Multicohort Trial of Different Schemes of PM14 in Monotherapy and in Combination with Radiotherapy in Soft Tissue Sarcomas and Other Solid Tumor

Inclusion Criteria:

Cohorts A, B, E, and F

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

2. Age: 18-75 years.

3. Patients must have a diagnosis of soft tissue sarcoma with metastasis, and notsuitable for metastasectomy or surgery resection or not oncologically recommendedmetastasectomy. A centralized diagnosis confirmation will be performed and the tumorsample must be available and sent prior to inclusion to this end.

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

5. A centralized diagnosis of other sarcomas includes: undifferentiated pleomorphicsarcoma (UPS), myxofibrosarcoma, synovial sarcoma, malignant peripheral nerve sheathtumors, sarcoma NOS, fibrosarcoma, pleomorphic rhabdomyosarcoma, pleomorphicliposarcoma, epithelioid sarcoma, clear cell sarcoma, dedifferentiated or aggressivefeatures in solitary fibrous tumor, extraskeletal myxoid chondrosarcoma,angiosarcoma, epithelioid hemangioendothelioma,

6. Patients must have received a previous chemotherapy line in advanced disease unlesscontraindicated or not indicated.

7. Radiological disease progression must be documented within 6 months prior to studyentry.

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

9. Measurable disease according to RECIST v1.1 criteria.

10. Performance status ≤1 (ECOG).

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

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

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

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

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

Cohort C

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

2. Age: 18-75 years.

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

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

5. Disease distribution must allow meeting with normal tissue constrains of radiationtherapy. Radiation oncologist must confirm this point at local sites.

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

7. Those lesions considered for radiation therapy have to be related to symptoms (forphase II).

8. It is allowed that not all the lesions will be under radiation fields. As a generalrule, the priority is to select, as target-irradiating lesions, those with greaterincrease in size and those largest lesions if related with symptoms. Irradiatingpulmonary lesions with infiltration of pleural serosa is discouraged.

9. Radiological disease progression must be documented within 6 months prior to studyentry.

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

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

12. Measurable disease according to RECIST v1.1 criteria.

13. Performance status ≤1 (ECOG).

14. Adequate respiratory functions: FEV1 > 1L; DLco > 40% (patients with pulmonarytarget lesions).

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

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

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

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

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

Cohort D

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

2. Age: 18-75 years.

3. Patients must have a diagnosis of localized soft tissue sarcoma that lacks one ormore 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.).

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

5. Patients must be diagnosed by central pathology review with one of the followingsubtypes: leiomyosarcoma, undifferentiated pleomorphic sarcoma (UPS),myxofibrosarcoma, synovial sarcoma, sarcoma NOS, fibrosarcoma, myxoidliposarcoma,dedifferentiated liposarcoma, solitary fibrous tumor (the formerlymalignant subtype).

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

7. Disease distribution allows meeting with normal tissue constraints of radiationtherapy. Radiation oncologist must confirm this point at local sites.

8. Patients must have resectable primary tumor while it is allowed to enroll patientswith metastatic spread that could be potentially resectable.

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

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

11. Measurable disease according to RECIST v1.1 criteria.

12. Patients have to be candidates for MRI test.

13. Performance status ≤ 1 (ECOG).

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

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

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

17. It should be performed HBV and HCV serologies prior to inclusion. If HbsAg ispositive it is recommended to reject the existence of replicative phase (HbaAg+, DNAVHB+). If these were positives the inclusion is not recommended, remaining atinvestigators' discretion the preventive treatment with lamivudine. If a potentialpatient is positive for anti-HCV antibodies, presence of the virus should be ruledout with a qualitative PCR, or the patient should NOT be included in the study (if aqualitative PCR cannot be performed then patient will not be able to enter thestudy).

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

Exclusion Criteria:

Cohorts A, B, E, and F

1. Performance status ≥ 2 (ECOG).

2. Plasma bilirubin > ULN.

3. Creatinine > 1.6 mg/dL.

4. History of other cancer with less than 5 years free of disease with the exception ofadequately treated basal cell carcinoma or in situ cervical cancer.

5. Patients who do not provide consent for mandatory biological samples (includingthose required for the translational study) cannot participate in the study.

6. Significant cardiovascular disease (for example, dyspnea > 2 NYHA).

7. Significant systemic diseases grade 3 or higher on the NCI-CTCAE v5.0 scale, thatlimit patient availability, or according to investigator judgment may significantlycontribute to treatment toxicity.

8. Uncontrolled bacterial, mycotic or viral infections.

9. Women who are pregnant or breastfeeding.

10. Psychological, family, social or geographic circumstances that limit the patients'ability to comply with the protocol or informed consent.

11. Patients participating in another clinical trial or receiving any otherinvestigational product.

12. Patients who had participated in another clinical trial and/or had received anyother investigational product in the last 30 days prior to inclusion.

13. Histologies other than those described in the inclusion criteria.

Cohort C

1. Previous treatment with radiotherapy (except if previous radiotherapy treatment plusplanned study radiotherapy treatment allow tissue constrains).

2. Performance status ≥ 2 (ECOG).

3. Plasma bilirubin > ULN.

4. Creatinine > 1.6 mg/dL.

5. History of other cancer with less than 5 years free of disease with the exceptionofadequately treated basal cell carcinoma or in situ cervical cancer.

6. Severe COPD or other severe pulmonary diseases.

7. Significant cardiovascular disease (for example, dyspnea > 2 NYHA).

8. Significant systemic diseases grade 3 or higher on the NCI-CTCAE v5.0 scale, thatlimit patient availability, or according to investigator judgment may significantlycontribute to treatment toxicity.

9. Patients who do not provide consent for mandatory biological samples (includingthose required for the translational study) cannot participate in the study.

10. Uncontrolled bacterial, mycotic or viral infections.

11. Women who are pregnant or breastfeeding.

12. Psychological, family, social or geographic circumstances that limit the patients'ability to comply with the protocol or informed consent.

13. Patients participating in another clinical trial or receiving any otherinvestigational product.

14. Patients who had participated in another clinical trial and/or had received anyother investigational product in the last 30 days prior to inclusion.

15. Histologies other than those described in inclusion criteria.

Cohort D

1. High-risk localized patients are not allowed to be enrolled (those G3, deep, andlarger than 5 cm or those with risk of death at least 40% by sarculator nomogram).

2. Previous treatment with radiotherapy.

3. Primary tumor location other than those indicated in the inclusion criteria.

4. Histological subtypes other than those indicated in the inclusion criteria.

5. Unresectable or inoperable primary tumor.

6. Patients who do not provide consent for mandatory biological samples (includingthose required for the translational study) cannot participate in the study.

7. Performance status ≥ 2 (ECOG).

8. Plasma bilirubin > ULN.

9. Creatinine > 1.6 mg/dL.

10. History of other cancer with less than 5 years free of disease with the exception ofadequately treated basal cell carcinoma or in situ cervical cancer.

11. Significant cardiovascular disease (for example, dyspnea > 2 NYHA).

12. Significant systemic diseases grade 3 or higher on the NCI-CTCAE v5.0 scale, thatlimit patient availability, or according to investigator judgment may significantlycontribute to treatment toxicity.

13. Uncontrolled bacterial, mycotic or viral infections.

14. Women who are pregnant or breastfeeding.

15. Psychological, family, social or geographic circumstances that limit the patients'ability to comply with the protocol or informed consent.

16. Patients participating in another clinical trial or receiving any otherinvestigational product.

17. Patients who had participated in another clinical trial and/or had received anyother investigational product in the last 30 days prior to inclusion.