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The vaccine is applied by s.c. injection with 300 μg IDH1R132H peptide emulsified in 0.5 ml 33% DMSO / 0.5 ml Montanide® per dose.

Patients receive 3 doses in two week intervals for 6 weeks, followed by re-resection. 4 weeks after surgery, treatment will be resumed consisting of 5 additional vaccinations in 4 week intervals, followed by maintenance vaccines until progression in three months intervals after a pause of 16 weeks.

IDH1R132H peptide vaccine

Avelumab is a humanized anti-PD-L1 antibody approved for patients with Merkel cell carcinoma and urothelial cancer. It is applied by i.v. infusion with 10 mg/kg per dose.

Patients receive 3 doses of Avelumab in 2week intervals for 6 weeks, followed by re-resection. Avelumab will be administered in monthly intervals starting 4 weeks after the surgery until progression.

Michael Platten, Prof. MD

The trial will address safety and tolerability of the combination of the IDH1R132H-specific vaccine with checkpoint blockade and seeks to explore predictive biomarkers for response to checkpoint blockade in post-treatment tumor tissue. The study will enroll 48 evaluable patients (presumably, 60 in total) with IDH1R132H-mutated gliomas with an unfavorable molecular profile (no 1p/19q co-deletion, nuclear ATRX- loss) progressive after radiotherapy and alkylating chemotherapy eligible for re-resection. After diagnosis of recurrent disease on imaging patients will be randomized assigned in a 1:1:2 ratio into three arms. Arm 1 (12 patients) will receive three IDH1R132H peptide vaccines alone in two week intervals. Arm 2 (12 patients) will receive three IDH1R132H peptide vaccines in combination with three doses of Avelumab in two week intervals. Arm 3 (24 patients) will receive three doses of Avelumab in two week intervals. After 6 weeks of treatment patients (Arms 1-3) will undergo planned re-resection. Four weeks after the operation treatment will be resumed consisting of five additional vaccines (Arm 1+2) in 4 week intervals, followed by maintenance vaccines until progression in three months' intervals after a pause of 16 weeks. Avelumab will be administered in monthly intervals in Arms 2 and 3 starting four weeks after the operation until progression.

Key outcome parameters will be safety and immunogenicity (Arms 1 and 2) based on peripheral and intratumoral immune analyses assessed 9 months after re-resection.

The standard of care (SOC) treatment of patients with malignant gliomas is - independent of molecular markers - still confined to surgery, irradiation and alkylating chemotherapy as targeted therapies to date have failed to prove superiority over standard of care in controlled trials. At the same time, novel concepts in immunotherapy have evolved with the identification of potential (neo)epitopes and phase III clinical trials investigating the efficacy of checkpoint inhibitors. Despite patients frequently undergoing resection of recurrent tumor, patient selection criteria for innovative immunotherapy in glioma have been hampered by the lack of availability of post-treatment tumor tissue. Neoepitope-specific vaccines have gained considerable interest also in a challenging disease such as glioma. IDH1R132H, a frequent driver mutation in gliomas, was previously identified to contain a neoepitope. A peptide vaccine targeting this epitope is currently tested in a phase I first-in-man multicenter clinical trial. The clinical phase of this trial was completed in Q3 2017 with 32 patients treated. The primary endpoints were met by demonstrating safety and immunogenicity. Checkpoint inhibitors are tested in unselected populations of glioma patients despite evidence that response is associated with high mutational load, which is infrequent in untreated gliomas, but may occur particularly after long periods of exposure to alkylating chemotherapy.

The trial will address safety and tolerability of the combination of the IDH1R132H-specific vaccine with checkpoint blockade and seeks to explore predictive biomarkers for response to checkpoint blockade in post-treatment tumor tissue. The study will enroll 48 evaluable patients (presumably, 60 in total) with IDH1R132H-mutated gliomas with an unfavorable molecular profile (no 1p/19q co-deletion, nuclear ATRX loss) progressive after radiotherapy and alkylating chemotherapy eligible for re-resection. After diagnosis of recurrent disease on imaging patients will be randomized assigned in a 1:1:2 ratio into three arms. Arm 1 (12 patients) will receive three IDH1R132H peptide vaccines alone in two week intervals. Arm 2 (12 patients) will receive three IDH1R132H peptide vaccines in combination with three doses of Avelumab, a humanized anti-PD-L1 antibody approved for patients with Merkel cell carcinoma and urothelial cancer, in two week intervals. Arm 3 (24 patients) will receive three doses of Avelumab in two week intervals. After 6 weeks of treatment patients (Arms 1-3) will undergo planned re-resection. A safety MRI will be performed three weeks after initiation of the experimental treatment. Four weeks after the operation treatment will be resumed consisting of five additional vaccines (Arm 1+2) in 4 week intervals, followed by maintenance vaccines until progression in three months' intervals after a pause of 16 weeks. Avelumab will be administered in monthly intervals in Arms 2 and 3 starting four weeks after the operation until progression.

Key outcome parameters will be safety and immunogenicity (Arms 1 and 2) based on peripheral and intratumoral immune analyses assessed 9 months after re-resection. Additional exploratory analyses will determine efficacy (all Arms), dependent on predictive molecular immune and imaging biomarkers, such as increased mutational load (Arm 3). Based on the experience in the NOA-04 and CATNON trials the expected time to second progression is 9-12 months.

The trial is supported by the German Cancer Consortium (DKTK) and the Neurooncology Working Group of the German Cancer Society (NOA).

AMPLIFYing NEOepitope-specific VACcine Responses in Progressive Diffuse Glioma

AMPLIFYing NEOepitope-specific VACcine Responses in Progressive Diffuse Glioma - a Randomized, Open Label, 3 Arm Multicenter Phase I Trial to Assess Safety, Tolerability and Immunogenicity of IDH1R132H-specific Peptide Vaccine in Combination With Checkpoint Inhibitor Avelumab

To determine safety and tolerability of repeated fixed dose vaccinations of the IDH1 peptide vaccine administered with topical imiquimod (Aldara®) alone (Arm 1) or in combination with Avelumab (Arm 2), or Avelumab alone (Arm 3).

Primary endpoint is the Regime Limiting Toxicity (RLT) until End of Primary Treatment Phase.

To assess immunogenicity of the IDH1 peptide vaccine alone or in combination with Avelumab. The main immunogenicity endpoint is the presence of IDH1R132H-specific T-cells and/or antibody responses in the peripheral circulation and/or the presence of IDH1R132H-specific T-cells in the tumor tissue

This endpoint includes all AEs (adverse event), their severity, SAEs (serious adverse event), the relation of AEs to the study treatment, dose modifications for toxicity and discontinuation of study treatment during the trial phase. Toxic effects will be graded according to CTCAE, current version.

The ORR, defined as the proportion of patients with a treatment-induced hypermutator phenotype compared with a non-hypermutator phenotype showing complete response (CR), partial response (PR) or stable disease (SD) at end of the Primary Treatment Phase and at EOS compared to the baseline value (MRI at visit 7). ORR analysis will be based on the central disease assessment according to the iRANO criteria

OS, defined as the time from the first study treatment date until death. For patients who do not die, time to death will be censored at the time of the end of observation. The end of observation is defined as the date of study termination as indicated by the corresponding entry of the CRF (case report form). If this date is not documented, the end of observation is defined as the last documented date.

The PFS, defined as time from the day of first study treatment date to the day of tumor progression or the day of death of any cause (whichever occurs first), censored by the end of the observation. The end of observation is defined as the date of study termination as indicated by the corresponding entry of the CRF. If this date is not documented, the end of observation is defined as the last documented date.

The ORR, defined as the proportion of patients showing complete response (CR), partial response (PR) or stable disease (SD) at end of the Primary Treatment Phase and at EOS compared to the baseline value (MRI at visit 7). ORR analysis will be based on the central disease assessment according to the iRANO criteria

To analyse the association between immunogenicity and the clinical outcome parameter. The clinical outcome will be evaluated by assessing the ORR. Logistic regression models will be used to explore the relationship between the relative changes in the immunologic parameters and ORR.

To analyse the association between immunogenicity and the clinical outcome parameter. The clinical outcome will be evaluated by assessing the PFS. Proportional Hazards models will be used to analyze the prognostic influence of relative changes in the immunologic parameters, for the PFS.

To analyse the association between immunogenicity and the clinical outcome parameters. The clinical outcome will be evaluated by assessing the OS. Proportional Hazards models will be used to analyze the prognostic influence of relative changes in the immunologic parameters, for the OS.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
AMPLIFYing NEOepitope-specific VACcine Responses in Progressive Diffuse Glioma	NCT03893903	Malignant Gliom...	IDH1R132H pepti... Avelumab	18 Years -	German Cancer Research Center
AMPLIFYing NEOepitope-specific VACcine Responses in Progressive Diffuse Glioma	NCT03893903	Malignant Gliom...	IDH1R132H pepti... Avelumab	18 Years -	German Cancer Research Center

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