A MultIceNTER Phase I Peptide VaCcine Trial for the Treatment of H3-Mutated Gliomas (INTERCEPT-H3)
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|ClinicalTrials.gov Identifier: NCT04808245
Recruitment Status : Recruiting
First Posted : March 22, 2021
Last Update Posted : March 29, 2023
|Condition or disease
|Newly Diagnosed H3-mutated Glioma
|Drug: Tecentriq 1200 MG in 20 ML Injection Biological: H3K27M peptide vaccine Other: Imiquimod (5%)
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.
|Study Type :
|Interventional (Clinical Trial)
|Estimated Enrollment :
|Single Group Assignment
|None (Open Label)
|A MultIceNTER Phase I Peptide VaCcine Trial to Exploit NeoePitope-Specific T Cells for the Treatment of H3-Mutated Gliomas - (INTERCEPT-H3)
|Actual Study Start Date :
|February 15, 2023
|Estimated Primary Completion Date :
|Estimated Study Completion Date :
Experimental: Standard patient cohort
All fifteen patients will receive in total 11 doses of H3K27M peptide vaccine starting with standard radiotherapy (RT) and 14 doses of the human anti-PD-L1 antibody Atezolizumab/ Tecentriq® (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. The H3K27M peptide vaccine is administered in combination with topical Imiquimod that serves as an adjuvant.
For safety reasons, the first three patients will be enrolled sequentially: Each patient will receive the first vaccination at the earliest 28 days after the previous patient has received the first vaccination.
Drug: Tecentriq 1200 MG in 20 ML Injection
One vial of Tecentriq® (1200 mg) will be administered as an intravenous (i.v.) infusion over 60 minutes every 3 weeks starting 4 weeks after radiotherapy. If the first infusion is tolerated, all subsequent infusions will be delivered over 30 minutes.
Other Name: Atezolizumab
Biological: H3K27M peptide vaccine
The H3K27M peptide vaccine is injected subcutaneously (s.c.). For a single vaccination 300 μg of the peptide will be emulsified in a total volume of 1 ml.
Other: Imiquimod (5%)
One sachet of Aldara® cream (250 mg) will be applied to an area of 5 x 5 cm around the injection site of the H3K27M peptide vaccine 15 min after vaccination and left on the skin for approximately 8 hours according to the instructions in the SmPC. 24 hours after the vaccination a second sachet of Aldara® will be applied by the patient as instructed above and left on the skin for approximately 8 hours.
Other Name: Aldara
- Assessment of safety of repeated fixed dose vaccinations with the H3K27M peptide vaccine administered with radiotherapy and Atezolizumab in patients with H3K27M-mutant gliomas. Primary safety endpoint is the Regime Limiting Toxicity (RLT). [ Time Frame: Through study completion, an average of one year ]Safety of H3K27M peptide vaccine administered with radiotherapy and Atezolizumab. Primary safety endpoint is the Regime Limiting Toxicity (RLT).
- Assessment of immunogenicity of repeated fixed dose vaccinations with the H3K27M peptide vaccine administered with radiotherapy and Atezolizumab in patients with H3K27M-mutant gliomas. [ Time Frame: From Day 1 until the date of study termination (until day 540); approximately 16 times ]Immunogenicity (Immune response Yes/No) will be assessed for all evaluable patients. The primary immunogenicity endpoint is the presence of an H3K27M-specific T-cell response. H3K27M-specific T cell responses are measured on Peripheral Blood Mononuclear Cells (PBMC) using IFN-gamma ELISpot.
- Progression-free survival (PFS) [ Time Frame: From day of first diagnosis until the date of first documented progression or date of death from any cause, whichever came first, assessed up to the date of study termination (approximately until day 540) ]PFS, defined as time from the day of first diagnosis to the day of local tumor progression or the day of death of any cause (whichever occurs first), censored by the end of the observation. PFS analysis will be based on the central disease assessment (refer to section 7.5.1). Patients lacking an evaluation of tumor response (based on radiological or clinical assessment) will have their PFS time censored on the date of first diagnosis with duration of 1 day.
- Overall response rate (ORR) [ Time Frame: Baseline visit to end of study (approximately until day 540) ]ORR, defined as the proportion of patients showing complete response (CR), partial response (PR) or stable disease (SD) at EOS compared to the baseline value (MRI at visit 1 for ORR under trial drug). ORR analysis will be based on the central disease assessment according to the iRANO criteria.
- Analyze the association between immunogenicity and the clinical outcome parameters ORR [ Time Frame: Through study completion, an average of one year ]
- Analyze the association between immunogenicity and the clinical outcome parameters PFS [ Time Frame: Through study completion, an average of one year ]
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04808245
|Contact: Michael Platten, Prof.
|49 621 383 2885
|University Medical Center Mannheim, Department of Neurology
|Mannheim, Baden-Wuerttemberg, Germany, 68167
|Contact: Michael Platten, Prof Dr
|University Clinic Tuebingen, Neurological Clinic, Department of Neurology
|Tuebingen, Baden-Wuerttemberg, Germany, 72076
|Contact: Ghazaleh Tabatabai, Prof Dr
|Department of Neurology and Polyclinic, Universitiy Clinic Heidelberg
|Not yet recruiting
|Heidelberg, Baden-Württemberg, Germany, 69120
|Contact: Antje Wick, PD. Dr. med.
|Dr. Senckenberg Institute for Neurooncology, University Hospital Frankfurt
|Not yet recruiting
|Frankfurt am Main, Hessen, Germany, 60528
|Contact: Michael Ronellenfitsch, PD Dr. med. Dr. rer. nat.
|Clinical Neuro-Oncology Section, University Hospital Bonn (UKB)
|Not yet recruiting
|Bonn, Nordrhein-Westfalen, Germany, 53127
|Contact: Ulrich Herrlinger, Prof. Dr. med.
|Neurooncology Department, University Hospital Essen
|Not yet recruiting
|Essen, Nordrhein-Westfalen, Germany, 45147
|Contact: Martin Glas, Prof. Dr. med.
|Clinic and Polyclinic for Neurosurgery, University Hospital Carl Gustav Carus Dresden
|Not yet recruiting
|Dresden, Sachsen, Germany, 1307
|Contact: Dietmar Krex, Prof. Dr. med.
|Department of Neurosurgery with Pediatric Neurosurgery
|Not yet recruiting
|Berlin, Germany, 10117
|Contact: Peter Vajkoczy, Prof. Dr. med.
|Michael Platten, Prof.
|German Cancer Research Center Germany