Clinical trial NCT03559413: 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
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Primary/Relapsed Acute Lymphoblastic Leukemia (ALL) of Childhood, Adolescents and Young Adults
Keywords: Individualized peptide vaccination
Immunotherapy
Tumor-specific mutations
Neoantigens
Lead sponsor: University Children's Hospital Tuebingen
Sponsor class: OTHER
Collaborators: name: German Cancer Research Center
name: Universität Tübingen
name: University Hospital Tuebingen
First posted: 2018-06-18
Enrollment: 30
Sex: ALL
Minimum age (years): 1
Maximum age (years): 30
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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).


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.

Primary outcomes:
measure: 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).
timeFrame: 120 days
Secondary outcomes:
measure: To evaluate CD4+ and/or CD8+ T-cell responses over the vaccination period.
timeFrame: 246 days
measure: To evaluate changes in minimal residual disease (MRD) during and after treatment.
timeFrame: 246 days
measure: To evaluate the relapse rate during and after treatment.
timeFrame: 246 days
measure: To evaluate the event-free survival (EFS) during and after treatment.
timeFrame: 246 days
Other outcomes:
Locations:
city: Heidelberg
country: Germany
facility: University Medical Center for Children and Adolescents Heidelberg
state: Baden-Württemberg
city: Tübingen
country: Germany
facility: University Children's Hospital Tübingen
state: Baden-Württemberg
city: München
country: Germany
facility: University Children's Hospital Munich, Center for Pediatric Hematology and Oncology
state: Bayern
city: Düsseldorf
country: Germany
facility: University Hospital Düsseldorf, Clinic for Pediatric Oncology, Hematology and Clinical Immunology
state: Nordrhein-Westfalen
city: Berlin
country: Germany
facility: Charite Universitätsmedizin Berlin, Department of Pediatric Oncology/Hematology
Study officials:
affiliation: University Children's Hospital Tuebingen
name: Peter Lang, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
References: