Personalized Vaccination in Fusion+ Sarcoma Patients (PerVision)

Inclusion Criteria, definition of partial remission plus (PRplus)

• Screening Stage 1:

• Confirmed metastatic fusion-driven rhabdomyosarcoma, Ewing- and synovialsarcoma 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 theINFORM (Individualized therapy for relapsed malignancies in childhood), MASTER (Register study Molecularly Aided Stratification for Tumor Eradication) orHEROES-AYA networks (Heterogeneity, evolution and resistance of fusion-drivensarcomas 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 endof adjuvant and/or maintenance cytotoxic treatment. Cytotoxic treatment as perstandard or trial recommendations has been completed. Definition of PRplus:Partial remission(plus) implicates that all remaining tumor residua includingall metastases have received local therapy by this time point: Either surgicalremoval or local irradiation. The assessment of which therapy modality and, inthe case of irradiation, which radiation dose is selected, lies with thetreating physician. Whether PRplus is achieved will be decided finally by theinvestigator 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 ofhuman immunodeficiency virus-1 or human immunodeficiency virus-2 (positiveantigen/antibody or nucleic acid tests [NAT]) and CD4-positive cells < 500/μl.Hepatitis B virus: positive for the presence of hepatitis B virus (positive forhepatitis 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 chainonly antibody [HCAb] or for nucleic acid amplification testing (NAT). Otherinfections that, in the opinion of the investigator, do not allow a participation inthe study.)

• Subjects with a known hypersensitivity / allergy to any component of the studydrugs.

• Subjects who have received a live, attenuated vaccine within 28 days prior to theadministration of the study drug (only stage 2).

• Subjects with a prior haematopoietic stem cell transplantation / prior organtransplantation.

• Patients suffering from other malignancies (with the exception of those with anegligible risk of metastasis or death and treated with curative outcome) within 5years prior to study start.

• Current or anticipated need for any of the following medications interfering with Tcell function from 14 days before 1st vaccination until 28 days after 1stvaccination: Immunosuppressive agents, which influence functionality and activity ofT cells, such as steroids (more than 0,5 mg/kg body weight prednisolone-equivalent),calcineurin-inhibitors, mofetil mycophenolate, sirolimus, everolimus, and cytotoxicmedication. Those drugs should be avoided until 28 days after third/finalvaccination 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, donot assure reliable participation in the present study.

• Uncontrolled seizure disorders (occurrence of at least one generalized seizure inthe last 3 months) or severe peripheral neuropathy/leucoencephalopathy (> grade 2according to NCI CTCAE v5.0 neurotoxicity criteria).

• Autoimmune disease (e.g. idiopathic thrombocytopenic purpura, autoimmune hemolyticanemia, autoimmune dermatitis) requiring immunosuppressive treatment

• Pregnant females

• Female subjects of childbearing potential (postmenarcheal, with an intact uterus andat least one ovary, and less than one year postmenopausal) not agreeing to useacceptable method(s) of contraception from 30 days prior to Screening stage 2 visitto 180 days after the last vaccination.

• Male subjects of reproductive capacity not agreeing to use effective contraceptionfrom 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 thestudy 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 limitedto: history of central nervous system or cardiovascular disease, history of relevantdrug allergies, history of psychiatric disorder, history or present of clinicallysignificant pathology.

• Karnofsky performance status of < 70% for subjects ≥ 16 years of age, Lanskyperformance status of < 70% for subjects < 16 years of age

• Participation or intended participation in another clinical phase I or II trial withan investigational drug or product within 28 days prior to enrollment (with theexception 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.