Safety Study of Repeated Dosing of a Cytotoxic Lymphocytes (CTL) Based Prostate Cancer Therapy (ALECSAT)

A Prospective, Open Phase I Study to Investigate the Tolerability and Efficacy of Administering Repeated Doses of ALECSAT to Prostate Cancer Patients.

This study is a phase I study of a cell based prostate cancer therapy, Autologous Lymphoid Effector Cells Specific Against Tumor-cells (ALECSAT). Safety and tolerability of a single dose has been shown in 13 prostate cancer patients. In this study 20 prostate cancer patients will receive 3 doses of the ALECSAT treatment. In this therapy specific cells from the patient's own immune system are isolated, activated and re-administered to the patient to boost a specific immune response against the cancer cells. The aim of the study is to show safety and tolerability for repeated dosing of this type of therapy. It is the hypothesis that the cells administered during the therapy will attack the tumor cells and in this way stop or slow down the progression of disease.

This study is a prospective open phase I study to investigate the safety and tolerability of administration of repeated doses of a cell based medicinal product (CBMP) ALECSAT. ALECSAT is an autologous CBMP that is made from the patient's own blood cells. ALECSAT contains a large amount of tumour specific cytotoxic Lymphocytes (CTL) and Natural Killer (NK) cells that are isolated activated and amplified in number. The CBMP is given as a slow i. v. injection to patients with prostate cancer. The patients are in the late stage of the disease where they have received hormone treatment but their disease is progressing. The primary objective of the study is to observe if any side effects or tolerability issues occur as a consequence of the repeated administration of ALECSAT, secondarily it will be observed if changes in Prostate-Specific Antigen (PSA) levels or any positive anti tumor effect may be observed. The study has the purpose to investigate whether repeated treatment with ALECSAT in any way is toxic. Trial Design: The study is an open, prospective phase I safety study of ALECSAT in prostate cancer patients. A group consisting of 4 patients will be treated twice with ALECSAT according to the protocol. Then an interim analysis will be done. If there are no signs of significant toxicity related to the treatment, the study will continue to the third treatment for these patients and with 14 more patients that will be treated with ALECSAT according to the protocol. Thus this study will include a total of 20 patients. The patients will after the first administration of ALECSAT be hospitalized for 2 days. Five and 10 weeks later the patients will be hospitalized for 1 day and receive the second and third administration of ALECSAT. Each patient will furthermore be followed closely for 12 weeks after the third treatment. During the course of the entire study the patients will be monitored by 11 planned study visits, by the investigators at Department of Urology, Fredrikssund Hospital, Denmark.

Autologous activated CTL and NK-cells injected as three intravenous injections interspaced by 5 weeks.

To show safety and tolerability patients was monitored closely after administration of ALECSAT and during the follow up period. Heart rate, temperature, blood pressure, Performance status was monitored. Blood samples analysed were: PSA, Alkaline Phosphatase (ALP), Lactate DeHydogenase (LDH), Creatinine (CREAT) and Standard haematology: Blood picture (complete blood count, haemogram), leucocytes, Differential count, electrolytes, renal function, and liver count (liver enzymes). AE and SAE was reported during the study period and the Investigator was urged to judge whether the event was related to the study product or not.

At planned study visit´s at study week 0, 4, 5, 6, 7, 9, 10, 11, 12, 14, 15, 16, 18, 21, 24 and at study visit week 25

Blood pressure, pulse and temperature were monitored frequently during 48 hours post injection of the study product, and thereafter at each follow up visit.

At planned study visit´s at study week 0, 4, 5, 6, 7, 9, 10, 11, 12, 14, 15, 16, 18, 21, 24 and at study visit week 25

The Secondary Endpoint for This Study is to Establish if Any Indications of a Positive Therapeutic Effect on the Prostate Cancer May be Observed.

No significant conclusion of efficacy is possible due to the study design with only one group of patients. However by analyzing and comparing the outcome with the data the individual patient presented at baseline some trends of efficacy, defined as stable disease or partial response, are possible. Trends towards possible treatment response were measured by monitoring PSA, a potential marker for prostate cancer disease progression; by other blood markers; and by Quality of life questionnaire (EORTC QLQ-C30) and WHO/ECOG (Eastern Cooperative Oncology Group). Control of any bone metastases were followed by hotspots and bone scan index measured by skeletal scintigraphy.

Inclusion Criteria: Serum castration levels of testosterone, (total testosterone under 1.7nmol/l). Three consecutive rises of PSA minimum 1 week apart, resulting in at least two 50 % increases over the PSA nadir. Antiandrogen withdrawal for at least 4 weeks, or PSA progression despite secondary hormonal manipulations, or progression of osseous or soft tissue lesions. Be over the age of 18 and capable of understanding the information and giving informed consent. Expected survival time (life expectancy) of over 6 months. Adequate performance status better than 2 (WHO/ECOG Performance status score). Exclusion Criteria: A low blood count (haemoglobin < 6.0 mmol/l). Lymphocyte counts below 0.8 x 109/l. Positive tests for anti-HIV-1/2; HBsAg, anti-HBc (Hepatitis B Core Antigen) and Anti-HCV (Hepatitis C Virus). Syphilis i.e. being positive in a Treponema Pallidum test. Uncontrolled serious bacterial, viral, fungal or parasitic infection. Clinically significant autoimmune disorders or conditions of immune suppression. Treatment with corticosteroids (steroid hormones) or bisphosphonates or have been in chemotherapy or radiation treatment one month prior to inclusion in the clinical trial. Blood transfusions within 48 hours prior to donation of blood for ALECSAT production. Inclusion in other clinical trials 6 weeks prior to inclusion in the trial or enrolment in other clinical trials during the ALECSAT clinical trial. Any medical condition that will render participation in the study risky or, according to the Investigator will make the assessment of side effects difficult.