MITIGATE-NeoBOM: A Study to Evaluate 68Ga- NeoBOMB1 in Patients With Advanced TKI-treated GIST Using PET/CT
|ClinicalTrials.gov Identifier: NCT02931929|
Recruitment Status : Completed
First Posted : October 13, 2016
Last Update Posted : July 19, 2019
|Condition or disease||Intervention/treatment||Phase|
|Gastrointestinal Stromal Tumors||Drug: 68Ga-NeoBOMB1, 2-vial kit||Phase 1 Phase 2|
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Rationale of the design:
This is a monocentric diagnostic Phase I/IIa study. Due to the very limited number of patients and the rare nature of the disease the study was designed as a combination of phases I and IIa.
The main objectives of such an early phase clinical trial are safety and tolerability, pharmacokinetics and (in the case of radiopharmaceuticals) dosimetry aspects. For the first 6 patients, the focus of the study will be on safety, tolerability and pharmacokinetics. Therefore, both TKI-resistant and TKI-sensitive GIST patients will be included. As resistant patients are typically in 2nd- or 3rd-line TKI treatment prone to substantial side effects and potentially suffer from a greater extent of disease, the study design includes a limited number of non-resistant GIST patients to address a possible bias regarding tolerability and side effects profile of 68Ga-NeoBOMB1.
After 6 included patients an interim analysis of safety and pharmacokinetic data including PBPK modelling and dosimetry calculation will be performed. Thereby it will be decided, whether the data generation is sufficient for a final calculation of dosimetry, if so pharmacological and dosimetric aspects can be omitted in the last 6 patients, reducing the burden for these patients considerably (less number of scans, no blood and urine sampling). This analysis will also reveal the optimal time window for PET/CT imaging.
After the establishment of these baseline findings, the second part of the study will emphasize the assessment of imaging data towards targeting properties of the GRP(gastrin releasing peptide)-receptor-specific radiopharmaceutical 68Ga-NeoBOMB1 as proof of the molecular imaging principle. In this phase only patients with confirmed GRPR receptor expression via Immunohistochemistry will be included. Nonetheless, safety and tolerability still remain a primary objectives in this part of the study.
As there are no preclinical indications that the GRP receptor status of TKI resistance is variable, all objectives should be met including targeting properties of 68Ga-NeoBOMB1 also in non-resistant patients. Nonetheless, changes in GRP-receptor expression under treatment pressure may still exist. Therefore in both phases a minimum of 50% of the patients have to show resistance to TKI treatment, where therapeutic option are extremely limited. This will allow providing data in patients that will most likely benefit most from an improved target characterisation and GRPR targeting therapy approaches.
Within 28 days after the patient's positive evaluation and written informed consent, the imaging study will be performed. During the study, patients will be shortly hospitalised. These pre-planned hospitalisations for study purposes will not be considered as (serious) adverse events. The radiopharmaceutical will be administered to the patient directly at the imaging system (PET-CT).
In the first phase of the trial including the first six patients a series of dynamic scans between 0 and 45 min and static whole-body PET images at 1, 2 and 3-4h will be obtained to determine pharmacokinetics and absorbed doses to normal organs and to tumorous lesions. Blood samples drawn concomitantly at the time of imaging will be collected to estimate residence times in blood and to derive the bone marrow absorbed dose (max. 10 samples during the hospitalisation). Urine will be collected to determine the bladder wall and kidney absorbed doses. Regions of interest for critical organs and tumour lesions will be drawn using the acquired images resulting in time-activity curves with quantitative fractions of administered activity. Residence times of radioactivity from this analysis will be calculated. All dosimetric calculations will be performed by feeding the residence times as well as blood and urine activities into an appropriate software program (OLINDA/EXAM).
The second phase is in principle conducted in the same way, if interim analysis returns sufficient data for dosimetry and pharmacokinetics, PET images will be reduced to 2 whole body scans within the optimal time window and blood and urine sampling can be omitted.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||9 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||MITIGATE-NeoBOMB1: A Phase I/IIa Study to Evaluate Safety, Biodistribution, Dosimetry+Preliminary Diagnostic Performance of 68Ga-NeoBOMB1 in Pat. With Advanced TKI-treated GIST Using Positron-emission Tomography/Computer Tomography (PET/CT)|
|Actual Study Start Date :||November 28, 2016|
|Actual Primary Completion Date :||April 9, 2019|
|Actual Study Completion Date :||April 9, 2019|
68Ga-NeoBOMB1, 2-vial kit for radiolabelling. I.v. Administration after radiolabelling
Drug: 68Ga-NeoBOMB1, 2-vial kit
intravenous application of a radiopharmaceutical for Positron Emission tomography (PET)
Other Name: NeoBOMB1
- Safety and tolerability: Number of participants with treatment-related adverse events as assessed by CTCAE v4.03 [ Time Frame: day 12-20 after administration ]Patients will undergo physical examinations, ECG, blood pressure measurements as well as analysis of blood biochemistry (haemoglobin, haematocrit, RBC count, WBC count, absolute neutrophil count, differential WBC count (neutrophils, eosinophils, basophils, lymphocytes, monocytes [%]), platelets), haematology (glucose, urea, creatinine, eGFR (calculated), bilirubin, Na, K, Cl, Ca, GOT [ASAT], GPT [ALAT], γGT, pancreas lipase and amylase, ALP, LDH, CK, CRP, serum albumin), coagulation parameters (Quick, INR, aPTT, fibrinogen) and semi-quantitative urine analysis (leukocytes, nitrite, erythrocytes, pH, protein). These measurements and assessments will be repeated during and after the application of 68Ga-NeoBOMB1. Prior to the study inclusion, prior to application of 68Ga-NeoBOMB1 and during the second follow-up a potential pregnancy will be assessed. The presence and severity of adverse events will be judged and reported according to CTCAE v4.03.
- Organ and compartment dosimetry data, human pharmacokinetics of 68Ga-NeoBOMB1 and identification of potentially dose-limiting organs [ Time Frame: 3-4 hours after administration ]
Pharmacokinetic data will be acquired by measuring 68Ga-NeoBOMB1 distribution over time through successive dynamic/semi-dynamic/static PET scans. Time activity curves will be generated to determine relative distribution among and doses for all relevant organs and compartments [% of injected radioactivity in MBq] through a physiology-based pharmacokinetic modelling approach (OLINDA/EXAM).
To gather more information, successive blood and urine sampling will also be used to provide blood activity and excretion information and estimate bloodpool/bone marrow doses.
- Preliminary targeting properties of 68Ga-NeoBOMB1 in advanced, GRP positive GIST tumours as assessed by SUV [ Time Frame: 3-4 hours after administration ]GIST lesion tracer accumulation will be assessed visually and measured as relative signal intensity (compared to blood pool activity, SUV) for known lesions.
- Targeting properties in comparison with standard imaging modalities such as FDG-PET or MRI as assessed by sensitivity and specificity [ Time Frame: 3-4 hours after administration ]The lesion demarcation from 68Ga-NeoBOMB1-PET will be compared to contrast-enhanced computed tomography and FDG-PET (if available).
- Qualitative comparison of targeting properties of 68Ga-NeoBOMB1 in resistant vs non-resistant tumour lesions in patients undergoing TKI Treatment as assessed by presence of tracer uptake and SUV [ Time Frame: 3-4 hours after administration ]Relative lesion growth tendency (as calculated from comparing current and previous CT scans) will be correlated to their respective tracer uptake (SUV).
- Identification of target tissue and improved target volume definition for potential locoregional treatment (RFA or external beam) [ Time Frame: 3-4 hours after administration ]
A comparison will be made whether 68Ga-NeoBOMB1-PET could offer additional information for a potential local therapy such as radiofrequency ablation (RFA) or external beam radiation as determined by definition of lesion amount and extent.
Therapeutic interventions will not be part of the current study
- To extrapolate absorbed tumour doses for potential application of 177Lu NeoBOMB1 (in first 6 patients) [ Time Frame: 3-4 hours after administration ]Estimation of tumour and organ/compartment doses will be performed by means of a physiology-based pharmacokinetic modelling to assess the potential feasibility of a therapeutic approach of 177Lu-NeoBOMB1
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02931929
|Medical University Innsbruck|
|Innsbruck, Tirol, Austria, 6020|
|Principal Investigator:||Irene Virgolini, Univ-Prof.Dr||Head of department of nuclear medicine|