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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Universitaetsklinikum Tuebingen AöR

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

16 Nov 2023 → ongoing

Decision date (initial)

2024-10-14

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Deutsches Krebsforschungszentrum

External identifiers

EU CT number

2024-511337-35-00

EudraCT number

2022-002793-91

ClinicalTrials.gov

NCT06094101

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy, Safety

To assess individualized fusion-petide and neopetide vaccination
induced T-cell response

Secondary objectives 3

1. To evaluate the feasibility of individualized fusion-petide and neopetide vaccination in a population of patients at very high risk of recurrance and mortality
2. To assess the safety/tolerability the indivdualized IPX-Vaccine
3. To gather very early efficacy data by monitoring event free and overall survival as major clinically relevant endpoints for potential planning of future confirmatory / pivotal trials

Conditions and MedDRA coding

The trial will include patients with so called "fusion-driven", metastatic sarcomas of the following types: - Ewing sarcoma, - alveolar rhabdomyosarcoma - or synovial sarcoma who are in first or second complete remission or partial response

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 4

1. 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.
2. Whole exome sequencing and 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 Version 2.0 19.06.2023 Seite 29 von 95 for Tumor Eradication) or HEROES-AYA networks (Heterogeneity, evolution and resistance of fusion-driven sarcomas in AYA) or similar evaluation
3. Design and production of the patient-individual vaccine cocktail was successful
4. 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 remissionplus 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 21

1. Age < 2 or > 40 years (only stage 1)
2. Ejection fraction < 25%
3. Creatinine-clearance < 40ml/min
4. Bilirubin > 4mg/dl
5. ALT > 400U/l and/or AST > 400U/l
6. 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.)
7. Subjects with a known hypersensitivity / allergy to any component of the study drugs
8. Subjects who have received a live, attenuated vaccine within 28 days prior to the administration of the study drug (only stage 2).
9. Subjects with a prior allogenic haematopoietic stem cell transplantation / prior organ transplantation.
10. 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
11. 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).
12. Significant psychiatric disabilities that, in the judgment of the investigator, do not assure reliable participation in the present study.
13. 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).
14. 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.
15. Pregnant females
16. 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.
17. Male subjects of reproductive capacity not agreeing to use effective contraception from first vaccination of this study to 180 days after the last vaccination.
18. Not willing and/or not able to comply with treatment plan, scheduled visits, laboratory tests, contraceptive guidelines and other study procedures
19. 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.
20. Karnofsky performance status of < 70% for subjects ≥ 16 years of age, Lansky performance status of < 70% for subjects < 16 years of age
21. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Primary endpoint is "success of treatment", defined as the patient showing a vaccination-induced T cell response to either of the two patient specific peptides without unacceptable toxicity until Follow-up visit (28 ± 7 days after last vaccination)

Secondary endpoints 5

1. A) 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).
2. B)CD8+ and/or CD4+ T-cell responses measured 2-fold above background in response to either of the two patient-specific peptides after completion of the study at day 180.
3. C) Event-free (EFS) at day 180.
4. D) Overall survival (OS) at day 180
5. E) Quality of life during study treatment.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Universitaetsklinikum Tuebingen AöR

Sponsor organisation

Universitaetsklinikum Tuebingen AöR

Address

Geissweg 3, Innenstadt Innenstadt

City

Tübingen

Postcode

72076

Country

Germany

Scientific contact point

Organisation

Universitaetsklinikum Tuebingen AöR

Contact name

Children's Hospital

Public contact point

Organisation

Universitaetsklinikum Tuebingen AöR

Contact name

Children's Hospital

Locations

1 EU/EEA country · 7 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 15 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications