Primary objective of this study is to assess the safety and tolerability, feasibility and biological activity (immunogenicity) of the actively personalized vaccination (APVAC) concept in newly diagnosed glioblastoma (GB) patients.Secondary study…
ID
Source
Brief title
Condition
- Nervous system neoplasms malignant and unspecified NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Safety: Descriptive summary of the safety and tolerability profile of
patient-tailored APVAC vaccines when administered with immunomodulators
concurrent to maintenance TMZ cycles.
Feasibility: Descriptive analysis of duration and success rates for APVAC1 and
APVAC2 processes and for vaccinations with APVAC drug products.
Biological activity: Descriptive analysis of induced T-cell responses after
vaccinations with APVAC1 and APVAC2 drug products plus poly-ICLC and GM CSF.
Reporting will at least include for APVAC1 and APVAC2 vaccines separately and
combined:
* Immunogenicity rate: Number of vaccine induced T-cell responses normalized to
the number of peptides vaccinated.
* Immune responder rate: Number of patients with at least one vaccine induced
T-cell response
* Multi-TUMAP responder rate: Number of patients with at least two vaccine
induced T-cell response
* Average number of immune responses per patient
Secondary outcome
Descriptive analysis of biomarkers that are associated with clinical outcome or
biological activity of the vaccine. Analyzed biomarkers may include:
* non-cellular parameters measured from tumor, plasma or serum samples (e.g.
TGF-beta concentrations)
* cellular parameters (e.g. regulatory T cells) measured from PBMCs,
leukapheresis samples or isolated tumor-infiltrating lymphocytes (TILs)
* any other physiological or demographic parameters (e.g. age)
Reporting may also include association analysis of identified biomarkers with
clinical outcome (e.g. OS or PFS) or with parameters for biological activity
(e.g. number of immune responses).
Descriptive analysis of clinical outcome of patients including OS (from
surgery) and PFS (from baseline MRI). Association analysis of these parameters
with immune response data may provide first hints on clinical activity of the
vaccine.
Background summary
GB is the most aggressive form and, also, the most prevalent form of glioma
with a very poor prognosis. Once diagnosed, the 1-year, 2-year, and 5-year
survival rates are only 33.7%, 11.9%, and 4.5% (exemplary data from the US),
respectively. With the current standard of care, i.e. tumor resection followed
by CRT with TMZ and thereafter maintenance TMZ, a median OS of 14.6 months has
been reported and not relevantly improved since then. Despite the relatively
low incidence of GB compared to other cancers, these data reflect the high
medical need for new and efficient therapies in this indication.
The combined use of APVAC1 and APVAC2 vaccines together with poly-ICLC is
expected to induce multiple tumor-directed CD8+ and CD4+ T-cell responses that
lead to the killing of tumor cells. As the vaccinated peptides will be selected
based on their tumor association and immunogenicity in the individual patient
(APVAC1 Drug Product) or as they even target patient-specific tumor mutations
(APVAC2 Drug Product), the induced immune responses may have a high potential
to be effective against the tumor. The destruction of tumor cells may result in
disease stabilization or protection from recurrence and eventually may lead to
prolonged survival and direct clinical benefit.
Study objective
Primary objective of this study is to assess the safety and tolerability,
feasibility and biological activity (immunogenicity) of the actively
personalized vaccination (APVAC) concept in newly diagnosed glioblastoma (GB)
patients.
Secondary study objectives include:
Identification of biomarkers putatively predictive for immunological response
and/or associated with clinical success or failure. Analyzed biomarkers may
include non-cellular parameters measured from tumor, plasma or serum, and
cellular parameters measured from peripheral blood mononuclear cells (PBMCs),
leukapheresis samples or isolated tumor-infiltrating lymphocytes (TILs).
Description of potential clinical activity of the APVAC drug products.
Descriptive analysis of clinical outcome in patients will be reported including
OS and PFS. Correlation analysis of these parameters with immune response data
may provide first hints on clinical activity of the vaccine.
Study design
This is a multi-center, multi-national, open-label, Phase I trial to
investigate actively personalized peptide vaccinations plus immunomodulators in
patients with newly diagnosed glioblastoma concurrent to first-line
temozolomide maintenance therapy.
Intervention
Administration of vaccination
At the first 6 vaccinations with APVAC1 and again at the first 6 vaccinations
with APVAC2 GM-CSF (300 µL, 75 µg) is injected into the skin (intradermal i.d.)
of the abdomen or thigh of a patient. 10-30 minutes after application of GM CSF
APVAC vaccinations and poly ICLC (Hiltonol®) injection follow. At remaining
vaccinations only APVAC and poly-ICLC (Hiltonol®) will be administered. Each
vaccination with APVAC vaccines consist of an intradermal (i.d.) injection of
the personalized APVAC drug product (500 µL; approx. 400 µg per peptide) in
very close proximity to the application of GM-CSF. APVAC injection is followed
by subcutaneous (s.c.) injection of 1.5 mg poly-ICLC (Hiltonol®) in close
proximity to the vaccination site with the exception of Visits V2 and V2* where
poly-ICLC is not co-applied with the vaccines.
Vaccination schedule
APVAC1 vaccine applications: Patients will be repeatedly vaccinated with APVAC1
vaccines usually beginning on day 15(±3) of the first maintenance TMZ cycle.
Patients will receive eleven APVAC1 vaccination on Days 1, 2, 4, 8, 15, 22, 36,
64, 92, 120 and 148 (defining the day of first APVAC1 vaccination as *Day 1*
and *Visit V1*). If the APVAC1 drug product is not ready-for-use in time, the
first vaccination can be shifted to day 15(±3) of the second maintenance TMZ
cycle.
APVAC2 vaccine applications: Patients will be repeatedly vaccinated with APVAC2
vaccines usually beginning on day 15(±3) of the fourth maintenance TMZ cycle.
Patients will receive eight APVAC2 vaccinations on Days 1*, 2*, 4*, 8*, 15*,
22*, 36*, and 64* (defining the day of first APVAC2 vaccination as *Day 1** and
*Visit V1**). If the APVAC2 drug product is not ready-for-use in time, the
first vaccination can be shifted to day 15(±3) of the fifth maintenance TMZ
cycle.
Poly-ICLC: The immunomodulator poly-ICLC (1.5 mg) will be applied s.c. with
every APVAC1 and 2 vaccination, except on Visits V2 and V2* (to avoid dose
accumulation on the two consecutive days). A total of up to 14 doses of
poly-ICLC will be applied. If APVAC1 and APVAC2 vaccines are applied at the
same day only one dose of poly-ICLC is given and both vaccines are given i.d.
in close proximity around the poly-ICLC injection site.
GM-CSF: The second immunomodulator GM-CSF (75 µg) will be applied i.d. with the
first six vaccinations with both, APVAC1 and APVAC2. A total of 12 GM-CSF doses
will be applied. GM-CSF will be applied in close proximity to the APVAC
vaccination site 10-30 min before vaccination with the APVACs.
Study burden and risks
An individual patient*s time on study from screening to his/her LEEV Visit will
be approx. 10 months consisting of
* approx. 4 weeks during screening and sample collection before enrollment - 2
visits (S1 resp. S1b + S2)
* approx. 12 weeks during the pre-vaccination phase - 2 visits (VA + VB)
* approx. 26 weeks during the vaccination phase until the LEEV Visit - 16
visits + 1 LEEV Visit
* approx. 15 - 38 months during the follow-up period for overall survival
assessment until EOT - one visit every 4 weeks only if patient receives
optional continuation of vaccinations during FU period.
The study-related burden an individual patient is going to be exposed to during
participation in the GAPVAC-101 clinical trial is summarized as follows
(without the participation in the optional continuation of vaccination):
* 21 visits at the hospital
* 13 blood samplings with a total volume of 743mL being withdrawn
* 2 leukaphereses
* 11 urine tests
* 2 assessments of medical history
* 9 assessments of Karnofsky-Performance-Status
* 9 examinations of vital signs
* 3 electrocardiograms
* 9 physical/neurological examinations
* No extra MRIs pertaining to the study will be performed. MRIs from routine
clinical practice (standard of care) will be used. Only in exceptional cases
where no adequate MRI is available (e.g. outside the required time window) a
separate (study-related) MRI will be performed.
* Application of IMPs consists of 11 intradermal APVAC1 injections, 8
intradermal APVAC2 injections, 12 intradermal Leukine injections and 14
subcutaneous Hiltonol injections.
Side effects associated with these interventions are:
APVAC injections:
Likely side effects: Injection site reactions incl. erythema, edema, pruritus,
irritation, pain, hypersensitivity and induration.
Rare but serious side effects seen with peptide vaccines (plus GM CSF):
Allergic reactions or anaphylaxis, autoimmune reactions. Brain edema may
occasionally be induced or intensified by vaccinations (especially if given
with poly-ICLC). In rare cases it may be possible to anticipate additional
risks for side effects from the individual APVAC vaccine formulation.
Leukine® injections:
Likely side effects: Bone pain, fatigue, muscle aches, stomach upset, diarrhea,
fever, skin irritation.
Patients receiving low doses of Leukine® into the skin may experience unwanted
side effects which are largely overlapping with side effects anticipated for
the APVAC vaccines itself. These side effects usually include injection site
reactions and occasionally systemic symptoms and are mild to moderate but not
serious.
Rare but serious side effects: Allergic reactions or anaphylaxis. A syndrome
characterized by respiratory distress, hypoxia, flushing, hypotension, syncope,
and/or tachycardia has been reported with the first administration of GM CSF in
a particular cycle. Signs resolved with symptomatic treatment and usually do
not recur. with subsequent doses in the same cycle of treatment
Hiltonol® injections:
Likely side effects: Injection-site reactions (subcutaneous application
sometimes results in moderate skin reactions), fever, flu-like symptoms,
fatigue, nausea, vomiting, musculoskeletal events (myalgia, arthralgias,
malaise), transient hematological events (drop in white or red blood cells or
blood platelets).
Blood withdrawal, infusion of fluid into veins, subcutaneous or intradermal
applications: Pain, bruising.
Side effects associated with apheresis procedure:
Likely side effects: Bruising/swelling around the needle site, fainting,
dizziness, nausea, mild chills, a tangling sensation on the face or body, or
lightheadedness.
The insertion of intravenous needles and the duration of the process (2-3h) are
the only uncomfortable parts of the apheresis process.
Rare but serious side effects: air entry in the blood stream, stroke,
myocardial infarction, infection, shock, irregular heartbeat or heart failure.
Further information on possible risks associated with study-related
interventions is given in section 6 of the informed Consent Forms *What side
effects or risks can I expect from being in this study?*.
A tabulated overview of all study-related interventions is provided on page 16
and 17 of the study protocol (table *Schedule of Events*).
Possible benefits:
A main goal of this study is to test the safety of the APVAC vaccines and the
reliability of the complicated analysis and manufacturing processes of the
vaccines that will be individually produced for each patient. Another main goal
is to test whether the vaccines are able to activate the immune system against
the tumour. Patients might get personal medical benefit from taking part in
this study, but this is not certain because there is not much information about
the vaccine*s effect on the individual patient*s cancer. The potential benefits
could include prolonged time until tumour recurrence or progression. It is not
known if a patient will benefit from taking part in this study, although the
knowledge gained from this study may help others in the future who have a
similar cancer.
Risk-benefit evaluation:
Based on available non-clinical and clinical data from similar vaccines and
taking into account the poor prognosis for glioblastoma patients and the
potential benefits of the personalized APVAC immunotherapy the anticipated
limited risks of this approach are considered justified. Moreover, measures for
mitigation of the identified main risks have been implemented in the study
protocol.
Paul-Ehrlich-Str. 15
Tübingen 72076
DE
Paul-Ehrlich-Str. 15
Tübingen 72076
DE
Listed location countries
Age
Inclusion criteria
1. Histologically confirmed, newly diagnosed GB (astrocytoma WHO grade IV)
2. HLA phenotype defined by warehouse composition (HLA-A*02:01 or HLA-A*24:02 positive patients only)
3. Gross total resection (as defined by less than 1 cm² residual tumor mass on the largest perpendicular axes in post-operative scan taken within 48 h post-surgery; standard MRI conformable to the present national and international guidelines is sufficient)
4. At least 0.5 g tumor tissue freshly cryopreserved during surgery (equivalent to at least 3 pea-sized tumor pieces). Note: a higher amount of collected tumor tissue is desirable and may increase the quality of the APVAC vaccine
5. Age: *18 years
6. KPS *70%
7. Life expectancy > 6 months
8. Patients is a candidate for and willing to receive standard CRT with TMZ followed by maintenance TMZ chemotherapy cycles
9. Patients not on steroids or on stable or decreasing steroid levels not exceeding 2 mg/day dexamethasone (or equivalent doses of other steroids) during the last 3 days prior to enrollment
10. ALC > 1.0 x 109/L (re-screening of lymphocyte counts is allowed)
11. Ability of subject to understand and the willingness to sign written informed consent for study participation. Written consent by a legally authorized representative is not sufficient.
12. Availability of an APVAC analysis and manufacturing slot confirmed by the sponsor
13. Female patients who are post-menopausal (no menstrual period for a minimum of 1 year), or surgically sterile (bilateral tubal ligation, bilateral oophorectomy, or hysterectomy), or practice a highly effective method of birth control, i.e. resulting in a failure rate of less than 1% per year when used consistently and correctly such as implants, injectables, combined oral contraceptives, some IUDs, sexual abstinence or vasectomized partner (ref. to ICH M3).
14. Male patients willing to use contraception (condoms with spermicidal jellies or cream) upon study entry and during the course of the study, have undergone vasectomy or are practicing total abstinence.
Exclusion criteria
1. Abnormal (* Grade 2 CTCAE v4.0) laboratory values for hematology (Hb, WBC, neutrophils, and platelets), liver (serum bilirubin, ALAT, ASAT, and GGT) and renal function (serum creatinine).
2. HIV infection or active Hepatitis B or C infection, or active infections requiring oral or intravenous antibiotics or that can cause a severe disease and pose a severe danger to lab personnel working on patients* blood or tissue (e.g. rabies).
3. Prior therapy for glioma (except surgery and steroids) including but not limited to carmustine wafers and immunotherapy. Note: History of low grade glioma that did not require prior treatment with chemotherapy or radiotherapy is not an exclusion criterion.
4. Any condition contraindicating leukapheresis from peripheral veins.
5. Concurrent participation in another interventional clinical trial studying a drug or treatment regimen.
6. Clinically relevant autoimmune diseases (with the exception of thyroid diseases).
7. Patients with known hypersensitivity/allergy to any component of the APVAC vaccines, GM-CSF or poly-ICLC (e.g. carboxymethylcellulose).
8. Immunosuppression, not related to prior treatment for malignancy.
9. Patients with prior stem cell transplantation or solid organ transplantation.
10. Any condition that in the judgment of the investigator interferes with the probability that an individual patient may receive and benefit from APVAC vaccinations (e.g. high risk of early disease progression / recurrence; immunocompromised status; anticipated compliance problems).
11. Serious illness or condition, which according to the investigator poses an undue risk for the patient when participating in the trial.
12. History of other malignancies (except for adequately treated basal or squamous cell carcinoma or carcinoma in situ) within the last 5 years.
13. Pregnancy or breastfeeding.
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 | EUCTR2013-002801-71-NL |
| ClinicalTrials.gov | NCT02149225 |
| CCMO | NL51127.000.14 |