Primary Objective- To determine safety and tolerability of a single dose of ZW800-1 in healthy volunteers.Secondary Objectives- To determine the pharmacokinetics of a single dose of ZW800-1 by measuring the fluorescence of blood and urine.- To…
ID
Source
Brief title
Condition
- Miscellaneous and site unspecified neoplasms malignant and unspecified
- Renal and urinary tract therapeutic procedures
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Safety and tolerability endpoints
- Treatment-emergent (serious) adverse events ((S)AEs).
- Clinical laboratory tests (urinalysis, serum biochemistry, hematology) Vital
signs
o Pulse Rate (bpm)
o Systolic blood pressure (mmHg)
o Diastolic blood pressure (mmHg)
- ECG (heart rate (bpm), PR, QRS, QT, QTcB, QTcF)
- Injection site status
- Physical examination findings
PK endpoints
- The following endpoints will be determined for ZW800-1 following each
treatment. They will be derived by non-compartmental analysis of the serum
concentration-time data:
o The area under the plasma concentration-time curve from zero to infinity
(AUC0-inf);
o The maximum plasma concentration (Cmax);
o The area under the plasma concentration-time curve from zero to t of the last
measured concentration above the limit of quantification (AUC0-last);
o The time to reach maximum plasma concentration (tmax);
o The terminal disposition rate constant (*z) with the respective half-life
(t*).
o Other parameters, including Vz, CL, and other parameters as appropriate, as
well as dose adjusted parameters, may be determined.
o Urinary excretion of ZW800-1 at specific time points (see table 1).
- Fluorescence intensity of the skin over time
Secondary outcome
N.A.
Background summary
Fluorescence imaging using near-infrared (NIR) light (i.e. 700-900 nm) can
assist surgeons to recognize structures that need to be spared, e.g. blood
vessels and ureters, and structures that need to be resected, e.g. sentinel
lymph nodes and tumors. For tumor-targeted NIR fluorescence imaging, a NIR
fluorophore needs to be conjugated to a targeting ligand, such as an antibody
or peptide. Currently, the only clinically available NIR fluorophores are
methylene blue, 5-ALA and indocyanine green (ICG), but these fluorophores
cannot easily be conjugated covalently to other molecules. Moreover, the
fluorescence emission intensity (i.e., the product of extinction coefficient
and quantum yield) and peak (600 nm and 700 nm, respectively) of 5-ALA and
methylene blue and the clearance route of ICG (primarily hepatic), are far from
optimal. Therefore, new fluorophores need to be developed. ZW800-1 has improved
in vivo properties, including low non-specific binding and uptake, high
extinction coefficient and quantum yield, and exclusive renal clearance of
intravenously injected drug. We believe that this first-in-class molecule will
form the foundation for the next generation of targeted NIR fluorophores;
however, the focus of this Phase 1 study will be ZW800-1 alone injected
intravenously.
Study objective
Primary Objective
- To determine safety and tolerability of a single dose of ZW800-1 in healthy
volunteers.
Secondary Objectives
- To determine the pharmacokinetics of a single dose of ZW800-1 by measuring
the fluorescence of blood and urine.
- To describe the relationship of any fluorescence of skin to the
administration of ZW800-1.
Study design
This is a single ascending dose, randomized, placebo-controlled study in
healthy volunteers. Three ascending dose levels of ZW800-1 will be investigated
in three non-overlapping 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 following cohorts 5
subjects will be randomized in a ratio of 4:1 active:placebo.
Intervention
Intravenous administration of ZW800-1 and fluorescence imaging.
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 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 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.
3. Female subjects need to be surgically sterile, post-menopausal or pre-menopausal with a negative urine pregnancy test at screening and just before administration of 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 has a normal or clinically acceptable medical history, physical examination, and vital signs findings at screening (within 21 days before administration of study drug).
5. 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.
6. The subject has negative screening test results for hepatitis B, hepatitis C, and human immunodeficiency virus.
7. The subject has negative test results for drug and alcohol screening.
8. 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.
9. 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 | EUCTR2016-003919-35-NL |
| CCMO | NL59365.056.16 |