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Perioperative FOLFOXIRI and Bevacizumab Compared With Postoperative FOLFOX in Patients With Resectable Liver Metastases From Colorectal Cancer (PERIMAX). A Randomized, Multidisciplinary DGAV(CAO-V/CALGP)/AIO Phase II Trial

Phase 2
18 Years
75 Years
Not Enrolling
Colon Cancer Liver Metastasis

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Trial Information

Perioperative FOLFOXIRI and Bevacizumab Compared With Postoperative FOLFOX in Patients With Resectable Liver Metastases From Colorectal Cancer (PERIMAX). A Randomized, Multidisciplinary DGAV(CAO-V/CALGP)/AIO Phase II Trial

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.

Inclusion Criteria

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.

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Failure-free survival (FFS@18)

Outcome Description:

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

Outcome Time Frame:

18 months

Safety Issue:


Principal Investigator

Hans J. Schlitt, Prof. MD

Investigator Role:

Study Chair

Investigator Affiliation:

Department of Surgery, University Medical Center Regensburg


Germany: Paul-Ehrlich-Institut

Study ID:




Start Date:

September 2012

Completion Date:

May 2013

Related Keywords:

  • Colon Cancer Liver Metastasis
  • Colorectal cancer
  • Liver metastases
  • Perioperative treatment
  • Liver resection
  • Colonic Neoplasms
  • Colorectal Neoplasms
  • Neoplasm Metastasis
  • Neoplasms, Second Primary
  • Liver Neoplasms