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Trial registered on ANZCTR


Registration number
ACTRN12611000029998
Ethics application status
Approved
Date submitted
3/12/2010
Date registered
10/01/2011
Date last updated
26/11/2015
Type of registration
Retrospectively registered

Titles & IDs
Public title
Phase I Trial of Dendritic Cell Vaccination and Temozolomide for Recurrent Glioblastoma Multiforme
Scientific title
Phase I Trial on the feasability and tolerance of treating Recurrent Glioblastoma Multiforme with Dendritic Cell Vaccination and Temozolomide
Secondary ID [1] 253231 0
nil
Universal Trial Number (UTN)
Nil
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Glioblastoma Multiforme (GBM) 258766 0
Condition category
Condition code
Cancer 258911 258911 0 0
Brain

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
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.
Intervention code [1] 257701 0
Treatment: Drugs
Intervention code [2] 257702 0
Treatment: Other
Comparator / control treatment
There is no standard comparator or control treatment.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 259768 0
Feasibility of using resected tissue from recurrent Temozolomide-treated GBM patients to generate autologous, tumour antigen-loaded, DCV. This outcome will be assessed by percentage of successful vaccines produced.
Timepoint [1] 259768 0
At completion of vaccine (DCV) production.
Primary outcome [2] 259769 0
Feasibility of treating recurrent GBM with combined surgery, DC immunotherapy and Temozolomide chemotherapy as assessed by percentage of study patients completing priming course of DCV and 2 cycles of Temozolomide.
Timepoint [2] 259769 0
At completion of priming course of DCV and 2 cycles of Temozolomide.
Primary outcome [3] 259770 0
Safety of treatment (as assessed by the frequency of premature withdrawal due to serious adverse events). Serious adverse events related to autologous dendritic cell vaccination are very rare. There is a small risk of anaphylaxis. Patients are monitored for half an hour after each vaccine prior to discharging home. There are no other serious adverse events expected related to the vaccine. Serious adverse events related to Temozolomide are also rare with neutropenia and thrombocytopenia being the most common occurring in up to 10% of patients. Given that all patients on this study have already demonstrated their tolerance to Temozolomide during their adjuvant treatment, the expectation is that serious adverse events related to Temozolomide would be less than the documented incidence.
Timepoint [3] 259770 0
3 months following completion of all study treatments.
Secondary outcome [1] 268542 0
Radiological response rate to salvage Temozolomide following DCV-treatment relative to salvage Temozolomide alone in historical controls. This outcome will be assessed by MRI
Timepoint [1] 268542 0
After every 2 cycles of Temozolomide.
Secondary outcome [2] 268543 0
Percent progression-free survival at 6 months (PFS6mo) of patients receiving salvage Temozolomide therapy following DCV-treatment relative to salvage Temozolomide alone in historical controls as assessed by clinical assessment by the clinican and MRI
Timepoint [2] 268543 0
6 months post-surgery.
Secondary outcome [3] 268544 0
Tolerability of treatment (Quality of Life assessment by questionnaire).
Timepoint [3] 268544 0
At several timepoints during the study (baseline, week 3, 8, 14 and 22) and after completion of treatment, thereafter at 8 weekly intervals till progressive disease.
Secondary outcome [4] 268545 0
Assessments of vaccine-generated immune responses by self reporting and assessments by trial staff
Timepoint [4] 268545 0
In vitro analysis of tumour-specific immune response in blood pre-vaccination, 2 and 5 weeks after initial vaccination, and every 4 weeks thereafter until 6 cycles of Temozolomide completed, or patient removed from trial. Analysis of delayed type hypersensitivity at day 33 after initial vaccination.

Eligibility
Key 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.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1
Type of endpoint(s)
Safety
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment outside Australia
Country [1] 3074 0
New Zealand
State/province [1] 3074 0

Funding & Sponsors
Funding source category [1] 258172 0
Charities/Societies/Foundations
Name [1] 258172 0
The Cancer Society of New Zealand
Address [1] 258172 0
The Cancer Society of New Zealand
Red Cross House
Level 2
69 Molesworth Street
Wellington 6011
Country [1] 258172 0
New Zealand
Primary sponsor type
Charities/Societies/Foundations
Name
Malaghan Institute of Medical Research
Address
PO Box 7060
Wellington 6242
Country
New Zealand
Secondary sponsor category [1] 257346 0
Hospital
Name [1] 257346 0
Capital and Coast District Health Board
Address [1] 257346 0
Wellington Blood and Cancer Centre
Wellington Hospital
Private Bag 7902
Wellington 6021
Country [1] 257346 0
New Zealand
Other collaborator category [1] 251720 0
Other Collaborative groups
Name [1] 251720 0
Cancer Trials New Zealand
Address [1] 251720 0
Cancer Trials New Zealand
Discipline of Oncology
Room 534-G13C
The University of Auckland
Private Bag 92019
Auckland, 1142
New Zealand
Country [1] 251720 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 260167 0
Central Ethics Comittee
Ethics committee address [1] 260167 0
c/- Ministry of Health
1-3 The Terrace
Level 1
Wellington, 6011
Ethics committee country [1] 260167 0
New Zealand
Date submitted for ethics approval [1] 260167 0
23/11/2007
Approval date [1] 260167 0
06/03/2008
Ethics approval number [1] 260167 0
CEN/07/12/086

Summary
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.
Trial website
Trial related presentations / publications
Hunn, M., Bauer, E., Wood, C., Gasser, O. et al (2015): Using immunotherapy to restore sensitivity to Temozolomide: A phase I trial in patients with recurrent glioblastoma multiforme. Journal of Neuro-Oncology, 121(2):319-29.
Public notes

Contacts
Principal investigator
Name 31985 0
Dr Dr David Hamilton
Address 31985 0
Wellington Blood and Cancer Centre, Wellington Hospital, Private Bag 7902, Wellington 6242
Country 31985 0
New Zealand
Phone 31985 0
+6443855999
Fax 31985 0
+6443855843
Email 31985 0
David.Hamilton@ccdhb.org.nz
Contact person for public queries
Name 15232 0
Ms Catherine Wood
Address 15232 0
Wellington Blood and Cancer Centre
Wellington Hospital
Private Bag 7902
Wellington 6021
Country 15232 0
New Zealand
Phone 15232 0
+ 64 4 806 2091
Fax 15232 0
+ 64 4 385 5843
Email 15232 0
Catherine.Wood@ccdhb.org.nz
Contact person for scientific queries
Name 6160 0
Dr Dr Martin Hunn
Address 6160 0
Consultant Neurosurgeon
Wellington Hospital
Private Bag 7902
Wellington 6021
Country 6160 0
New Zealand
Phone 6160 0
+ 64 4 385 5999
Fax 6160 0
Email 6160 0
Martin.Hunn@ccdhb.org.nz

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary