None listed
Conditions
Brief summary
The development of drug resistance is a major cause for the failure of chemotherapy in the treatment of cancer patients. We wish to explore the possibility that this therapeutic impasse can be overcome by appropriately sequenced immunotherapy and chemotherapy. We hypothesise that many of the proteins involved in developing drug resistance will be over-expressed in tumour tissue relative to normal tissue, and can therefore serve as targets for vaccine-induced immune attack. A course of immunotherapy designed to drive immune responses towards drug-induced proteins may therefore 'sensitise' tumour tissue to further chemotherapy by selectively removing drug-resistant cells. We wish to explore this possibility in patients with glioblastoma multiforme, as this aggressive disease recurs in all patients post-chemotherapy, and current salvage chemotherapies are ineffective. The aims of this safety trial are: 1) To investigate the feasibility of generating vaccines using surgically-removed tissue from patients who have recurred after treatment with the chemotherapeutic drug temozolomide 2) To investigate the feasibility and safety of administering these vaccines prior to, and during, subsequent rounds of temozolomide therapy 3) To investigate whether the vaccination procedure generated from temozolomide-exposed tissue sensitises progressing tumours to subsequent temozolomide.
Interventions
Autologous dendritic cells cultured from peripheral white blood cells and loaded in vitro with irradiated autologous tumour tissue obtained by surgery, day 0. Surgery is often performed to debulk recurrent tumour. There is no "standard" treatment for recurrent GBM and outwith trials, each case is assessed on individual circumstances. Suitability for second surgery is however a prerequisite of this study.
The dendritic cell-based vaccines (DCV) will be administered intradermally. Patients will re
Autologous dendritic cells cultured from peripheral white blood cells and loaded in vitro with irradiated autologous tumour tissue obtained by surgery, day 0. Surgery is often performed to debulk recurrent tumour. There is no "standard" treatment for recurrent GBM and outwith trials, each case is assessed on individual circumstances. Suitability for second surgery is however a prerequisite of this study. The dendritic cell-based vaccines (DCV) will be administered intradermally. Patients will receive an initial priming course of three DC vaccinations of 4 x 10^6 cells, administered at week 3, 5 and 7. Further booster DCV vaccinations (1 x 10^6 cells) will start at week 10 and then alternate with courses of temozolomide on a 28 day cycle. Patients will receive a maximum of 6 booster DCV vaccinations over a period of 6 months. Temozolomide will be administered at an adjuvant dose of 150-200 mg/m2 Body Surface Area (BSA) for 5 days every 28 days, a maximum of 6 cycles of Temozolomide over a period of 6 months, with total duration of the treatment up to 26 weeks. The 6 cycles of boost DCV vaccine alternate fortnightly with the 6 cycles of Temozolomide.
Sponsors
Malaghan Institute of Medical Research
Study design
Allocation
Non-randomised trial
Intervention model
Single group
Primary purpose
Treatment
Masking
Open (masking not used)
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Able to give written informed consent and aged 18 or over. 2. Confirmed diagnosis of WHO Grade 4 Diffuse Astrocytoma (also known as Glioblastoma Multiforme) at original presentation and has relapsed. 3. Has completed treatment with external beam radiotherapy and concomitant Temozolomide, and at least the first 3 cycles of adjuvant Temozolomide. 4. Tumour is surgically accessible with acceptable risk of morbidity. 5. Has at least 1cm3 tumour tissue available as source for tumour antigen. 6. ECOG Performance Status = 2 7. Geographically accessible to the Wellington Blood and Cancer Centre and/or prepared to travel regularly to Wellington for treatment and follow-up for the duration of the study. 8. If fertile, prepared to use contraception for the duration of the trial. Postmenopausal women must have been amenorrhoea for at least 12 months to be considered of non-childbearing potential.
Exclusion criteria
1. Pregnant or breastfeeding women. 2. Diagnosis of another malignancy within 5 years or presence of other serious unstable medical condition. 3. Serology indicating active infection with Hepatitis B or C, or HIV. 4. Uncontrolled or unstable auto-immune disease such as SLE, sarcoidosis, rheumatoid arthritis, glomerulonephritis or vasculitis. 5. Previous use of long term immunosuppressive therapy in recent months. (NB perioperative short term dexamethasone, which is normal treatment, does not preclude inclusion in the trial). 6. Treatment with any chemotherapeutic agent other than Temozolomide since first diagnosis with GBM. 7. Concurrent major organ dysfunction, unstable medical condition, or significant abnormality of haematological, liver or renal function parameters.(Hb < 100 g/l, platelet count < 100 x 10^9/L, neutrophil count < 1.5x10^9/L , LFT or creatinine > 2 x upper limit normal). 8. Unfit for general anaesthesia. 9. Significant dysphasia or other neurological deficit likely to impair reliable communication between the participant and the investigators
Outcome results
None listed