The main objective of this study is to determine whether tumor concentrations of kinase inhibitors at pharmacological active doses can be predicted from PET studies using tracer amounts (microdosing) of corresponding radiolabeled kinase inhibitors.…
ID
Source
Brief title
Condition
- Miscellaneous and site unspecified neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
1) Tumor uptake of [11C]sorafenib cq [11C]erlotinib before and on treatment (%
injected dose and activity concentration in tumor lesions)
2) Image derived imput function of [11C]sorafenib cq [11C]erlotinib before and
on treatment (% injected dose and activity concentration in large bloodvessels)
3) Pharmacokinetics [11C]sorafenib cq [11C]erlotinib before and on treatment
(plasma and whole blood; % injected dose and activity concentration/g)
4)On treatment tumor concentration of sorafenib cq erlotinib.
Secondary outcome
5) Tumor perfusion as measured with [15O]water before and on treatment (%
injected dose and activity concentration in tumor lesions)
6) Image derived imput function of [15O]water before and on treatment (%
injected dose and activity concentration in large bloodvessels)
7) Kinase activity in tumor biopsies before and after treatment with sorafenib
cq erlotinib.
8) Phosphoproteomics analysisin tumor biopsies before and after treatment with
sorafenib cq erlotinib.
Background summary
Multiple agents targeting specific signaling proteins important for tumor
growth and angiogenesis, including (tyrosine) kinase inhibitors and monoclonal
antibodies, have been developed and have reached clinical approval. In general,
however, these targeted agents induce a response only in a subgroup of cancer
patients, while all are exposed to potential toxic therapies. Prior to
treatment, it is unknown which patients will respond and why kinase inhibitors
are only effective in some, but not all, patients. Clearly, there is a need for
a non-invasive in vivo technique to identify those patients who may benefit
from treatment with a specific drug.
Positron emission tomography (PET) is a non-invasive technique that enables
quantitative measurements of molecular pathways and interactions with picomolar
sensitivity and, as such, it has the potential to fulfill the need mentioned
above. We expect that response to kinase inhibitors is dependent on achieving
active drug levels in tumor tissue. Currently, intratumoral kinase inhibitor
levels are being investigated at our institution (ICK study). However, these
measurements require fresh tumor biopsies. We hypothesize that radiolabeled
kinase inhibitor PET imaging can quantify concentrations of labeled drug in
tumor lesions, thereby avoiding burdensome biopsies in the future.
Study objective
The main objective of this study is to determine whether tumor concentrations
of kinase inhibitors at pharmacological active doses can be predicted from PET
studies using tracer amounts (microdosing) of corresponding radiolabeled kinase
inhibitors. This objective includes the development and validation of
pharmacokinetic models for radiolabeled kinase inhibitors as well as validation
of the microdosing concept for kinase inhibitors.
The secondary objectives include exploration whether kinase inhibitor kinetics
depend on perfusion (as measured by [15O]water PET) or size (as measured by
diagnostic CT/MRI) of tumor lesions and to investigate (in)activation of key
pathways targeted by the specific kinase inhibitor.
Study design
Single center, non-randomized, interventional proof of concept study.
Intervention
Patients will be treated with the kinase inhibitor according to standard
treatment. Patients with an indication to start the investigated kinase
inhibitor (i.e. sorafenib and erlotinib in this study, with the aim to
investigate others in future studies, such as pazopanib and axitinib among
others) will have a [11C] kinase inhibitor PET-CT and [15O]water PET-CT before
and after two weeks of treatment. Tumor biopsies will be performed before and
during therapy (category 1). Patients already on treatment with the
investigated kinase inhibitor and who have stable disease for at least 4
months, a partial or a complete response will only have a [11C] kinase
inhibitor PET-CT and [15O]water PET-CT during treatment and one tumor biopsy
performed during treatment (category 2).
Study burden and risks
Enrolment in this study will require two tumor biopsies, 2x [11C] kinase
inhibitor PET-CT, 2x [15O]water PET-CT and arterial blood sampling for patients
with an indication to start the investigated kinase inhibitor (category 1).
Patients already on treatment with the invastigated kinase inhibitor with
stable disease for at least 4 months, a partial response or complete response
will require one tumor biopsy, 1x [11C] kinase inhibitor PET-CT, 1x [15O]water
PET-CT and arterial blood sampling (category 2). The biopsies may cause
physical discomfort. During therapy, follow-up will include standard laboratory
analysis as well as regular visits to the outpatient clinic. The radiation
exposure is acceptable. Patients treated with a kinase inhibitor as standard
therapy may benefit from disease regression or stabilization as it has proven
clinical benefit in the patient population under investigation. The results of
this kinase inhibitor PET imaging study will be strongly supportive for the
development of non-invasive, personalized treatment strategies thereby avoiding
cumbersome tumor biopsies and unwanted exposure to potentially toxic drugs.
Boelelaan 1117
Amsterdam 1081HV
NL
Boelelaan 1117
Amsterdam 1081HV
NL
Listed location countries
Age
Inclusion criteria
* Patients must have a histologically confirmed diagnosis of an advanced or metastatic solid malignancy. ;* A. Patients must have confirmed radiological or clinical progressive disease with a standard indication to start sorafenib or erlotinib (category 1).
OR B. Patients must have stable disease for at least 4 months, a partial response or a complete response established with RECIST version 1.1 within 21 days before the radiolabeled kinase inhibitor scan if they are already on treatment with sorafenib or erlotinib (category 2).;* Patients must have at least one measurable tumor lesion outside the liver.;* Indication for standard use of palliative systemic treatment, with sorafenib or erlotinib.;* Age * 18 years. ;* ECOG Performance Status * 2.;* Life expectancy of at least 12 weeks.;* Patients should be able to swallow oral medication.;* Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements to be conducted within 7 days prior to screening:;o Hemoglobin * 6.0 mmol/L;o Absolute neutrophil count (ANC) * 1,5 x 10*9/L ;o Platelet count * 100 x 10*9/L;o Total bilirubin * 2 times the upper limit of normal (ULN);o ALT and AST* 2.5 x ULN; * 5x ULN in case of liver metastases, except for patients with hepatocellular carcinoma, than Child Pugh classification A-B.;o Alkaline phosphatase < 4 x ULN; * 5x ULN in case of liver metastases, except for patients with hepatocellular carcinoma, than Child Pugh classification A-B.;o Serum creatinine eGFR * 50 mL/min. ;o PT-INR/PTT < 1.5 x ULN, unless coumarin derivatives are used.;o Activated partial thromboplastin time < 1.25 x ULN (therapeutic anticoagulation therapy is allowed, if this treatment can be interrupted for a biopsy as judged by the treating physician).
Exclusion criteria
* Concurrent treatment with other anticancer agents or experimental drugs.;* History of cardiac disease: ;o Congestive heart failure >NYHA class 2. ;o Active Coronary Artery Disease (defined as myocardial infarction within 6 months prior to screening).;* Cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted). ;* Uncontrolled hypertension. Blood pressure must be *160/95 mmHg at the time of screening on a stable antihypertensive regimen. Blood pressure must be stable on at least 2 separate measurements.;* Uncontrolled infections (> grade 2 NCI-CTC version 4.0).;* Subjects with serious non-healing wound, ulcer, or bone fracture.;* Patients with thromboembolic events within 3 months prior to study inclusion.;* Significant skin condition interfering with treatment;* Patients undergoing renal dialysis.;* 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, or 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 the study kinase inhibitor.;* Concomitant use of dexamethasone, anti-convulsants and anti-arrhythmic drugs other than digoxin or beta blockers.;* Major surgery within 28 days prior to start of treatment.;* 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
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In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2012-004961-42-NL |
| CCMO | NL42402.029.12 |