Perioperative Treatment of Resectable Liver Metastases

NCT01540435 | Withdrawn Phase 2 DMC

• 2 other identifiers: KKSH0882010-023575-25
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

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.

Conditions

Colon Cancer Liver Metastasis

Keywords

Colorectal cancer; Liver metastases; Perioperative treatment; Liver resection

Outcome Measures

Primary Outcomes (1)

• Failure-free survival (FFS@18)

  Failure will be defined as no R0 resection, local or distant recurrence or death from any cause.

  18 months

Secondary Outcomes (7)

• Disease Free Survival (DFS)

  5 years

• Overall survival (OS)

  5 years

• Perioperative morbidity

  30 days (hospital stay)

• Quality of life

  12 months

• Achievability of R0 resection

  intraoperative

Study Arms (2)

Postoperative Arm (Arm A)

NO INTERVENTION

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.

Perioperative Arm (Arm B)

EXPERIMENTAL

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.

Drug: Bevacizumab

Interventions

Bevacizumab 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

Also known as: VEGF antibody

Perioperative Arm (Arm B)

Eligibility Criteria

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

Main selection criteria: 1. Histological proven CRC with completely resectable metachronous or synchronous liver metastases (as judged by the treating surgeon). 2. Patients must have undergone complete resection (R0) of the primary tumor at least 4 weeks before randomization. Or in case of synchronous disease with intact primary; the primary tumor have to be R0 resectable together with the liver metastases and the patient has a non-obstructive primary tumor and is able to receive preoperative chemotherapy before surgery. Synchronous rectal primary is not allowed. 3. Measurable hepatic disease by Response Evaluation Criteria in Solid Tumors (RECIST version 1.1). 4. No evidence of extra-hepatic metastasis of CRC. 5. Patients must be from 18 to 75 years. 6. ECOG Performance status ≤ 1 7. No previous chemotherapy for metastatic disease. Radiotherapy alone is allowed if given pre or post protocol treatment. 8. Previous adjuvant chemotherapy for primary CRC is allowed if completed at least 6 months before inclusion in this study. 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.

Contact the study team to discuss eligibility requirements. They can help determine if this study is right for you.

Sponsors & Collaborators

• University of Regensburg: lead
• University of Halle Medical Faculty: collaborator

Related Publications (1)

• 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.

  PMID: 22897915 BACKGROUND

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

Bevacizumab

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)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Hans J. Schlitt, Prof. MD

  Department of Surgery, University Medical Center Regensburg

  STUDY CHAIR

• Hans-Joachim Schmoll, Prof. MD

  Department of Internal Medicine IV, University Hospital Halle

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: February 16, 2012
• First Posted: February 28, 2012
• Study Start: September 1, 2012
• Primary Completion: May 1, 2013
• Study Completion: May 1, 2013
• Last Updated: May 29, 2013

Record last verified: 2013-05