GAPVAC Phase I Trial in Newly Diagnosed Glioblastoma Patients

NCT ID: NCT02149225

Last Updated: 2018-08-07

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 16 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-10-31
• Study Completion Date: 2018-06-30

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.

Conditions

Glioblastoma

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

APVAC1 and 2 vaccine plus polyICLC and GMCSF concurrent to TMZ

Group Type: EXPERIMENTAL

APVAC1 vaccine plus Poly-ICLC and GM-CSF

Intervention Type: DRUG

APVAC1 vaccines (i.d.) will be individually assembled for each patient and can be applied to the patient approx. 3 months after enrollment. APVAC1 drug products are composed of 5 to 10 peptides from the GAPVAC warehouse. The APVAC1 vaccine will be applied concurrent to maintenance TMZ cycles after completion of chemoradiation therapy (CRT). Beginning on day 15 of the first maintenance TMZ cycle, patients will receive 11 vaccinations with APVAC1 drug products during 22 weeks. 578 μg per peptide per vial are used.

Poly ICLC (1.5 mg s.c.) will be used as immunomodulator with all vaccinations except the second applications of APVAC1 (Day 2) and APVAC2 vaccines (Day 2*) to avoid dose accumulation on consecutive days.

The 2. immunomodulator GM-CSF (75 μg) will be applied i.d. with the first six vaccinations with both vaccines, APVAC1 and APVAC2. A total of 12 GM-CSF doses will be applied. GM-CSF will be applied to the APVAC vaccination site 10-30 min before injection of the APVACs.

APVAC2 vaccine plus Poly-ICLC and GM-CSF

Intervention Type: DRUG

APVAC2 vaccines (i.d.) will be ready for use ca. 6 months after enrollment, as these peptides have to be newly synthesized for each patient following identification of the mutanome and corresponding mutated peptides in the HLA ligandome. APVAC2 drug products are composed of 1 or 2 peptides de novo synthesized for an individual patient. Patients will be repeatedly vaccinated with APVAC2 drug products beginning on day 15 of the 4. maintenance TMZ cycle. Patients will receive 8 vaccinations within 10 weeks. 578 μg per peptide per vial are used.

Poly-ICLC (1.5 mg s.c.) will be used as immunomodulator with all vaccinations except the second applications of APVAC1 (Day 2) and APVAC2 vaccines (Day 2*) to avoid dose accumulation on consecutive days.

GM-CSF (75 μg) will be applied i.d. with the first six vaccinations with both vaccines, APVAC1 and APVAC2. A total of 12 GM-CSF doses will be applied. GM-CSF will be applied to the APVAC vaccination site 10-30 min before injection of the APVACs.

Interventions

APVAC1 vaccine plus Poly-ICLC and GM-CSF

APVAC1 vaccines (i.d.) will be individually assembled for each patient and can be applied to the patient approx. 3 months after enrollment. APVAC1 drug products are composed of 5 to 10 peptides from the GAPVAC warehouse. The APVAC1 vaccine will be applied concurrent to maintenance TMZ cycles after completion of chemoradiation therapy (CRT). Beginning on day 15 of the first maintenance TMZ cycle, patients will receive 11 vaccinations with APVAC1 drug products during 22 weeks. 578 μg per peptide per vial are used.

Poly ICLC (1.5 mg s.c.) will be used as immunomodulator with all vaccinations except the second applications of APVAC1 (Day 2) and APVAC2 vaccines (Day 2*) to avoid dose accumulation on consecutive days.

The 2. immunomodulator GM-CSF (75 μg) will be applied i.d. with the first six vaccinations with both vaccines, APVAC1 and APVAC2. A total of 12 GM-CSF doses will be applied. GM-CSF will be applied to the APVAC vaccination site 10-30 min before injection of the APVACs.

Intervention Type: DRUG

APVAC2 vaccine plus Poly-ICLC and GM-CSF

APVAC2 vaccines (i.d.) will be ready for use ca. 6 months after enrollment, as these peptides have to be newly synthesized for each patient following identification of the mutanome and corresponding mutated peptides in the HLA ligandome. APVAC2 drug products are composed of 1 or 2 peptides de novo synthesized for an individual patient. Patients will be repeatedly vaccinated with APVAC2 drug products beginning on day 15 of the 4. maintenance TMZ cycle. Patients will receive 8 vaccinations within 10 weeks. 578 μg per peptide per vial are used.

Poly-ICLC (1.5 mg s.c.) will be used as immunomodulator with all vaccinations except the second applications of APVAC1 (Day 2) and APVAC2 vaccines (Day 2*) to avoid dose accumulation on consecutive days.

GM-CSF (75 μg) will be applied i.d. with the first six vaccinations with both vaccines, APVAC1 and APVAC2. A total of 12 GM-CSF doses will be applied. GM-CSF will be applied to the APVAC vaccination site 10-30 min before injection of the APVACs.

Intervention Type: DRUG

Other Intervention Names

Actively Personalized Vaccine; Hiltonol; Leukine; Actively Personalized Vaccine; Hiltonol; Leukine

Eligibility Criteria

Inclusion Criteria

1. Histologically confirmed, newly diagnosed GB (astrocytoma WHO grade IV)

2. 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)

3. 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)

4. At least 0.5 g tumor tissue freshly cryopreserved during surgery

5. Age ≥18 years

6. KPS ≥70%

7. Life expectancy > 6 months

8. Patient is a candidate for and willing to receive standard CRT with TMZ followed by maintenance TMZ cycles

9. 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

10. Absolute lymphocyte count (ALC) >1.0 x109/L (re-screening of lymphocyte counts is allowed)

11. 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.

12. Availability of an APVAC analysis and manufacturing slot confirmed by the sponsor

13. Female patients who are post-menopausal (no menstrual period for a minimum of 1 year), or surgically sterile (bilateral tubal ligation, bilateral oophorectomy, or hysterectomy), practice one of the following medically acceptable methods of birth control (hormonal methods, intrauterine device or double-barrier methods) or practice total abstinence

14. Male patients willing to use contraception (condoms with spermicidal jellies or cream) upon study entry and during the course of the study, have undergone vasectomy or are practicing total abstinence

Exclusion Criteria

1. Hemoglobin < 10 g/dL (6.2 mmol/L)

2. White blood cell count (WBC) decrease (<3.0 x109/L) or increase (>10.0 x109/L)

3. Absolute neutrophil count (ANC) decrease < 1.5 x109/L

4. Platelet count decrease < 75 x109/L

5. Bilirubin > 1.5 x ULN (upper limit of normal according to the performing lab's reference range)

6. ALAT > 3 x ULN

7. ASAT > 3 x ULN

8. GGT6 > 2.5 x ULN

9. Serum creatinine increased > 1.5 x ULN

2. HIV infection or active Hepatitis B or C infection, or active infections requiring oral or intravenous antibiotics or that can cause a severe disease and pose a severe danger to lab personnel working on patients' blood or tissue (e.g. rabies).

3. Prior therapy for glioma (except surgery and steroids) including but not limited to carmustine wafers and immunotherapy

4. Any condition contraindicating leukapheresis from peripheral veins

5. Concurrent participation in another interventional clinical trial studying a drug or treatment regimen.

6. Clinically relevant autoimmune diseases (with the exception of thyroid diseases)

7. Immunosuppression, not related to prior treatment for malignancy, or prior drug reaction

8. Any condition that in the judgment of the investigator interferes with the probability that an individual patient may receive and benefit from APVAC vaccinations (e.g. high risk of early disease progression / recurrence; immunocompromised status; anticipated compliance problems)

9. Serious illness or condition, which according to the investigator, poses an undue risk for the patient when participating in the trial, including, but not limited to, any of the following:

• Clinically significant cardiovascular disease
• New York Heart Association class III-IV congestive heart failure
• Symptomatic peripheral vascular disease
• Severe pulmonary dysfunction
• Severe diabetes
• Severe mental retardation

10. History of other malignancies (except for adequately treated basal or squamous cell carcinoma or carcinoma in situ) within the last 5 years unless the patient has been disease-free for 5 years

11. Pregnancy or breastfeeding

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

BioNTech SE

INDUSTRY

Sponsor Role: collaborator

University Hospital Tuebingen

OTHER

Sponsor Role: collaborator

BCN Peptides

INDUSTRY

Sponsor Role: collaborator

EU-funded GAPVAC Consortium

UNKNOWN

Sponsor Role: collaborator

Immatics Biotechnologies GmbH

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Wolfgang Wick, Professor

Role: PRINCIPAL_INVESTIGATOR

University of Heidelberg Medical Center

Pierre-Yves Dietrich, Professor

Role: PRINCIPAL_INVESTIGATOR

University Hospital, Geneva

Locations

Rigshospitalet, The Finsen Centre, Department of Oncology

Copenhagen, , Denmark

Neurologische Klinik & Nationales Centrum für Tumorerkrankungen Heidelberg

Heidelberg, , Germany

Zentrum für Neurologie und Klinik für Neurochirurgie

Tübingen, , Germany

Leiden University Medical Center, Department of Medical Oncology

Leiden, , Netherlands

Vall d'Hebron University Hospital

Barcelona, , Spain

Hôpitaux Universitaires de Genève

Geneva, , Switzerland

Countries

Denmark; Germany; Netherlands; Spain; Switzerland

Other Identifiers

2013-002801-71

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

GAPVAC-101

Identifier Type: -

Identifier Source: org_study_id