Perioperative Treatment of Resectable Liver Metastases

NCT ID: NCT01540435

Last Updated: 2013-05-29

Basic Information

• Recruitment Status: WITHDRAWN
• Clinical Phase: PHASE2
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-09-30
• Study Completion Date: 2013-05-31

Brief Summary

This randomized, controlled, multicenter, non-comparative phase II trial compares an intensified perioperative treatment of patients with resectable synchronous or metachronous colorectal liver metastases to primary surgery and adjuvant systemic chemotherapy.

Detailed Description

Recurrence rates after R0-resection of colorectal liver metastases are still very high (about 60-70 %). Therefore, multidisciplinary treatment of these patients is frequently used in order to achieve a beneficial impact regarding progression-free and overall survival. The point in time of treatment, pre- and/or postoperative, is still a matter of debate. In the EORTC 40983 trial, perioperative chemotherapy with 5-Fluorouracil and oxaliplatin (FOLFOX-Regimen) displayed a non-significant benefit in 3 year disease free survival in the intent to treat population (HR 0.79, 95% CI 0.62 to 1.02) (Nordlinger, Sorbye et al. 2008). The combined analysis of two adjuvant trials, with a (non-contemporary) 5-FU Bolus regimen, showed a non-significant prolongation of median disease free survival (DFS) from 18.8 to 27.9 months (p=0.058) and OS from 47.3 to 62.2 months (p=0.095) (Mitry, Fields et al. 2008). However, postoperative treatment with 6 months of FOLFOX is often used in daily practise. Thus, further investigation is urgently warranted.

This phase II trial evaluates two strategies with intensified perioperative or postoperative treatment regimens. Current studies established the role of the FOLFOXIRI regimen in the metastatic setting (Falcone, Ricci et al. 2007). A further intensification of a three drug regimen with bevacizumab seem to be feasible yielding response rates up to 84% and a disease control rate up to 100% (Falcone 2008; Bruera, Santomaggio et al. 2010; Masi, Loupakis et al. 2010). Regarding the efficacy, evaluation of FOLFOXIRI and bevacizumab in preoperative treatment for resectable CLM seems to be promising. Postoperative treatment with FOLFOX for 6 months was chosen for arm A.

Conditions

Colon Cancer Liver Metastasis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Postoperative Arm (Arm A)

FOLFOX:

Oxaliplatin at a dose of 85 mg/m2 iv over two hours (day 1) I-LV at a dose of 200 mg/m2 iv over two hours (day 1) 5-FU at a dose of 3200 mg/m2 iv over 48 hours (day 1-3)

Duration of treatment:

Treatment will be administered for 12 cycles (6 months) postoperatively starting 6 weeks after surgery.

Group Type: NO_INTERVENTION

No interventions assigned to this group

Perioperative Arm (Arm B)

Therapy will be administered in a biweekly schedule. First preoperative cycle will be administered with 75% of dosage for FOLFOXIRI, if no diarrhea ≥ grade 3 occurs, following cycles should be administered in full dosage.

FOLFOXIRI + bevacizumab:

bevacizumab at a dose of 5 mg/kg iv over 30 to 90 min (day 1) irinotecan at a dose of 165 mg/m2 iv over two hours (day 1) oxaliplatin at a dose of 85 mg/m2 iv over two hours (day 1) I-LV at a dose of 200 mg/m2 iv over two hours (day 1) 5-FU at a dose of 3200 mg/m2 iv over 48 hours (day 1-3)

Duration of treatment:

Treatment will be administered for 6 cycles (3 months) preoperatively (last cycle without bevacizumab), after 6 weeks followed by liver surgery, after further 6 weeks followed by 6 cycles (3 months) postoperatively.

Group Type: EXPERIMENTAL

Bevacizumab

Intervention Type: DRUG

Bevacizumab at a dose of 5 mg/kg iv over 30 to 90 min (day 1) + FOLFOXIRI in a biweekly schedule, 6 cycles preoperatively, 6 cycles postoperatively

Interventions

Bevacizumab

Bevacizumab at a dose of 5 mg/kg iv over 30 to 90 min (day 1) + FOLFOXIRI in a biweekly schedule, 6 cycles preoperatively, 6 cycles postoperatively

Intervention Type: DRUG

Other Intervention Names

VEGF antibody

Eligibility Criteria

Inclusion Criteria

9. All the following tests should be done within 4 weeks prior to randomization

• Absolute neutrophil count > 1.5 x 109/L, platelets > 100 x 109/L, and hemoglobin > 9 g/dL or 5.59 mmol/l.
• Serum creatinine less than 1.5 times the upper limit of normal (ULN) (to exclude severe renal impairment); no significant proteinuria (urine dipstick for proteinuria ³ 2+. If urine dipstick is ³ 2+, 24-hour urine must demonstrate £ 1 g of protein in 24 hours for patient to be eligible).
• Absence of major hepatic insufficiency (bilirubin < 1.5 x ULN and aspartate aminotransferase (ASAT)/alanine aminotransferase (ALAT) < 5 x ULN).
• Patients not receiving therapeutic anticoagulation must have an INR < 1.5 ULN and aPTT < 1.5 ULN within 7 days prior to registration. The use of full dose anticoagulants is allowed as long as the INR or aPTT is within therapeutic limits (according to the medical standard in the institution) and the patient has been on a stable dose for anticoagulants for at least two weeks at the time of registration.

10. No pregnancy or breast feeding. Negative serum pregnancy test within 7 days of starting study treatment in pre-menopausal women and women < 1 year after the onset of menopause is required before entering in the trial. Note: a negative test has to be reconfirmed by a urine test, should the 7-day window be exceeded.

11. Adequate contraception is required during and for 3 months after study treatment for both male and female patients if the risk of conception exists.

12. No major surgical procedure, open biopsy, or significant traumatic injury within 4 weeks prior to randomization.

13. No previous exposure to VEGF/VEGFR-targeting therapy within the last 12 months.

14. No thrombosis or severe bleeding within 6 months prior to entry into the study (except for bleeding of the tumor before its surgical resection) and no evidence of bleeding diathesis or coagulopathy.

15. Absence of peripheral neuropathy NCI CTCAE-grade ≥ 1, active inflammatory bowel disease or other bowel disease causing chronic diarrhea (defined as > 4 loose stools per day), serious wound complications, ulcers, or bone fractures.

16. No evidence of any other disease, metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or puts the patient at high risk for treatment-related complications.

17. No concomitant treatment with ASS > 325 mg or NSAIDs, known to inhibit platelet function, sorivudin or analog compounds or preparations of St. John's wort.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Halle Medical Faculty

OTHER

Sponsor Role: collaborator

University of Regensburg

OTHER

Sponsor Role: lead

Responsible Party

Hans J Schlitt, Prof. MD

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Hans J. Schlitt, Prof. MD

Role: STUDY_CHAIR

Department of Surgery, University Medical Center Regensburg

Hans-Joachim Schmoll, Prof. MD

Role: STUDY_DIRECTOR

Department of Internal Medicine IV, University Hospital Halle

References

Stein A, Glockzin G, Wienke A, Arnold D, Edelmann T, Hildebrandt B, Hollerbach S, Illerhaus G, Konigsrainer A, Richter M, Schlitt HJ, Schmoll HJ. Treatment with bevacizumab and FOLFOXIRI in patients with advanced colorectal cancer: presentation of two novel trials (CHARTA and PERIMAX) and review of the literature. BMC Cancer. 2012 Aug 16;12:356. doi: 10.1186/1471-2407-12-356.

Reference Type: BACKGROUND

PMID: 22897915 (View on PubMed)

Other Identifiers

2010-023575-25

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

KKSH088

Identifier Type: -

Identifier Source: org_study_id