Treatment Optimization of Cetuximab in Patients With Metastatic Colorectal Cancer Based on Tumor Uptake of 89Zr-labeled Cetuximab Assessed by PET

This study is currently recruiting participants. (see Contacts and Locations)
Verified February 2014 by VU University Medical Center
Sponsor:
Information provided by (Responsible Party):
Laura Pijpers, VU University Medical Center
ClinicalTrials.gov Identifier:
NCT01691391
First received: May 15, 2012
Last updated: February 21, 2014
Last verified: February 2014
  Purpose

3rd line standard treatment of patients with metastatic colorectal cancer (CRC) harboring K-ras wild type consists of anti-EGFR treatment with either cetuximab or panitumumab. This type of treatment has a modest but significant beneficial activity in this patient group with improved progression-free and overall survival. Although it is well known that patients with advanced CRC harboring a K-Ras mutation will not respond to anti-EGFR treatment, it is not understood why patients with K-Ras wild type CRC do not all benefit from this type of therapy. In order to optimize treatment of these patients as well as health care costs, it is extremely important to identify those patients who will respond to treatment with an EGFR inhibitor at an early stage.

The investigators hypothesize that the differences in response to treatment with cetuximab are due to variability in the pharmacokinetics and -dynamics of the antibody. Thus, the investigators hypothesize that patients who do not respond to anti-EGFR treatment, have insufficient drug levels in tumor tissue. The investigators hypothesize that this is due to pharmacodynamic processes such as sequestration of cetuximab in the liver which expresses high levels of EGF receptor.

With the introduction of immuno-positron emission tomography (PET), an attractive novel option to visualize molecular interactions has been developed using the combination of PET with labeled mAbs. Cetuximab labeled with zirconium-89 (89Zr) has been successfully generated (GMP) and is available for this study. Previous studies have shown excellent stability of this compound and 89Zr is shown to be safe in humans. The investigators will use 89Zr-cetuximab to demonstrate tumor targeting by imaging and explore the relation of uptake with treatment response. With this approach the investigators hope to achieve a better understanding of the mechanisms of action of this therapeutic mAb in metastasized CRC and eventually develop strategies that may improve efficacy of cetuximab treatment.


Condition Intervention
Colorectal Cancer
Behavioral: pharmacodynamic purposes of 89Zr-labelled cetuximab and kinase activity profiles

Study Type: Observational
Study Design: Observational Model: Cohort
Time Perspective: Prospective
Official Title: Treatment Optimization of Cetuximab in Patients With Metastatic Colorectal Cancer Based on Tumor Uptake of 89Zr-labeled Cetuximab Assessed by PET

Resource links provided by NLM:


Further study details as provided by VU University Medical Center:

Primary Outcome Measures:
  • The detection of 89Zr-cetuximab uptake in non-hepatic tumor lesions [ Time Frame: At 0-2h, day 2,3,4 and 7 after administration of 89Zr -cetuximab ] [ Designated as safety issue: No ]
    The detection of 89Zr-cetuximab uptake in non-hepatic tumor lesions (present/absent; present being defined as levels measured in ROI's > standard deviation of background +1).

  • The % uptake (of total injected) 89Zr-cetuximab in non-hepatic tumor lesions [ Time Frame: At 0-2h, day 2,3,4 and 7 after administration of 89Zr -cetuximab ] [ Designated as safety issue: No ]
    The % uptake (of total injected) 89Zr-cetuximab in non-hepatic tumor lesions as measured in ROI's corrected for background levels.


Secondary Outcome Measures:
  • The % uptake (of total injected) 89Zr-cetuximab in liver lesions [ Time Frame: At 0-2h, day 2,3,4 and 7 after administration of 89Zr -cetuximab ] [ Designated as safety issue: No ]
    The % uptake (of total injected) 89Zr-cetuximab in liver lesions as measured in ROI's corrected for background levels.

  • [18F-]FDG PET measurements [ Time Frame: 4 weeks before start and 4 weeks after start ] [ Designated as safety issue: No ]
    [18F-]FDG PET measurements (SUVmax) before and after 4 weeks of treatment with cetuximab.

  • Grade of skin toxicity [ Time Frame: every 4 weeks until progressive disease ] [ Designated as safety issue: No ]
    Grade of skin toxicity as measured by predefined criteria (see below).


Estimated Enrollment: 25
Study Start Date: January 2012
Estimated Primary Completion Date: January 2015 (Final data collection date for primary outcome measure)
Groups/Cohorts Assigned Interventions
Advanced CRC, candidates for anti-EGFR antibody monotherapy
Patients with histopathologically confirmed advanced CRC with K-Ras wild type, aged ≥ 18 years, with a life expectancy of at least 12 weeks, who are candidates for anti-EGFR antibody monotherapy (3rd line palliative treatment).
Behavioral: pharmacodynamic purposes of 89Zr-labelled cetuximab and kinase activity profiles
Patients will be treated with cetuximab. For pharmacodynamic purposes PET-imaging with 89Zr-labelled cetuximab will be performed. In addition, two [18F-]-FDG PET-CT will be performed to explore early response. Patients will undergo blood sampling and two skin biopsies for pharmacodynamic purposes of 89Zr-labelled cetuximab and kinase activity profiles, respectively.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population

Patients with histopathologically confirmed advanced CRC with K-Ras wild type, aged ≥ 18 years, with a life expectancy of at least 12 weeks, who are candidates for anti-EGFR antibody monotherapy (3rd line palliative treatment).

Criteria

Inclusion Criteria:

  • Advanced colorectal adenocarcinoma
  • Subjects must have been treated according to standard care with a fluoropyrimidine (e.g. fluorouracil or capecitabine), irinotecan, and oxaliplatin or had contra-indications to treatment with these drugs.
  • Age ≥18 years.
  • Histological or cytological documentation of cancer is required.
  • Tumor material must be tested wild type for the K-Ras gene.
  • Subjects have at least one measurable lesion outside the liver. Lesions must be evaluated by CT-scan or MRI according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1).
  • ECOG Performance Status of 0, 1 or 2
  • Adequate liver and renal functions as assessed by the following laboratory requirements to be conducted within 7 days prior to screening:

    • Total bilirubin ≤ 1.5 times the upper limit of normal
    • ALT and AST ≤ 2.5 times upper limit of normal (≤ 5 times upper limit of normal for subjects with liver involvement of their cancer)
    • Serum creatinin ≤ 1.5 times upper limit of normal or a calculated creatinin clearance ≥ 50 ml/min
  • Signed informed consent must be obtained prior to any study specific procedures.

Exclusion Criteria:

  • Previous exposure to an anti-EGFR therapy
  • Significant skin condition interfering with treatment
  • Insulin dependency
  • Pregnant or breast-feeding subjects. Women of childbearing potential must have a negative pregnancy test performed within 7 days of the start of treatment. Both men and women enrolled in this trial must agree to use adequate barrier birth control measures (e.g., cervical cap, condom, and diaphragm) during the course of the trial. Oral birth control methods alone will not be considered adequate on this study, because of the potential pharmacokinetic interaction between study drug and oral contraceptives. Concomitant use of oral and barrier contraceptives is advised. Contraception is necessary for at least 6 months after receiving study drug.
  • Concurrent anticancer chemotherapy, immunotherapy or investigational drug therapy during the study or within 4 weeks of the start of study drug.
  • Radiotherapy to the target lesions during study or within 4 weeks of the start of study drug. Palliative radiotherapy will be allowed.
  • Major surgery within 28 days of start of study drug.
  • Substance abuse, medical, psychological or social conditions that may interfere with the subject's participation in the study or evaluation of the study results.
  • Any condition that is unstable or could jeopardize the safety of the subject and their compliance in the study.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01691391

Contacts
Contact: C W Menke, Dr. +31 (0) 20-4444300

Locations
Netherlands
VU University Medical Center Recruiting
Amsterdam, Noord Holland, Netherlands, 1081 HV
Sponsors and Collaborators
VU University Medical Center
  More Information

No publications provided

Responsible Party: Laura Pijpers, Datamanager, VU University Medical Center
ClinicalTrials.gov Identifier: NCT01691391     History of Changes
Other Study ID Numbers: 2010/323
Study First Received: May 15, 2012
Last Updated: February 21, 2014
Health Authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Keywords provided by VU University Medical Center:
Advanced CRC

Additional relevant MeSH terms:
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Cetuximab
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on August 19, 2014