The study "A MultIceNTER Phase I Peptide VaCcine Trial to Exploit NeoePitope-Specific T Cells
for the Treatment of H3K27M-Mutated Gliomas - (INTERCEPT H3)" is a non-controlled,
open-label, single arm, multicenter phase I trial involving patients with gliomas carrying an
H3.1K27M or H3.3K27M mutation.
The patient population will be molecularly defined and include adult patients with newly
diagnosed K27M-mutant histone-3.1 (H3.1K27M) or histone-3.3 (H3.3K27M) diffuse midline
gliomas (DMG).
Within this trial, a long peptide vaccine containing a K27M-mutated histone-3 sequence, will
be administered subcutaneously in addition to standard radiotherapy and thereafter in
combination with the human anti-PD-L1 antibody Atezolizumab.
Fifteen patients (pts. 1-15) will receive 11 doses of H3K27M peptide vaccine in total
starting with standard radiotherapy (RT) and 14 doses of the human anti-PD-L1 antibody
Atezolizumab (every three weeks, q3w) starting four weeks after completion of RT. The first 3
vaccines will be given bi-weekly (q2w) in combination with RT. One dose of vaccination will
be given at the beginning of recovery (RE) period following RT. Vaccines 5-11 (q6w) will be
initiated with Atezolizumab after completion of RE. In a safety lead-in, the first three
patients (pts. 1-3) will be enrolled sequentially.
Following the last IMP administration, a safety / immunogenicity follow-up is planned for 24
weeks until end of study (EOS). To be able to assess safety, tolerability and immunogenicity
of the peptide vaccine in combination with Atezolizumab 15 evaluable patients will be
enrolled.
Diffuse gliomas of the thalamus, brain stem, spinal cord or other midline structures
represent 3-4% of high-grade glioma and harbor H3.1K27M or H3.3K27M mutations as a
characteristic founder mutation in > 70% of cases. H3K27M-mutant gliomas typically occur in
children and adolescents but also in adult patients. After biopsy or resection, the standard
of care consists of involved-field radiotherapy. Adding alkylating chemotherapy to
radiotherapy does not offer additional benefit in retrospective case series and prospective
clinical trials in children with pontine gliomas, probably as hypermethylation of the MGMT
promoter in DMG is typically lacking. After radiotherapy gliomas frequently recur with a
median 12-month progression-free survival of 20 %. Importantly, at recurrence particularly in
the adult patient population, there is frequent distant progression and leptomeningeal
dissemination, arguing for the necessity of systemic therapy upfront.
From an immunological point of view H3K27M represents an attractive tumor antigen
specifically expressed in tumor but not normal cells. Patients with H3K27M-mutant gliomas may
harbor mutation-specific T cells, indicating that H3K27M is specifically presented to and
recognized by the immune system in a mutation-specific manner. Vaccination of humanized mice
with a long H3K27M vaccine results in an anti-tumor immune response effective in controlling
H3K27M-expressing tumors in a preventive and a therapeutic manner without causing toxicity.
In addition, eight adult patients with H3.3K27M-mutated gliomas were treated with an H3K27M
27 amino acid long peptide vaccine on a compassionate-use basis. None of the patients treated
either with the peptide vaccine alone or in combination with an anti-human PD(L)-1 antibody
showed any clinical or laboratory sign of treatment-related toxicity except for grade 1
injection site reactions. Importantly, all patients developed H3K27M-specific T cell
responses with one patient of the combination treatment group showing long-term response with
no sign of tumor progression for >24 months after vaccination and one patient experiencing
complete response after pseudoprogression (unpublished observations). Based on these
observations we hypothesize that checkpoint inhibition targeting PD-L1 is required for
optimal amplification of a vaccine-induced H3K27M-specific T cell response.
The aim of this phase I trial is to evaluate the safety and immune response to the H3K27M
peptide vaccine in combination with Atezolizumab in patients with H3K27M-mutant diffuse
midline gliomas.
Inclusion Criteria:
- Patients present with histologically confirmed diagnosis of an H3.1K27M or
H3.3K27M-mutated diffuse midline glioma WHO grade IV (with or without measurable
residual tumor after tumor resection or biopsy after primary diagnosis)
- Tumoral H3.1K27M or H3.3K27M mutation proven by immunohistochemistry or H3 DNA
sequencing
- No previous treatment except for surgery
- Estimated creatinine clearance ≥ 30 mL/min according to the Cockcroft-Gault formula
(or local institutional standard method)
- Availability of tumor tissue for translational analyses (FFPE bulk tissue or biopsy)
- Patients are scheduled to receive radiotherapy
- Patients should be immunocompetent (i.e. no concomitant treatment with dexamethasone
(or equivalent), or receive stable/decreasing steroid levels not exceeding 2 mg/day
dexamethasone (or equivalent) during the last 3 days prior to clinical screening; no
severe lymphopenia)
- minimum 18 years old, smoking or non-smoking, of any ethnic origin and sex
- Karnofsky Performance Status minimum 60. For patients with spinal gliomas,
paralysis-caused mobility impairments will not be considered
- Ability of patient to understand character and individual consequences of the clinical
trial
- Evidence of informed consent document personally signed and dated by the patient (or a
witness in case the patient is unable to write) covering all trial-related procedures
and indicating that the patient has been informed of all pertinent aspects of the
study and that the patient consents to participate in the trial.
- Non-nursing and non-pregnant women: Women of child-bearing potential (WOCBP) must have
a negative urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of
HCG) prior to the start of the investigational medicinal product (IMP). A woman is
considered of childbearing potential, i.e. fertile, following menarche and until
becoming post-menopausal unless permanently sterile. Permanent sterilization methods
include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A
postmenopausal state is defined as no menses for 12 months without an alternative
medical cause. In case of possible postmenopausal status or doubtful childbearing
potential, assessment of serum FSH (follicle-stimulating hormone) level will be
performed once at baseline visit to confirm postmenopausal status. In this case, urine
pregnancy tests during the trial as well as contraception are not necessary. However,
in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.
- WOCBP must be using a highly effective method of birth control (failure rate of less
than 1% per year) to avoid pregnancy throughout the study and at least 5 months after
the last dose of the IMP. Such methods include:
- combined (estrogen and progestogen containing) hormonal contraception associated
with inhibition of ovulation: oral intravaginal transdermal
- progestogen-only hormonal contraception associated with inhibition of ovulation:
oral injectable implantable
- intrauterine device (IUD)
- intrauterine hormone-releasing system (IUS)
- bilateral tubal occlusion
- vasectomised partner
- sexual abstinence
- Fertile men must be willing and able to use an effective method of birth control
(condom) throughout the study for up to at least 5 months after the last dose of the
IMP, if their sexual partners are WOCBP, using an effective method as well (acceptable
methods see above). A man is considered fertile after puberty unless permanently
sterile by bilateral orchidectomy.
- Patients who are willing and able to comply with scheduled visits, treatment plan,
laboratory tests, and other study procedures
Exclusion Criteria:
- Current use of immunosuppressive medication including treatment with systemic
immunomodulatory agents at least 4 weeks or five half-lives of the drug, prior to
starting study treatment, EXCEPT for the following: a. intranasal, inhaled, topical
steroids, or local steroid injection (e.g., intra-articular injection); b. Systemic
corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or equivalent; c.
Steroids as premedication for hypersensitivity reactions (e.g., CT scan
premedication).
- Previous or concurrent standard or experimental treatment for the tumor other than
resection. This includes local therapies such as interstitial radiotherapy or local
chemotherapy (i.e. BCNU wafers), loco-regional hyperthermia, electric fields, and
antiangiogenic therapy (such as Bevacizumab).
- Abnormal (≥ Grade 2 CTCAE v5.0) laboratory values for thyroid gland: free T4 and TSH
- Abnormal (≥ Grade 2 CTCAE v5.0) laboratory values for hematology, liver and renal
function (serum creatinine). In detail, the following values apply as exclusion
criteria:
1. Hemoglobin < 9 g/dL (5.59 mmol/L)
2. White blood cell count (WBC) decrease (<3.0 x 109/L) or increase (> 10.0 x 109/L)
3. Absolute neutrophil count (ANC) decrease (< 1.5 x 109/L)
4. Platelet count decrease (< 100 x 109/L)
5. Bilirubin > 1.5 x ULN (upper limit of normal according to the performing lab´s
reference range)
6. ALT > 2.5 x ULN
7. AST > 2.5 x ULN
8. GGT > 2.5 x ULN
9. Serum creatinine increase (> 1.5 x ULN)
- Patients with history or presence of HIV and/or HBV/HCV positivity (testing performed
according to local standards)
- Patients with history or known presence of tuberculosis (positive QuantiFERON®-TB Gold
test or tuberculin skin test). Patients with an indeterminate result of the
QuantiFERON®-TB Gold test are not eligible unless additional testing demonstrates a
negative result (tuberculin skin test or repeated QuantiFERON®-TB Gold test). If a
tuberculin skin test is performed, an induration of > 6 mm is "positive" for a patient
with history of BCG vaccine, while an induration of > 10 mm is "positive" for a
patient without history of BCG vaccine. If necessary, a QuantiFERON®-TB Gold test
might be complemented by additional specific diagnostic tests as per standard
procedures.
- Patients with severe infection(s) or signs/symptoms of infection within 2 weeks prior
to start of treatment including radiotherapy and IMP
- Active infection requiring systemic therapy
- Patients who have received a live, attenuated vaccine within 4 weeks prior to start of
treatment including radiotherapy and IMP
- Patients with a prior solid organ transplantation or hematopoietic stem cell
transplantation
- Active autoimmune disease including history of severe autoimmune disease that might
deteriorate when receiving an immuno-stimulatory agent. Patients with diabetes type I,
vitiligo, psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressive
treatment are eligible
- Clinically significant (i.e. active) cardiovascular disease: Cerebral vascular
accident/stroke (< 6 months prior to enrolment), myocardial infarction (< 6 months
prior to enrolment), unstable angina, congestive heart failure (≥ New York Heart
Association Classification Class II), or serious cardiac arrhythmia requiring
medication
- History of other malignancies (except for adequately treated basal or squamous cell
carcinoma or carcinoma in situ) within the last 5 years unless the patient has been
diseasefree for 5 years.
- Other severe acute or chronic medical conditions including colitis, inflammatory bowel
disease, pneumonitis, pulmonary fibrosis or psychiatric conditions including recent
(within the past year) or active suicidal ideation or behavior; or laboratory
abnormalities that may increase the risk associated with study participation or study
treatment administration or may interfere with the interpretation of study results
and, in the judgment of the investigator, would make the patient inappropriate for
entry into this study
- History of hypersensitivity to the investigational medicinal product or to any drug
with similar chemical structure or to any excipient present in the pharmaceutical form
of the investigational medicinal product, including known severe hypersensitivity
reactions to monoclonal antibodies (NCI CTCAE v5.0 Grade ≥ 3)
- Participation in other clinical trials or their observation period during the last 30
days before start of treatment including radiotherapy and IMP
No patient will be allowed to enroll in this trial more than once.
