Personalized Vaccination in Fusion+ Sarcoma Patients (PerVision)

Study Overview
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Brief Summary
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The PerVision trial utilizes an approach of a patient-individual cancer vaccine with sarcoma-specific peptides in metastasized fusion-driven sarcoma patients determined by next generation whole exome sequencing of tumor and normal tissue as well as RNA sequencing of the tumor. This approach is applicable to all patients independent of the expression of distinct tumor associated antigens, and independent of their human leukocyte antigen-typing (HLA-typing). The results of this study can directly be translated to other tumor entities. It is an interventional, multicenter, open-label, phase I/II feasibility and early proof of concept study evaluating a personalized peptide vaccine. Primary objective is to evaluate safety and success of treatment, the latter be defined as vaccination-induced T-cell response without unacceptable toxicity.

Detailed Description
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The PerVision trial utilizes an approach of a patient-individual cancer vaccine with sarcoma-specific peptides (one peptide derived from the sarcoma-specific fusion breakpoint, 'fusion-peptide', and a second peptide derived from neoantigens derived from patient-specific non-synonymous mutations with the highest prediction score, 'mutation-based neopeptide') in metastasized fusion-driven sarcoma patients determined by next generation whole exome sequencing of tumor and normal tissue as well as RNA sequencing of the tumor. This approach is applicable to all patients independent of the expression of distinct tumor associated antigens, and independent of their human leukocyte antigen-typing (HLA-typing). The results of this study can directly be translated to other tumor entities. It is an interventional, multicenter, open-label, phase I/II feasibility and early proof of concept study evaluating a personalized peptide vaccine and the toll like receptor (TLR) 1/2 ligand XS15 emulsified in Montanide ISA 51 VG in fusion driven sarcoma patients. The principal questions are: To investigate, whether it is possible to induce a mutation-specific immune response in sarcoma patients and young adults after salvage chemotherapy To investigate possible side effects and toxicity of the treatment To gather indications if our approach has a beneficial effect on residual disease as well as event free survival (EFS) of the patients. EFS and overall survival (OS) data will be compared within this single arm study to non-vaccinated patients of a historic control cohort. Patients will be recruited through the Society for Pediatric Oncology/Hematology (GPOH) networks Cooperative Soft Tissue Sarcoma Group (CWS) and Cooperative Ewing Sarcoma Group (CESS) and through the Deutsches Konsortium für Translationale Krebsforschung (DKTK) programs MASTER and INFORM as well as HEROES-AYA. For the screening phase, n=30 patients will be recruited, n=23 patients should be treated with at least one vaccine dose, with a drop-out rate we need n=21 patients for sufficient statistical power. Primary objective is to evaluate the safety, toxicity and in vivo immunological effects of a patient-individualized peptide vaccination (IPX vaccine) in patients with primary or relapsed metastasized fusion-driven sarcoma (FDS, rhabdomyosarcoma, Ewing- and synovial sarcoma) with an age ≥ 2 to < 40 years in first or second complete remission or stable partial remission. Primary endpoint is success of treatment, defined as the patient showing a vaccination-induced T cell response without unacceptable toxicity until Follow-up visit (28 ± 7 days after last vaccination).

Official Title
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Prospective Phase I/II Trial of an Individualized Peptide Vaccine in Pediatric and AYA Patients With Metastasized Fusion-driven Sarcomas Following Standard Treatment

Conditions
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Rhabdomyosarcoma, Synovial Sarcoma, Ewing Sarcoma

Intervention / Treatment
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* Biological: Peptide vaccine IPX


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria, definition of partial remission plus (PRplus) Screening Stage 1: Confirmed metastatic fusion-driven rhabdomyosarcoma, Ewing- and synovial sarcoma in first or second complete remission (CR) or partial response (PR) after local therapy and intensive standard chemotherapy protocols. Whole exome sequencing and RNA sequencing data of the gene fusion (fusion-breakpoint RNA sequence) must be available by registration to the INFORM (Individualized therapy for relapsed malignancies in childhood), MASTER (Register study Molecularly Aided Stratification for Tumor Eradication) or HEROES-AYA networks (Heterogeneity, evolution and resistance of fusion-driven sarcomas in AYA) or similar evaluation. Screening stage 2: Design and production of the patient-individual vaccine cocktail was successful Patients have reached a complete or stable partial remission (CR or PR) the end of adjuvant and/or maintenance cytotoxic treatment. Cytotoxic treatment as per standard or trial recommendations has been completed. Definition of PRplus: Partial remission(plus) implicates that all remaining tumor residua including all metastases have received local therapy by this time point: Either surgical removal or local irradiation. The assessment of which therapy modality and, in the case of irradiation, which radiation dose is selected, lies with the treating physician. Whether PRplus is achieved will be decided finally by the investigator after review of the patient records. Exclusion Criteria: Ejection fraction < 25% Creatinine-clearance < 40ml/min Bilirubin > 4mg/dl Alanine aminotransferase (ALT) > 400 units (U)/l and/or aspartate aminotransferase (AST) > 400 U/l Severe infection (Human immunodeficiency virus (HIV): positive for the presence of human immunodeficiency virus-1 or human immunodeficiency virus-2 (positive antigen/antibody or nucleic acid tests [NAT]) and CD4-positive cells < 500/μl. Hepatitis B virus: positive for the presence of hepatitis B virus (positive for hepatitis B core antibody [HBcAb] or positive hepatitis B surface antigen [HBsAg]) and hepatitis B NAT test > 2000 IU/ml). Hepatitis C virus: positive for heavy chain only antibody [HCAb] or for nucleic acid amplification testing (NAT). Other infections that, in the opinion of the investigator, do not allow a participation in the study.) Subjects with a known hypersensitivity / allergy to any component of the study drugs. Subjects who have received a live, attenuated vaccine within 28 days prior to the administration of the study drug (only stage 2). Subjects with a prior haematopoietic stem cell transplantation / prior organ transplantation. Patients suffering from other malignancies (with the exception of those with a negligible risk of metastasis or death and treated with curative outcome) within 5 years prior to study start. Current or anticipated need for any of the following medications interfering with T cell function from 14 days before 1st vaccination until 28 days after 1st vaccination: Immunosuppressive agents, which influence functionality and activity of T cells, such as steroids (more than 0,5 mg/kg body weight prednisolone-equivalent), calcineurin-inhibitors, mofetil mycophenolate, sirolimus, everolimus, and cytotoxic medication. Those drugs should be avoided until 28 days after third/final vaccination but may be given after discussion with the principal investigator. Application of tyrosine kinase inhibitors is permitted during the trial (only stage 2). Significant psychiatric disabilities that, in the judgment of the investigator, do not assure reliable participation in the present study. Uncontrolled seizure disorders (occurrence of at least one generalized seizure in the last 3 months) or severe peripheral neuropathy/leucoencephalopathy (> grade 2 according to NCI CTCAE v5.0 neurotoxicity criteria). Autoimmune disease (e.g. idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, autoimmune dermatitis) requiring immunosuppressive treatment Pregnant females Female subjects of childbearing potential (postmenarcheal, with an intact uterus and at least one ovary, and less than one year postmenopausal) not agreeing to use acceptable method(s) of contraception from 30 days prior to Screening stage 2 visit to 180 days after the last vaccination. Male subjects of reproductive capacity not agreeing to use effective contraception from first vaccination of this study to 180 days after the last vaccination. Not willing and/or not able to comply with treatment plan, scheduled visits, laboratory tests, contraceptive guidelines and other study procedures. History of any illness or clinical condition that might confound the results of the study or pose an additional risk in administering study drug to the subject, according to the judgement of the investigator. This may include but is not limited to: history of central nervous system or cardiovascular disease, history of relevant drug allergies, history of psychiatric disorder, history or present of clinically significant pathology. Karnofsky performance status of < 70% for subjects ≥ 16 years of age, Lansky performance status of < 70% for subjects < 16 years of age Participation or intended participation in another clinical phase I or II trial with an investigational drug or product within 28 days prior to enrollment (with the exception to participation of the frontline and relapsed rhabdomyosarcoma study( (FaR-RMS) after completion of the maintenance therapy (EudraCT-2018-000515-24)). Commonly used drugs as per standard or phase III-trials are permitted.

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: interventional, multicenter, open-label, phase I/II feasibility and early proof of concept study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Peptide vaccination<br>Peptides will be administered subcutaneously (s.c.) together with the novel toll like receptor (TLR) 1/2 ligand XS15 emulsified in Montanide ISA 51 VG as adjuvant. Three vaccinations will be applied every 28 days. | Biological: Peptide vaccine IPX<br>* Peptide vaccine is a combination of class II peptide spanning the sarcoma-specific fusion-breakpoint (fusion-peptide) class-II neopeptide based on a patient-individual nonsynonymous mutation with a high immunogenicity (mutation-based neopeptide). control peptide derived from Survivin. adjuvant: toll like receptor (TLR) 1/2 ligand XS15.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Success of treatment | The primary composite safety/efficacy outcome of treatment success is defined as number of patients without unacceptable toxicity (any toxicity > grade 3 according to NCI-CTC) until Follow-up visit (28 ± 7 days after last vaccination) and with vaccination-induced response of cluster of differentiation 4+ (CD4+) and/or cluster of differentiation 8+ (CD8+) T cells to the patient-specific peptides at Follow-up visit (28 ± 7 days after last vaccination). CD4+ and CD8+ T cells will be measured by flow cytometry. | Follow-up visit at 28 +/- 7 days after last vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| T-cell response at follow up | Number of patients with CD8+ and/or CD4+ T-cell responses measured 2-fold above background in response to either of the two patient-specific peptides (fusion-peptide and mutation-based neopeptide). | Beginning of trial phase until follow-up visit at 28 +/- 7 days after last vaccination | 
| T-cell response at final follow up | Number of patients with CD8+ and/or CD4+ T-cell responses measured 2-fold above background in response to either of the two patient-specific peptides (fusion-peptide and mutation-based neopeptide). | Beginning of trial phase until final follow-up at 120 +/- 14 days after last vaccination | 
| Event free survival | Rate of patients that survived without progression according to RECIST criteria, stratified for immune response yes/no | Beginning of trial phase until final follow-up at 120 +/- 14 days after last vaccination | 
| Overall survival | Rate of patients that survived. stratified for immune response yes/no | Beginning of trial phase until final follow-up at 120 +/- 14 days after last vaccination | 
| Quality of life (QoL) defined as overall quality of life in children | QoL (Quality of life) is defined as overall quality of life measured by Pediatric Quality of Life InventoryTM PedsQL (4.0). The PedsQL uses a 0 to 4 scale with 0=never and 4=almost always. | Beginning of trial phase until final follow-up at 120 +/- 14 days after last vaccination | 
| Quality of life (QoL) defined as overall quality of life in adults | QoL (Quality of life) is defined as overall quality of life measured by European Organisation for Research and Treatment of Cancer EORTC quality of life questionnaire (QLQ) C-30 (3.0). EORTC QLQ C-30 uses a 1-4 scale with 1=not at all and 4=very much and a 1-7 scale with 1=very poor and 7=excellent. | Beginning of trial phase until final follow-up at 120 +/- 14 days after last vaccination | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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metastasized fusion-driven sarcoma, clinical study, phase I/II