Clinical Trial Details
— Status: Active, not recruiting
Administrative data
NCT number |
NCT03665545 |
Other study ID # |
IMA950-106/CER 2018-00718 |
Secondary ID |
MK3475-480 |
Status |
Active, not recruiting |
Phase |
Phase 1/Phase 2
|
First received |
|
Last updated |
|
Start date |
October 25, 2018 |
Est. completion date |
December 31, 2023 |
Study information
Verified date |
December 2022 |
Source |
University Hospital, Geneva |
Contact |
n/a |
Is FDA regulated |
No |
Health authority |
|
Study type |
Interventional
|
Clinical Trial Summary
Monocentric randomized phase I/II trial, including 24 patients diagnosed with relapsing
glioblastoma (GBM) irrespective of MGMT and IDH gene status.
Following diagnosis of relapsing glioblastoma by either brain CT scan or MRI, patients will
be randomized in 2 arms:
1. Arm 1: IMA950 mixed with Poly-ICLC administered subcutaneously
2. Arm 2: Pembrolizumab 200mg q3w IV and IMA950 mixed with Poly-ICLC administered
subcutaneously
The first phase of treatment will last 6 weeks, then surgery will be performed (done if
clinically possible ad indicated). In case of available brain tissue, extensive analysis of
the tumor immune response will be performed. Assessment of systemic immune response by PBMC
immunomonitoring will be systematically done before and after surgery.
Description:
Brain tumors are the first cause of cancer mortality in children and the 3rd cause in young
adults. The most frequent brain tumors are gliomas and among them the most common type is
astrocytoma. The most malignant astrocytoma is Glioblastoma (GBM). Standard therapy of newly
diagnosed GBM patients includes surgery, irradiation and temozolomide (TMZ) chemotherapy with
1-year and 5-year survival rates at 30% and 3%, respectively. For the treatment of recurrent
GBM, TMZ is widely used even if the optimal dosing schedule and the minimal time interval
from first line are unknown. Other appropriate therapeutic options include Lomustine, an
alkylating drug, and Bevacizumab, an anti-angiogenic agent targeting VEGF-A, approved only in
selected countries (i.e. North America, Switzerland). Controlled trials are rare for
recurrent glioblastoma, consequently therapeutic decisions are mostly based on low-level
evidence.
Amongst innovative strategies, immunotherapy is considered as one of the most promising.
Immunotherapy stimulates the natural properties of the immune system to protect against
cancer growth. Therapeutic vaccines (active immunotherapy) are expected to elicit a cytotoxic
immune response to tumor-associated antigens, destroying malignant cells without harming
normal cells. The cells involved in this response are T lymphocytes, which can sense abnormal
peptides at the tumor cells surface. One critical step towards the development of therapeutic
vaccines was the identification and validation of glioma antigens. This is an obstacle the
investigators have circumvented with the characterization of several immunogenic glioma
peptides by screening the peptidome of ex vivo human glioma samples. This led to the
development of a multipeptide vaccine called IMA950.
IMA950 is composed of 9 synthetic tumor-associated HLA-A2-restricted peptides (TUMAPs), two
MHC class II-binding peptides and one HLA-A2-restricted HBV-derived peptide, the latter used
as marker of vaccine immunogenicity. The HLA-A2 allele is expressed by approximately 45% of
the Swiss population. As the interactions between peptides and their corresponding HLA
molecule are highly specific, only HLA-A*02 positive patients will be included in this trial.
The reasons why this set of peptides is very promising for vaccination are as follows:
1. Tumor peptides have been isolated from ex vivo samples:
2. They are over-expressed in glioma (compared to normal tissues)
3. They are derived from proteins involved in the malignant process
4. They are immunogenic in vitro in healthy donors and in glioma patients
5. This is a MULTI-peptide vaccine IMA950 was investigated in a monocentric phase I/II
trial for newly diagnosed glioblastoma and WHO grade III gliomas using poly-ICLC as
adjuvant (PI: P-Y. Dietrich, NCT01920191, study completed, final results in preparation
for publication). A total of 19 patients (16 with GBM and 3 with anaplastic astrocytoma)
were included, with a median number of 9 injections received per patient (range: 4-11).
The multipeptide vaccine did not show any serious safety issues, apart from some mild
inflammatory reactions at the injection site, peritumoral or resection cavity
edema/tumor flare manageable with steroids, as well as peri-vaccinational transient mild
headache, fatigue and flu-like syndrome (grade 3 events: 42.1%, grade 4 events: 21%, no
grade 5 events). Regarding vaccine immunogenicity, CD4 T-cell responses were detected in
the majority of patients (58%) and were usually sustained. The CD8 T-cell responses were
detected in 63% of patients, with 37% of them being multi-TUMAP responders. Median
overall survival from date of surgery was 21 months (range: 10 - 41 months) for the
overall cohort, with a 19 months survival for the GBM-only cohort (range: 10-41 months),
which compares favorably with the reported median survival of 15 months with the
reference treatment of temozolomide-based chemoradiation. PFS was 93% and 56% at 6 and 9
months respectively.
Despite the T cell ability to detect tumor peptides that are naturally presented by tumor
cells, these T cells do not normally become activated and do not protect the body against the
cancer, as tumor cells on their own are only poorly immunogenic. For effective T cell
activation, the help of co-stimulatory molecules, which are expressed on activated
professional APCs, e.g. dendritic cells, is required. During infections, the activation of
APCs is triggered by molecular patterns common to all pathogens of a class (e.g. RNA
viruses). These patterns, also referred to as "danger signals", are not provided by peptides
themselves. Consequently, artificial danger signals have to be provided with a tumor vaccine
to induce the required co-stimulation on APCs. In combination with a vaccine, such substances
with a non-specific immunostimulatory effect are called adjuvants. Poly-ICLC, (Hiltonol®,
Oncovir) is a synthetic double-stranded ribo-nucleic acid (dsRNA) mimicking viral pathogen
associated molecular patterns (PAMP) that activates multiple elements of innate and adaptive
immunity.
The importance of intact immune surveillance in controlling outgrowth of neoplastic cells has
been known for decades. The PD-1 receptor-ligand interaction is a major pathway hijacked by
tumors to suppress immune control. The normal function of PD-1, expressed on the cell surface
of activated T-cells under healthy conditions, is to down-regulate unwanted or excessive
immune responses, including autoimmune reactions. Binding of PD-1 ligands (PD-L1 and PD-L2)
to the PD-1 receptor inhibits T-cell activation triggered through the T-cell receptor.
Pembrolizumab (Keytruda™) is a potent and highly selective humanized monoclonal antibody
(mAb) designed to directly block the interaction between PD-1 and its ligands. Impressive
response rate and prolonged survival were first observed for metastatic melanoma, but the
clinical benefit of this mAb was recently shown to extend to several other cancer types.
There is a strong rationale to investigate the role of PD-1/PD-L1 blockade in malignant
glioma, since (i) we and others have previously reported that PD-L1 expression by glioma
cells may contribute to tumor-related immunoresistance; (ii) PD-L1 is also expressed by
tumor-infiltrating macrophages and circulating monocytes; (iii) expression of PD-L1 on
circulating monocytes was shown to correlate with worsened survival in patients who received
the HSPPC-96 vaccine for newly diagnosed and recurrent GBM. The 200 mg Q3W dose will maintain
individual patient exposures within the exposure range demonstrated to be well tolerated,
safe and established in melanoma as associated with maximal efficacy response. A fixed dose
regimen simplifies the dosing regimen so as to be more convenient for physicians and to
reduce the potential for dosing errors.
The combination of pembrolizumab with a vaccine therapy is currently being tested in several
trials for different tumors, such as melanoma, bladder, colorectal and prostate cancer
(NCT02574533, NCT02054520, NCT02432963, NCT02499835, NCT02515227). Here the investigators
postulate that Pembrolizumab may improve the immunogenicity of the IMA950 vaccine and the
function of vaccine-induced glioma-specific T cells, and that the multipeptide vaccine may
help to focus the immune response against antigens overexpressed by glioma, leading together
to an optimization of the antitumor immune effect whilst reducing the risk of collateral
damage to the brain.
The study aims to answer questions regarding safety (for the future clinical development of
this strategy), immunogenicity (synergy between multipeptide vaccine and pembrolizumab) and
clinical outcome. Ancillary translational research should help to identify possible
correlation between neo-epitopes, methylation status, immune response and clinical outcome.