A Phase I Trial of Actively Personalized Peptide Vaccinations Plus Immunomodulators in Patients With Newly Diagnosed Glioblastoma Concurrent to First Line Temozolomide Maintenance Therapy
Overview
- Phase
- Phase 1
- Intervention
- APVAC1 vaccine plus Poly-ICLC and GM-CSF
- Conditions
- Glioblastoma
- Sponsor
- Immatics Biotechnologies GmbH
- Enrollment
- 16
- Locations
- 6
- Primary Endpoint
- Safety profile of patient-tailored APVAC vaccines when administered with immunomodulators concurrent to maintenance TMZ cycles
- Status
- Completed
- Last Updated
- 7 years ago
Overview
Brief Summary
The primary objective of this study is to assess the safety and tolerability, feasibility and biological activity (immunogenicity) of the actively personalized vaccination (APVAC) concept in newly diagnosed glioblastoma (GB) patients.
Detailed Description
This is a multicenter, open-label, single arm, first-in-man phase I trial to investigate the safety, feasibility and immunogenicity of the novel APVAC approach in patients with newly diagnosed GB. Primary Endpoints: * Safety: Determine the safety and tolerability profile of patient-tailored APVAC vaccines when administered with immunomodulators concurrent to maintenance temozolomide (TMZ) cycles. * Feasibility: Determine duration and success rates for APVAC1 and APVAC2 processes and for vaccinations with APVAC drug products. * Biological activity: Descriptive analysis of induced T-cell responses after vaccinations with APVAC1 and APVAC2 drug products plus immunomodulators. Secondary Study Objectives: * Identification of biomarkers putatively predictive for immunological response and/or associated with clinical success or failure. Analyzed biomarkers may include non-cellular parameters measured from tumor, plasma or serum, and cellular parameters measured from peripheral blood mononuclear cells (PBMCs), leukapheresis samples or isolated tumor-infiltrating lymphocytes (TILs). * Description of potential clinical activity of the APVAC drug products. Descriptive analysis of clinical outcome in patients will be reported including OS and PFS. Correlation analysis of these parameters with immune response data may provide first hints on clinical activity of the vaccine. After the standard chemoradiotherapy with TMZ has been completed and as soon as the start of the first maintenance TMZ cycle the vaccination phase begins. It starts with the first APVAC1 vaccination, followed by additional APVAC2 vaccinations at a later time point and ends with the Last Endpoint Evaluation Visit (LEEV) of a patient. Single vaccinations with APVAC vaccines consist of an intradermal (i.d.) injection of the personalized APVAC drug product into the skin of the thigh, shoulder or abdomen followed by subcutaneous (s.c.) injection of 1.5 mg poly-ICLC (Hiltonol®) in close proximity to the vaccination site. The second immunomodulator GM-CSF (75 μg) will be applied i.d. to the APVAC vaccination site 10-30 min before injection of the APVACs.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Histologically confirmed, newly diagnosed GB (astrocytoma WHO grade IV)
- •HLA phenotype defined by warehouse composition (HLA-A\*02:01 or HLA-A\*24:02 positive patients only; both as determined by a PCR-based 4-digit typing method)
- •Gross total resection (as defined by less than 1 cm2 residual tumor mass on the largest perpendicular axes in post-operative scan taken within 48 h post-surgery; standard MRI conformable to the present national and international guidelines is sufficient)
- •At least 0.5 g tumor tissue freshly cryopreserved during surgery
- •Age ≥18 years
- •Life expectancy \> 6 months
- •Patient is a candidate for and willing to receive standard CRT with TMZ followed by maintenance TMZ cycles
- •Patient is not on steroids or on stable or decreasing steroid levels not exceeding 2 mg/day dexamethasone (or equivalent doses of other steroids) during the last 3 days prior to enrollment
- •Absolute lymphocyte count (ALC) \>1.0 x109/L (re-screening of lymphocyte counts is allowed)
- •Ability of subject to understand and the willingness to sign written informed consent for study participation. Written consent by a legally authorized representative is not sufficient.
Exclusion Criteria
- •Abnormal (≥ Grade 2 CTCAE v4.0) laboratory values for hematology, liver and renal function (serum creatinine). In detail the following values apply as exclusion criteria:
- •Hemoglobin \< 10 g/dL (6.2 mmol/L)
- •White blood cell count (WBC) decrease (\<3.0 x109/L) or increase (\>10.0 x109/L)
- •Absolute neutrophil count (ANC) decrease \< 1.5 x109/L
- •Platelet count decrease \< 75 x109/L
- •Bilirubin \> 1.5 x ULN (upper limit of normal according to the performing lab's reference range)
- •ALAT \> 3 x ULN
- •ASAT \> 3 x ULN
- •GGT6 \> 2.5 x ULN
- •Serum creatinine increased \> 1.5 x ULN
Arms & Interventions
APVAC1 and 2 vaccine plus polyICLC and GMCSF concurrent to TMZ
Intervention: APVAC1 vaccine plus Poly-ICLC and GM-CSF
APVAC1 and 2 vaccine plus polyICLC and GMCSF concurrent to TMZ
Intervention: APVAC2 vaccine plus Poly-ICLC and GM-CSF
Outcomes
Primary Outcomes
Safety profile of patient-tailored APVAC vaccines when administered with immunomodulators concurrent to maintenance TMZ cycles
Time Frame: Continously for about 40 weeks plus follow-up
Number of Adverse Events (AEs) and Serious Adverse Events (SAEs) and percentage of patients with AEs and SAEs (listed per grade and MedDRA (Medical Dictionary for Regulatory Activities ) preferred terms) will be reported.
Frequency of CD8 T cells specific for vaccinated APVAC peptides as measure of immunological response to and biological activity of the vaccine
Time Frame: Till 17 weeks of vaccination
To analyze whether vaccinations with APVAC drug products plus poly-ICLC and GM-CSF induce immune responses in the patients. Peripheral blood mononuclear cells will be analyzed for the presence and functionality of T cells recognizing the peptides vaccinated within the individualized APVACs. * Immunogenicity rate: Number of vaccine induced T-cell responses normalized to the number of peptides vaccinated. * Immune responder rate: Number of patients with at least one vaccine induced T-cell response * Multi-TUMAP responder rate: Number of patients with at least two vaccine induced T-cell response * Average number of immune responses per patient
Secondary Outcomes
- Progression-free survival(At 6 months)
- Overall survival(2018 (estimated))
- Frequency of immune cell populations in the blood and concentrations of a large panel of serum and plasma proteins with immunological relevance as a measure of the immune status of the patient(Up to 10 months)