Safety Study of Whole Body Hyperthermia for Advanced Cancer

Inclusion criteria:

1. Patients between 18- and 75-years of age at time of signing the informed consent

2. Patients with advanced solid cancer (for cohort A1, A2 only) or metastaticpancreatic adenocarcinoma confirmed by histology (for cohort B/C/D only)

3. Patients previously treated or under treatment with standard of care treatment (cohort B/C/D only) or patients without treatment options

4. WHO performance status ≤ 1(see appendix V)

5. Maximum waist circumference ≤ 150 cm

6. Weight ≤ 100 kg

7. Height ≤ 1,90 m

8. Adequate liver structure (confirmed by CT scan) allowing the placement of the liversensor

9. No (prostate) pathology that would interfere with the placement of the bladdercatheter

10. Adequate bone marrow function defined as

11. white blood cell count ≥ 2000/µl

12. neutrophils ≥ 1500 cells/μL

13. platelets ≥ 100 x 109/L

14. hemoglobin ≥ 10 g/dl documented within 1 week prior to first treatment

15. Adequate coagulation defined as

16. PT (%) ≥ 70%

17. aPTT ≤ ULN

18. Von Willebrand Factor Antigen ≥ LLN

19. Von Willebrand Factor Activity ≥ LLN

20. PFA COL/EPI CT ≤ 1.15 ULN

21. PFA COL/ADP CT ≤ 1.15 ULN

22. Adequate liver function defined as

23. Transaminases (AST, ALT) ≤ 2.5 x ULN or ≤ 5.0 in presence of liver metastasis

24. bilirubin ≤ 2 x ULN documented

25. Adequate renal function defined as

26. serum creatinine ≤ 1.6 mg/dL (male); ≤ 1.3 mg/dL (female);

27. albumin ≥ 30g/L

28. calculated eGFR ≥ 60 mL/min (CKD-EPI equation) documented within 1 week priorto randomization

29. No blood donation 3 months prior to the WBHT treatment

30. No participation in other clinical trial 4 weeks prior to the WBHT treatment

31. No biological therapy 4 weeks prior to the WBHT treatment or during WBHT treatment

32. No surgery 4 weeks prior to the WBHT treatment

33. No radiotherapy 3 weeks prior to the WBHT treatment or during WBHT treatment

34. No chemotherapy 1 week prior to the WBHT treatment (for cohort A/B/C/D) or duringWBHT treatment (for Cohort A1/A2)

35. No anti-platelet aggregation medication intake from 5 days prior to the first WBHTtreatment until 5 days after the last treatment

36. No anticoagulant medication intake between screening and last follow-up visit.However, if deemed necessary by the investigator, the patient may receiveprophylactic Low Molecular Weight Heparin on the day prior to the first WBHTtreatment until 10 days after the last WBHT treatment

37. No transdermal patches during participation in the study

38. No piercings (internally or externally)during WBHT treatment

39. Life expectancy of at least 18 weeks

40. Effective contraception for both male and female patients if applicable. Women ofchildbearing potential must have negative blood pregnancy test at screening visit.

41. Written informed consent must be given according to good clinical practice andnational/local regulations.

Exclusion criteria:

1. Pregnant or breastfeeding women (based on HCG levels)

2. Presence of brain metastasis (known or suspected)

3. Other malignant diseases in the medical history during the last 5 years (exceptions:carcinoma in situ of the cervix or adequately treated basal cell carcinoma of theskin)

4. Serious medical risk factors involving any of the major organ systems, includinghigh cardiovascular risk, coronary stenting or myocardial infarction in the lastyear

5. Clinically significant pulmonary disease which might interfere with mechanicalventilation

6. History of autonomic dysfunction (due to the influence on skin blood flow)

7. History of malignant hyperthermia or a positive diagnostic test (Caffeine-HalothaneContracture test) in case of family history of malignant hyperthermia.

8. History of untreated endocrine pathology (e.g. diabetes type II, hyper- orhypothyroidism).

9. Primary diabetes type I (due to vascular complications)

10. Known allergies to drugs that will be used during the trial (e.g. anesthetic,analgesic, (chemotherapy used in cohort B/C/D))

11. Active infections not controlled by medication

12. Severe, non-healing wounds, ulcers or bone fractures

13. Organ allografts requiring immunosuppressive therapy

14. (History of) clinically significant (investigator decision) psychiatric disorderand/or psychosocial disorder that may interfere with adequate compliance to theprotocol or signature of the informed consent

15. Other clinically significant disease which could impair the patient's ability toparticipate in the study according to the investigator's opinion

16. Participation in another clinical trial during this trial