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Patient-individualized Peptide Vaccination Based on Tumor-specific Mutations in Children and Young Adults With Primary/Relapsed ALL

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ClinicalTrials.gov Identifier: NCT03559413
Recruitment Status : Recruiting
First Posted : June 18, 2018
Last Update Posted : June 18, 2018
Sponsor:
Collaborators:
German Cancer Research Center
Universität Tübingen
University Hospital Tuebingen
Information provided by (Responsible Party):
Peter Lang, University Children’s Hospital Tuebingen

Brief Summary:
The aim of this clinical study is to evaluate the feasibility and safety of an individualized peptide vaccination approach in patients with acute lymphoblastic leukemia (ALL). For this purpose, tumor-specific mutations are analyzed by comparative exome sequencing of tumor and healthy reference tissue. Expression of variants is further validated by RNA sequencing. In a second step, HLA-binding (human leukocyte antigen-binding) peptides derived from mutated protein sequences are selected for vaccination. The peptides are administered as a vaccination cocktail with adjuvant GM-CSF and Imiquimod over a course of 9 months and a total of 16 vaccinations. Primary objective is the de novo induction of a specific T cell response without unacceptable toxicity and acute GvHD (graft versus host disease).

Condition or disease Intervention/treatment Phase
Primary/Relapsed Acute Lymphoblastic Leukemia (ALL) of Childhood, Adolescents and Young Adults Biological: Individual peptide vaccination with adjuvant GM-CSF and Imiquimod Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Prospective Phase I/II Study: Patient-individualized Peptide Vaccination Based on Whole Exome Sequencing With Adjuvant GM-CSF (Granulocyte Macrophage Colony-stimulating Factor) in Children and Young Adults With Primary/Relapsed Acute Lymphoblastic Leukemia
Actual Study Start Date : June 2016
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : June 2020


Arm Intervention/treatment
Experimental: Intervention group Biological: Individual peptide vaccination with adjuvant GM-CSF and Imiquimod
Intradermal injection of a cocktail of 3-5 individual HLA-binding peptides. Subcutaneous injection of adjuvant GM-CSF at vaccination site. Topical administration of Imiquimod at vaccination site.




Primary Outcome Measures :
  1. Primary endpoint is "success of treatment" defined as a patient showing a vaccination-induced T-cell response without unacceptable toxicity and acute GvHD of Grade III or higher or extensive chronic GvHD until day 120 (after 10 vaccinations). [ Time Frame: 120 days ]
    Side effects wil be assessed according to NCI common toxicity criteria V4.0. GvHD will be graded according to Glucksberg criteria. A vaccine-specific response will be defined by an at least 2-fold elevated cytokine expression of CD4+ and/or CD8+ T cells over background in response to stimulation with the vaccine peptides. A vaccine-induced response will be defined by an at least 2-fold elevated response at a certain timepoint compared to pre-vaccination.


Secondary Outcome Measures :
  1. To evaluate CD4+ and/or CD8+ T-cell responses over the vaccination period. [ Time Frame: 246 days ]
    T-cell responses will be measured after completion of the study at day 246 and will be analyzed with regard to the T-cell responses at day 120.

  2. To evaluate changes in minimal residual disease (MRD) during and after treatment. [ Time Frame: 246 days ]
    Possible reduction of MRD levels on days 36, 120 and 246 (after 7, 10 and 16 vaccinations) measured as reduction of 1 log compared to baseline yes/no.

  3. To evaluate the relapse rate during and after treatment. [ Time Frame: 246 days ]
    Relapse rates will be assessed on days 120 and 246.

  4. To evaluate the event-free survival (EFS) during and after treatment. [ Time Frame: 246 days ]
    EFS will be assessed on days 120 and 246.



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Ages Eligible for Study:   1 Year to 30 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Pediatric patients and young adults with ALL (T, B, pro-B, pre-B or c-ALL) ≥CR3 or with ≥1st relapse after stem cell transplantation (SCT); or patients in ≤CR2 who have received SCT without having reached a sufficient molecular remission prior to, or after SCT (defined as MRD ≥10^-4); or patients with initially refractory disease to standard treatment who could proceed to stem cell transplantation with alternative treatment options.
  • Hematological remission has to be reached (<5% blasts in bone marrow or detectable minimal residual disease (MRD) ≤5x10^-2) after salvage chemotherapy and/or subsequent SCT.

Exclusion Criteria:

  • Frank relapse (>5% leukemic blasts).
  • Ejection fraction <25%; Creatinine-clearance <40ml/min; Bilirubin >4mg/dl, Transaminases >400 units/ml; severe infection (HIV, Hepatitis), acute GvHD III-IV or chronic GvHD.
  • Significant psychiatric disabilities, uncontrolled seizure disorders or severe peripheral neuropathy/ leukoencephalopathy.
  • Signs of autoimmune disease (i.e. idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia).
  • Need for immunosuppressive drugs.
  • No tumor material available for exome sequencing.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03559413


Contacts
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Contact: Peter Lang, Prof. Dr. +497071-2983781 peter.lang@med.uni-tuebingen.de
Contact: Armin Rabsteyn, Dr. rer. nat. +497071-2981644 armin.rabsteyn@med.uni-tuebingen.de

Locations
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Germany
University Medical Center for Children and Adolescents Heidelberg Recruiting
Heidelberg, Baden-Württemberg, Germany, 69120
Contact: Olaf Witt, Prof. Dr.    +496221 423272    o.witt@dkfz-heidelberg.de   
University Children's Hospital Tübingen Recruiting
Tübingen, Baden-Württemberg, Germany, 72076
Contact: Peter Lang, Prof. Dr.    +497071-2983781    peter.lang@med.uni-tuebingen.de   
Contact: Armin Rabsteyn, Dr. rer. nat.    +497071-2981644    armin.rabsteyn@med.uni-tuebingen.de   
University Children's Hospital Munich, Center for Pediatric Hematology and Oncology Recruiting
München, Bayern, Germany, 80337
Contact: Tobias Feuchtinger, Prof. Dr.    +4989-440052759    tobias.feuchtinger@med.uni-muenchen.de   
University Hospital Düsseldorf, Clinic for Pediatric Oncology, Hematology and Clinical Immunology Recruiting
Düsseldorf, Nordrhein-Westfalen, Germany, 40225
Contact: Roland Meisel, Prof. Dr.    +49211-8118907    meisel@med.uni-duesseldorf.de   
Charite Universitätsmedizin Berlin, Department of Pediatric Oncology/Hematology Recruiting
Berlin, Germany, 13353
Contact: Christiane Chen-Santel, Dr. med.    +4930-450566074    christiane.chen-santel@charite.de   
Sponsors and Collaborators
University Children’s Hospital Tuebingen
German Cancer Research Center
Universität Tübingen
University Hospital Tuebingen
Investigators
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Principal Investigator: Peter Lang, Prof. Dr. University Children’s Hospital Tuebingen

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Responsible Party: Peter Lang, Prof. Dr. med., University Children’s Hospital Tuebingen
ClinicalTrials.gov Identifier: NCT03559413     History of Changes
Other Study ID Numbers: IVAC-ALL-1
2015-005281-29 ( EudraCT Number )
First Posted: June 18, 2018    Key Record Dates
Last Update Posted: June 18, 2018
Last Verified: June 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: all IPD that underlie results in a publication
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Clinical Study Report (CSR)
Time Frame: starting at time of publication
Access Criteria: Anyone, upon request to PI

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Peter Lang, University Children’s Hospital Tuebingen:
Individualized peptide vaccination
Immunotherapy
Tumor-specific mutations
Neoantigens
Additional relevant MeSH terms:
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Precursor Cell Lymphoblastic Leukemia-Lymphoma
Sargramostim
Leukemia
Leukemia, Lymphoid
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Imiquimod
Vaccines
Immunologic Factors
Physiological Effects of Drugs
Adjuvants, Immunologic
Antineoplastic Agents
Interferon Inducers