Prospective phase I/II trial of an individualized peptide vaccine in pediatric and AYA patients with metastasized fusion-driven sarcomas following standard treatment

Prior treatment

• 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 30 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).
• 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.
• 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 FaR-RMS study after completion of the maintenance therapy (EudraCT-2018-000515-24)). Commonly used drugs as per standard or phase III-trials are permitted.
• 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 allogenic haematopoietic stem cell transplantation / prior organ transplantation.

Other illness

• 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/leukencephalopathy (> 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. Less acute autoimmune diseases like diabetes mellitus type 1, Vitiligo and Hashimoto-Thyreoiditis not requiring immunosuppressive therapy are no exclusion criteria.
• 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.
• 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 antibody [HCAb] or for NAT test. 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

Lab values

• Not willing and/or not able to comply with treatment plan, scheduled visits, laboratory tests, contraceptive guidelines and other study procedures
• Ejection fraction < 25%
• Creatinine-clearance < 40ml/min (Schwartz clearance is accepted as sufficient for creatinine clearance assessment. No 24h urine collection required.)
• Bilirubin > 4mg/dl
• ALT > 400U/l and/or AST > 400U/l

Age

• Age < 2 or > 40 years (only stage 1)
• Karnofsky performance status of < 7080% for subjects ≥ 16 years of age, Lansky performance status of < 7080% for subjects < 16 years of age.

Other

• Pregnant females
• Male subjects of reproductive capacity not agreeing to use effective contraception from first vaccination of this study to 180 days after the last vaccination.

• Confirmed metastatic fusion-driven rhabdomyo-, Ewing- and synovial sarcoma in complete remission (CR) or partial response (PR) after local therapy and intensive standard chemotherapy protocols, as well as patients with clinically stable persistent disease or relapse if outpatient vaccination is feasible, Karnofsky/Lansky Index is >= 80%, and there is no current or immediate need for cytotoxic antitumour treatment..
• RNAseq 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 other sequencing programs.
• Design and production of the patient-individual vaccine cocktail was successful
• Patients have reached a complete remission or stable partial remission response (CR or PR) at the end of adjuvant and/or maintenance cytotoxic treatment, and/or are in a clinically stable situation despite persistent disease or relapse, without expected/actual need of cytotoxic treatment for at least three months.
• Performance status is adequate for outpatient vaccination treatment (Karnofsky/Lansky Index ≥ 80%).
• Cytotoxic treatment as per standard or trial recommendations has been completed or terminated by the treating team without immediate indication for urgent cytotoxic antitumor treatment that would preclude vaccination.