Based on the encouraging results from prostate cancer trials, clinical trials have been conducted where patients with brain cancer are treated with ALECSAT immunotherapy. Patients with Glioblastoma Multiforme (GBM) brain cancer have a very significant need for better treatment options. Current existing treatments only have limited overall survival effect and many have serious side effects.
Glioblastoma (stage IV) patients, that could not be given any further standard treatments, have been treated with repeated doses of ALECSAT and evaluated in this clinical phase I study. Due to the very serious and rapid development of this cancer disease, it was not possible to give all the patients the intended 3 ALECSAT treatments. However, repeated ALECSAT treatments were seen to be well tolerated and no side effects were seen that could be associated to the treatments.
In the study, it was also seen that some patients receiving ALECSAT treatments experienced prolonged survival. For some patients, that received the three treatments according to the protocol, reductions in tumor size and some apparent improved Quality of life was also seen.
Data and conclusion from this study is seen:
End of study report/publication CV003
The study was an open-labelled, randomized multicenter study, aimed at comparing progression-free survival (PFS) in patients with relapsed GBM when the subjects were treated either with ALECSAT immunotherapy or the Danish standard second line therapy with Avastin/Irinotecan. The patients in the study were recurrent GBM stage IV patients that had received both first and second line treatments. 25 subjects were analyzed, 15 patients in the ALECSAT arm and 10 patients in the Avastin/Irinotecan control arm. The study was terminated by sponsor as it was evaluated that the study would not reach the intended primary endpoint and advice from the European Medicines Agency (EMA) suggested that several protocol amendments should be applied.
Data and conclusion from this study is seen:
End of study report/publication CV005
An open-label, randomized, phase II multicentre study to investigate the efficacy and safety of ALECSAT treatment as an add-on therapy to standard of care (SOC) in patients with newly diagnosed GBM. The objective is to compare Overall Survival (OS) between patients who receive SOC treatment only – to patients that also receive ALECSAT as an add-on therapy.
In this study ALECSAT immunotherapy treatment is initiated already at the time of diagnosis, in addition to normal standard of care treatment.
This clinical phase II study is ongoing at five clinical centres in Sweden, the primary investigator site is Sahlgrenska University hospital in Gothenburg. The study is also conducted at clinical sites at the Karolinska Universty hospital in Stockholm, the university hospitals in Uppsala and Lund, and the hospital in Jonköping.
The outline of this study is seen:
Aim and plan for the ongoing CV006 study
|MR scanning||MR scanning||PET scanning||PET scanning|
|Tumor volume estimated by MR scanning indicates that the tumor volume for this patient is reduced 76% over 11 months||The PET active tumor tissue is seen to be reduced over 5 months of ALECSAT treatments.|
The data from this study indicate no safety concerns related to repeated administrations of ALECSAT to relapsed GBM patients, even though these GBM patients are a considerably more fragile group of patients compared to prostate cancer patients that participated in the CV001 and CV002 studies.
Brain Scanning of the 10 patients completing the study protocol, in 6 patients MRI of the brain showed stable disease at some time point during the trial. Several patients showed a continued shrinkage of tumour volume with a remarkable reduction of tumour size.
The therapeutic effect seems to be mediated by several mechanisms. After systemic injection of ALECSAT cells, we observed
Preliminary conclusions suggest that ALECSAT treatments may have a clinically relevant positive effect on these patients disease regarding both survival, tumor size / growth and quality of life.
This figure shows how long the 10 patients that received 3 ALECSAT treatments have lived after entering the ALECSAT study. The 1. 2. and 3. ALECSAT treatment is given at the end of the blue, red and green part of the bars. The green part of the bars is follow up period where additional treatmens are given every 3 – 4 months.
Survival and preliminary conclusion CV003
This clinical phase I study that was designed to show safety and tolerability, and the conclusion is that ALECSAT treatments are safe and well tolerated by GBM patients. For the 10 patients that received 3 or more ALECSAT treatments there are good indications for prolonged survival the average survival was 25,6 months. Furthermore there are patients where the brain tumor size has reduced considerably during and after the study – which is quite unusual for late stage recurrent GBM patients. These encouraging results warranted that clinical phase II trials were initiated to verify if ALECSAT could be applied to the treatment of late stage recurrent Glioblastoma Multiforme.
So far only few brain cancer patients have been treated with ALECSAT – so the clinical efficacy observations that are seen in this study are not yet statistically significant. The clinical effect of ALECSAT is therefore not finally proven. The ongoing Phase II clinical trial will include a sufficient number of study subjects and a control group so the statistical significance may be demonstrated.
A phase I study to investigate tolerability and efficacy of Autologous Lymphoid Effector Cells Specific against Tumour-cells (ALECSAT) to patients with Glioblastoma multiforme (GBM)
Study investigators and sites: There was one principal investigator at Department of Neurosurgery at Copenhagen University Hospital, Rigshospitalet, and the Principal coordinating and signatory investigator was staff doctor Walter Fischer, Department of neurology, Copenhagen University Hospital, Rigshospitalet, 2100 Copenhagen, Denmark.
Studied period: First Subject Enrolled 18 August 2011 – Last Subject Completed 19 March 2013
The primary objective for this study was to establish if any side effects or toxicity issues occur, that will prevent further clinical development of the ALECSAT therapy in GBM or to establish if there were side effects or toxicity issues, that will suggest that the further clinical development planned, has to change course significantly.
The secondary objective for this study was to establish if any indications of a positive therapeutic or palliative effect could be observed.
The key parameters were measurements of Magnetic Resonance Imaging (MRI) and F-fluorethyltyrosine labelled Positron Emission Tomography (FET-PET). The potential accumulation of ALECSAT cells in the subject brain was measured by white blood cell (WBC) scintigraphy. The assessment of Quality of Life and Karnofsky Index was logged to detect indications of possible beneficial therapeutic or palliative effects. Planned Number of Study Participants: 14 evaluable subjects Number of Study Participants analysed: 23 subjects for safety, 14 subjects for efficacy trends
Planned Number of Study Participants: 14 evaluable subjects
Number of Study Participants analysed: 23 subjects for safety, 14 subjects for efficacy trends
Diagnosis and main criteria for inclusion
Subjects having received all available standard treatment where the GBM tumour disease is progressing:
Test product, Dose, Mode of administration, Batch Numbers and Duration of Treatment
Test product: ALECSAT
Dose: In total 47 doses were administered during the study period. The mean number of cells in the above mentioned batches were 156 million (range 5. 4 million – 1. 8 billion; median 68 million) and the mean viability 94 % (range 83 – 100%, median 95%).
Administration: Slowly intravenously over a period of approximately 5 minutes through a venflon.
Test product: ALECSAT
Based on this study, immunotherapy with ALECSAT, as stand-alone treatment, show trends of efficacy in terms of stable disease in some of the subjects measured by MRI and PET. The trend of efficacy is remarkable in the light of that the ALECSAT treated subject had received all possible treatments before entering the study. The results from the study show no unexpected, adverse events. The result from the study encourages us to proceed to next study phase, a controlled study with the ALECSAT product.
The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice.
Date of Report 26 March 2015
An Open-labelled, Randomized Phase II Multicentre Study to Investigate Efficacy of Autologous Lymphoid Effector Cells Specific Against Tumour-Cells (ALECSAT) in Patients with Glioblastoma Multiforme Measured as Progression Free Survival Compared to Avastin/Irinotecan
Study investigators and sites: Charlotte Aaquist Haslund, Aalborg University Hospital, Aalborg, Denmark (Coordinating Principal Investigator), Aida Muhic, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark and Slávka Lukacova, Aarhus University Hospital, Aarhus, Denmark
Study period: 22-Apr-2014 to 12-Jun-2015
To compare progression-free survival (PFS) in subjects with relapsed glioblastoma multiforme (GBM) when the subjects were treated either with ALECSAT immunotherapy or standard praxis therapy with Avastin/Irinotecan.
Secondary Efficacy Objectives
This study was a prospective, open-label, randomised, parallel group study with ALECSAT compared to Avastin/Irinotecan in GBM patients with verified relapsed disease after or during treatment with standard regimen or another recognised first-line treatment.
The subjects in the two treatment groups were to be followed at 18 planned study visits for up to 62 weeks. After informed consent and check of inclusion and exclusion criteria, baseline evaluations were performed, including medical history, electrocardiogram (ECG) and baseline MRI scan of tumour.
Subjects in the ALECSAT group donated blood for production of the ALECSAT product 3 weeks prior to each ALECSAT treatment (at weeks 4, 9, 14, 26 and 46).
Subjects in the Avastin/Irinotecan group were treated with Avastin/Irinotecan on visit 1 (day 0) and every 2 weeks according to standard practice.
MRI scan, QoL and performance status was performed regularly for efficacy assessments. In addition to MRI scan, 18F-fluoro-ethyl-tyrosine (18F-FET) Positron emission tomography (PET) scan was performed at Copenhagen University Hospital, Rigshospitalet.
Safety blood samples, vital signs, physical examination and adverse event monitoring were performed frequently during the study.
Number of subjects planned and treated:
A total of 175 subjects were planned, distributed as 105 subjects in the ALECSAT group and 70 subjects in the Avastin/Irinotecan group. Since the study was terminated early, 25 subjects were analysed, 15 subjects in the ALECSAT group and 10 subjects in the Avastin/Irinotecan group.
Diagnosis and main criteria for inclusion
The subjects enrolled in this clinical study were patients with advanced GBM with documented relapse during, or after completing, first line treatments.
Test product, dose and mode of administration, batch number
The ALECSAT treatment contained 1×107 – 1×109 cytotoxic T-lymphocytes (CTL) and natural killer (NK) cells generated from autologous blood donated by the individual study subject prior to each treatment cycle. Each batch of ALECSAT was therefore a subject-specific single dose.
The first ALECSAT treatment was given on visit 2 (week 4). The following administrations were given in uneven intervals at weeks 9, 14, 26 and 46. Due to early termination of the study, no subjects received study product at weeks 26 and 46.
Duration of treatment: Treatment duration was planned for up to 62 weeks.
Reference therapy, dose and mode of administration, batch number
Subjects allocated to the Avastin/Irinotecan treatment were treated in accordance with standard practice in Denmark for GBM patients. Treatment with Avastin/Irinotecan started at study visit 1 (day 0) and was given as up to 16 treatment cycles with 4 weeks duration. Each cycle consisted of 2 dosing days; day 1 and day 15 in the cycle.
Criteria for Evaluation
Since the study was terminated early, some endpoints deemed irrelevant or unfeasible to analyse as planned. Some endpoints were re-defined, and others (especially exploratory analyses) were deemed irrelevant and not performed.
PFS measured by MRI. Progression of disease was defined according to the response evaluation criteria for solid tumours (Response Assessment in Neuro-Oncology Criteria, RANO).
Secondary Efficacy Endpoints:
The safety and tolerability of ALECSAT in this study was measured by:
Descriptive statistics of demographics and other baseline characteristics were presented by treatment group
Demography of study population
The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice.
An open-label, randomised, phase II study to investigate the efficacy and safety of ALECSAT treatment as an add-on therapy to radiotherapy and Temozolomide in patients with newly diagnosed Glioblastoma
Investigator study sites:
This study will be conducted at multiple clinical sites located in Sweden, currently Sahlgrenska University hospital is actively recruiting patients.
To compare Overall Survival (OS) between patients who received ALECSAT as an add-on therapy to standard of care (SOC) and patients who received SOC treatment only.
This is a randomised, open-label, multi-centre, Phase II study in patients with newly diagnosed glioblastoma multiforme brain cancer. Up to 87 patients with newly diagnosed glioblastoma will be enrolled in the study in a 1:2 allocation (SOC: ALECSAT as an adjunct therapy to SOC).
Data from further 29 patients collected from an ongoing observational study of Glioblastoma patients treated according to SOC at Sahlgrenska University hospital in Göteborg, Sweden will be used as historical control data and combined with the randomised control data in performing the statistical analysis.
Patients recruited into this study will receive either:
The allocation ratio will be 1:2 (SOC: ALECSAT as an adjunct therapy to SOC).
Patients will be screened (Week -4 – 0) and will enter the study within six weeks of their glioblastoma resection. Eligible patients will be randomised to either ALECSAT treatment as an add-on therapy to SOC, or SOC only.
All patients will complete the radiotherapy phase of the Stupp regimen (radiotherapy five days per week combined with daily TMZ) for approximately six weeks (Weeks 1-6). Then all patients will begin TMZ treatment four to five weeks after completion of radiotherapy, typically six cycles of TMZ will be given (daily for five days every 28 days). Patients who terminate radiotherapy or TMZ treatment early for any reason will be allowed to remain in the study. For all patients first line Stupp treatment will be followed by second line treatments at the discretion of the Investigator.
Patients randomised to the ALECSAT treatment arm will after the radiotherapy phase – alongside (adjuvant to) TMZ treatment – receive three doses of ALECSAT at four week intervals during the loading phase of the study (Weeks 8-16). Following the loading phase, patients in the ALECSAT treatment arm will enter the maintenance phase, where they will receive further ALECSAT administrations during the maintenance phase at 12 week intervals (Week 17 onwards). Patients in the ALECSAT treatment arm may also receive second line therapy at the Investigator’s discretion. The maintenance phase of ALECSAT administrations will continue for patients in the ALECSAT treatment arm until death or until a patient discontinuation criterion is observed or until closure of the study (24 months after recruitment has closed).
Patients randomised to the control arm will follow the same study plan and undergo the same study procedures as patients in the ALECSAT treatment arm (with the exception of blood donations for ALECSAT production, ALECSAT administrations and vital signs).
The study discontinuation criteria are as follows:
Patients randomised to the ALECSAT treatment arm will be allowed to remain on ALECSAT treatment if disease progression is observed and second line treatment is initiated.
The final analysis will be carried out when 86 events (deaths) have been observed, including those from historical controls. Twenty-four months after recruitment to the study has closed, treatment and data collection for any patients still alive will end and the study will close. Any data collected for patients still alive after the point of final analysis (86 events) until study closure (24 months after recruitment has closed) will be analysed and included as an addendum to the final report.
There will be two interim analyses. The first analysis will be carried out 18 months after the start of recruitment and will be used to confirm continuation of the study. The second interim analysis will be carried out before all patients have been recruited and will be used to make any study recommendations such as adjustments to the sample size. There will be an independent Data Safety Monitoring Board (DSMB) that will evaluate the data collected during the interim analysis and provide recommendations on further conduct of the trial.
Number of patients: Up to 87 patients will be enrolled.
Product name: ALECSAT (Autologous Lymphoid Effector Cells Specific Against Tumour cells)
Dose: 1 x 107- 1 x 109 cells suspended in 20 ml plasmalyte solution.
Dosing schedule: Loading phase (Weeks 8-16) – approximately three doses administered at approximately four week intervals. Maintenance phase (from Week 17) – dose administered every 12 weeks until death or until a patient discontinuation criterion is observed or until closure of the study (24 months after the recruitment has closed).
Pharmaceutical form: Suspension for injection
Route of administration: Intravenous
Patients randomised to ALECSAT treatment will also receive the reference treatment as stated below.
The reference treatment is standard of care first line therapy for newly diagnosed Glioblastoma according to the Stupp regimen. Stupp treatment includes a combination of external radiotherapy (daily fractions of 2 Gy per fraction five days per week up to a total dose of 60 Gy) and temozolomide (75 mg/m2) daily for approximately six weeks. Patients who terminate radiotherapy or TMZ treatment early for any reason will be allowed to remain in the study. Patients then begin adjuvant TMZ treatment four to five weeks after completion of radiotherapy. Typically, six cycles of TMZ will be given (daily for five days every 28 days). TMZ will be administered orally at a dose of 150 mg/m2 per day for the first treatment cycle. The dose of TMZ will increase to 200 mg/m2 per day in the subsequent treatment cycles, in the absence of haematological toxicity. Patients may also receive second line therapy, at the discretion of the Investigator as part of standard of care.
The data gathered from this study will be combined with data gathered from an ongoing observational study of glioblastoma patients treated according to standard of care at Sahlgrenska University hospital in Gothenburg, Sweden.
Criteria for evaluation
Overall Survival (OS). OS time is measured from time of resection until death for any reason.
Secondary efficacy endpoints:
All data will be presented in patient data listings. Data will be summarized by treatment groups. For continuous variables, descriptive statistics (n, mean, median, standard deviation, minimum, and maximum) will be presented. For categorical variables, frequencies and percentages will be presented. Graphical displays will be presented as appropriate.
Power and Sample Size:
The assumptions of the sample size calculation are:
Under these assumptions, the number of events (deaths) required for the final analysis is 86. Contributing to this number will be data from 29 historical controls, whose time of death has been observed. The remaining 57 events will come from the 87 patients randomised to the study in a 1:2 allocation (SOC: ALECSAT as an adjunct therapy to the SOC). Assuming 25 months for recruitment of the 87 patients, the final analysis will occur when 57 deaths have been observed among randomised study subjects, or approximately 46 months after study initiation.
Two interim analyses and one final analysis are planned. The first interim analysis will take place 18 months after the start of recruitment, at which time 61 patients are expected to have been randomised into the study and at least 14 deaths have been observed. The second interim analysis will be performed when 50% of the events (24 deaths) have been observed or 6 weeks before all patients have been recruited (after approximately 85 patients have been recruited), whichever time point is first. At this time, the selection of historical controls to be included in the trial will be performed.
The final analysis will be performed when 86 events (deaths) have been observed including those from historical controls. Any data collected after this time point up to study closure (24 months after recruitment has closed) will be analysed and included as an addendum to the final report. The error probability will be adjusted for multiple testing (interim analyses) according to the Haybittle-Peto boundaries  i.e. that p1=0.001, p2=0.001 and p3=0.05. Demographics and Baseline Characteristics: Demographic data – age, gender – will be described using n, mean, median, standard deviation, minimum, and maximum for age and percentages for gender.
Baseline characteristics with respect to the disease:
The primary endpoint – Overall Survival – will be analysed using the Kaplan-Meier survival estimate and compared between the treatment groups using a log-rank test. Progression Free Survival will be analysed in the same manner. Estimates of median Overall Survival and median Progression Free Survival will be calculated using the Kaplan-Meier method. The data gathered from an ongoing observational study of glioblastoma patients at Sahlgrenska University hospital in Göteborg, Sweden will be included into the randomised trial as historical control data.
To combine the data from historical controls with the randomised controls, the method described by Stuart Pocock will be used. According to the algorithm described, the number of concurrent controls in the randomised trial can be limited. The calculation takes into account the number of historical controls and a bias in the median survival time estimated from the historical controls, as well as the total number of patients in the trial. The comparison will include demographic data, patients’ baseline characteristics and other prognostic factors as covariates in a COX proportional hazard model.
Adverse events will be displayed using frequency table methods, presenting number of patients and percentages. Safety laboratory parameters will be presented as mean values, standard deviations, medians and minimum and maximum values.