‣ Cohorts A, B, E, and F

• The patient must voluntarily sign the informed consent before any study test is conducted that is not part of routine patient care.

• Age: 18-75 years.

• Patients must have a diagnosis of soft tissue sarcoma with metastasis, and not suitable for metastasectomy or surgery resection or not oncologically recommended metastasectomy. A centralized diagnosis confirmation will be performed and the tumor sample must be available and sent prior to inclusion to this end.

• A centralized diagnosis of DD liposarcoma or mixoid/hypercellular liposarcoma or leiomyosarcoma must be confirmed for patients in cohort E.

• A centralized diagnosis of other sarcomas includes: undifferentiated pleomorphic sarcoma (UPS), myxofibrosarcoma, synovial sarcoma, malignant peripheral nerve sheath tumors, sarcoma NOS, fibrosarcoma, pleomorphic rhabdomyosarcoma, pleomorphic liposarcoma, epithelioid sarcoma, clear cell sarcoma, dedifferentiated or aggressive features in solitary fibrous tumor, extraskeletal myxoid chondrosarcoma, angiosarcoma, epithelioid hemangioendothelioma,

• Patients must have received a previous chemotherapy line in advanced disease unless contraindicated or not indicated.

• Radiological disease progression must be documented within 6 months prior to study entry.

• The patient must have been considered eligible for systemic chemotherapy. A maximum of two previous lines for advanced/metastatic disease are allowed.

• Measurable disease according to RECIST v1.1 criteria.

⁃ Performance status ≤1 (ECOG).

⁃ Adequate bone marrow function (hemoglobin \>10 g/dL, neutrophils ≥ 1,500/mm3, platelets ≥ 100,000/mm3). Patients with creatinine clearance ≥ 30 mL/min (Cockcroft and Gault's formula), transaminases ≤ 3.0 times the ULN, total bilirubin ≤ ULN, are acceptable.

⁃ Men or women of childbearing potential must be using an effective method of contraception before entry into the study and throughout the same and for 3 months (men) and 6 months (women) after ending study treatment. Women of childbearing potential must have a negative serum or urine pregnancy test before study entry.

⁃ Normal cardiac function with a LVEF ≥ 50% by echocardiogram or MUGA.

⁃ HBV and HCV serologies must be performed prior to inclusion. If HbsAg is positive it is recommended to reject the existence of replicative phase (HbaAg+, DNA VHB+). If these were positives the inclusion is not recommended, remaining at investigators' discretion the preventive treatment with lamivudine. If a potential patient is positive for anti-HCV antibodies, presence of the virus should be ruled out with a qualitative PCR, or the patient should NOT be included in the study (if a qualitative PCR cannot be performed then patient will not be able to enter the study).

⁃ Patient must have a central venous catheter for PM14 treatment.

‣ Cohort C

• The patient must voluntarily sign the informed consent before any study test is conducted that is not part of routine patient care.

• Age: 18-75 years.

• Patients must have a diagnosis of advanced soft tissue sarcoma, or recurrent head \& neck suitable for reirradiation or other advanced or metastatic solid tumor not suitable for metastasectomy or surgery resection or not oncologically recommended metastasectomy. A centralized diagnosis will be performed and the tumor sample must be available and sent prior to inclusion to this end. For phase II part, onlysoft tissue sarcomas will be enrolled.

• Patients must have received a previous chemotherapy line in advanced disease.

• Disease distribution must allow meeting with normal tissue constrains of radiation therapy. Radiation oncologist must confirm this point at local sites.

• Metastatic spread could be present in several organs (i.e. lungs and pelvic fossa) however, not all the locations have to be irradiated.

• Those lesions considered for radiation therapy have to be related to symptoms (for phase II).

• It is allowed that not all the lesions will be under radiation fields. As a general rule, the priority is to select, as target-irradiating lesions, those with greater increase in size and those largest lesions if related with symptoms. Irradiating pulmonary lesions with infiltration of pleural serosa is discouraged.

• Radiological disease progression must be documented within 6 months prior to study entry.

⁃ The patient must have been considered eligible for systemic chemotherapy. A maximum of two previous lines for advanced/metastatic disease are allowed.

⁃ The following histological subtypes can be included for the phase II part (central pathology review is mandatory before accrual): undifferentiated pleomorphic sarcoma (UPS), leiomyosarcoma, angiosarcoma, epithelial hemangioendothelioma, liposarcoma and its variants (well differentiated, dedifferentiated, myxoid/round cell, pleomorphic), synovial sarcoma, fibrosarcoma and its variants (epithelial fibrosarcoma/low grade fibromyxoid sarcoma), solitary fibrous tumor, malignant peripheral nerve sheath tumor (MPNST), myxofibrosarcoma, epithelioid sarcoma and (NOS) unclassified sarcoma.

⁃ Measurable disease according to RECIST v1.1 criteria.

⁃ Performance status ≤1 (ECOG).

⁃ Adequate respiratory functions: FEV1 \> 1L; DLco \> 40% (patients with pulmonary target lesions).

⁃ Adequate bone marrow function (hemoglobin \> 10 g/dL, neutrophils ≥ 1,500/mm3, platelets ≥ 100,000/mm3). Patients withcreatinine clearance ≥ 30 mL/min (Cockcroft and Gault's formula), transaminases ≤ 2.5 times the ULN, total bilirubin ≤ ULN are acceptable.

⁃ Men or women of childbearing potential must be using an effective method of contraception before entry into the study and throughout the same and for 3 months (men) and 6 months (women) after ending study treatment. Women of childbearing potential must have a negative serum or urine pregnancy test before study entry.

⁃ Normal cardiac function with a LVEF ≥ 50% by echocardiogram or MUGA.

⁃ HBV and HCV serologies must be performed prior to inclusion. If HbsAg is positive it is recommended to reject the existence of replicative phase (HbaAg+, DNA VHB+). If these were positives the inclusion is not recommended, remaining at investigators' discretion the preventive treatment with lamivudine. If a potential patient is positive for anti-HCV antibodies, presence of the virus should be ruled out with a qualitative PCR, or the patient should NOT be included in the study (if a qualitative PCR cannot be performed then patient will not be able to enter the study).

⁃ Patient must have a central venous catheter for PM14 treatment.

‣ Cohort D

• The patient must voluntarily sign the informed consent before any study test is conducted that is not part of routine patient care.

• Age: 18-75 years.

• Patients must have a diagnosis of localized soft tissue sarcoma that lacks one or more of the following risk criteria: G3, deep and \> 5 cm. At least G2 is required (i.e. G3, superficial and \> 5 cm; or G3 \< 5 cm deep; or G2, deep and \> 5 cm, etc.).

• Patients must be diagnosed by core-biopsy and the elapsed time between biopsy and enrollment must be shorter than 6 weeks.

• Patients must be diagnosed by central pathology review with one of the following subtypes: leiomyosarcoma, undifferentiated pleomorphic sarcoma (UPS), myxofibrosarcoma, synovial sarcoma, sarcoma NOS, fibrosarcoma, myxoid liposarcoma,dedifferentiated liposarcoma, solitary fibrous tumor (the formerly malignant subtype).

• Only those sarcomas of limbs or trunk wall will be eligible for this cohort.

• Disease distribution allows meeting with normal tissue constraints of radiation therapy. Radiation oncologist must confirm this point at local sites.

• Patients must have resectable primary tumor while it is allowed to enroll patients with metastatic spread that could be potentially resectable.

• Patients must have criteria of operability for the primary tumor.

⁃ The patient must have been considered eligible for systemic chemotherapy.

⁃ Measurable disease according to RECIST v1.1 criteria.

⁃ Patients have to be candidates for MRI test.

⁃ Performance status ≤ 1 (ECOG).

⁃ Adequate bone marrow function (hemoglobin \> 10 g/dL, neutrophils ≥ 1,500/mm3, platelets ≥ 100,000/mm3). Patients withcreatinine clearance ≥ 30 mL/min (Cockcroft and Gault's formula), transaminases ≤ 2.5 times the ULN, total bilirubin ≤ ULN are acceptable.

⁃ Men or women of childbearing potential must be using an effective method of contraception before entry into the study and throughout the same and for 3 months (men) and 6 months (women) after ending study treatment. Women of childbearing potential must have a negative serum or urine pregnancy test before study entry.

⁃ Normal cardiac function with a LVEF ≥ 50% by echocardiogram or MUGA.

⁃ It should be performed HBV and HCV serologies prior to inclusion. If HbsAg is positive it is recommended to reject the existence of replicative phase (HbaAg+, DNA VHB+). If these were positives the inclusion is not recommended, remaining at investigators' discretion the preventive treatment with lamivudine. If a potential patient is positive for anti-HCV antibodies, presence of the virus should be ruled out with a qualitative PCR, or the patient should NOT be included in the study (if a qualitative PCR cannot be performed then patient will not be able to enter the study).

⁃ Patient must have a central venous catheter for treatment with PM14.