A Study Comparing Whole-Body Heat Treatment Plus Systemic Therapy to Systemic Therapy Alone, for Advanced Pancreatic Cancer

• Whole-body hyperthermia (Device), also known as WBHT, WBH, Systemic hyperthermia, Whole-body thermal treatment, WBTT: Initially every 2 weeks, until a total of 3 treatments is reached. Thereafter every 4 weeks. The treatment will raise the body temperature to 41,50 °C for a total of 4 hours.
• Standard-of-Care Systemic therapy (Drug): Standard-of-care systemic therapy for patients with metastatic pancreatic ductal adenocarcinoma (mPDAC, stage IV) after failure of first-line treatment.

Primary outcomes

• Overall survival (OS) [From randomization until death from any cause, assessed up to study completion (primary analysis triggered upon occurrence of 66 death events), an (expected) average of 12 months]: To compare Overall Survival (OS) between WBHT + standard-of-care (SoC) and SoC treatment group
• Safety and tolerability of WBHT + SoC and SoC alone [From moment of enrollment (ICF signature) up to End of Treatment visit, an (expected) average of 10 months]: Incidence of Adverse Events (AE), Serious Adverse Events (SAE), treatment-related AE/SAE and Adverse Device Effects (ADE). They will be reported from moment of enrollment (ICF signature) up to End of Treatment visit and will be assessed for seriousness, severity and relationship to the device and to WBHT treatment.

Secondary outcomes

• Progression-free survival (PFS) [Up to time of progression, death or study discontinuation; an (expected) average of 8 months]: To compare Progression-Free Survival (PFS) between WBHT +SoC and SoC treatment group based on RECIST 1.1. criteria.
• Disease control rate (DCR) [Until death, end of treatment visit or study discontinuation; an (expected) average of 10 months]: To compare Disease Control Rate (DCR) between WBHT +SoC and SoC treatment group based on RECIST 1.1 criteria.
• Objective response rate (ORR) [Until death, end of treatment visit or study discontinuation; an (expected) average of 10 months]: To compare Objective Response Rate (ORR) between WBHT +SoC and SoC treatment group based on RECIST 1.1 criteria and further described with duration of response (DOR) and time to response (TTR).
• Quality of Life assessments (EORTC-QLQ-C30 version 3) [Until death, end of treatment visit or study discontinuation; an (expected) average of 10 months]: Quality of Life (QoL) according to EORTC-QLQ-C30 version 3 scoring changes from baseline (at 4-weeks, 8-weeks and End of Treatment)
• Quality of Life assessments (QLQ Pan 26) [Until death, end of treatment visit or study discontinuation; an (expected) average of 10 months]: Quality of Life (QoL) according to QLQ Pan 26 scoring changes from baseline (at 4-weeks, 8-weeks and End of Treatment)
• Evolution of CA19-9 [Until death, end of treatment visit or study discontinuation; an (expected) average of 10 months]: To evaluate CA19-9 changes from baseline in WBHT +SoC and SoC treatment groups (at 4-weeks, 8-weeks and End of Treatment)

Other outcomes

• Exploratory analyses [Until death, end of treatment visit or study discontinuation; an (expected) average of 10 months]: To explore potential biomarkers and molecular correlates through the analysis of blood and tumor tissue samples.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. Subjects at least 18 years of age at time of signing the informed consent
2. Subjects with metastatic pancreatic adenocarcinoma (PDAC) confirmed by histology
3. Measurable disease per RECIST 1.1
4. Subjects previously treated with chemotherapy in first line for metastatic disease
5. ECOG performance status ≤ 1
6. Height ≤ 2,00 m, BMI maximal 40 or positive fitting session
7. Adequate liver structure (accessible metastasis-free and functional liver parenchyma) allowing stable liver sensor positioning without unacceptable risks of bleeding and perforation, based on echographic assessment (or any imaging modality)
8. Adequate bone marrow function defined as

   1. white blood cell count ≥ 2000/µl
   2. neutrophils ≥ 1500 cells/μL
   3. platelets ≥ 100 x 109/L
   4. hemoglobin ≥ 9 g/dl (female) and ≥10 g/dl (male) documented
9. Adequate coagulation defined as

   1. PT (%) ≥ 70%
   2. aPTT ≤ ULN
10. Adequate liver function defined as

    1. Transaminases (AST, ALT) ≤ 2.5 x ULN or ≤ 5.0 in presence of liver metastasis
    2. bilirubin ≤ 2 x ULN
11. Adequate renal function defined as calculated eGFR ≥ 60 mL/min (CKD-EPI equation)
12. Normal ionogram
13. Effective contraception for both male and female subjects if applicable. Women of childbearing potential must have a negative pregnancy test at screening visit.
14. Written informed consent must be given according to good clinical practice and national/local regulations.

Exclusion Criteria:

1. Pregnant or breastfeeding women
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 the skin)
4. Serious medical risk factors involving any of the major organ systems, including high cardiovascular risk defined as recent major cardiovascular events (such as myocardial infarction or stroke), clinically relevant heart failure due to structural or mechanical cardiac abnormalities (e.g., valvular disease or myocardial dysfunction), and clinically significant arrhythmias.
5. Pathology that would interfere with the placement of the bladder catheter
6. Clinically significant pulmonary disease which might interfere with mechanical ventilation
7. History of autonomic dysfunction (due to the influence on skin blood flow)
8. History of malignant hyperthermia
9. History of untreated endocrine pathology (e.g. diabetes type II, hyper- or hypothyroidism).
10. Primary untreated diabetes type I not related to the oncological condition (due to vascular complications).
11. Known allergies to drugs that will be used during the trial (e.g. anesthetic, analgesic, chemotherapy)
12. Active infections not controlled by medication
13. Presence of clinically significant ascites and/or decompensated cirrhosis/portal hypertension
14. Severe, non-healing wounds, ulcers or bone fractures
15. Organ allografts requiring immunosuppressive therapy
16. Implants that are not compatible with temperature changes
17. (History of) clinically significant (investigator decision) psychiatric disorder and/or psychosocial disorder that may interfere with adequate compliance to the protocol or signature of the informed consent
18. Other clinically significant disease which could impair the subject's ability to participate in the study according to the investigator's opinion
19. Participation in another clinical trial 2 weeks prior to the randomization
20. Biological therapy during the 2 weeks prior to the randomization
21. Radiotherapy up to 2 weeks prior to the randomization
22. Major surgery up to 6 weeks prior to the randomization (port-a-cath placement is minor)