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NCT Number: NCT03559413

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

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).

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Key information

Conditions

Primary/Relapsed Acute Lymphoblastic Leukemia (ALL) of Childhood, Adolescents and Young Adults Hematologic Diseases Hemic and Lymphatic Diseases Immune System Diseases Immunoproliferative Disorders Leukemia Leukemia, Lymphoid Lymphatic Diseases Lymphoproliferative Disorders Neoplasms Neoplasms by Histologic Type Precursor Cell Lymphoblastic Leukemia-Lymphoma

Age range

1 year–30 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1 / Phase 2

Primary location

University Medical Center for Children and Adolescents Heidelberg, Heidelberg, Baden-Wurttemberg, Germany

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

Individual peptide vaccination with adjuvant GM-CSF and Imiquimod

Biological

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 outcomes

  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 outcomes

  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.

Sponsors and collaborators

Lead sponsor

University Children's Hospital Tuebingen

Other

Collaborators

  • German Cancer Research Center
  • University Hospital Tuebingen
  • Universität Tübingen

Registry information

Official study 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

Important dates

Study start
2016
Primary completion
2022
Study completion
2023
First posted
Jun 18, 2018
Registry last updated
Dec 4, 2023

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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