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

Primary Purpose

Colorectal Cancer, Liver Metastases

Status

Completed

Phase

Phase 2

Locations

France

Study Type

Interventional

Intervention

oxaliplatin

raltitrexed

other intravenous chemotherapy drugs

About this trial

This is an interventional treatment trial for Colorectal Cancer focused on measuring non resectable metastases, liver of colic or rectal origin, after failure of the conventional treatments

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

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

Exclusion Criteria:

extra-hepatic metastases (presence of 1 to 3 pulmonary nodules, of a maximal diameter of 5 mm with non specific aspect on CTScan and with no fixation on TEP Scan does not constitute a criterion of exclusion)
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)
Current participation or in the 30 days preceding the inclusion in the study in another therapeutic trial with an experimental molecule
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
Pregnancy (pregnancy test compulsory for the inclusion), breast-feeding
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

Sites / Locations

Centre Georges François Leclerc

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

ARM A

ARM B

Arm Description

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.

Intravenous standard chemotherapy.

Outcomes

Primary Outcome Measures

progression-free survival

Secondary Outcome Measures

Estimate the parameters of tumor perfusion using arterial CT Scan data

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

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

Estimate the rate of secondary resectable hepatic metastases

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

Estimate the quality of life (QLQ C30) and the fatigue MFI20

Full Information

NCT ID

NCT01348412

First Posted

April 27, 2011

Last Updated

July 12, 2018

Sponsor

Centre Georges Francois Leclerc

Collaborators

National Cancer Institute, France, Hospira, now a wholly owned subsidiary of Pfizer

1. Study Identification

Unique Protocol Identification Number

NCT01348412

Brief Title

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

Acronym

HEARTO

Official Title

Phase II Randomized Study Comparing the Association of Intraarterial Perfusion of Raltitrexed and Oxaliplatin Versus Standard Chemotherapy Using Intravenous Perfusion for Colorectal Cancer Patient With Metastases Localized to Liver After Failure of Conventional Treatments.

Study Type

Interventional

2. Study Status

Record Verification Date

July 2018

Overall Recruitment Status

Completed

Study Start Date

December 15, 2010 (Actual)

Primary Completion Date

December 15, 2010 (Actual)

Study Completion Date

April 18, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Centre Georges Francois Leclerc

Collaborators

National Cancer Institute, France, Hospira, now a wholly owned subsidiary of Pfizer

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Colorectal Cancer, Liver Metastases

Keywords

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

31 (Actual)

8. Arms, Groups, and Interventions

Arm Title

ARM A

Arm Type

Experimental

Arm Description

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.

Arm Title

ARM B

Arm Type

Active Comparator

Arm Description

Intravenous standard chemotherapy.

Intervention Type

Drug

Intervention Name(s)

oxaliplatin

Intervention Description

130 mg/m²Every 21 days

Intervention Type

Drug

Intervention Name(s)

raltitrexed

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

other intravenous chemotherapy drugs

Primary Outcome Measure Information:

Title

progression-free survival

Time Frame

for each patient after the 6 months of treatment

Secondary Outcome Measure Information:

Title

Estimate the parameters of tumor perfusion using arterial CT Scan data

Time Frame

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

Title

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

Time Frame

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

Title

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

Time Frame

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

Title

Estimate the rate of secondary resectable hepatic metastases

Time Frame

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

Title

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

Time Frame

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

Title

Estimate the quality of life (QLQ C30) and the fatigue MFI20

Time Frame

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

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

75 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: 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 Exclusion Criteria: extra-hepatic metastases (presence of 1 to 3 pulmonary nodules, of a maximal diameter of 5 mm with non specific aspect on CTScan and with no fixation on TEP Scan does not constitute a criterion of exclusion) 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) Current participation or in the 30 days preceding the inclusion in the study in another therapeutic trial with an experimental molecule 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 Pregnancy (pregnancy test compulsory for the inclusion), breast-feeding 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

Facility Information:

Facility Name

Centre Georges François Leclerc

City

Dijon

ZIP/Postal Code

21000

Country

France

12. IPD Sharing Statement

Learn more about this trial

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

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