Primary objective:* To evaluate the safety of vaccination with XAGE1B peptides emulsified in Montanide ISA 51 co-mixed with the adjuvant Hiltonol® (Poly-ICLC) in patients with pulmonary adenocarcinoma.Secondary objective* To evaluate the capacity of…
ID
Source
Brief title
Condition
- Respiratory and mediastinal neoplasms malignant and unspecified
- Respiratory tract neoplasms
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Safety will be assessed during the whole study by collecting all adverse events
according to the CTC version 3 and by monitoring vital signs, blood chemistry
and hematological parameters.
Secondary outcome
Immunological assessments will be performed in all vaccinated patients using a
blood sample drawn at several time points (day 1, 22 and 43) and a skin biopsy
of the last vaccination site. Immunological responses will be monitored using
peripheral blood lymphocytes that are tested by IFN*-ELISPOT and intracellular
IFN*/IL-2 staining for directly ex-vivo detection and enumeration of
antigen-specific CD4+ and/or CD8+ T-cells, as well as following one round of in
vitro stimulation. In addition, proliferation (lymphocyte stimulation test:
LST) and associated cytokine production (IFN*, TNF*, IL-4, IL-5, IL-10, and
IL-2) will be assessed. Furthermore, biopsy samples of the last vaccination
site will be used to assess the migratory capacity of vaccine-induced T-cells.
Background summary
In the Netherlands, approximately 10000 new cases of lung cancer are diagnosed
each year. 80% of cases are comprised by non-small cell lung cancer (NSCLC).
The majority of patients present with advanced disease (stage III/IV).
Morbidity and mortality rates are high and survival rates are poor. The overall
5-year survival is 12-15%. Therefore, research efforts in the field of lung
cancer should focus on finding new treatment strategies.
Immunotherapeutic treatment of cancer, aimed at enhancing the anti-tumor
immunity, is a very promising new anti-cancer treatment. Progress in this field
has recently led to the FDA approval of a vaccine for the treatment of prostate
cancer (sipuleucel-T) as well as a therapeutic antibody for the treatment of
advanced melanoma (Ipilimumab). At the LUMC, we have extensive experience and
expertise in the field of immunotherapy in which we successfully use long
peptide based vaccines in patients. We have demonstrated clinical results in
patients with HPV-16 induced (pre)malignant lesions and showed a clear link
between the kinetics and phenotype of the immune response and complete
regression of lesions.
Identifying suitable target antigens is a prerequisite for immunotherapy of
cancer. XAGE1B is a relevant tumor antigen for lung adenocarcinoma (a subtype
accounting for 40% of NSCLC) as in these tumors it is highly expressed and able
to spontaneously induce humoral and cellular immune responses, at least in
Asian patients. We are currently conducting a preclinical study on the
expression and immunogenicity of XAGE1B in lung adenocarcinoma to confirm these
findings in a Dutch population. Our (yet unpublished) data confirm the reported
XAGE1b overexpression in pulmonary adenocarcinoma. Importantly, in these
patients we have found both humoral and cellular XAGE1b specific immune
responses systemically (peripheral blood) as well as locally (tumor draining
lymph node, tumor itself). These data will be published in a peer reviewed
journal in the near future.
Using this background knowledge on the spontaneous XAGE1B specific immunity in
pulmonary adenocarcinoma, we have designed a phase I clinical study in which a
new XAGE1B synthetic long peptide (SLP) vaccine combined with a TLR3-agonist
(polyICLC, Hiltonol®) will be investigated in adenocarcinoma patients who have
finished their standard therapy schedules.
Study objective
Primary objective:
* To evaluate the safety of vaccination with XAGE1B peptides emulsified in
Montanide ISA 51 co-mixed with the adjuvant Hiltonol® (Poly-ICLC) in patients
with pulmonary adenocarcinoma.
Secondary objective
* To evaluate the capacity of the vaccination strategy to induce
XAGE1B-specific humoral and cellular immune responses in lung adenocarcinoma
patients, including the migratory capacity of XAGE-1B vaccine-induced T-cells
into the vaccine injection site
Study design
Phase I interventional study
Intervention
Patients will be given a subcutaneous injection of a vaccine consisting of 5
overlapping peptides covering the entire XAGE1B protein emulsified in Montanide
ISA 51 co-mixed with the adjuvant Hiltonol® (Poly-ICLC). The first 2 groups of
5 patients (stage I&II and stage III&IV adenocarcinoma) will be vaccinated with
a peptide dose of 50 *g together with the adjuvant (dose 1 mg). The groups will
start simultaneously. In the next 2 groups of 5 patients (stage I&II and stage
III&IV adenocarcinoma), the dose of peptides will be simultaneously increased
to 150 *g together with the adjuvant (dose: 1 mg). The last 2 groups of 5
patients (stage I&II and stage III&IV adenocarcinoma) will be simultaneously
vaccinated with a peptide dose of 300 *g together with the adjuvant (dose: 1
mg).
Study burden and risks
During the trial, patients will visit the Department of Pulmonology of the
Leiden University Medical Center five times more compared to routine follow up
in a period of 12 weeks. During the visits, patients are 4 times vaccinated in
combination with Montanide and Hiltonol® , blood is drawn (total 250 ml) and a
skin biopsy from the second vaccination site is taken.
To our knowledge, this is the first in-man study in which a XAGE1b based SLP®
combined with Montanide and Hiltonol® vaccine is used in human subjects.
Therefore, no clinical data currently exist on vaccine-induced XAGE1b specific
immunity or on clinical efficacy of a XAGE1b vaccine. We expect that adverse
events in this trial mainly consist of swelling and redness of the vaccination
site, due to the vaccine induced immune response.
This expectation (described in detail in the Investigator's Brochure) is based
on:
- a preclinical toxicology study in which the referred to vaccine scheme was
tested in New Zealand rabbits. No mortality or systemic toxicity was observed.
However, local injection site reactions were observed.
- A recently published phase I trial in which a comparable peptide vaccine
(NY-ESO-1, like XAGE1B a member of the cancer-testis gene family) was combined
with Montanide and Hiltonol® . Again, no mortality or systemic toxicity was
observed. However, local injection site reactions were observed.
- our extensive experience with previous SLP (p53, HPV16) vaccines that were
used in several clinical trials, in which generally no adverse events > grade 2
were observed, mainly consisting of local injection site reactions or transient
fever after vaccination.
Albinusdreef 2
Leiden 2300 RC
NL
Albinusdreef 2
Leiden 2300 RC
NL
Listed location countries
Age
Inclusion criteria
For stage I&II pulmonary adenocarcinoma patients:
* Histologically proven pulmonary adenocarcinoma stage I or II according to recent guidelines on TNM classification of NSCLC
* Age * 18 years
* Completion of curative resection or SBRT and adjuvant chemotherapy or radiotherapy if necessary according to guidelines.
* Good WHO performance status (0-2)
* Adequate bone marrow function: WBC * 2.0 x 109/l, platelets > 100 x 109/l, hemoglobin > 5.0 mmol/L
* Survival expectation > 3 months
* Written informed consent according to the local Ethics Committee requirements;For stage III pulmonary adenocarcinoma patients:;* Histologically proven pulmonary adenocarcinoma stage IIIb according to recent guidelines on TNM classification of NSCLC.
* Age * 18 years
* Completion of standard chemo-radiotherapy
* No intention for further chemotherapy treatment
* Good WHO performance status (0-2)
* Adequate bone marrow function: WBC * 2.0 x 109/l, platelets > 100 x 109/l, hemoglobin > 5.0 mmol/L
* Survival expectation > 3 months
* Written informed consent according to the local Ethics Committee requirements;For stage IV pulmonary adenocarcinoma patients:
* Histologically proven pulmonary adenocarcinoma stage IV according to recent guidelines on TNM classification of NSCLC 1.
* Age * 18 years
* Completion of standard (platinum-based) chemotherapy schedules with no intention for further chemotherapy treatment
* Good WHO performance status (0-2)
* Adequate bone marrow function: WBC * 2.0 x 109/l, platelets > 100 x 109/l, hemoglobin > 5.0 mmol/L
* Survival expectation > 3 months
* Written informed consent according to the local Ethics Committee requirements
Exclusion criteria
* Progressive disease after finishing standard treatment
* Inadequate bone marrow function more than 3 weeks after last chemotherapy treatment.
* Poor WHO performance status (3-5)
* Eligibility for treatment with Tyrosine Kinase Inhibitors (e.g. erlotinib)
* History of an autoimmune disease or other systemic intercurrent disease that might affect the immunocompetence of the patient, or patients receiving immunosuppressive therapy including transplant recipients
* Second primary tumor of non-pulmonary origin
* CD4 cell count < 200/m3 at baseline
* Known seropositivity for Hepatitis B Virus and/or HIV
* History of serious liver or kidney dysfunction, heart condition or thyroid disorder
* Pregnancy or Lactating
* Known hypersensitivity reaction to any of the components used during treatment
* Medical or psychological condition which in the opinion of the treating chest physician and investigator would not permit the patient to participate in or to complete the study
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 | EUCTR2013-001254-95-NL |
| CCMO | NL44189.000.13 |