Systemic induction / expansion of vaccine antigen-specific T cells.
ID
Source
Brief title
Condition
- Reproductive neoplasms female malignant and unspecified
- Ovarian and fallopian tube disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Systemic induction / expansion of vaccine antigen-specific T cells
Secondary outcome
1) Intratumoral induction / expansion of vaccine antigen-specific T cells
2) Progression-free survival of primary OC patients treated with the vaccines
in combination with carboplatin/paclitaxel
3) Assessing the safety and tolerability of repetitive doses of the vaccine in
combination with carboplatin/paclitaxel
Background summary
Advanced stage serous ovarian cancer (OC) is the leading cause of death from
gynaecological malignancies with a 5-year survival of no more than 40%. Current
treatment (surgery and chemotherapy) is initially effective, but almost all
patients suffer from chemotherapy-resistant relapse. Moreover, despite
adjustment of chemotherapeutic schedules and the introduction of innovative
targeted drugs, survival and quality of life have barely improved. A promising
new approach that may improve outcome for these patients is immunotherapy. In
particular, immune checkpoint inhibition (CPI) therapy targeting e.g. PD-L1 or
PD-1 have improved patient survival rates across malignancies, with some
responses also observed in ovarian cancer patients. Nevertheless, response to
CPIs is almost always dependent on a pre-existing anti-cancer immune response,
frequently absent in ovarian cancer patients. In order to increase/ induce an
anti-tumor response an optimized liposomal formulated RNA vaccine targeting
tumor-associated antigens (TAA) is developed. This vaccine protects RNA from
degradation by plasma RNAses and shows an almost 100% targeted accumulation of
RNA in the spleen suggesting a direct delivery to dendritic cells. Here, we
therefore propose to increase/induce an anti-tumor immune response in patients
with ovarian cancer while receiving neoadjuvant chemotherapy by use of the
BNT115 vaccine. The simultaneous treatment with vaccinations and neoadjuvant
chemotherapy provides a tumor immune environment where immune defences are
decreased. Thereby enhancing the effectiveness of a vaccine induced immune
response. Making it a perfect setting for the induction of a tumor specific
immune response, with the ultimate aim of moving towards combination therapy of
chemotherapy/vaccination with checkpoint inhibition for these patients.
Study objective
Systemic induction / expansion of vaccine antigen-specific T cells.
Study design
A GMP-grade RNA vaccine targeting serous OC antigens will be used to induce a
systemic immune response and more importantly tumor accumulation of
vaccine-induced T cells.
Patients with primary epithelial ovarian carcinoma will receive eight
vaccinations, in the same period they will receive three cycles of neoadjuvant
chemotherapy, an operation and adjuvant chemotherapy (standard treatment). We
will need to include 10 evaluable patients to determine the primary outcome.
Data collected for analyzing vaccine-specific systmic immune response is
obtained before and after vaccinations by collection of PBMCs by leukapheresis
and/or venous blood collections.
Data collected for analyzing vaccine-specific intra-tumoral immune response is
obtained by collection of tumor material by biopsy before vaccination and
surgery after 5th vaccination (standard care).
To determine the safety and tolerability of the vaccine, adverse events will be
recorded during the study, also ECOG-status is measured and bloodchemistry and
heamatology is monitored.
To assess the exploratory endpoint, results from the intratumoral
visualization of CD25+ T cells by the [18F]FB-IL2 PET-CT imaging (expressed as
standardized uptake values (SUV)) is compared to CD25+ T-cell infiltration in
matching tumor material (evaluated by immunohistochemistry).
Intervention
Intravenous administration of the vaccine (8 times)
Study burden and risks
Patients in this phase I pilot trial have an active disease and might
experience benefit from this study. The intended goal of the study is to induce
a specific anti-cancer immune response which may ultimately lead to eradication
of the malignant lesions. When long-lasting immunity is induced, the
immunotherapy may also sensitize patients for further treatment with ICB or
even prevent recurrence of the disease.
For each patients study procedures will take approximately 9 months. The study
includes 16 hospital visits, we expect to combine at least 6 visits with SOC
visits.
Eight vaccinations by intravenous (i.v.) injection are performed with
additional vena punctures for bio / immune monitoring. Visits and study related
blood collections are aligned to and combined with SoC procedures as much as
possible.
Initial clinical data from RNA(LIP) studies demonstrated that a dosage of 100
µg total RNA is safe and sufficient for induction of a potent immune response.
We will monitor the safety and toxicity of this cancer vaccine in the current
trial, using GCP guidelines. Toxicity will be graded according to the NCI CTCAE
Version 5.0. Earlier clinical studies indicate that liposome delivery of RNA
further augments this immunogenicity in the absence of any toxicity.
Hanzeplein 1
Groningen 9713 GZ
NL
Hanzeplein 1
Groningen 9713 GZ
NL
Listed location countries
Age
Inclusion criteria
- Primary epithelial OC patients with measurable tumor lesions (determined by
CT or MRI), who are intended to be treated with neo-adjuvant chemotherapy,
carboplatin/paclitaxel, subsequent surgery and adjuvant chemotherapy
- Age >= 18 years
- Signed informed consent in accordance with institutional and regulatory
guidelines
- Adequate access of the tumor for image-guided biopsy
- Adequate (according to the institutional standards) hematology, liver and
kidney function to undergo chemotherapy with carboplatin and paclitaxel
- ECOG-performance status of 0 or 1 at screening
- Current BMI > 18.5 and no weight loss of >5% over the past month. Notably,
weight loss due to drainage of ascites is not applicable.
Exclusion criteria
- History of a second malignancy except for curatively treated low-stage tumors
with a histology that can be differentiated from the epithelial OC type
-Patients must have no ongoing or recent evidence (within the last 5 years) of
significant autoimmune disease that required treatment with systemic
immunosuppressive treatments which may suggest risk for immune-related adverse
events (irAEs).
Note: Patients with autoimmune-related hyperthyroidism, autoimmune-related
hypothyroidism who are in remission, or on a stable dose of thyroid-replacement
hormone, vitiligo, or psoriasis may be included.
- Patients must have no uncontrolled infection with human immunodeficiency
virus, hepatitis B or hepatitis C infection; or diagnosis of immunodeficiency
that is related to, or results in chronic infection. Mild cancer-related
immunodeficiency (such as immunodeficiency treated with gamma globulin and
without chronic or recurrent infection) is allowed.
o Patients with known HIV who have controlled infection (undetectable viral
load and CD4 count above 350 either spontaneously or on a stable antiviral
regimen) are permitted. For patients with controlled HIV infection, monitoring
will be performed per local standards.
o Patients with known hepatitis B (HepBsAg+) who have controlled infection
(serum hepatitis B virus DNA PCR that is below the limit of detection AND
receiving antiviral therapy for hepatitis B) are permitted. Patients with
controlled infections must undergo periodic monitoring of HBV DNA per local
standards. Patients must remain on anti-viral therapy for at least 6 months
beyond the last dose of trial treatment.
o Patients who are known hepatitis C virus antibody positive (HCV Ab+) who have
controlled infection (undetectable HCV RNA by PCR either spontaneously or in
response to a successful prior course of anti-HCV therapy) are permitted.
- Use of systemic continuous corticosteroid therapy (e.g. prednisone i.v. or
p.o. >7.5 mg / day).
- Pregnancy or breast feeding
- Participation in a trial with another investigational drug within 30 days
prior to the enrolment in this trial
- Any condition that in the opinion of the investigator could interfere with
the conduct of the trial.
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 | EUCTR2017-004585-10-NL |
| ClinicalTrials.gov | NCT04163094 |
| CCMO | NL66895.000.18 |