TACE With Irinotecan Drug-eluting Beads and Intravenous (IV) Cetuximab in Refractory Colorectal Cancer (DEBIRITUX)

A Randomized Phase II Trial of Irinotecan Drug-eluting Beads Administered by Hepatic Chemoembolization With Intravenous Cetuximab (DEBIRITUX) Versus Systemic Treatment With Intravenous Cetuximab and Irinotecan in Patients With Refractory Metastatic Colorectal Cancer and K-ras Wild-type Tumours

The primary objective of this study is to evaluate the efficacy of Irinotecan Beads in combination with intravenous cetuximab versus intravenous irinotecan in combination with intravenous cetuximab in the treatment of patients with unresectable liver metastases from colorectal cancer.

Secondary objectives are safety and tolerability of hepatic chemoembolization and the question if the addition of aprepitant to standard antiemetic prophylaxis in patients treated by hepatic chemoembolization is safe and will reduce the rate of acute and delayed nausea and emesis.

Study Overview

• Status: Terminated
• Conditions: Colorectal Cancer
• Intervention / Treatment: Drug: Cetuximab; Device: Irinotecan eluting BEADS; Drug: Irinotecan

Detailed Description

About half of patients with newly diagnosed colorectal cancer will develop metastatic disease and, however, in spite of the significant progress in the therapeutical strategies for metastatic disease, virtually all patients will eventually succumb to their illness. Based on prior clinical data there is a good rationale for the expectation that the combination of systemic chemotherapy and arterial chemoembolization with drug eluting beads may be effective in the setting of patients with unresectable or chemorefractory liver metastases. The aim of this study is therefore to assess whether the combination of Irinotecan eluting beads and intravenous cetuximab is safe and effective in the treatment of patients with unresectable liver metastases from refractory colorectal cancer and will result in a prolongation of disease control when compared to standard systemic treatment with intravenous irinotecan and intravenous cetuximab. In this patient group, intravenous irinotecan plus intravenous cetuximab may represent the "standard of care", with a previously described activity. The patient group is defined in terms of pretreatment, and the scientific question is whether the way of irinotecan administration by eluting beads in feasible and somehow beneficial.

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Bad Berka, Germany, 99437
    • Zentralklinik Bad Berka GmbH, Abteilung für Interventionelle Radiologie
  • Dresden, Germany, 01307
    • Universitatsklinikum Carl Gustav Carus An Der Technischen Universitat Dresden
  • Essen, Germany, 45136
    • Kliniken Essen-Mitte, Klinik für Innere Medizin IV
  • Esslingen, Germany, 73730
    • Klinikum Esslingen, Klinik für Onkologie, Gastroenterologie und Allgemeine Innere Medizin
  • Frankfurt/M., Germany, 60488
    • Krankenhaus Nordwest
  • Frankfurt/M., Germany, 60590
    • Universitätsklinikum der Johann Wolfgang Goethe Universität Frankfurt
  • Halle (Saale), Germany, 06097
    • Martin-Luther-Universität Halle-Wittenberg
  • Hamburg, Germany, 20246
    • Universitatsklinikum Hamburg-Eppendorf
  • Heilbronn, Germany, 74078
    • SLK-Kliniken Heilbronn
  • Magdeburg, Germany, 39120
    • Otto-von-Guericke-Universität Magdeburg
  • Regensburg, Germany, 93053
    • Universitätsklinikum Regensburg
  • Tübingen, Germany, 72076
    • Universitätsklinikum Tübingen, Medizinische Klinik und Poliklinik II
  • Würzburg, Germany, 97080
    • Universitätsklinikum Würzburg, Institut für Röntgendiagnostik

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Patients with confirmed diagnosis of stage IV (UICC) colorectal cancer with unresectable liver metastases (primary tumour may be present) and k-ras wild-type tumours
2. Patients had been treated and shown to be refractory to 5-FU (Capecitabine allowed)/oxaliplatin and/or 5-FU/irinotecan. Prior therapy with VEGF-inhibitors (e.g bevacizumab) is allowed
3. Patients with at least one measurable liver metastasis, with size > 1cm (RECIST criteria)
4. Patients with liver only or liver dominant disease (defined as ≥ 50 % tumour burden confined to the liver)
5. Patients with a portal vein not interfering with transarterial chemoembolization (e.g. no thrombosis) as judged by the investigator
6. ECOG Performance status ≤ 2
7. Life expectancy > 3 months
8. Age ≥ 18 years.
9. At least 4 weeks since last administration of last chemotherapy and/or radiotherapy (bone metastases may be allowed)
10. Patients who received VEGF-inhibition (e.g. with bevacizumab) in prior therapy are eligible if stopped since 4-6 weeks before randomization
11. Haematologic function: ANC ≥ 1.5 x 109/L, platelets ≥ 75 x109/L
12. INR < 1.5 (patients on therapeutic anticoagulants are not eligible)
13. Adequate liver function as measured by serum transaminases (AST & ALT) ≤ 3 x ULN and total bilirubin ≤ 1.5 x ULN
14. Adequate renal function: Serum creatinine ≤ 1.5 x ULN
15. Normal level of serum magnesium
16. Women of child bearing potential and fertile men are required to use effective contraception (negative serum βHCG for women of child-bearing age
17. Signed, written informed consent

Exclusion Criteria:

1. Presence of CNS metastases
2. Contraindications to irinotecan therapy (Chronic inflammatory bowel disease and/or bowel obstruction, history of severe hypersensitivity reactions to irinotecan hydrochloride trihydrate)
3. Active bacterial, viral or fungal infection within 72 hours of study entry
4. Women who are pregnant or breast feeding
5. Allergy to contrast media
6. Presence of another concurrent malignancy. Prior malignancy in the last 5 years except adequately treated basal or squamous cell skin cancer or carcinoma in situ of the cervix

7. Any contraindication for hepatic embolisation procedures:

   • Large shunt as determined by the investigator (pretesting with lung perfusion scan not required)
   • Severe atheromatosis
   • Hepatofugal blood flow
8. Other significant medical or surgical condition, or any medication or treatment, that would place the patient at undue risk, that would preclude the safe use of chemoembolization or would interfere with study participation
9. Known hypersensitivity or contraindication to the drugs used in the trial (eg: cetuximab, 5-HT3 receptor antagonist, dexamethasone, or any component of aprepitant)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: hepatic TACE with irinotecan eluting beads and iv cetuximab; Irinotecan drug-eluting beads administered by hepatic chemoembolization with intravenous cetuximab (DEBIRITUX)	Drug: Cetuximab; Starting dose of 400mg/m2, followed by weekly 250mg/m2; Other Names: Erbitux; Device: Irinotecan eluting BEADS; A minimum of two treatments per lobe (four bi-weekly sessions in the event of bilobar disease) at week 0 and 4 with up to 4ml (100-300µm DC Bead loaded with up to 200mg irinotecan) will be scheduled (i.e. for bilobar disease right lobe: week 0, left lobe: week 2, right lobe: week 4 and left lobe: week 6: following toxicity and extending interval if toxicity seen).; Other Names: DC Bead
ACTIVE_COMPARATOR: iv cetuximab and irinotecan; systemic treatment with intravenous cetuximab and irinotecan	Drug: Cetuximab; Starting dose of 400mg/m2, followed by weekly 250mg/m2; Other Names: Erbitux; Drug: Irinotecan; Irinotecan 180 mg/m² to be administered every two weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Progression free survival rate	6 months after first administration of study medication

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tumour Response (according to RECIST v1.1)	extent of treated lesions	every three months up to progression of disease, maximum 12 months from the date of patient enrolment
Time to progression		every three months, until death of patient, maximum 12 months from the date of patient enrolment
Number of adverse events in study patients		whole study, every two weeks until 28 days from the date of last administration of study medication
Local tumour response	extent of necrosis in the treated lesions	every three months up to progression of disease, maximum 12 months from the date of patient enrolment
Overall survival		every three months, until death of patient, maximum 12 months from the date of last patient enrolment

Collaborators and Investigators

• Sponsor: Hans-Joachim Schmoll, MD
• Collaborators: Biocompatibles UK Ltd
• Investigators: Principal Investigator: Dirk Arnold, MD, Universitätsklinikum Eppendorf, Universitäres Cancer Center

Study record dates

Study Major Dates

• Study Start: February 1, 2010
• Primary Completion (ACTUAL): December 1, 2012
• Study Completion (ACTUAL): May 1, 2015

Study Registration Dates

• First Submitted: January 27, 2010
• First Submitted That Met QC Criteria: February 1, 2010
• First Posted (ESTIMATE): February 2, 2010

Study Record Updates

• Last Update Posted (ESTIMATE): October 26, 2016
• Last Update Submitted That Met QC Criteria: October 25, 2016
• Last Verified: October 1, 2016

More Information

Terms related to this study

• Keywords: liver metastasis; colorectal; chemoembolization; KRAS wildtype; irinotecan eluting beads
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Topoisomerase I Inhibitors; Irinotecan; Cetuximab
• Other Study ID Numbers: EudraCT: 2009-014728-44