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

Phase 1

Completed

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

• Registration Number: NCT03559413
• Lead Sponsor: 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).

Detailed Description

Not available

Study Timeline

• Study Start: 2016-06
• Study First Submitted: 2018-06-13
• Study First Submitted QC: 2018-06-15
• Study First Posted: 2018-06-18
• Primary Completion: 2022-03
• Status Verified: 2023-12
• Study Completion: 2023-12
• Last Update Submitted: 2023-12-01
• Last Update Posted: 2023-12-04

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 30

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Primary Outcome Measures

Name	Time	Method
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).	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

Name	Time	Method
To evaluate CD4+ and/or CD8+ T-cell responses over the vaccination period.	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.
To evaluate the relapse rate during and after treatment.	246 days	Relapse rates will be assessed on days 120 and 246.
To evaluate changes in minimal residual disease (MRD) during and after treatment.	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.
To evaluate the event-free survival (EFS) during and after treatment.	246 days	EFS will be assessed on days 120 and 246.

Trial Locations

Locations (5)

University Medical Center for Children and Adolescents Heidelberg; 🇩🇪 Heidelberg, Baden-Württemberg, Germany

University Children's Hospital Tübingen; 🇩🇪 Tübingen, Baden-Württemberg, Germany

University Children's Hospital Munich, Center for Pediatric Hematology and Oncology; 🇩🇪 München, Bayern, Germany

University Hospital Düsseldorf, Clinic for Pediatric Oncology, Hematology and Clinical Immunology; 🇩🇪 Düsseldorf, Nordrhein-Westfalen, Germany

Charite Universitätsmedizin Berlin, Department of Pediatric Oncology/Hematology; 🇩🇪 Berlin, Germany