Back to resultsPatient-individualized Peptide Vaccination Based on Tumor-specific Mutations in Children and Young Adults With Primary/Relapsed ALL
Primary Purpose
Primary/Relapsed Acute Lymphoblastic Leukemia (ALL) of Childhood, Adolescents and Young Adults
Status
Unknown status
Phase
Phase 1
Locations
Germany
Study Type
Interventional
Intervention
Individual peptide vaccination with adjuvant GM-CSF and Imiquimod
Sponsored by
About this trial
This is an interventional treatment trial for Primary/Relapsed Acute Lymphoblastic Leukemia (ALL) of Childhood, Adolescents and Young Adults focused on measuring Individualized peptide vaccination, Immunotherapy, Tumor-specific mutations, Neoantigens
Eligibility 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.
Sites / Locations
- University Medical Center for Children and Adolescents Heidelberg
- University Children's Hospital Tübingen
- University Children's Hospital Munich, Center for Pediatric Hematology and Oncology
- University Hospital Düsseldorf, Clinic for Pediatric Oncology, Hematology and Clinical Immunology
- Charite Universitätsmedizin Berlin, Department of Pediatric Oncology/Hematology
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Intervention group
Arm Description
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
To evaluate CD4+ and/or CD8+ T-cell responses over the vaccination period.
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.
To evaluate changes in minimal residual disease (MRD) during and after treatment.
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.
To evaluate the relapse rate during and after treatment.
Relapse rates will be assessed on days 120 and 246.
To evaluate the event-free survival (EFS) during and after treatment.
EFS will be assessed on days 120 and 246.
Full Information
NCT ID
NCT03559413
First Posted
June 13, 2018
Last Updated
March 25, 2020
Sponsor
University Children's Hospital Tuebingen
Collaborators
German Cancer Research Center, Universität Tübingen, University Hospital Tuebingen
1. Study Identification
Unique Protocol Identification Number
NCT03559413
Brief Title
Patient-individualized Peptide Vaccination Based on Tumor-specific Mutations in Children and Young Adults With Primary/Relapsed ALL
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
Study Type
Interventional
2. Study Status
Record Verification Date
March 2020
Overall Recruitment Status
Unknown status
Study Start Date
June 2016 (Actual)
Primary Completion Date
March 2021 (Anticipated)
Study Completion Date
August 2021 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University Children's Hospital Tuebingen
Collaborators
German Cancer Research Center, Universität Tübingen, University Hospital Tuebingen
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
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).
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Primary/Relapsed Acute Lymphoblastic Leukemia (ALL) of Childhood, Adolescents and Young Adults
Keywords
Individualized peptide vaccination, Immunotherapy, Tumor-specific mutations, Neoantigens
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
30 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Intervention group
Arm Type
Experimental
Intervention Type
Biological
Intervention Name(s)
Individual peptide vaccination with adjuvant GM-CSF and Imiquimod
Intervention Description
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 Measure Information:
Title
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).
Description
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.
Time Frame
120 days
Secondary Outcome Measure Information:
Title
To evaluate CD4+ and/or CD8+ T-cell responses over the vaccination period.
Description
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.
Time Frame
246 days
Title
To evaluate changes in minimal residual disease (MRD) during and after treatment.
Description
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.
Time Frame
246 days
Title
To evaluate the relapse rate during and after treatment.
Description
Relapse rates will be assessed on days 120 and 246.
Time Frame
246 days
Title
To evaluate the event-free survival (EFS) during and after treatment.
Description
EFS will be assessed on days 120 and 246.
Time Frame
246 days
10. Eligibility
Sex
All
Minimum Age & Unit of Time
1 Year
Maximum Age & Unit of Time
30 Years
Accepts Healthy Volunteers
No
Eligibility 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Peter Lang, Prof. Dr.
Organizational Affiliation
University Children's Hospital Tuebingen
Official's Role
Principal Investigator
Facility Information:
Facility Name
University Medical Center for Children and Adolescents Heidelberg
City
Heidelberg
State/Province
Baden-Württemberg
ZIP/Postal Code
69120
Country
Germany
Facility Name
University Children's Hospital Tübingen
City
Tübingen
State/Province
Baden-Württemberg
ZIP/Postal Code
72076
Country
Germany
Facility Name
University Children's Hospital Munich, Center for Pediatric Hematology and Oncology
City
München
State/Province
Bayern
ZIP/Postal Code
80337
Country
Germany
Facility Name
University Hospital Düsseldorf, Clinic for Pediatric Oncology, Hematology and Clinical Immunology
City
Düsseldorf
State/Province
Nordrhein-Westfalen
ZIP/Postal Code
40225
Country
Germany
Facility Name
Charite Universitätsmedizin Berlin, Department of Pediatric Oncology/Hematology
City
Berlin
ZIP/Postal Code
13353
Country
Germany
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
all IPD that underlie results in a publication
IPD Sharing Time Frame
starting at time of publication
IPD Sharing Access Criteria
Anyone, upon request to PI
Learn more about this trial
Patient-individualized Peptide Vaccination Based on Tumor-specific Mutations in Children and Young Adults With Primary/Relapsed ALL
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