Primary objective- To determine safety and tolerability of a single dose of cRGD-ZW800-1 in healthy volunteers.Secondary objectives- To determine the pharmacokinetics of a single dose of cRGD-ZW800-1 by measuring the fluorescence of blood and urine…
ID
Source
Brief title
Condition
- Miscellaneous and site unspecified neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Safety and tolerability is the primary endpoint of the study. This will be
assessed from data on the occurrence of treatment-emergent adverse events
(TEAEs) from the time of administration throughout the study period, and
changes in serum biochemistry, hematology, urinalysis, vital signs, ECG,
injection site status, and physical examination findings. In addition, analysis
of the PK of cRGD-ZW800-1 will be conducted.
Secondary outcome
Not Applicable
Background summary
Accurate and real-time detection of tumors during surgery remains challenging.
Sensitivity of available imaging modalities is often inadequate with respect to
margin or metastasis detection. Following SPECT and PET agents, tumor targeted
ligands can also be conjugated to NIR (near-infrared, 700-900 nm) fluorophores
and being visualized using specific intraoperative near-infrared imaging
systems. Traditionally, NIR fluorophores have been developed for a variety of
preclinical applications, including labeling to specific ligands, and can be
used to understand the fate of intravenously administered anticancer
therapeutics, in determining biodistribution, tissue penetration and cellular
localization. Currently, NIR fluorescent labeled vehicles are also being used
as a diagnostic tool for accurate localization of cancer cells in real-time
during surgery.
Here we study cRGD-ZW800-1, a cyclic pentapeptide (cRGD) conjugated to the 800
nm NIR fluorophore ZW800-1. The cyclic 3-amino acid sequence (RGD) is
clinically a well-known peptide that binds to various integrins (αvβ1, αVβ3,
αvβ5, αvβ6, αvβ8, α5β1, α8β1 and αIIbβ3), mostly associated with
neoangiogenesis. Tumors larger than 1-2 mm depend on the formation of new blood
vessels to acquire sufficient amounts of oxygen and nutrients. Some of these
integrins are therefore overexpressed on malignant cells and in tumor stroma,
for example in breast, colorectal, pancreas and lung cancer. RGD based
molecules have already been investigated in various phase I and phase II
imaging studies using PET and SPECT and in a phase III study as an anticancer
therapy (cilengitide).
Extensive preliminary work on the cRGD-ZW800-1 agent has been performed by our
group and showed clear delineation of melanomas and colorectal, liver,
pancreatic, lung, and head and neck tumors in xenograft mouse models while due
to its renal clearance route also ureters could be recognized.
As there is no clinical experience with cRGD-ZW800-1, this will be the first in
human study in which cRGD-ZW800-1 will be investigated in healthy volunteers.
In this study, two single ascending i.v. doses of cRGD-ZW800-1 or placebo will
be administrated to healthy volunteers.
Study objective
Primary objective
- To determine safety and tolerability of a single dose of cRGD-ZW800-1 in
healthy volunteers.
Secondary objectives
- To determine the pharmacokinetics of a single dose of cRGD-ZW800-1 by
measuring the fluorescence of blood and urine.
- To describe the temporal relationship of any fluorescence of superficial
tissues (skin, veins) to the administration of cRGD-ZW800-1.
Study design
This is a single ascending dose, randomized, placebo-controlled design in
healthy volunteers. Two ascending dose levels of cRGD-ZW800-1 will be
investigated in two cohorts. Within the first cohort a sentinel approach will
be used: on the first day 2 subjects will be administered study drug in a 1:1
ratio for active and placebo. The other subjects in this cohort will be
randomized to active:placebo in a 3:1 ratio. In the second cohort 5 subjects
will be randomized in a ratio of 4:1 active:placebo.
Study burden and risks
Burden: The burden for participants consists of a time investment of 1 full day
and 2 1-hour visits, possible side effects and compliance with lifestyle
restriction.
Risks: The risks to subjects related to cRGD-ZW800-1 are unknown at this time;
safety is therefore a primary study objective in the current study. Other risks
to subjects mainly relate to the i.v. injection and venous blood sampling.
Intravenous injection and the use of cannulas (1 cannula for i.v. injection and
1 cannula for venous blood sampling) are known to carry a small risk of
infection and hematoma. Based on consistent observations in the preclinical
efficacy and safety pharmacology studies, it is expected that discoloration of
the skin and urine may occur. Based on experience with other fluorescent
probes, it cannot be excluded that hypersensitivity reactions may occur,
although there are no indications for cRGD-ZW800-1.
Benefits: There are no expected direct benefits to subjects who participate in
this trial, but participants may help others prospectively by contributing to
the knowledge base for designing future studies in cancer patients.
Zernikedreef 8
Leiden 2333CL
NL
Zernikedreef 8
Leiden 2333CL
NL
Listed location countries
Age
Inclusion criteria
1. The subject is 18-65 years old at screening.
2. The subject is able and willing to comply with study procedures, and signed and dated informed consent is obtained before any study-related procedure is performed.
3. Female subjects need to be either surgically sterile, post-menopausal or pre-menopausal with a negative urine pregnancy test at screening and just before administration of cRGD-ZW800-1. Pre-menopausal female subjects who are not surgically sterile should also employ an effective method of birth control for at least 90 days post dosing when it consists of a hormonal contraceptive method or IUD. For other contraceptive methods premenopausal females who are not surgically sterile have to agree to use an effective method of contraception.
4. The subject*s body weight is <=90 kg and the body mass index is <=30 kg/m2.
5. The subject has a normal or clinically acceptable medical history, physical examination, and vital signs findings at screening (within 21 days before administration of study drug).
6. The subject*s screening ECG and clinical laboratory test results are within normal limits, or if any are outside of normal limits they are considered to be clinically insignificant.
7. The subject has negative screening test results for hepatitis B, hepatitis C, and human immunodeficiency virus.
8. The subject has negative test results for drug and alcohol screening.
9. Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.
10. Before patient registration, written informed consent must be given according to ICH/GCP, and national/local regulations.
Exclusion criteria
1. Female subjects that are lactating or pregnant.
2. Unacceptable known diagnoses or diseases at baseline, e.g., known cardiovascular or pulmonary disease, renal or liver dysfunction, ECG or laboratory abnormalities, etc.
3. Use of prescription drugs, with the exception of contraceptive drugs.
4. Previous inclusion in this study.
5. Participation in a clinical trial within 90 days of screening or more than 4 times in the previous year.
6. History of anaphylactic reactions.
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 | EUCTR2016-000397-38-NL |
| CCMO | NL56621.058.16 |