The objective of the present trial is to investigate the safety of an allogenic tumor cell lysate loaded onto autologuous dendritic cells (AlloDen) in patients with malignant mesothelioma (MM). Heretoo we will perform a phase I study with a…
Source
Brief title
Condition
- Mesotheliomas
Synonym
Research involving
Sponsors and support
Intervention
No registrations found.
Outcome measures
Primary outcome
The aim of this phase I protocol is to study the toxicity and safety of AlloDen
(DC-based immunotherapy) in MM patients. Toxicities will be scored according to
CTC criteria version 4.0. The following toxicities occurring during 8 weeks
after the first vaccination, will be considered as dose-limiting (DLTs):
Hematological:
Thrombocytopenia grade 3 during longer then 7 days or grade 4
Neutropenia grade 3 during longer then 7 days or grade 4
Non-hematological:
Any grade 3/4 toxicity except for diarrhea, nausea, vomiting, hypertension if
not adequately treatable, skin toxicity.
Immune related:
Any grade 4 except for rash and (drug related) fever
Secondary outcome
Secondary end-points include the establishment of an immune response against
tumor asscoiated antigens and the model antigen KLH. Read-out parameters are
the side effects, immune responses, anti-tumor response and survival of this
DC-based immunotherapy* both in vivo and in vitro.
Background summary
Malignant mesothelioma is an aggressive malignant pleural disease, related to
asbestos exposure. Due to the long time interval between exposure and disease
and the abundant environmental presence of asbest, incidence is still rising.
Prognosis is poor with a median survival of 12 months even with cytotoxic
chemotherapy. At present cytotoxic chemotherapy is the only evidence based
treatment for the disease, but efficacy is limited. No major improvements were
made with so-called targeted agents in mesothelioma. Surgery may have a role in
a limited number of patients, but recurrences do often occur. No curative
treatment options are available.
We have shown both in a murine model, as for the first time in patients, that
dendritic cell-based immunotherapy induces tumor specific T-cell responses. In
two trials, 20 patients were treated with this autologuous vaccin. The
dendritic cells were loaded with tumor material which was obtained from the
patient before the start of chemotherapy. It was found to be a safe treatment.
Apart from a flu like syndrome for 2 to 4 days in a minority of patients no
side effects were detected. In the patients a tumor specific immune response
was generated which was not present before the treatment. Survival rates in the
patients were encouraging, with 4 patients still alive with a shortest follow
up of 2 years.
However the quality and quantity of the autologuous tumor cell lysate to load
the dendritic cells was a major impediment for this trial. In most patients the
lysate is generated from pleural effusions. In others from pleural biopsies.
Only in 20% of screened patients, these patient materials were of sufficient
quality to generate the tumor lysate. As in mesothelioma no common tumor
antigen is present it is not possible to load the dendritic cells using such an
antigen. Apart from that, it is now becoming more and more evident that
multipotent targeting of a tumor by the immune system may be more efficient
then the single antigen targeting.
We have now developed a clinical grade allogeneous tumor cell lysate which can
be used to load dendritic cells of patients. The allogeneous lysate is composed
of a mixture of tumorantigens derived from 5 cellines obtained from 5 patients.
The patients were selected based on the difference in their growth pattern to
cover the whole scala of MM. These cellines are immortal and provide an off the
shelf source of tumor antigens with constant quality and quantity. In a murine
model this way of loading of dendritic cells was equally effective to the
autologuous treatment.
Study objective
The objective of the present trial is to investigate the safety of an allogenic
tumor cell lysate loaded onto autologuous dendritic cells (AlloDen) in patients
with malignant mesothelioma (MM). Heretoo we will perform a phase I study with
a classical 3*3 design.
The aim of this phase I protocol is to study the toxicity and safety of AlloDen
(DC-based immunotherapy) in MM patients. Secondary end-points include the
establishment of an immune response against TAA and KLH and overal survival.
Read-out parameters are the side effects, immune responses, anti-tumor response
both in vivo and in vitro.
In case no major toxicity problems will occur, the dose found to be safe
established with this trial will be taken into phase II.
Study design
In the phase I study, a 3x3 design will be applied and 3 different dose levels
of AlloDen (10*106 cells, 25*106 cells and 50*106 cells). If no dose-limiting
toxicity (DTL) is encountered among the first three evaluable patients treated
at a particular dose level, the next dose level can be opened. In case there is
one DLT among the first three patients at a certain dose level, then 3 other
patients will be treated at this dose-level. If in these total 6 patients, no
other DLTs are seen (so in total 1/6 patients with a DLT), the next dose level
can be opened. If there are more than 2 DLTs in a particular dose level, this
level is considered to exceed the maximum tolerated dose and the dose level one
level lower will be considered as the recommended dose for further studies.
This approach implies that in the phase I part at least three and maximum 18
patients are needed
A leukapheresis is performed of which the monocytes are used for
differentiation to DCs using different cytokines. The procedure to grow DCs in
vitro and pulse them with tumor lysate is performed according to our former
DC-immunotherapy protocols that were approved by the ethics committee (as in
our former protocol METC-2008-109, CCMO NL24050.000.08).
Pulsed autologous DCs (AlloDen) are re-injected every two weeks. Quality
control tests will be performed before the cellular vaccine is released (see
IMPD [version 6]). After the third injection with AlloDen, revaccinations to
boost the immunsystem are given in a 3 monthly interval until unacceptable
toxicity.
Intervention
Patients will be injected with autologuous dendritic cells which are generated
from monocytes obtainend from the patient via leucapheresis.
Patients will be injected both intravenously and intradermal with their own
dendritic cells. These cells have been loaded with an allogenic tumor cell
lysate.
Study burden and risks
The impact of our study on the participants is relatively high. Normally
patients should be followed up every 6 weeks with radiographic examinations.
Most patients do suffer from a disease which is killing in short notice.
The riks of the interventions are limited and no standard treatment is
prohbited due to our study as there is none. From our former trials we knwo
that patients are highly motivated to participate.
Patients have to undergo a couple of standard procedures especially for this
trial, like a cathether in a blood vessel. This is an invasive procedure but
risks are limited,. This iv entrance is neccesary everytime, for the
leucopheresis, for blood samples and for the injection of the dendritic cells.
A leucopheresis is a standard procedure and will be performed according to
guidelines. There is a limited risk for transient trombocytopenia and
leucopenia.
The administration of cells who have been loaded with materials not derived
from the patient is a potential risk and that is the subject of the study.
Because not the lysate itself is administered to the patients but only when it
is processed by the cells of the patient we expect these risks to be small.
The dendritic cells are equipped to digest foreign materials in their function
as antigen presenting cell.
To determine the side effects a low dose will be given in first instance. In
our formed trials no side effects were foudn with 50 million cells and we now
start at 10 million. In case of side effects an immune response could occur
against the patients one cells, which can then be treated with
immunosuppressive drugs.
dr molewaterplein 50
Rotterdam 3015 GD
NL
dr molewaterplein 50
Rotterdam 3015 GD
NL
Listed location countries
Age
Inclusion criteria
The study population consists of adult patients with malignant mesothelioma who have been or have not been treated with chemotherapy. Patients treated with chemotherapy must not experience progressive disease during chemotherapy. In selected cases with low disease burden as determined by the multidisciplinary tumor board of Erasmus MC Rotterdam, patients can be included after diagnosis before any treatment.
Exclusion criteria
patients with mesothelioma progressive after chemotherapy
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 | EUCTR2014-000800-84-NL |
CCMO | NL44330.000.14 |