Trial Information

Clinical Study of OncoSorb® in Patients With Advanced Cancer Entities

STUDY PURPOSE: The purpose of this study is to collect further data for safety and
feasibility for the use of the medical device OncoSorb® in clinical routine for the
treatment of patients with solid metastatic cancer entities who have failed standard
therapies.

MEDICAL DEVICE: The medical device used in this clinical study is the OncoSorb® column. It
is used with a specially modified Fresenius ART apheresis machine, associated tubing sets
and an Albuflow plasma filter, also from Fresenius. These components comprise the
extracorporeal immune apheresis system. The OncoSorb® column was CE certified in April 2008.
The OncoSorb® device is intended to specifically adsorb three soluble receptors (sTNF-R1,
sTNF-R2 and sIL-2R α), which are known to inhibit the natural immune response of cancer
patients mediated via tumor necrosis factor α (TNF- α).

OBJECTIVES: Primary objective:

The primary objective is to evaluate the use of OncoSorb® therapy in clinical practice in
terms of both safety and feasibility. This involves the evaluation of system-immanent issues
(particularly occurrence of possible catheter infections and suitability of citrate/heparin
anticoagulation) during the course of the clinical study prior the initiation of a phase II
study.

Primary variables:

Occurrence of

- Possible catheter infection

- Suitability of citrate/heparin anticoagulation (with clogging of the extracorporeal
circuit or bleeding as potential consequences)

- Adverse events/serious adverse events in general including changes of clinically
relevant laboratory parameters, changes of vital signs, ECG changes)

Secondary objectives Evaluation of clinical efficacy as defined as objective response to
treatment (according to RECIST), progression free survival (PFS), time to progression
(TTP), clinical benefit, quality of life (QoL) and kinetics of soluble receptors.

Secondary variables:

- Objective response rate (ORR) to OncoSorb® therapy, defined as the proportion of
patients with a confirmed CR or PR according to RECIST at efficacy evaluations I, II
and III (after monthly Cycles 2, 4 and 6 and continuation until disease progression)

- Progression free survival (PFS)

- Time to progression (TTP)

- Clinical benefit of OncoSorb® therapy (defined as the proportion of patients with
confirmed CR, PR and stable disease [SD]) in the evaluable patient population

- QoL (as assessed by EORTC QLQ-C30 rev. 3.0)

- Kinetics of sTNF-R1, sTNF-R2 and sIL-2R α (concentration levels pre-/post-apheresis as
well as determination of receptor levels during treatments). Soluble receptor levels
will be measured in the first 3 recruited patients at day 4 to 5 (hourly for the first
3 hours, every 2 hours for the following 6 hours and every 3 hours until treatment
start on day 5).

STUDY POPULATION: A total of 5 evaluable patients will be recruited, aged 18 or older.
Eligible patients will be identified at the NCT, Department of Medical Oncology or
Department of Dermatology (Prof. Enk). Patient 5 will be a patient with cutaneous metastatic
melanoma. One tumor lesion will be biopsied (tumor excision) in order to evaluate the
induction of apoptosis triggered by TNF-α. The staging examination according to RECIST
criteria will be conducted at the radiological department of the University of Heidelberg.
Patients will receive a central venous catheter for the extracorporeal treatment at the site
of Prof. Quentmeyer (St. Josefskrankenhaus, Heidelberg). The OncoSorb® treatment of the
patients with OncoSorb® as extracorporeal immune apheresis device will be conducted either
at the site of Prof. Rohmeiss (ze:ro dialysis center Schwetzingen) or at the site of Prof.
Zeier (Nierenzentrum Heidelberg). For security reasons the recruitment of patients will be
in consecutive order for patients 1 and 2: Patient 2 can be recruited only in the case that
patient 1 has finalized OncoSorb treatments until the end of cycle 2. For the recruitment of
subsequent patients (patients 3 to 5), no consecutive recruitment is planned. Patient 5 will
optionally receive another biopsy (tumor excision) on day 5 of week 3 of the second
treatment cycle to evaluate the biological effect of the OncoSorb treatment with respect to
induction of apoptosis in response to TNF-α.

STUDY TREATMENTS: The study will start with a screening visit (day -21 to day 0) after
obtaining informed consent of the patient. Patients screened for recruitment of patient 5
must give their consent for a baseline biopsy (tumor excision) and optional for a follow-up
biopsy (after end of week 3 of cycle 2; tumor excision). Patients, who qualify for
participation and are willing to participate, will receive in this period a central venous
catheter for the conduction of the extracorporeal OncoSorb® therapy. During the treatment
period all patients will receive OncoSorb® treatments consisting of daily immune adsorption
treatment procedures 5 days per week for 3 weeks, followed by a resting period of one week.
Due to safety reasons all patients will be hospitalized at the NCT during the first week of
OncoSorb® treatment. Since currently no information exists about the counterregulation
kinetics of sTNF-R1, sTNF-R2 and sIL-2Rα upon OnsoSorb® treatment, the collection of
pharmacokinetic (PK) data is planned for the first 3 recruited patients. Blood samples for
PK measurements of these patients will be taken between day 4 and 5 of the first treatment
cycle under hospitalized conditions. PK data will be essential for designing an optimized
treatment schedule (potential reduction of both frequency and apheresis time) of subsequent
patients on trial. The schedule of the first 3 patients constitutes a one monthly treatment
cycle. For the 2 remaining patients of this study the treatment plan will be re-designed
according to the PK data obtained from the first 3 patients on treatment. The efficacy
evaluation will be carried out 8 weeks after beginning of treatment. Patients with
progression of disease may be withdrawn from OncoSorb® treatment. Patients with complete
response (CR), partial response (PR) or stable disease (SD) will be offered to continue
OncoSorb® treatments until disease progression. In this case efficacy evaluation (CT scans)
will be performed every 8 weeks.