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Image Guided Treatment Optimization With Cetuximab for Patients With Metastatic Colorectal Cancer

NCT02117466

Description:

In this study the investigators will evaluate the uptake of 89Zirconium labeled cetuximab in extra-hepatic colorectal metastases. The investigators hypothesize that uptake of 89Zr-cetuximab is required for response to cetuximab. If no uptake is present the investigators will escalate the dose cetuximab and repeat the 89Zr-cetuximab PET. The investigators will evaluate the clinical benefit rate of cetuximab in the patients with and without uptake. The ultimate goal is to create a selection tool that can predict response of cetuximab.

Related Conditions:
  • Colorectal Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Image Guided Treatment Optimization With Cetuximab for Patients With Metastatic Colorectal Cancer
  • Official Title: Image Guided Treatment Optimization With Cetuximab for Patients With Metastatic Colorectal Cancer

Clinical Trial IDs

  • ORG STUDY ID: 2013.265
  • SECONDARY ID: 2013-002023-41
  • NCT ID: NCT02117466

Conditions

  • Metastatic Colorectal Cancer

Interventions

DrugSynonymsArms
Dose escalation cetuximabDose escalation cetuximab
Standard dose cetuximabStandard dose cetuximab

Purpose

In this study the investigators will evaluate the uptake of 89Zirconium labeled cetuximab in extra-hepatic colorectal metastases. The investigators hypothesize that uptake of 89Zr-cetuximab is required for response to cetuximab. If no uptake is present the investigators will escalate the dose cetuximab and repeat the 89Zr-cetuximab PET. The investigators will evaluate the clinical benefit rate of cetuximab in the patients with and without uptake. The ultimate goal is to create a selection tool that can predict response of cetuximab.

Detailed Description

      Rationale: Currently, third line systemic treatment for patients with advanced, wild type
      K-RAS and as has recently been demonstrated with wild type N-RAS (thereafter referred to as
      wild type RAS) colorectal cancer (CRC) includes epidermal growth factor receptor (EGFR)
      inhibition with the anti-EGFR antibody cetuximab. 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 known that patients with advanced wild type RAS CRC will not
      respond to anti-EGFR treatment, it is not understood why patients with wild type RAS CRC do
      not all benefit from this type of therapy. Apart from other potential gene mutations involved
      in response to treatment, differences in the variability of pharmacokinetics may play a
      crucial role in the response to anti-EGFR treatment. In non-responders insufficient drug
      accumulation may occur in the tumor due to pharmacokinetic processes, such as cetuximab
      sequestration in the liver which expresses high levels of EGFR, or due to low levels of EGFR
      expression in tumor lesions. Our main hypothesis is that uptake of cetuximab in metastases is
      required for response and that achieving cetuximab uptake by increasing its dose will result
      in improved clinical benefit in patients with advanced CRC with wild type RAS.

      Objectives:

      PART I:

        1. to demonstrate 89Zr-cetuximab uptake in non-hepatic metastases at standard dose or at
           cohort wise increased cetuximab doses (dose escalation).

        2. to determine the association between 89Zr-cetuximab uptake in non-hepatic metastases and
           treatment response.

      PART II To determine the response rate with an optimized dose of cetuximab as has been
      selected in part 1 in patients without 89Zr-cetuximab tumor uptake at standard dose of
      cetuximab (dose extension).

      Study design: This is a multicentre non-randomized intervention study; phase I-II dose
      escalation/extension study.

      Study population: Patients with histopathologically confirmed advanced CRC with wild type
      RAS, without local treatment options, aged ≥ 18 years, with a life expectancy of at least 12
      weeks, who are candidates for anti-EGFR antibody monotherapy (3rd line palliative treatment).

      Intervention: In the first part we will perform an exploratory PET study in patients with
      metastasized, RAS wild type CRC without local treatment options, who will be treated with
      cetuximab. We hypothesize that uptake of 89Zr-cetuximab in metastases is required for
      response to cetuximab. We will analyze targeting of 89Zr-cetuximab to metastases and the
      association between 89Zr-cetuximab tumor uptake and tumor response. Early response evaluation
      will be done with 18F-FDG PET. In a subgroup of 20 patients with metastasis within the field
      of view (18 cm) including the heart, tumor perfusion will be measured with 15O-water PET
      scans. In addition, we will investigate the hypothesis that increasing the cetuximab dose
      results in uptake in patients without uptake in metastases of 89Zr-cetuximab when cetuximab
      is given at the standard dose regimen. In the second part we will study whether dose
      adjustments based on 89Zr-cetuximab targeting results in an improved response and clinical
      benefit rate. In addition, EGFR expression and saturation with cetuximab is studied in tumor
      biopsies obtained during treatment. Molecular pathways activated by EGFR and kinase
      activities as well as phosphoproteomics will be studied in tumor biopsies and skin biopsies
      before and after start of treatment. In addition, the relation of microRNA (miRNA) and
      peptide profiles in relation to response to therapy will be studied.
    

Trial Arms

NameTypeDescriptionInterventions
Standard dose cetuximabOtherUptake of 89Zr-cetuximab: continue standard dose (500mg/m2 bsa) (standard care)
  • Standard dose cetuximab
Dose escalation cetuximabExperimentalNo 89Zr-cetuximab uptake: dose escalation in a 3x3 cohort design (with maximal 50% dose increase each cohort; with a maximum of 2000 mg/m2 bsa every two weeks)
  • Dose escalation cetuximab

Eligibility Criteria

        Inclusion Criteria:

        Subjects are eligible if they meet the following criteria:

          -  Advanced colorectal adenocarcinoma

          -  Subjects must have been treated according to standard care with palliative
             chemotherapy including a fluoropyrimidine (e.g. fluorouracil or capecitabine),
             irinotecan, and oxaliplatin or had contra-indications to treatment with these drugs.

          -  No local treatment options

          -  Life expectancy of at least 12 weeks.

          -  Age => 18 years.

          -  Histological or cytological documentation of cancer is required.

          -  Tumor material must be tested wild type for the K-RAS (codon 12, 13, 61, 117, 146) and
             N-RAS (codon 12, 13, 61, 117, 146) genes.

          -  Subjects have at least one measurable lesion ≥ 2 cm outside the liver. Lesions must be
             evaluable by CT or MRI according to Response Evaluation Criteria in Solid Tumors
             (RECIST 1.1).

          -  ECOG (Eastern Cooperative Oncology Group) 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 start of treatment:

               -  Total bilirubin ≤ 1.5 times the upper limit of normal

               -  ALT (alanine aminotransferase) and AST (aspartate aminotransferase) ≤ 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:

        Subjects who meet the following criteria at the time of screening will be excluded:

          -  Previous exposure to an anti-EGFR therapy

          -  Significant skin condition interfering with treatment

          -  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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Uptake (SUV) of 89Zr-cetuximab in extra-hepatic metastases on PET-scan
Time Frame:6 days post injection
Safety Issue:
Description:Complete response, partial response and stable disease (according to RECIST 1.1) on CT-scan (every 2 months)

Secondary Outcome Measures

Measure:Early response evaluation with 18F-FDG PET
Time Frame:two weeks after start treatment
Safety Issue:
Description:Compare baseline 18F-FDG PET and the on treatment 18F-FDG PET (after 2 weeks of treatment).
Measure:Tumor perfusion as early response evaluation (measured with 15O-H2O-PET)
Time Frame:two weeks after start treatment
Safety Issue:
Description:Compare baseline 15O-H2O-PET and the on treatment 15O-H2O-PET (after 2 weeks of treatment). The 15O-H2O-PET will be done in a subgroup of 20 patients, which have metastases within 18 cm field of view including the heart/ aorta.
Measure:Overall survival
Time Frame:From date first cetuximab injection until the date of death (median overall survival 10 months)
Safety Issue:
Description:
Measure:Progression Free Survival
Time Frame:From date of first cetuximab injection until the date of first documented progression (median time to progression 2.5 months)
Safety Issue:
Description:First year: CT-scan every 2 months (RECIST 1.1) After 1 year: CT-scan every 3 months (RECIST 1.1)
Measure:Skin toxicity and hypomagnesemia as early response marker
Time Frame:From date of first cetuximab injection until the date of first documented progression (median time to progression 2.5 months)
Safety Issue:
Description:Every two weeks, graded according to CTCAE v 4.0
Measure:Quality of life (QoL) and health related QoL
Time Frame:From date of first cetuximab injection until the date of first documented progression (median time to progression 2.5 months)
Safety Issue:
Description:Graded using: EQ-5D-3L (quality of Life questionnaire); every 2 months FACT-EGFRI-18 (quality of Life questionnaire, specially for skin toxicity caused by anti-EGFR therapy); every 2 weeks untill week 8, hereafter every two months

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:VU University Medical Center

Trial Keywords

  • cetuximab
  • PET-imaging

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