PART I: 1) to demonstrate 89Zr-cetuximab uptake in non-hepatic tumor lesions at standard dose or at cohort wise increased cetuximab doses (dose escalation). 2) to determine the association between 89Zr-cetuximab uptake in non-hepatic tumor lesions…
ID
Source
Brief title
Condition
- Gastrointestinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Part 1A:
89Zr-cetuximab uptake in non-hepatic tumor lesions (corrected VOIs);
Clinical benefit rate
Part 1B:
89Zr-cetuximab uptake in non-hepatic tumor lesions with increased dosing of
cetuximab (corrected VOIs).
Part 2:
Association between CBR and early response evaluation using 18F-FDG PET.
CBR is defined as the sum of CR, PR and SD according to RECIST 1.1 at 3 months
after treatment start.
Corrected VOIs are defined as measurements in VOI corrected for background
levels.
Secondary outcome
1) The % uptake (of total injected) 89Zr-cetuximab in non-tumor liver tissue
and hepatic tumor lesions (corrected VOIs).
2) 18F FDG-PET uptake before and after 2 weeks of cetuximab/ panitumumab
treatment.
3) Grade of skin toxicity as measured by predefined criteria in a skin biopsy
(collected untill july 2020).
Background summary
Currently, third line systemic treatment for advanced, wild type K-RAS, N-RAS
and B-RAF CRC includes 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 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 and N-RAS wild type 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 tumor lesions 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 K-RAS, N-RAS and
B-RAF.
Study objective
PART I:
1) to demonstrate 89Zr-cetuximab uptake in non-hepatic tumor lesions at
standard dose or at cohort wise increased cetuximab doses (dose escalation).
2) to determine the association between 89Zr-cetuximab uptake in non-hepatic
tumor lesions and treatment response.
3) to determine the association between metabolic change (evaluated with
18F-FDG PET after 2 weeks of treatment) and treatment response.
PART II
1)Validate early response evaluation with 18F-FDG PET and the association with
treatment benefit.
2) Evaluate optimal quantification methods for 18F-FDG PET images
Study design
In the first part we will perform an exploratory PET study in patients with
metastasized, K-RAS, N-RAS and B-RAF wild type CRC who will be treated with
cetuximab. We hypothesize that uptake of 89Zr-cetuximab in tumor lesions is
required for response to cetuximab. We will analyze targeting of 89Zr-cetuximab
to tumor lesions and the association between 89Zr-cetuximab tumor uptake and
tumor response. Early response evaluation will be done with 18F-FDG PET and
tumor lesion perfusion will be measured with H215O PET scans. In addition, we
will investigate the hypothesis that increasing the cetuximab dose results in
uptake in patients without uptake in tumor lesions 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 (with patients included untill july 2020, after
this skin biopsies will no longer be collected). In addition, the relation of
microRNA (miRNA) and peptide profiles as well as circulating tumor DNA in
relation to response to therapy will be studied.
Intervention
Part I: two-weekly cetuximab infusion in dosis escalataion/extension protocol
Part I: observational two-weekly cetuximab/ panitumumab infusion protocol
Study burden and risks
Upon enrolment in this study, patients will be asked to undergo two tumor
biopsies and (optional) skin biopsies, one before and one during treatment.
During therapy, follow-up will include standard laboratory analysis, collection
of blood for expermental purposes, immuno-PET and 18F-FDG PET on regular
visits to the outpatient clinic. Side effects of the medication and adverse
events as a consequence of the tumor- and skin biopsies (skin biopsies
collected up to july 2020) may occur. The radiation exposure is acceptable and
requires no shielding after injection of 89Zr-labeled cetuximab. Patients may
benefit from disease regression or stabilization as cetuximab has proven
clinical benefit in this patient population.
De Boelelaan 1117
Amsterdam 1081HV
NL
De Boelelaan 1117
Amsterdam 1081HV
NL
Listed location countries
Age
Inclusion criteria
Subjects are eligible if they meet the following 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, N-RAS and B-RAF genes.
* Tumor lesions:
- Part 1: 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).
- Parts 2: Subjects have at least one measurable tumor lesion * 1 cm, including
liver tumor lesion. Lesions must be evaluable by CT 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
* Signed informed consent must be obtained prior to any study specific
procedures.
* Life expectancy * 12 wk
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 2 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.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2013-002023-41-NL |
| ClinicalTrials.gov | NCT01691391 |
| CCMO | NL45039.029.13 |