Immunotherapy With Autologous Tumor Lysate-Loaded Dendritic Cells In Patients With Newly Diagnosed Glioblastoma Multiforme

NCT ID: NCT04801147

Last Updated: 2024-11-08

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 76 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-06-26
• Study Completion Date: 2024-12-31

Brief Summary

Rationale of the Study: Treatment for GBM currently consists of surgical resection of the tumour mass followed by radio- and chemotherapy ((1)Stupp et al., 2005). Nonetheless overall prognosis still remains bleak, recurrence is universal, and recurrent GBM patients clearly need innovative therapies. Dendritic cells (DC) immunotherapy could represent a well-tolerated, long-term tumour-specific treatment to kill all (residual) tumour cells which infiltrate in the adjacent areas of the brain. Preclinical investigations for the development of therapeutic vaccines against high grade gliomas, based on the use of DC loaded with a mixture of glioma-derived tumor have been carried out in rat as well as in mouse models, showing the capacity to generate a glioma-specific immune response. Mature DC loaded with autologous tumor lysate have been used also for the treatment of patients with recurrent malignant brain tumors; no major adverse events have been registered. Results about the use of immunotherapy for GBM patients are encouraging, but further studies are necessary to find out the most effective and safe combination of immunotherapy with radio- and chemotherapy after exeresis of the tumour mass.

Aim of the study. Primary objective of the study is to evaluate treatment tolerability and to get preliminary information about efficacy. Secondary objective is to evaluate the treatment effect on the immune response. Additional objective is to identify a possible correlation between methylation status of MGMT promoter and tumor response to treatment.

A two-stage Simon design ((2)Simon, 1989) will be considered for the study. Assuming as outcome measure the percentage of PFS12 patients and of clinical interest an increase to 42% (P1) of the historical control rate of 27% (P0) ((1)Stupp et al., 2005), the alternative hypothesis will be rejected at the end of the first stage if the PFS12 rate will be less than 8/24 treated patients (Fisher's exact test). In the second stage patients will be enrolled up to 76 overall. The null hypothesis will be rejected (a=0.05, b=0.2) if at least 27 subjects out of 76 are alive and progression free 12 months after the beginning of the treatment.

Detailed Description

Background and significance. The therapeutic program will include radical surgical resection of the tumor, followed by radiotherapy (fractionated local field irradiation in daily fractions of 2 Gy given 5 days per week, Monday through Friday for 6 weeks, for a total of 60 Gy) plus temozolomide (TMZ) chemotherapy (75 mg per square meter of body-surface area per day, 7 days per week from the first to the last day of radiotherapy). After a 4-week break, up to 6 cycles of maintenance TMZ (mTMZ) will be administered according to the standard 5-day (oral intake) schedule every 28 days. TMZ dose will be 150 mg per square meter for the first cycle and will be increased to 200 mg per square meter beginning with the second cycle, so long as there is no hematologic toxic effect. Immunotherapy will follow radiochemotherapy and will comprise 4 vaccinations every second week (injections I, II, III, IV), 2 further monthly vaccinations (injections V, VI) and a final vaccination (injection VII) 2 months after the sixth one. Injections I, V, VI and VII will contain 10 million tumor lysate-loaded DC, while the others will be of 5 million cells only. In correspondence to the third vaccine injection (week 13), mTMZ will start. On the basis of the patient clinical status, further vaccine boosts will be considered as appropriate addition at the standard vaccination cycle.

Conditions

Glioblastoma

Study Design

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

Study Groups

Immunotherapy

Autologous DC loaded with a autologous tumor lysate, in order to stimulate the immune response of the patient.

Group Type: EXPERIMENTAL

Dendritic Cells Vaccine

Intervention Type: BIOLOGICAL

Right after the surgical resection of the tumor, leukapheresis will be performed.

At least 5x109 PBMC must be collected by leukapheresis, so as to make the whole immunotherapy schedule workable.

Immunotherapy will follow radiochemotherapy and will comprise 4 vaccinations every second week (injections I, II, III, IV), 2 further monthly vaccinations (injections V, VI) and a final vaccination (injection VII) 2 months after the sixth one. Injections I, V, VI and VII will contain 10 million tumor lysate-loaded DC, while the others will be of 5 million cells only. In correspondence to the third vaccine injection (week 13), mTMZ will start.

Vaccine doses will be injected in the forearm of the patient.

Interventions

Dendritic Cells Vaccine

Right after the surgical resection of the tumor, leukapheresis will be performed.

At least 5x109 PBMC must be collected by leukapheresis, so as to make the whole immunotherapy schedule workable.

Immunotherapy will follow radiochemotherapy and will comprise 4 vaccinations every second week (injections I, II, III, IV), 2 further monthly vaccinations (injections V, VI) and a final vaccination (injection VII) 2 months after the sixth one. Injections I, V, VI and VII will contain 10 million tumor lysate-loaded DC, while the others will be of 5 million cells only. In correspondence to the third vaccine injection (week 13), mTMZ will start.

Vaccine doses will be injected in the forearm of the patient.

Intervention Type: BIOLOGICAL

Eligibility Criteria

Inclusion Criteria

• Age ≥18 years and ≤70 years.
• Postoperative Karnofsky Performance Status ≥70.
• First diagnosis of GBM (World Health Organization [WHO] grade IV astrocytoma).
• Diagnosis confirmed by the reference histopathology.
• Residual tumor volume after resection <10 cc, confirmed by postoperative MRI assessment
• Total or subtotal resection of tumor mass, confirmed by assessment of the neurosurgeon and by postoperative radiological assessment.
• Amount of non-necrotic tissue for lysate preparation and DC loading ≥1 gr, stored at -80°C.
• Corticosteroids daily dose ≤4 mg during the 2 days prior to leukapheresis.
• Clinical indication for radiochemotherapy according to the Stupp protocol (Stupp et al., 2005).
• Life expectancy > 3 months.
• Informed consent

Exclusion Criteria

• Pregnancy.
• Participation in other clinical trials with experimental drugs simultaneously or within 1 month before this trial entry.
• Presence of acute infection requiring active treatment.
• Mandatory treatment with corticosteroids or salicylates in anti-inflammatory dose.
• Presence of sub-ependymal diffusion of the tumor.
• Presence of multi-focal GBM lesions.
• Haematology: leukocytes < 3,000/μl, lymphocytes < 500/μl, neutrophils < 1,000/μl, hemoglobin <9 g/100 ml, thrombocytes < 100,000/μl one or two days prior to leukapheresis.
• Documented immune deficiency.
• Documented autoimmune disease.
• Positive serology for HIV, HBs antigen, HCV, TPHA.
• Allergies to any component of the DC vaccine.
• Known intolerance to TMZ.
• Other active malignancy.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

UOC Neuro-oncologia Molecolare

Milan, , Italy

Site Status: RECRUITING

Countries

Italy

Central Contacts

Marica Eoli, MD

Role: CONTACT

marica.eoli@istituto-besta.it

+022394 ext. 2285

Facility Contacts

Marica Eoli, MD

Role: primary

marica.eoli@istituto-besta.it

+022394 ext. 2285

Other Identifiers

DENDR1

Identifier Type: -

Identifier Source: org_study_id