Clinical data

Pancreas cancer

Pancreas cancer studies

As for Glioblastma Brain cancer there is a very significant need for better treatment options for Pancreatic cancer. As also here current existing treatments only have limited overall survival effect and many have serious side effects.

CV004 (Clinical phase I) Safety and applicability of ALECSAT in the treatment of Pancreatic cancer.

A small pancreas cancer clinical phase I study focused on safety and applicability has been performed. The study showed that ALECSAT is safe, well tolerated and these immunotherapy treatments can be applied to late stage pancreatic cancer patients.

So in conclusion, ALECSAT is shown to be well tolerated safe and applicable, however, due to the low number of patients, no efficacy conclusions could be made.

ALECSAT may, based on this clinical phase I safety and applicability data, move towards clinical phase II testing where statistically relevant efficacy data may be obtained. CytoVac aims to explore this opportunity in collaboration with a partner.

Data and conclusions from this study is seen:
GBM Phase I – End of study report/publication CV003

cytovac_blue_4-1130-300

A prospective, open phase I study to investigate the tolerability and efficacy of administering ALECSAT to Pancreas cancer patients

Study investigator and site
Principal investigator was Chief Physician dr. med, dr. pharm. Lars Tue Sørensen. The study site was Digestive Disease Centre, Copenhagen University Hospital (Bispebjerg), Bispebjerg Bakke 23, DK-2400 Copenhagen NV, Denmark.

Primary Objective
The primary objective of this study was to investigate the safety and tolerability of administrating repeated doses of an adoptive immunotherapy, comprising mainly of autologous CD8+ antigen-specific cytotoxic T-lymphocytes (CTLs) and Natural Killer (NK) cells.

Secondary Objective

  • To investigate change in disease involvement during the study period by computerized tomography (CT).
  • To investigate change in pancreatic cancer marker CA19-9, and other blood tests that may show trends of clinical effect during the study period.
  • To investigate change in the patients Quality of Life (QoL) and performance status during the study period.
  • To investigate any changes in leucocytes and other blood markers during the study period.
  • To investigate the possibility to increase the number of lymphocytes at blood donation by a shorter time span between injection of Autologous Lymphoid Effector Cells Specific Against Tumour (ALECSAT) and the following donation.
  • To investigate the possibility for ALECSAT activated leucocytes to accumulate in the tumour.

Methodology
The primary objective for this study was to investigate safety and tolerability of administrating repeated doses of an adoptive immunotherapy. Potential clinical effect parameters were observed during the study, as the individual patients’ blood concentration of the specific pancreatic cancer marker CA19-9, serum concentration of ASAT, ALAT, amylase, bilirubin, LDH, sodium, and potassium was compared to baseline. Computerised tomography (CT) was used to investigate change in disease involvement during the study period, measuring images performed during the study period compared to findings at baseline. The images were described and evaluated using the Response Evaluation Criteria for Solid Tumours (RECIST) criteria.

For patients with verified metastases at baseline, the development of metastases were followed with appropriate assessments such as e.g. Imaging, biopsy or by clinical examination.

Changes in QoL (EORTC QLQ-C30, EORTC QLQ-PAN26 and Performance status (WHO / ECOG) were also monitored during the study period.

Number of patients planned and analyze
The number of planned patients was 15; however, due to premature study closure 12 patients were enrolled, 11 patients received first dose with ALECSAT, 10 patients received two doses, and 6 out of the ten patients received the third dose. One patient, was screened and enrolled, but never received any ALECSAT treatments.

Diagnosis and main criteria for inclusion
The selected groups of patients suffered from histologically verified pancreatic cancer and had been treated with first line treatment regimens (e.g. surgery, radiotherapy, and/or Folfirinox®) and were followed at Digestive Disease Centre, Bispebjerg Hospital, Denmark.

Inclusion criteria:

  • Patients suffering from histologically verified pancreatic cancer, who have terminated oncological treatment with Folfirinox® due to inacceptable side effects or disease progression, or who have declined to receive oncological treatment with Folfirinox®
  • Minimum age of 18 years old and be capable of understanding the information and giving informed consent,
  • Minimum height of 155 cm,
  • Expected survival time (life expectancy) of over 6 months,
  • Adequate performance status ≤ 2*
    * Performance was monitored according to the WHO / ECOG Performance status score:
    1. Asymptomatic (Fully active, able to carry on all pre-disease activities without restriction).
    2. Symptomatic but completely ambulatory (Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature. For ex. light housework, office work).
    3. Symptomatic, <50% in bed during the day (Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about more than 50% of waking hours).
    4. Symptomatic, >50% in bed, but not bedbound (Capable of only limited self-care, confined to bed or chair 50% or more of waking hours).
    5. Bedbound (Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair).
    6. Death.

Exclusion criteria:

  • Positive tests for anti-HIV-1/2; HBsAg, anti-HBc, Anti-HCV or being positive in a Treponema Pallidum test (syphilis),
  • Patient´s which have visited an area where there is an outbreak of West Nile virus or Dengue virus within 28 days prior to donation or may have been exposed to HTLV-I virus should be excluded unless the patient has been tested negative.
  • Concurrent illness, e.g. uncontrolled epilepsy, cardiovascular-, cerebrovascular-, and/or respiratory disease which can worsen or cause complications in connection with blood donation,
  • Clinically significant autoimmune disorders or conditions of immune suppression,
  • Haemoglobin count ≤ 7.0 mmol/l (men) and ≤ 6.5 mmol/l (women)
  • Lymphocytes below 0.3 x 109/l,
  • Clinically abnormal Erythrocyte Volume Fraction (EVF),
  • Body weight below 40 kg (men) and 50 kg (women),
  • Pregnant or breast feeding women. Fertile women can only be included with a negative pregnancy test at screening and must use contraceptives during the study,
  • Patients with uncontrolled serious bacterial, viral, fungal or parasitic infection,
  • Blood transfusions within 48 hours prior to donation of blood for ALECSAT production,
  • Any medical condition that will render participation in the study risky or, according to the Investigator will make assessment of the study endpoints difficult.
  • Exclusion criteria which possibly disqualify the patient for continuing the study are:
  • Patients that either may be put at risk due to the blood donation or where it is not expected that an ALECSAT product of good quality can be produced, i.e. low haemoglobin count (judged by the Investiga-tor) or lymphocyte-numbers below 0.3 x 109/l,
  • Patients where it has become known during the study period that the patient’s blood can expose operators or other patients’ blood samples / products at risks,
  • Patients with uncontrolled serious bacterial, viral, fungal or parasitic infections.

Test product: ALECSAT

Dose: 20 ml cell suspension containing between 10 million and 1 billion cells.

Mode of administration

Each treatment was an i.v. administration of repeated doses of the drug product, re-suspended in plasmalyte injection fluid, administered slowly through a peripheral venous catheter in the arm over 5 minutes. Each patient should receive minimum two injections of ALECSAT at 3-week intervals to be able to demonstrate safety, tolerability and trends of clinical effect.

Duration of treatment

ALECSAT was administered as repeated doses at weeks 4, 7 and 10.

 

Criteria for Evaluation

Criteria for evaluation – efficacy

Clinical effect was not a primary objective for this study, but some potential clinical effect parameters were measured during the study to detect signs of clinical effect: Individual patient´s blood concentration of the specific pancreatic cancer marker CA19-9, serum concentration of ASAT, ALAT, amylase, bilirubin, LDH, sodium, and potassium was compared to baseline.

An indication of measurable changes in tumour involvement by CT was done by measuring images performed during the study period compared to findings at baseline. Evaluation of the image evaluation was expressed by using the RECIST criteria. The RECIST criteria is a simplified, conservative, extraction of images in two dimensions:

  • CR (complete response) = disappearance of all target lesions
  • PR (partial response) = 30% decrease in the sum of the longest diameter of target lesions
  • PD (progressive disease) = 20% increase in the sum of the longest diameter of target lesions
  • SD (stable disease) = small changes that do not meet above criteria

For patients with verified metastases at baseline, the development of metastases were followed with appropriate assessments such as e.g. Imaging, biopsy or by clinical examination.

Changes in QoL (EORTC QLQ-C30 (version 3.0), and Performance status (WHO / ECOG) were also monitored during the study period.

Criteria for evaluation – safety

Frequency and type of adverse events (AEs) and signs of abnormalities in standard blood measurements:

Presence of AEs and serious adverse events (SAEs) during the study period.

Presence of clinically significant changes in blood parameters (haemoglobin, EVF, lymphocytes, leucocytes, ASAT, ALAT, amylase, bilirubin, glucose, LDH, sodium and potassium), performance status and QoL question-naire measured at specific time points during the study period.

Statistical methods

The data collected in the study was evaluated case by case where each patient was its own control by comparing the result with baseline data. Data was presented as maximum, minimum, mean and median values as appropriate or as tumour response according to RECIST.

Data was presented by use of descriptive statistics, using count of valid observations (N), average, median, minimum, and maximum as appropriate. No statistical tests were used.

Demography of study population

The demography was described by age, gender, blood pressure, height, performance status body temperature and weight.

 

Results:

Efficacy results

  • Due to the high dropout rate from baseline to visit 7, the change in tumour involvement assessed by CT scans was not possible
  • The number of patients left at visit 7 was low (only 4 out of 12 remaining), hence it was not possible to demonstrate any change in tumour involvement over time by assessment of CT scans as the dropout rate was too high
  • Overall, no improvement in performance status levels was observed in comparison with the baseline value, however a slight insignificant decrease was seen
  • Quality of life monitoring did not reveal any significant changes in the treated patients during the study period.
  • Overall, no trends in either performance status or the QoL EORC QLQ-C30 and WHO/ECOG QLQ-PAN26 were observed

Safety results

  • A total of 15 AEs were reported by 8 patients during the study, of which one AE was reported in the pre-treatment period and 14 AEs were reported in the post-treatment period, by 7 patients.
  • The most frequently reported AE was haemoglobin decreased, with 2 events reported by 2 patients (SOC ”Investigations”),
  • The majority of the AEs were mild to moderate (12 out of 15 AEs), and only 3 AEs were reported as severe
  • In total, 5 patients reported 5 SAEs during the study, however none of the SAEs were considered related to treatment by the Investigator (progression of pancreatic cancer, 2 events of death, icterus, clotted stent, primary peritonitis)
  • During the first 4 weeks production time, the Investigator withdrew one patient from the study (patient no 407) due to progressive disease; this event is reported as SAE
  • The deaths of two patients (nos. 401, and 407) were reported as adverse events. Patient no 407 was reported dead after study closure. None of the deaths were judged as related to the study product.
  • No clinical significant changes in the level of lymphocytes over time were observed for the dosed patients
  • No clinical significant changes in vital signs were observed

 

CONCLUSION

In conclusion, ALECSAT was well tolerated. However, due to the low number of patients, no efficacy conclusions could be made.

The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice.

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