Clinical trial NCT02275286 (phase 1/phase 2, status: recruiting)
Conditions: liposarcoma, myxoid, sarcoma, soft tissue, leiomyosarcoma, liposarcoma, pleomorphic liposarcoma
ICD codes: C46.1
Drugs: trabectedin
SMILES: [H][C@@]12[C@@H]3SC[C@]4(NCCC5=C4C=C(OC)C(O)=C5)C(=O)OC[C@H](N1[C@@H](O)[C@@H]1CC4=CC(C)=C(OC)C(O)=C4[C@H]2N1C)C1=C2OCOC2=C(C)C(OC(C)=O)=C31
Eligibility criteria:

        Cohort A: STS

        Inclusion Criteria:

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

          2. Aged equal or over 18.

          3. Patients must have a diagnostic of Soft Tissue Sarcoma with metastasis limited to
             lung, and not suitable for metastasectomy or surgery resection or not oncologically
             recommended metastasectomy.A centralized diagnostic will be performed, the tumor
             sample must be available and sent prior to inclusion.

          4. Disease distribution allows meeting with normal tissue constraints of radiation
             therapy. Radiation oncologist must confirm this point.

          5. Metastatic spread could be present in two organs at maximum (i.e. lungs and pelvic
             fosa).

          6. Those lesions considered for radiation therapy have to be considered as target lesions
             as well. (i.e. in a patient with nodules in lungs, those lesions selected for
             radiation therapy have to include at least the target lesions)

          7. It is allowed that not all the lesions will be under radiation fields. As a general
             rule, it will be prioritized to select, as target-irradiating lesions, those with
             greater increase in size and those largest lesions. It should be discouraged to
             irradiate pulmonary lesions with infiltration of pleural serosa.

          8. Patients must have documentation of disease progression within 6 months prior to study
             entry.

          9. The patient must have been considered eligible for systemic chemotherapy. A maximum of
             two previous lines for advanced/metastatic disease are allowed as long as trabectedin
             has not been included.

         10. The following histological subtypes can be included:

             Undifferentiated pleomorphic sarcoma (previously, malignant fibrous histiocytoma)
             Leiomyosarcoma Angiosarcoma/ epithelial hemangioendothelioma Liposarcoma and its
             variants (well differentiated, dedifferentiated, myxoid/round cells, pleomorphic).

             Synovial sarcoma Fibrosarcoma and its variants (epithelial fibrosarcoma/low grade
             fibromyxoid sarcoma) Hemangiopericytoma/solitary fibroid tumor Neurogenic sarcoma
             (Malignant peripheral nerve sheath tumor, MPNST) Myxofibrosarcoma Epithelioid Sarcoma
             Unclassified sarcoma (spindle cell/epithelioid/pleomorphic/myxoid)

         11. Measurable disease, according to RECIST V 1.1 criteria

         12. Performance status ≤1 (ECOG).

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

         14. Adequate bone marrow function (hemoglobin > 10 g/dl, leukocytes ≥ 3.000/mm3,
             neutrophils ≥ 1.500/mm3, platelets ≥ 100.000/mm3). Patients with plasma creatinine ≤
             1,6 mg/dl, transaminases ≤ 2.5 times the UNL, total bilirubin ≤ UNL, CPK ≤ 2.5 times
             UNL, alkaline phosphatase ≤ 2.5 times the UNL are acceptable. If the increase of
             alkaline phosphatase is > 2.5 times the UNL, then the alkaline phosphatase liver
             fraction and/or GGT must be ≤ UNL.

         15. Men or women of child bearing potential should be using an effective method of
             contraception before entry into the study and throughout the same and for 6 months
             after ending the study. Women of childbearing potential must have a negative 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 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)

         18. Patient must have a Central Venous Catheter for treatment

        Exclusion Criteria:

          1. Previous treatment with trabectedin or previous treatment with radiotherapy (except if
             previous radiotherapy treatment plus planned study radiotherapy treatment allow
             tissues constrains)

          2. Performance status ≥ 2 (ECOG).

          3. Plasma bilirubin > UNL.

          4. Creatinine > 1.6 mg/dL.

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

          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 v4.03 scale, that
             limit patient availability, or according to investigator judgment may contribute
             significantly to treatment toxicity.

          9. Uncontrolled bacterial, mycotic or viral infections.

         10. Known positive test for infection by human immunodeficiency virus (HIV).

         11. Women who are pregnant or breast-feeding.

         12. Psychological, familial, social or geographic circumstances that limit the patient"s
             ability to comply with the protocol or informed consent.

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

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

         15. Histologies other than those described in inclusion criteria.

        Cohort B: ML

        Inclusion criteria:

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

          2. Age ≥18 years old.

          3. Pathological diagnosis of Myxoid Liposarcoma, deep located and more than 5 cm or
             superficial more than 10 cm. A centralized diagnostic will be performed to confirm
             that the patient can be included in the study.

          4. Tumor must be resectable and without evidence of regional or distal spread after
             adequate staging procedure. Tumor must be located in limbs or superficial trunk wall.

          5. Disease distribution allows meeting with normal tissue constraints of radiation
             therapy. Radiation oncologist must confirm this point.

          6. Measurable disease, according to RECIST V 1.1 criteria

          7. Performance status 0-1 (ECOG).

          8. Adequate bone marrow function (hemoglobin > 10 g/dL, leukocytes ≥ 3.000/mm3,
             neutrophils ≥ 1.500/mm3, platelets ≥ 100.000/mm3). Patients with plasma creatinine ≤
             1,6 mg/dL, transaminases ≤ 2.5 times the UNL, total bilirubin ≤ UNL, CPK ≤ 2.5 times
             UNL, alkaline phosphatase ≤ 2.5 times the UNL are acceptable. If the increase of
             alkaline phosphatase is > 2.5 times the UNL, then the alkaline phosphatase liver
             fraction and/or GGT must be ≤ UNL.

          9. Men or women of child bearing potential should be using an effective method of
             contraception before entry into the study and throughout the same and for 6 months
             after ending the study. Women of childbearing potential must have a negative urine
             pregnancy test before study entry.

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

         11. 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 HBV+). 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).

         12. Patient may have had one previous chemotherapy line.

         13. Patient must have a Central Venous Catheter for treatment.

        Exclusion criteria:

          1. Unresectable tumors (with limb sparing surgery)

          2. More than one previous chemotherapy treatment for local disease including trabectedin.

          3. Radiotherapy involving the tumoral bed.

          4. Performance status ≥ 2 (ECOG).

          5. Presence of metastases or lymph node involvement by the tumor.

          6. Location other than limb or superficial trunk wall.

          7. Plasma bilirubin > UNL.

          8. Creatinine > 1.6 mg/dL.

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

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

         11. Significant systemic diseases grade 3 or higher on the NCI-CTCAE v4.03 scale, that
             limit patient availability, or according to investigator judgment may contribute
             significantly to treatment toxicity.

         12. Uncontrolled bacterial, mycotic or viral infections.

         13. Known positive test for infection by human immunodeficiency virus (HIV).

         14. Women who are pregnant or breast-feeding.

         15. Psychological, familial, social or geographic circumstances that limit the patient"s
             ability to comply with the protocol or informed consent.

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

        Cohort C: Retroperitoneum sarcoma

        Inclusion criteria:

          1. The patient must voluntarily sign the informed consent form before performing any
             study-specific test that is not part of the patient's usual care.

          2. Aged between 18 and 75 years.

          3. The following histological subtypes may be included: High grade leiomyosarcoma (G2-3),
             liposarcoma, if at least 30% of the tumour is dedifferentiated, pleomorphic
             liposarcoma. A centralised diagnosis will be made to confirm that the patient can be
             included in the study.

          4. The tumour must be located in the retroperitoneum and it must be resectable and
             without evidence of regional or distal spread after the appropriate staging process.

          5. The location and size of the disease in the retroperitoneum must allow for compliance
             with radiotherapy limitations in healthy tissue. This point must be confirmed by the
             site's radiation oncologist.

          6. Measurable disease according to RECIST V 1.1 criteria.

          7. ECOG performance status 0-1.

          8. Adequate haematological parameters (haemoglobin >10 g/dl, leukocytes ≥3,000/mm3,
             neutrophils ≥1,500/mm3, platelets ≥100,000/mm3). Patients with plasma creatinine ≤1.6
             mg/dl, transaminases ≤2.5 times the ULN, total bilirubin ≤ ULN, CPK ≤2.5 times ULN,
             alkaline phosphatase ≤2.5 times ULN are acceptable. If the increase in alkaline
             phosphatase is >2.5 times the ULN, the liver fraction of alkaline phosphatase and/or
             GGT should be ≤ULN.

          9. Fertile men or women must use an effective contraceptive method before starting the
             study, during the study and for 6 months following the conclusion thereof. Women of
             childbearing potential who participate in the study must undergo a pregnancy test
             before starting the study.

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

         11. HBV and HCV serology must be performed before including the patient in the study. If
             HbsAg is positive, it is advisable to rule out a replicative phase (HbsAg*, DNA HBV+).
             If positive, the patient's inclusion in the trial is not recommended, and it is at the
             discretion of the investigator to administer preventive treatment with lamivudine. If
             a potential patient is positive to anti-HCV antibodies, the presence of the virus will
             be ruled out with a qualitative PCR, or the patient cannot be included in the study
             (if the qualitative PCR test cannot be performed on the patient, they cannot be
             included in the study).

         12. Patient may have had one previous chemotherapy line.

         13. The patient must have a central venous catheter for the administration of the
             treatment.

        Exclusion criteria

          1. Unresectable tumours.

          2. Location other than the retroperitoneum

          3. Patients who have previously received systemic treatment (chemotherapy or
             trabectedin).

          4. Patients who underwent prior local treatment for retroperitoneal sarcoma: surgery or
             radiotherapy in the tumour bed.

          5. ECOG performance status ≥2.

          6. Presence of metastasis or lymph node involvement of the tumour.

          7. Previous history of another neoplastic disease with less than 5 years free of disease
             except for basal cell carcinoma or properly treated in situ cervical cancer.

          8. Significant cardiovascular disease (e.g. dyspnoea >2 NYHA).

          9. A significant grade 3 or greater systemic disease on the NCI-CTCAE v4.03 scale, which
             may limit the availability of the patient or which, in the opinion of the
             investigator, may contribute to the toxicity caused by the study treatment.

         10. Uncontrolled viral, mycotic or bacterial infections.

         11. Known HIV-positive patients.

         12. Pregnant or breast-feeding women.

         13. Psychological, familial, social or geographical circumstances that limit the patient's
             ability to comply with the protocol or informed consent form.

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