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

NCT03559413 | Completed Phase 1 DMC

• 2 other identifiers: IVAC-ALL-12015-005281-29
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 5

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).

Conditions

Primary/Relapsed Acute Lymphoblastic Leukemia (ALL) of Childhood, Adolescents and Young Adults

Keywords

Individualized peptide vaccination; Immunotherapy; Tumor-specific mutations; Neoantigens

Outcome Measures

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).

  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.

  120 days

Secondary Outcomes (4)

• To evaluate CD4+ and/or CD8+ T-cell responses over the vaccination period.

  246 days

• To evaluate changes in minimal residual disease (MRD) during and after treatment.

  246 days

• To evaluate the relapse rate during and after treatment.

  246 days

• To evaluate the event-free survival (EFS) during and after treatment.

  246 days

Study Arms (1)

Intervention group

EXPERIMENTAL

Biological: Individual peptide vaccination with adjuvant GM-CSF and Imiquimod

Interventions

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.

Intervention group

Eligibility Criteria

• Age: 1 Year - 30 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• University Children's Hospital Tuebingen: lead
• German Cancer Research Center: collaborator
• Universität Tübingen: collaborator
• University Hospital Tuebingen: collaborator

Study Sites (5)

University Medical Center for Children and Adolescents Heidelberg

Heidelberg, Baden-Wurttemberg, 69120, Germany

Location

University Children's Hospital Tübingen

Tübingen, Baden-Wurttemberg, 72076, Germany

Location

University Children's Hospital Munich, Center for Pediatric Hematology and Oncology

München, Bavaria, 80337, Germany

Location

University Hospital Düsseldorf, Clinic for Pediatric Oncology, Hematology and Clinical Immunology

Düsseldorf, North Rhine-Westphalia, 40225, Germany

Location

Charite Universitätsmedizin Berlin, Department of Pediatric Oncology/Hematology

Berlin, 13353, Germany

Location

MeSH Terms

Conditions

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Interventions

Imiquimod

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Aminoquinolines; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Peter Lang, Prof. Dr.

  University Children's Hospital Tuebingen

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof. Dr. med.

Study Record Dates

• First Submitted: June 13, 2018
• First Posted: June 18, 2018
• Study Start: June 1, 2016
• Primary Completion: March 1, 2022
• Study Completion: December 1, 2023
• Last Updated: December 4, 2023

Record last verified: 2023-12

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, CSR
• Time Frame: starting at time of publication
• Access Criteria: Anyone, upon request to PI

Locations

DE (5)