Particle-based Partial Tumor Irradiation of Unresectable Bulky Tumors

Inclusion Criteria:

1. Written informed consent obtained from the patient prior to performing anytreatment-related procedures.

2. Biopsy proven malignant unresectable solid bulky primary or recurrent tumor (diameter of at least 6 cm or greater, except for the Central Nervous System (CNS)tumors), or in a case of lack of recent biopsy progression on at least twoconsecutive radiological examinations, with biopsy proof in the past. Presence oflocally advanced (cN+) and/or metastatic disease will be accepted in order to allowfor assessment of the abscopal effects.

3. Ineligibility for standard treatments including surgery, conventional (whole tumor)radiotherapy and systemic therapy, or being in progression or stable (with noresponse to systemic treatment) under systemic therapy.

4. A minimum time interval from last dose of systemic therapy before radiotherapy oftwo weeks; Systemic therapy may be resumed 4 weeks following radiotherapy in orderto permit assessment of the treatment efficacy.

5. Median life expectancy of >2 months.

6. Age > 18 years.

7. Adequate bone marrow function as follows below: Haemoglobin ≥ 8.0 g/d; Absoluteneutrophil count (ANC) ≥ 1.5 x 10ꝰ/L (> 1500 per mm3); Platelet count ≥ 100 x 10ꝰ/L (>100,000 per mm3).

8. Female patients must either be of non-reproductive potential (i.e. post-menopausalby history: ≥60 years old and no menses for ≥1 year without an alternative medicalcause; OR history of hysterectomy, OR history of bilateral tubal ligation, ORhistory of bilateral oophorectomy) OR women of fertile age must have adequateconception prevention measures and must have a negative serum pregnancy test uponstudy entry.

9. Patient is willing and able to comply with the follow up including scheduled visitsand examinations.

Exclusion Criteria:

1. Patients without bulky lesions.

2. Tumors suitable for the standard therapies including surgery, conventional (wholetumor) irradiation and systemic therapies.

3. Median life expectancy of less than 2 months.

4. Contraindication to i.v. Computer Tomography and Magnetic Resonance Tomographycontrast medium administration, particularly estimated glomerular filtration rate (GFR) less than 45 mL/min/1.73 m2.

5. History of autoimmune disease.

6. Current or prior use of immunosuppressive medication within 14 days beforeenrollment with the exceptions of intranasal and inhaled corticosteroids or systemiccorticosteroids at physiological doses, which are not to exceed 10 mg/day ofprednisone, or an equivalent corticosteroid.

7. History of primary immunodeficiency.

8. History of allogeneic organ transplant.

9. Uncontrolled intercurrent comorbidity including, but not limited to, ongoing oractive infection, symptomatic congestive heart failure, uncontrolled hypertension,unstable angina pectoris, active bleeding diatheses including any patient known tohave evidence of acute or chronic hepatitis B, hepatitis C or human immunodeficiencyvirus (HIV), or psychiatric illness/social situations that would limit compliancewith study requirements or compromise the ability of the patient to give writteninformed consent.

10. Female patients who are pregnant, breast-feeding or male or female patients ofreproductive potential who are not employing an effective method of birth control.

11. Any condition that, in the opinion of the investigator, would interfere withevaluation of study treatment or interpretation of patient safety or study results. (Note: criterion will be evaluated on the four eyes principle, evaluated by bothPrinciple Investigator and Sub-Investigators.)

12. Patients with uncontrolled seizures.