To assess safety, tolerability and pharmacokinetics of a single subcutaneous administration of HPV-NIRD1.
ID
Source
Brief title
Condition
- Other condition
- Miscellaneous and site unspecified neoplasms malignant and unspecified
Synonym
Health condition
HPV16 associated cancer
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Safety and tolerability endpoints
* Treatment-emergent (serious) adverse events ((S)AEs).
* Concomitant medication
* Clinical laboratory tests (Haematology, Chemistry, Urinalysis)
* Vital signs (Pulse Rate (bpm), Systolic blood pressure (mmHg), Diastolic
blood pressure (mmHg))
* Injection site status
* Physical examination findings
Pharmacokinetic endpoints
The following endpoints will be determined for HPV-NIRD1 and ICG following
administration. They will be derived by imaging of injection site and draining
inguinal lymph nodes:
* Absolute fluorescent signal of injection site or draining inguinal lymph node
at different time points and doses
* SBR (signal to background ratio), defined as fluorescent signal of injection
site or draining inguinal lymph node compared to fluorescence signal of tissue
surrounding the injection side or lymph node, at different time points and
doses.
Secondary outcome
n/a
Background summary
Following our improved understanding of the cellular and molecular details of
the immune system, great progress has been made in the immunotherapy of cancer.
An already established example is immunotherapy with monoclonal antibodies that
has developed into multiple established cancer therapies. Although successful
for treatment of premalignant lesions, the current vaccination approach appears
to be insufficient for eradication of established tumors. We aim to develop
improved peptide vaccine strategies using better adjuvants, formulations, and
dosing schedules to be able to eradicate highly aggressive metastatic cancer.
Since the in vivo distribution of peptide vaccine antigens is largely unknown,
we propose to track the peptides conjugated with the near-infrared imaging dye
1 (NIRD1). Using this approach, our recent animal data demonstrate major
differences in duration and localization of peptide antigen exposure. These
pharmacokinetics depend on dose and formulation, and will likely determine the
kinetics and extent of subsequent peptide-specific T cell responses and
therapeutic efficacy. As animal models have limited predictive value for the
design of optimal peptide vaccines that efficiently stimulate human T cell
responses in vivo, we produced a clinical grade near-infrared labelled HPV16
peptide (HPV-NIRD1). This labelled peptide can be used as a tool to investigate
the effect of dosing schedules and formulations on the pharmacokinetics and T
cell kinetics of HPV16 peptide vaccination in clinical studies. In this first
clinical trial, we aim to study the safety of HPV-NIRD1 vaccination in healthy
adult volunteers, and the feasibility of obtaining pharmacokinetic data by
optical imaging.
Study objective
To assess safety, tolerability and pharmacokinetics of a single subcutaneous
administration of HPV-NIRD1.
Study design
This is an open label, single ascending dose study in healthy volunteers. Two
ascending dose levels of HPV-NIRD1 (80µg and 400µg) will be investigated in two
cohorts of 3 subjects.
After the first dose level, a dose-escalation meeting will take place to review
all (safety) data collected up to 24 hours. Escalation to the next dose level
will only take place after this review does not indicate a safety concern.
The total duration of the study for each subject will be up to 49 days divided
as follows:
* Screening: Up to 21 days before dosing;
* Treatment and study assessments: Days 0 to 28
* In Clinic period: Days 0 to 1 (single subcutaneous administration of
HPV-NIRD1 on day 0)
* Follow-up visit: 2,3,7, and 28 days after dose administration.
Subjects will be admitted to the study unit on Day 0 and will be discharged
approximately 24 hours after study drug administration.
Intervention
HPV-NIRD1 contains HPV-16 E6 peptide 71-95 conjugated to Near-Infrared Dye 1
and has been manufactured at the Interdivisional GMP Facility LUMC (IGFL) of
the department of Clinical Pharmacy and Toxicology, LUMC. For technical details
reference is made to the IMPD that accompanies this protocol. Study drug
HPV-NIRD1 will be administered as a single subcutaneous injection to the
subjects on day 0 of the study. Two strengths of HPV-NIRD1 will be
administered: 80ug, which corresponds to 60 ug of the HPV peptide and 20 ug
NIRD1 label and 400ug which corresponds to 300 ug HPV peptide and 100 ug NIRD1
label.
ICG is registered for diagnostic assessment of heart, circulation,
microcirculation, liver function and perfusion of the choroidea. ICG is a 775
Da di-sulfonated small molecule. It has a spectral absorption peak at 800 nm
and a spectral emission peak at 810 nm. ICG can be used as a lymphatic tracer.
A solution of 1mL containing either 20*g or 100*g ICG will be administered as a
single subcutaneous injection to the subjects on day 0 of the study.
Study burden and risks
Burden: The burden for participants consists of a time investment of 1 full day
and 5 1-hour visits, possible side effects and compliance with lifestyle
restriction.
Risks: The risks of participation for the subjects in the trial include local
injection site reactions
and hypersensitivity reactions. In the absence of any adjuvants and based on
the low and local dose of the study drug, the risks are deemed very limited.
Nevertheless precautionary measures (supervised administration by qualified
staff and availability of medical treatment to treat hypersensitivity
reactions) are in place and these effects are generally well manageable
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 to
improve therapeutic HPV vaccination 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 HPV-NIRD1.Pre-menopausal female subjects who are not surgically sterile should also employ an
effective method of birth control for at least three months post dosing.
4. The subject*s body mass index is 18-22 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.
Exclusion criteria
1. The subjects uses prescription drugs or OTC-drugs that may have an impact on the study objectives.
2. Previous exposure to the investigational drug.
3. Participation in a clinical trial within 90 days of screening or more than 4 times in the previous year.
4. Known hypersensitivity to the investigational drug or comparative drug or drugs of the same class, or any of their excipients.
5. Any known factor, condition, or disease that might interfere with treatment compliance, study conduct or interpretation of the results such as drug or alcohol dependence or psychiatric disease.
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 | EUCTR2015-004995-31-NL |
| CCMO | NL55681.058.15 |