Primary objectives- To investigate the safety and tolerability profile of hVEGF26-104/RFASE.- To determine the effective dose of hVEGF26-104/RFASE required to neutralize VEGF in serum, defined as a VEGF level below 9,0 pg/mL.Secondary objectives- To…
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 of hVEGF26-104/RFASE, measured by the number of
participants with serious and non-serious adverse events
- Neutralization of endogenous VEGF in serum, defined as a VEGF level below 9.0
pg/mL as determined by sandwich ELISA.
Secondary outcome
- Anti-VEGF antibody titer in serum, plasma and a platelet sample, as
determined by indirect ELISA.
- VEGF concentration in plasma as determined by sandwich ELISA.
- VEGF concentration in a platelet sample as determined by sandwich ELISA.
- Functional VEGF neutralization, as determined in a Ba/F3-R2-R2 cell
proliferation bio-assay.
- Cellular (T-cell) immune response, as determined by ELISPOT
- Immune modulation
- Angiogenesis suppression: Within the tumor, by assessing microvessel density
(MVD), quantity of proliferating endothelial cells and pericyt coverage.
Background summary
Angiogenesis (the formation of new blood vessels from pre-existing blood
vessels) plays an important role in the growth and spread of tumors.
Angiogenesis is regulated by a balance of activators and inhibitors. One of the
angiogenic activators is the vascular endothelial growth factor (VEGF, also
referred to as VEGF-A). Over the past decade, several angiogenesis inhibitors
have been discovered and implemented in the therapy of cancer patients.
Bevacizumab (a humanized monoclonal antibody that inhibits VEGF-A) has been
shown to improve survival in different tumor types in first and second line
therapy when given in various chemotherapy combinations. Furthermore, research
has shown a survival benefit of continued VEGF suppression with bevacizumab
beyond first progression in metastatic colorectal cancer. So although repeated
use of bevacizumab as a chronic therapy is much desired, currently this is not
feasible because of substantial disadvantages of bevacizumab therapy. First,
since bevacizumab only offers temporary VEGF neutralization, it needs frequent
repeated administration. Secondly, bevacizumab is an intravenous therapy, which
requires hospitalization on each administration. Third, bevacizumab has very
high production costs.
These specific drawbacks of longer term monoclonal antibody therapy could be
circumvented by the use of a therapeutic cancer vaccine targeting VEGF. A
vaccine is able to induce sustained VEGF suppression and can be administered
via an intramuscular (IM) injection. In addition, a vaccine will likely inhibit
VEGF more effectively as compared to bevacizumab, because a vaccine induces a
polyclonal antibody response, resulting in higher avidity binding. Furthermore,
it is believed that endogenous antibodies have a better tumor penetrating
capacity, as compared to exogenously administered antibodies.
The vaccine hVEGF26-104 is a truncated synthetic peptide mimic of the VEGF
protein and consists of 79 amino acids (residue 26-104). The vaccine contains
an antigen that directs the body*s own polyclonal antibody response towards the
active site of the endogenous VEGF molecule. After binding of the antibodies to
endogenous VEGF this hormone will no longer be able to bind to its receptors
(VEGFR1 and VEGFR2) and consequently will no longer exert its pro-angiogenic
effect. To enhance the immune response, RFASE, which belongs to the adjuvant
group of sulpholipopolysaccharides, will be used as an adjuvant.
Study objective
Primary objectives
- To investigate the safety and tolerability profile of hVEGF26-104/RFASE.
- To determine the effective dose of hVEGF26-104/RFASE required to neutralize
VEGF in serum, defined as a VEGF level below 9,0 pg/mL.
Secondary objectives
- To determine the anti-VEGF antibody titer, induced by hVEGF26-104/RFASE
administration.
- To determine the effective dose of hVEGF26-104/RFASE required to neutralize
VEGF in plasma and in a platelet sample.
- To assess the effect of VEGF neutralization in a functional Ba/F3-R2 cell
proliferation assay.
Exploratory objectives
- To assess the cellular anti-tumor immune response induced by
hVEGF26-104/RFASE administration.
- To assess immunomodulatory effects upon hVEGF26-104/RFASE administration.
- To make a preliminary assessment of hVEGF26-104/RFASE to suppress
angiogenesis within the tumor.
- To assess the immune infiltration and the regulation of endothelial cell
adhesion molecules within the tumor.
Study design
This is an open label single center phase I study.
A *3 + 3 * dose escalation design will be used. The study will investigate
sequential cohorts consisting of 3 patients to be enrolled and treated at the
applicable dose level. The study medication consists of 1.0 mL hVEGF26-104 (in
escalating doses of 62.5, 125, 250, 500, 1000, 2000 and 4000 µg). The lowest
dose of RFASE is 20 mg and this can be escalated to 40 mg, 80 mg and max. 160
mg. Eligible subjects will receive three IM injections with hVEGF26-104/RFASE
on days 0 (primer), 14 and 28 (boosters). To assess potential toxicity of the
adjuvant RFASE, the 3 patients enrolled in the first cohort of the study (62.5
*g) will receive a single injection with RFASE (fixed dose of 20 mg) as a
single agent 14 days prior to the first immunisation with hVEGF26-104/RFASE. If
no DLT occurs within 14 days after the RFASE administration, the patients will
continue with 3 immunisations hVEGF26-104/RFASE. If none out of 3 patients
experiences a DLT at a certain dose level, one can proceed to the next dose
level. If one patient experiences a DLT at a certain dose level, another 3
patients will be assigned at the same dose level. In the highest dose
escalation cohort, at least 6 patients will be enrolled.
In case insufficient VEGF neutralization (< 50 % reduction in serum VEGF levels
compared to pre-treatment) is achieved in dose cohort 3 (hVEGF26-104 250 ug)
while administration of the vaccine showed to be safe (< DLT in this cohort),
RFASE dose will be escalated to 40 mg while the dose of hVEGF26-104 will remain
similar (250 ug) (dose cohort 3B). When there is again insufficient VEGF
neutralization, RFASE dose can again be escalated to 80 mg (cohort 3C). The
maximum RFASE dose that can be given in this study is 160 mg (cohort 3D).
In case of sufficient VEGF neutralization (> 50% reduction in serum VEGF levels
compared to pre-treatment) and administration showed to be safe (< DLT in this
cohort), hVEGF26-104 dose will be escalated to 500 ug (cohort 4), 1000 ug
(cohort 5), 2000 ug (cohort 6) and 4000 ug (cohort 7) but RFASE dose will
remain the same (40 mg).
If VEGF is no longer neutralized, but there is no sign of progression either;
the patient will receive another booster of hVEGF26-104/RFASE in order to
achieve VEGF neutralization again. This booster can be repeated until
progressive disease, death or other reasons for withdrawal from the study.
Intervention
Eligible subjects will receive three intramuscular injections with
hVEGF26-104/RFASE in dose-escalation on days 0 (primer), 14 and 28 (boosters),
followed by an observation period of 6 weeks. Blood will be drawn at given
timepoints to assess safety, immunogenicity and angiogenesis parameters. At
screening, a tumor biopsy will be performed for a baseline assessment of
angiogenesis and immune infiltration. In the case that VEGF is neutralized 8
weeks after first hVEGF26-104 administration, the patient will be asked to
undergo another biopsy at week 10 to assess any possible change in angiogenesis
and immune infiltration in the tumor. In patients whom there is no VEGF
neutralization 6 weeks after primer immunization, the DLT period will be
terminated.
If VEGF is no longer neutralized, but there is no sign of progression either;
the patient will receive another booster of hVEGF26-104/RFASE in order to
achieve VEGF neutralization again.
Study burden and risks
Patients participating in the study will receive a total of 3 IM injections
with hVEGF26-104/RFASE. Blood will be drawn at given timepoints to assess
safety, immunogenicity, angiogenesis and effects on circulating immune effector
subsets and endothelial cells and precursors. At baseline patients will be
asked to undergo a tumor biopsy. If the blood work indicates VEGF
neutralization, patients will be asked to undergo a second tumor biopsy at week
10. During the follow-up period, blood will be drawn every 4 weeks.
Furthermore, radiological imaging will be performed every 8 weeks.
Given that this is the first study in which hVEGF26-104/RFASE is applied in
man, there are no published data on the risks of this vaccine. However,
pre-clinical research in mice and rats did not show any serious toxicity or
adverse events. The most important side effects observed were a temporary rise
in body temperature, erythema/edema at the injection site and an acute phase
reaction observed in blood.
Since hVEGF26-104/RFASE is supposed to act on the same site of the VEGF
molecule as bevacizumab, the potential side-effect profile is expected to be
comparable. Side effects that can be expected include hypertension, impaired
wound healing, bleeding events, thrombosis, proteinuria, leukopenia and bowel
perforation.
De Boelelaan 1117
Amsterdam 1081HV
NL
De Boelelaan 1117
Amsterdam 1081HV
NL
Listed location countries
Age
Inclusion criteria
1. Histologically confirmed advanced, solid malignancy.
2. Refractory or not amenable to standard therapy
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
4. Willing and able to give written informed consent
5. Patient is * 18 years of age at the time of signature of the informed consent
6. Adequate hematological function: Absolute neutrophil count (ANC) * 1.5 x 109/L, platelets * 100 x 109/L, Hemoglobin * 6.0 mmol/L.
7. Adequate hepatic function: serum bilirubin * 1.5 times the upper limit of normal (ULN), ALT and AST * 2.5 x ULN (or * 5 times ULN if liver metastases are present).
8. Adequate renal function: eGFR * 50ml/min
9. PT-INR/PTT < 1.5 x ULN, unless coumarin derivatives are used
10. Activated partial thromboplastin time (APTT) < 1.25 x ULN (therapeutic anticoagulation therapy is allowed, if this treatment can be interrupted for a biopsy as judged by the treating physician)
11. Female patients of childbearing potential may be enrolled in the study, if the patient
- Has practiced adequate contraception for 30 days prior to first hVEGF26-104/RFASE administration.
- Negative pregnancy test
- Has agreed to continue adequate contraception for as long as VEGF is neutralized.
Exclusion criteria
1. Major surgery within 28 days before the initiation of study treatment
2. Any serious non-healing wounds, ulcers, or bone fractures within 28 days prior to the initiation of study treatment.
3. Deep venous thrombosis (DVT) or pulmonary embolus (PE) within 1 year prior to the initiation of study treatment.
4. Uncontrolled hypertension (systolic > 150 mmHg and/or diastolic > 100 mmHg)
5. The patient is scheduled to receive another vaccination during the DLT period.
6. A previous serious allergic reaction to a vaccine such as angioedema and anaphylaxis.
7. Treatment with bevacizumab within 6 weeks prior to the initiation of study treatment.
8. Uncontrolled auto-immune diseases
9. Primary or secondary immunodeficiency, including HIV
10. Treatment with a glucocorticoid derivative in an equivalent dose of * 10mg prednisone a day.
11. Female patients: the patient is pregnant or lactating.
12. When the patient is scheduled to receive any other anticancer treatments.
13. Chemotherapy within 28 days prior to the initiation of study treatment.
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 | EUCTR2013-002663-25-NL |
| ClinicalTrials.gov | NCT02237638 |
| CCMO | NL45279.000.13 |