bevacizumab, cetuximab or panitumumab given for tumor expressing wild type Ki-Ras)
• Bilirubinemia\< 1,5 times the superior limit of the normal ( N ),
• ASAT and ALAT \< 5 N,
• Creatinemia \< 1.5 N and creatinine clearance \> 65ml/mn,
• Neutrophils \> 1,5 x 109/L, platelets 100 x 109/L, hemoglobin \> 9 g/dL (patients includables even after red blood cell transfusion)-Reference CTScan +/-MRI performed in 21 days preceding the first cycle of treatment

You may not qualify if:

• Symptomatic primary colorectal tumor in place
• Contraindication for allergy of rank 3-4 for one of the compounds of chemotherapy- Peripheral neuropathy \> 2 (Levy Scale)
• Concomitant systemic treatment by immunotherapy, chemotherapy or hormonotherapy- Unbalanced serious illness, unchecked active infection or the other underlying serious disorder susceptible to prevent the patient from receiving the treatment
• Intestinal occlusion or sub-occlusion or history of inflammatory intestinal disease
• Other cancer during the 5 years preceding entry in the trial or concomitant (except in situ cancer of the cervix or skin basal cell carcinoma)Patient in custody or under guardianship, Impossibility to adhere to the medical follow-up for geographical, social or psychiatric reason

Sponsors & Collaborators

• Centre Georges Francois Leclerc: lead
• National Cancer Institute, France: collaborator
• Hospira, now a wholly owned subsidiary of Pfizer: collaborator

Study Sites (1)

Centre Georges François Leclerc

Dijon, 21000, France

Location

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

Oxaliplatin; raltitrexed

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Coordination Complexes; Organic Chemicals

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 27, 2011
• First Posted: May 5, 2011
• Study Start: December 15, 2010
• Primary Completion: December 15, 2010
• Study Completion: April 18, 2018
• Last Updated: July 16, 2018

Record last verified: 2018-07

Locations

FR (1)