1. safety and tolerability: Regime Limiting Toxicity (Time Frame - Primary treatment phase (week 43)): 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.
Secondary outcome:
1. immunogenicity of the IDH1 peptide vaccine (Time Frame - End of primary treatment phase (week 43)): 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
2. Frequency of Treatment-Emergent Adverse Events (Assessment of Tolerability) (Time Frame - Time from baseline until EOS (end of study) (12 weeks after last treatment administration); up to 38 months): 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.
3. Objective response rate (ORR) to assess the efficacy of Avelumab in association with the number of non-synonymous mutations in the tumor tissue. (Time Frame - Time from baseline until end of the primary treatment phase (week 43) and at EOS (12 weeks after last treatment administration); up to 38 months): 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
4. Overall survival (OS) (Time Frame - Time from the first study treatment date until death or end of observation (up to 38 months)): 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.
5. Progression-free survival (PFS) (Time Frame - Time from the day of first study treatment date, censored by the end of the observation (up to 38 months)): 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.
6. Objective response rate (ORR) (Time Frame - Time from baseline until end of the primary treatment phase (week 43) and at EOS (12 weeks after last treatment administration); up to 38 months): 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
7. Association between immunogenicity and Objective response rate (ORR) (Time Frame - Time from baseline until EOS (12 weeks after last treatment administration); up to 38 months): 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.
8. Association between immunogenicity and Progression-free Survival (PFS) (Time Frame - Time from baseline until EOS (12 weeks after last treatment administration); up to 38 months): 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.
9. Association between immunogenicity and Overall survival (OS) (Time Frame - Time from baseline until EOS (12 weeks after last treatment administration); up to 38 months): 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.
IDH1R132H peptide vaccine: 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.
Avelumab: 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.
Quelle: ClinicalTrials.gov
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