Personalized Vaccination in Fusion+ Sarcoma Patients (PerVision)

Studien-Informationen Einschlusskriterien Studien-Rationale Geprüfte Regime

Rekrutierend

NCT-Nummer:
NCT06094101

Studienbeginn:
September 2023

Letztes Update:
22.11.2023

Wirkstoff:
Peptide vaccine IPX

Indikation (Clinical Trials):
Sarcoma, Rhabdomyosarcoma, Sarcoma, Ewing, Sarcoma, Synovial

Geschlecht:
Alle

Altersgruppe:
Alle

Phase:
-

Sponsor:
University Hospital Tuebingen

Collaborator:
Deutsches Konsortium fürTranslationale Krebsforschung (DKTK), Cooperative Ewing Sarkom Studiengruppe, Cooperative Weichteilsarkom Study Group,

Studienleiter

Martin Ebinger, Prof. Dr.
Principal Investigator
University children's hospital Tübingen

Kontakt

Martin Ebinger, Prof. Dr.
Kontakt:
Phone: +49 7071 2983781
E-Mail: martin.ebinger@med.uni-tuebingen.de» Kontaktdaten anzeigen

Joachim Rupprecht, Dr.
Kontakt:
E-Mail: joachim.rupprecht@med.uni-tuebingen.de» Kontaktdaten anzeigen

Studienlocations
(3 von 4)

Pediatrics III, West German Cancer Centre, University Hospital
45147 Essen
(Nordrhein-Westfalen)
GermanyNoch nicht rekrutierend» Google-Maps
Ansprechpartner:
Uta Dirksen, Prof.
Phone: 0049.201.7238084
E-Mail: uta.dirksen@uk-essen.de

Dirk Reinhardt
Phone: 0049-201-7233784
E-Mail: dirk.reinhardt@uk-essen.de» Ansprechpartner anzeigen

Universitätsklinikum, Klinik für Kinder- und Jugendmedizin
60590 Frankfurt am Main
(Hessen)
GermanyNoch nicht rekrutierend» Google-Maps
Ansprechpartner:
Konrad Bochennek, Dr.
Phone: +49 69 6301-5243

Eva Rettinger, Dr.
Phone: +49 69 6301-5040» Ansprechpartner anzeigen

Zentrum für Kinder- und Jugendmedizin, Universitätsklinikum
79106 Freiburg
(Baden-Württemberg)
GermanyNoch nicht rekrutierend» Google-Maps
Ansprechpartner:
Simone Hettmer, Prof. Dr.
Phone: +49 761 27043000
E-Mail: simone.hettmer@uniklinik-freiburg.de

Christian Flotho, Prof. Dr.
Phone: +49 761 27046280
E-Mail: christian.flotho@uniklinik-freiburg.de» Ansprechpartner anzeigen

University Children's Hostpital
72076 Tübingen
(Baden-Württemberg)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Martin Ebinger, Prof. Dr.
Phone: +49 7071 2983781
E-Mail: martin.ebinger@med.uni-tuebingen.de

Joachim Rupprecht, Dr.
E-Mail: joachim.rupprecht@med.uni-tuebingen.de» Ansprechpartner anzeigen

Alle anzeigen

Studien-Informationen

Detailed Description:

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:

1. To investigate, whether it is possible to induce a mutation-specific immune response in

sarcoma patients and young adults after salvage chemotherapy

2. To investigate possible side effects and toxicity of the treatment

3. 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).

Ein-/Ausschlusskriterien

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.

Studien-Rationale

Primary outcome:

1. Success of treatment (Time Frame - Follow-up visit at 28 +/- 7 days after last vaccination):
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.

Secondary outcome:

1. T-cell response at follow up (Time Frame - Beginning of trial phase until follow-up visit at 28 +/- 7 days after last vaccination):
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).

2. T-cell response at final follow up (Time Frame - Beginning of trial phase until final follow-up at 120 +/- 14 days after last vaccination):
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).

3. Event free survival (Time Frame - Beginning of trial phase until final follow-up at 120 +/- 14 days after last vaccination):
Rate of patients that survived without progression according to RECIST criteria, stratified for immune response yes/no

4. Overall survival (Time Frame - Beginning of trial phase until final follow-up at 120 +/- 14 days after last vaccination):
Rate of patients that survived. stratified for immune response yes/no

5. Quality of life (QoL) defined as overall quality of life in children (Time Frame - Beginning of trial phase until final follow-up at 120 +/- 14 days after last vaccination):
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.

6. Quality of life (QoL) defined as overall quality of life in adults (Time Frame - Beginning of trial phase until final follow-up at 120 +/- 14 days after last vaccination):
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.

Geprüfte Regime

Peptide vaccine IPX:
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.

Quelle: ClinicalTrials.gov

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