We expect to finalize the current phase I study by the May 2008 demonstrating that injection of tumor lysate-pulsed autologous DCs injected in patients with MM after chemotherapy is safe and well tolerated with induction of immune responses. New…
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Source
Brief title
Condition
- Pleural disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To define the safety and toxicity of tumor lysate-pulsed dendritic cells (DCs)
combined with a low dose cyclophosphamide in patients with malignant pleural
mesothelioma
Secondary outcome
To determine if vaccination with DCs results in a detectable immune response
To determine if low-dose cyclophosphamide leads to a decrease in regulatory T
cells in the blood of patients
To observe and document anti-cancer activity by clinical evaluation (CT-scan)
Background summary
Cancer immunotherapy attempts to harness the exquisite power and specificity of
the immune system to recognize and destroy tumor cells or to prevent tumor
recurrence. The fact that some patients with malignant pleural mesothelioma
(MM) have tumors that regress spontaneously or respond to immunotherapy
suggests that the immune system can generate anti-tumor reactivity under some
circumstances. One such cancer immunotherapy approach uses the patients* own
dendritic cells (DCs) to present tumor-associated antigens and thereby generate
tumor-specific immunity. DCs are extremely potent antigen presenting cells
specialized for inducing activation and proliferation of lymphocytes essential
for tumor killing. If the DCs can be made to attack mesothelioma cells, it
would mean a non-toxic treatment (unlike chemo- and radiotherapy) with minor
side-effects, and long-lasting immunological memory (similar to vaccines
providing long-term protection against viruses). Several studies in other
cancers in humans, e.g. renal cell carcinoma, melanoma, glioma and lung cancer,
have shown that DC-based immunotherapy can induce tumor-specific cytotoxic T
lymphocyte (CTL) responses that lead to shrinkage of the tumor and sometimes
prolonged survival. However, tumors frequently interfere with the development
and function of immune responses and can actively down-regulate anti-tumor
immunity. With increasing knowledge of the basic aspects of tumor immunology,
immunotherapy might hold the key to the clinical realization of effective
therapeutic treatment for mesothelioma.
The results from the phase I study (MEC-2005-269) showed that injection of DCs
was overall well tolerated without systemic toxicity, with the exception of a
low-grade flu-like symptoms: fever, rigors (chills), and a temporarily local
skin reaction after DC injection (mild grade 1 or 2) (appendix 1). Local
accumulation of CD4+ and CD8+ T cells were found at the vaccination sites. Body
temperature was increased in 5 patients but did not exceed 39*C mainly after
the second and third vaccination. All participants thus far experienced no rash
or lymphadenopathy or developed any clinical evidence of autoimmunity or
rheumatoid disease. DTH and strong antibody immune responses (IgM and IgG) on
KLH were seen in all patients indicating that immune responses were generated.
CT scans and X-rays from a few patients revealed small to substantial
regressions of the tumor during the DC treatment.
Study objective
We expect to finalize the current phase I study by the May 2008 demonstrating
that injection of tumor lysate-pulsed autologous DCs injected in patients with
MM after chemotherapy is safe and well tolerated with induction of immune
responses. New insights have anticipated that better effects may be achieved by
perfecting the strategy by depleting regulatory T cells (Tregs) using low-dose
cyclophosphamide in order to improve the anti-tumor immune responses elicited
by DC vaccines (preliminary studies im mice from our group have demonstrated
this). In the here proposed phase I clinical trial, ten patients will be
treated with DC vaccination plus cyclophosphamide after chemotherapy (appendix
3).
Study design
Ten patients are receive DC vaccination in conjunction with low-dose
cyclophosphamide. Cyclophosphamide (Endoxan) will be taken orally the week
proceeding (week 22), the weeks in between (week 24, 26), and one week after
(week 28) the DC vaccinations. The dose is 100 mg (two [2] tablets)/day. The
patient will take medication 2 hours after breakfast. The subject will be asked
to increase their fluid intake by extra drinking water or other non-caffeinated
beverage throughout the day. This dose is well tolerated without toxicity.
We want to emphasize that no changes will be made in preparing and loading of
dendritic cells, dosing, timing, and schedule (or other variables) compared to
the phase I study.
Intervention
Ten patients will be treated with DC immunotherapy (3 times with 2-weekly
interval). In de time inbetween an oral administration of one tablet of
cyclophosphamide is taken with a large amount of water (4 x 7 days, 1 tablet
daily).
Study burden and risks
All extra examinations for patients are performed by qualified personnel and
according to appropriate rules.
MEC-2005-269 has shown that the risks associated with the injection of
dendritic cells is minimal (appendix 1). The results from this study showed
that injection of dendritic cells was overall well tolerated without systemic
toxicity, with the exception of a low-grade flu-like symptoms: fever, rigors
(chills), and a temporarily local skin reaction after DC injection (mild grade
1 or 2). Local accumulation of CD4+ and CD8+ T cells were found at the
vaccination sites. Body temperature was increased in 5 patients but did not
exceed 39*C mainly after the second and third vaccination. All participants
thus far experienced no rash or lymphadenopathy or developed any clinical
evidence of autoimmunity or rheumatoid disease. DTH and strong antibody immune
responses (IgM and IgG) on a model antigen (KLH) were seen in all patients
indicating that immune responses were generated.
However during the whole procedure, several punctures are necessary and are
considered as (average) painful. First, the apheresis method is based on blood
being drawn from one vein and returned to another vein continuously, normally
using a vein in both arms, whilst the blood is processed with a view to
monocyte extraction, in the machine. The collection of cells, takes 3 to 4
hours, having to keep the elbow stretched and immobilized for so long can be
quite uncomfortable and sometimes even painful for the patient or donor.
However, this procedure takes place under strict guidance of the department of
Hematology (years of experience). Second, a skin test is performed in which
small volumes (max. 50 ul) of cells or antigens are injected in the skin of the
lower arm to induce a delayed type hypersensitivity test. Furthermore,
venapunctures are performed bi-weekly to determine the side-effects and
efficacy of dendritic cell immunotherapy in patients.
The adaptation in this amendment compared to MEC-2005-269 is the oral intake of
cyclophosphamide in the weeks in between dendritic cell vaccination.
Dr. Molewaterplein 50
3015 GE Rotterdam
NL
Dr. Molewaterplein 50
3015 GE Rotterdam
NL
Listed location countries
Age
Inclusion criteria
As for our earlier study (MEC-2005-269):;Patients with clinically and histological or cytological confirmed newly diagnosed mesothelioma, that can be measured in two dimensions by a radiologic imaging study.
Patients must be at least 18 years old and must be able to give written informed consent.
Patients must be ambulatory (Karnofsky scale > 70, or WHO-ECOG performance status 0,1, or 2) and in stable medical condition. The expected survival must be at least 4 months.
Patients must have normal organ function and adequate bone marrow reserve: absolute neutrophil count > 1.5*109/l, platelet count > 100*109/l, and Hb > 6.0 mmol/l.
Positive delayed type hypersensitivity skin test (induration > 2mm after 48hrs) against at least one positive control antigen of MULTITEST CMI (Pasteur merieux).
Stable disease or response after chemotherapy.
Availability of sufficient tumor material of the patient.
Ability to return to the Erasmus MC for adequate follow-up as required by this protocol. ;New for this study (in comparison to MEC-2005-269) are:
Able to tolerate oral therapy
No impairment of gastrointestinal (GI) function or GI disease that may affect or alter absorption of cyclophosphamide (e.g., mal-absorption syndrome, history of total gastrectomy/significant small bowel resection)
No history of allergic reactions (>= grade 3 or 4) to compounds of similar chemical or biologic composition to cyclophosphamide (i.e., alkylating agents)
No known intolerance or hypersensitivity reaction to cyclophosphamide
Exclusion criteria
As for our earlier study (MEC-2005-269):;Conditions that make the patient unfit for chemotherapy or progressive disease after 4 cycles of chemotherapy.
Pleurodesis at the affected side before the pleural fluid is obtained.
Medical or psychological impediment to probable compliance with the protocol.
Patients on steroid (or other immunosuppressive agents) are excluded on the basis of potential immune suppression. Patients must have had 6 weeks of discontinuation and must stop of any such treatment during the time of the study.
No prior malignancy is allowed except for adequately treated basal cell or squamous cell skin cancer, superficial or in-situ cancer of the bladder or other cancer for which the patient has been disease-free for five years.
Serious concomitant disease, no active infections. Patients with a history of autoimmune disease or organ allografts, or with active acute or chronic infection, including HIV and viral hepatitis.
Patients with serious intercurrent chronic or acute illness such as pulmonary (asthma or COPD) or cardiac (NYHA class III or IV) or hepatic disease or other illness considered by the study coordinators to constitute an unwarranted high risk for investigational DC treatment.
Patients with a known allergy to shell fish (contains KLH).
Pregnant or lactating women.
Patients with inadequate peripheral vein access to perform leukapheresis
Concomitant participation in another clinical trial
An organic brain syndrome or other significant psychiatric abnormality which would comprise the ability to give informed consent, and preclude participation in the full protocol and follow-up.
Absence of assurance of compliance with the protocol. Lack of availability for follow-up assessment. ;No additiona exclusion criteria in comparison to MEC-2005-269
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
In other registers
| Register | ID |
|---|---|
| Other | 00280982 |
| EudraCT | EUCTR2008-000957-36-NL |
| CCMO | NL24050.000.08 |
| OMON | NL-OMON24867 |