Primary Objective• To characterize preliminary targeting properties of [68Ga]-NeoBOMB1 in patients with malignancies known to overexpress GRPR.Secondary objectives• To assess safety and tolerability of a single diagnostic dose of [68Ga]-NeoBOMB1…
ID
Source
Brief title
Condition
- Miscellaneous and site unspecified neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Study Endpoint
•*Number and location of tumour lesions detected by [68Ga]-NeoBOMB1 overall and
for
each tumour type
•*Calculation of the ratio tumour/background SUV and calculation of percentage
absorbed dose in tumour overall and for each tumour type.
Secondary outcome
Secondary Study Endpoints
•*Standard safety parameters (clinical monitoring, laboratory, ECG)
•*Tolerability and safety of the administration of a diagnostic dose of
[68Ga]-NeoBOMB1
in patients with malignancies known to overexpress GRPR as determined by absence
of:
- increased number of SAEs compared to other peptide-based radiotracers;
- clinically relevant changes of physiological parameters (blood pressure, heart
rate, ECG findings)
•*Generation of decay corrected tissue TACs from [68Ga]-NeoBOMB1 PET/CT images
in normal organs, tumour lesions.
•*Quantification of urinary excretion of [68Ga]-NeoBOMB1
•*Calculation of half-life of [68Ga]-NeoBOMB1 in blood
•*Generation of non-decay-corrected TACs from [68Ga]-NeoBOMB1 PET/CT images in
normal organs, tumour lesions
•*Calculation of residence times in organs and tumour lesions of [68Ga]-NeoBOMB1
•*Calculation of absorbed doses and effective whole body dose of [68Ga]-NeoBOMB1
•*Calculation of the SUV of each lesion
•*Number and location of tumour lesion detected by [68Ga]-NeoBOMB1 in
comparison with comparable standard imaging modalities such as FDG-PET
•*Calculation of the [68Ga]-NeoBOMB1 PET overall, positive and negative on a
lesion-by-lesion basis as
well as on a patient basis relative to the standard imaging overall and for
each tumour
type
•*Comparison of number of patients with tumour lesions detected and number of
tumour lesions detected by [68Ga]-NeoBOMB1 with cytology and/or histopathology
from archival and/or recent biopsy specimens
•*Calculation of the [68Ga]-NeoBOMB1 PET sensitivity and specificity on a
lesion-bylesion
basis for all lesions with associated biopsy data, and on a patient basis
relative
to histopathology / cytology data
Exploratory Study Endpoints
•*Absorbed tumour doses of [177Lu]-NeoBOMB1 extrapolated from 68Ga-dosimetric
data
and definition of dose limiting organ for radionuclide therapy
Background summary
GRP is a bombesin-like peptide growth factor implicated in the regulation of
numerous central and peripheral functions. By binding to a GRP extracellular
receptor (GRPR), it activates an intracellular G-protein that triggers further
chain reactions. Beside its physiological widespread role, GRP has been
demonstrated to be a potent mitogen for normal and neoplastic tissues and may
be involved in growth dysregulation and carcinogenesis.
In fact, upregulation of GRP/GRPR has been reported in several cancers,
including breast, prostate, colon, lung (small cell and non-small cell),
stomach, pancreas, uterus, ovaries, head and neck squamous cell cancer and in
various central nervous system malignancies.
For instance, GRPR expression has been investigated in primary and metastatic
breast cancer among different molecular subtypes. GRPR overexpression was most
strongly associated with estrogen receptor (ER) positivity and found in over
75% of the primary tumour samples and in over 90% of their metastatic lymph
nodes.
In parallel, a massive GRP receptor overexpression has been demonstrated in
prostate tissues that are already neoplastic or in the process of malignant
transformation (i.e. prostatic intraepithelial neoplasias). In this specific
case, GRP receptors have been thought of as markers for early molecular events
in prostate carcinogenesis and useful in differentiating prostate hyperplasia
from prostate neoplasia.
In the lung, GRP has been found in the pulmonary neuroendocrine cells and is
responsible for lung development and maturation. Nevertheless, GRP has also
been reported in relation to growth dysregulation and carcinogenesis on non-
small cell lung cancer (NSCLC) proliferation. In fact, increased levels of GRP
have led to increased release of pro-ligands for epidermal growth factor
receptor (EGFR) with subsequent activation of EGF and mitogen-activated protein
kinase downstream pathways.
Presence of GRP and/or expression GRPR have also been investigated in
colorectal cancer samples (primary tumour, lymph nodes and metastatic lesions)
where over 80% samples expressed GRP/GRPR as opposed to adjacent normal healthy
epithelium.
Overall, the literature accounts with a growing body of evidence suggesting
that GRPR might be a valuable target.
Peptide receptor agonists have long been the ligands of choice for tracer
development and utilization in nuclear medicine thanks to their high
radioactive accumulation inside the target cells after receptor-radioligand
complex internalization. However, GRPR antagonists have been compared to GRPR
agonists and showed greater tumour uptake and better image contrast.
Furthermore, GRPR antagonists allow for a safer clinical use, since no acute
biological adverse effects are expected.
The Sponsor has therefore designed the current protocol to establish whether
the ligand NeoBOMB1, a high affinity antagonist for GRPR, radiolabelled with a
well-established PET isotope, Gallium-68 (68Ga) is a suitable radiotracer for
in vivo detection of GRPR-expressing malignancies, currently focusing on
breast, prostate, lung (small cell and non-small cell) and colon-rectum.
Study objective
Primary Objective
• To characterize preliminary targeting properties of [68Ga]-NeoBOMB1 in
patients with malignancies known to overexpress GRPR.
Secondary objectives
• To assess safety and tolerability of a single diagnostic dose of
[68Ga]-NeoBOMB1 administered as an intravenous bolus injection.
• To assess the bio-distribution, pharmacokinetics, radiation dosimetry, and
absorbed doses in critical organs for [68Ga]-NeoBOMB1 in a limited set of
patients.
• To establish the optimal threshold, expressed as Standardized Uptake Value
(SUV), to discriminate Positron Emission Tomography (PET) imaging positive
results from negative ones.
• To estimate the [68Ga]-NeoBOMB1 PET lesion-based and patient-based imaging
performance relative to a comparable standard imaging.
• To estimate the [68Ga]-NeoBOMB1 PET diagnostic performance lesion-based and
patient-based relative to the GRPR histopathology findings (e.g. IHC)
Exploratory objective
• To evaluate absorbed tumour doses for potential application of
[177Lu]-NeoBOMB1.
Study design
This is a Phase II, multi-center, open label, single dose study in patients
with tumour types known to overexpress GRPR, including breast, prostate,
colorectal, non-small cell lung (NSCL) and small-cell lung (SCL) cancer.
Population will be divided into two groups:
• a Phase-II dosimetry group, accounting with 10 patients (splitted into breast
cancer: n=5 female patients and prostate cancer: n=5 male patients) who will
undergo several assessments to confirm previous data on tracer
bio-distribution, radiation dosimetry, residence time for critical organs, and
absorbed dose critical organs for [68Ga]-NeoBOMB1. Venous whole blood and urine
samples will be collected for activity-based pharmacokinetics characterization;
• a Phase-II non-dosimetry group, accounting with 40 patients splitted into :
* Breast cancer: n=5
* Prostate cancer: n=5
* Colorectal cancer: n=10.
* NSCLC: n=10
* SCLC: n=10
Patients included in the non-dosimetry group will undergo one early and one
late whole-body PET-imaging acquisition, with no blood and urine sampling. Only
prostate tumour patients will undergo an additional early 5-min static PET scan
to better assess lymphe node metastases.
GRPR expression must be assessed while the study is ongoing within 4 weeks
after IMP injection by Immunohistochemistry staining from archival or recent
biopsy specimens (not older than 6 months prior to IMP injection).
The objectives of the study will be applicable for the whole study population
excepted the secondary objective relative to the biodistribution and dosimetry
that will be applicable only for the dosimetry group.
Intervention
Each study subject will receive a single dose (5.5mL) of study product by IV
injection on visit "Day 1"
Study burden and risks
The study subjects will undergo a physical examination and are expected to not
become pregnant or make their partner pregnant. Furthermore, ECGs, blood draws
and urine collections will be performed. The study product will be administered
by IV injection. PET/CT will be performed.
The amount of blood draws varies per group. In total there will be 4 to 5 blood
draws. The total volume of these blood draws is approximately 66 to 91 mL of
blood.
The amount of PET/CT scans varies per group. There will be 2 to 4 scans. The
estimated total dose of radiation is approximately 13.9 mSV with a low dose CT
and 29.6 mSV with a high dose CT.
The risk of participation is approximated as low and is limited to potential
side-effects of the study product and the accompanying tests. The study product
is tolerated well as indicated by current findings. The results of the study
can attribute to an improved diagnostic method to detect (refractory) GRPR
malignancies.
Rue de la Tour lîle 4
Geneva 1204
CH
Rue de la Tour lîle 4
Geneva 1204
CH
Listed location countries
Age
Inclusion criteria
• Subjects must be at least 18 years of age
• Subjects must have signed and dated an informed consent prior to any study-specific procedures.
• Subjects with histologically-confirmed tumour, for whom a less than 6-month-old biopsy has been performed.
• Dosimetry group:
- Luminal breast cancer
- Adenocarcinoma of the prostate
• Non-dosimetry group:
- Luminal breast cancer
- Adenocarcinoma of the prostate
- Small-cell lung cancer
- Non-small cell lung cancer
- Colorectal carcinoma
• At least one malignant lesion detected via functional or morphological imaging (PET combined to appropriate tracer according to tumour type, CT, MRI) within 3 months prior to the administration of [68Ga]-NeoBOMB1.
• The Eastern Cooperative Oncology (ECOG) performance status 0-2.
• Subjects must agree to use highly effective methods of contraception (female partners of male participants should use highly effective methods of contraception) during the trial.
Exclusion criteria
• Renal insufficiency or an estimated Glomerular Filtration Rate (eGFR) <50 ml/min/1.73m2..
• Haematological toxicity grade > 2 (Toxicity Grading Scale in vaccine clinical trials)
• Participation in any other investigational trial within 30 days of study entry.
• Subjects with positive pregnancy test (Urine dipstick), and/or currently breast-feeding
• Concurrent severe illness or clinically relevant trauma within 2 weeks before the administration of the investigational product that might preclude study completion or interfere with study results.
• Concurrent bladder outflow obstruction or unmanageable urinary incontinence.
• Known or expected hypersensitivity to 68Gallium, NeoBOMB1, or any excipient present in [68Ga]-NeoBOMB1.
• Any condition that precludes raised arms position
• Prior administration of a radiopharmaceutical within a period corresponding to 8 half-lives of the radionuclide.
• History of somatic or psychiatric disease/condition that may interfere with the objectives and assessments of the study.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
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Other (possibly less up-to-date) registrations in this register
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In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2017-003432-37-NL |
| CCMO | NL63628.078.17 |