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Trabectedin Plus Radiotherapy in Soft Tissue Sarcoma Patients (TRASTS)

Primary Purpose

Liposarcoma, Myxoid, Sarcoma, Soft Tissue, Leiomyosarcoma

Status
Recruiting
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
Trabectedin
Radiotherapy
Sponsored by
Grupo Espanol de Investigacion en Sarcomas
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Liposarcoma, Myxoid focused on measuring sarcoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Institut BergoniéRecruiting
  • Centre Léon BerardRecruiting
  • Istituto Clinico Humanitas
  • Centro di Referimento Ocologico
  • Istituto Ortopedico Rizzoli
  • Candiolo Cancer InstituteRecruiting
  • Istituto Nazionale dei TumoriRecruiting
  • Hospital Miguel ServetRecruiting
  • Hospital Sant PauRecruiting
  • Hospital Son EspasesRecruiting
  • Hospital Universitario CanariasRecruiting
  • Hospital Vall d'HebrónRecruiting
  • Hospital Puerta de HierroRecruiting
  • Hospital Universitario Gregorio MarañónRecruiting
  • Hospital Uniersitario La PazRecruiting
  • Jiménez Díaz Foundation University HospitalRecruiting
  • Hospital Virgen del RocíoRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Trabectedin+Radiotherapy

Arm Description

Trabectedin 1.3 or 1.5mg/m2 and radiotherapy 30Gy or 45Gy.

Outcomes

Primary Outcome Measures

Tumor size
Image tumor assessment: RECIST response for the combination of trabectedin plus radiation therapy in cohorts A and B. CHOI response for the combination of trabectedin plus radiation therapy in cohort C.
Relapse-free survival.
In cohort D to improve 5-year relapse-free survival (RFS), decreasing the 5-year relapse percentage from 30% to 10% in patients with well differentiated liposarcoma with cellular component and dedifferentiated G2 retroperitoneal resected liposarcoma (20% increase in RFS).

Secondary Outcome Measures

Number and grade of adverse events
CTCAE v4.03 adverse events registration to evaluate safety
Number of months without progression
Progression free survival (PFS)
Number of months alive
Overall survival (OS)
Tumor size
Image tumor assessment measured by Choi criteria.
Questionnaire
QLQ-C30 EORTC questionnaire to evaluate patient quality of life
Overall response rate (ORR)
Sum of complete responses, partial responses and stable diseases
relapse free survival (RFS) at 3 years (cohorts C and D)
percentage of relapses from diagnosis at 3 years
relapse at 5 years (cohorts C and D)
number of months without relapse from treatment initiation until 5 years.
Tumor cells response to the treatment
Number of tumor necrotic cells
Predictive and prognostic biomarker
percentage of protein and RNA expression of FAS, Ca2+ and NER pathways in tumor samples obtained at baseline and at surgery (approx week 11)

Full Information

First Posted
October 17, 2014
Last Updated
May 29, 2023
Sponsor
Grupo Espanol de Investigacion en Sarcomas
Collaborators
Centre Leon Berard, Italian Sarcoma Group
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1. Study Identification

Unique Protocol Identification Number
NCT02275286
Brief Title
Trabectedin Plus Radiotherapy in Soft Tissue Sarcoma Patients
Acronym
TRASTS
Official Title
Phase I-II Prospective Trial, Multicenter, Open Label, Exploring the Combination of Trabectedin Plus Radiotherapy in Soft Tissue Sarcoma Patients
Study Type
Interventional

2. Study Status

Record Verification Date
May 2023
Overall Recruitment Status
Recruiting
Study Start Date
November 2014 (Actual)
Primary Completion Date
June 2028 (Anticipated)
Study Completion Date
June 2028 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Grupo Espanol de Investigacion en Sarcomas
Collaborators
Centre Leon Berard, Italian Sarcoma Group

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
Phase I-II trial that combines trabectedin plus radiotherapy for tumor reduction response measure in four cohorts of patients: Cohort A: Patients with diagnosis of non-operable or unresectable or not oncologically recommended metastasectomy of limited to lung metastases soft tissue sarcoma. Cohort B: Patients with locally advanced resectable Myxoid Liposarcoma. Cohort C: Patients with retroperitoneal and resectable soft tissue sarcoma (liposarcoma and leiomyosarcoma). Cohort D (Phase II only): Patients with well differentiated liposarcoma and G2 dedifferentiated liposarcoma (with less than 30% dedifferentiated component). Phase I: escalating dose of 1.3 or 1.5 mg/m2. Phase I for cohort C: de-escalating dose of 1.5 or 1.3mg/m2 Radiotherapy for cohort A: 30Gy in 10 fractions (3Gy/fraction). Radiotherapy for cohort B: 45Gy in 25 fractions (1.8Gy/fraction). Radiotherapy for cohort C: 45Gy in 25 fractions (1.8Gy/fraction). Radiotherapy for cohort D: 45Gy in 25 fractions (1.8Gy/fraction). A translational substudy is developed to analyse different biomarkers predictive value. Cohorts A and B are closed to recruitment in 2023.
Detailed Description
In this study investigators plan to measure tumor response (RECIST and Choi criteria) when administering trabectedin standard dose or inferior with simultaneous radiotherapy treatment. The hypothesis states that administering trabectedin at 1.3mg/m2 or ≤1.5mg/m2 plus Radiotherapy 30-45Gy shows synergic activity that turns into tumor shrinkage. A phase I trial (dose escalation -or de-escalation for cohort C- level of 1.3 or 1.5 mg/m2) will provide the proper dose level to perform a phase II trial to measure RECIST and Choi response, progression free survival, overall survival and register safety and quality of life details. Four cohorts are indicated for this trial: Cohort A: Patients with diagnosis of non-operable or unresectable or not oncologically recommended metastasectomy of limited to lung metastases soft tissue sarcoma. Cohort B: Patients with locally advanced resectable Myxoid Liposarcoma, Cohort C:Patients with retroperitoneal and resectable soft tissue sarcoma (liposarcoma and leiomyosarcoma). Cohort D: Patients with well differentiated liposarcoma and G2 dedifferentiated liposarcoma (with less than 30% dedifferentiated component) Unlimited cycles of chemotherapy are considered to be beneficial for cohort A patients, whereas cohort B and C only 3 cycles are indicated. About radiotherapy treatment, 30Gy will be given to cohort A patients, whereas cohort B and C will receive 45Gy. TCs and MRI are selected for imaging purposes. Phase I: For cohorts A and B:Trabectedin at two dose escalation levels: 0 1.3 mg/m2 as a 24h I.V. infusion 1 1.5 mg/m2 as a 24h I.V. infusion For cohort C:Trabectedin at two dose de-escalation levels: 0 1.5 mg/m2 as a 24h I.V. infusion -1 1.3 mg/m2 as a 24h I.V. infusion Administration of trabectedin with a portable pump, i.v infusion of 24h, in cycles of 3 weeks. Premedication: 4 mg oral dexamethasone 24h and 12h before chemotherapy administration. 20 mg I.V. dexamethasone 30minutes before treatment. Ondansetron or analogue will also be given prior to trabectedin. Pathology review, radiology review and radiotherapy review are performed to each patient. Several biomarkers are selected to perform FFPE tumor assays in relation to prediction

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Liposarcoma, Myxoid, Sarcoma, Soft Tissue, Leiomyosarcoma, Liposarcoma, Pleomorphic Liposarcoma
Keywords
sarcoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
199 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Trabectedin+Radiotherapy
Arm Type
Experimental
Arm Description
Trabectedin 1.3 or 1.5mg/m2 and radiotherapy 30Gy or 45Gy.
Intervention Type
Drug
Intervention Name(s)
Trabectedin
Other Intervention Name(s)
Yondelis
Intervention Description
Escalating or deescalating dose of 1.3 or 1.5mg/m2, i.v 24h, once every 3 weeks. Cohort A: unlimited cycles. Cohort B: 3 cycles. Cohort C: 3 cycles. Cohort D: cycles of trabectedin will be provided and patients will subsequently be evaluated for surgery.
Intervention Type
Radiation
Intervention Name(s)
Radiotherapy
Intervention Description
3D conformal radiotherapy (3D-CRT) or intensity modulated radiotherapy (IMRT) providing: Cohort A: 30Gy in 10 fractions (3Gy/fraction). Cohort B: 45Gy in 25 fractions (1.8Gy/fraction). Cohort C: 45Gy in 25 fractions (1.8Gy/fraction). Cohort D: 45Gy in 25 fractions (1.8Gy/fraction).
Primary Outcome Measure Information:
Title
Tumor size
Description
Image tumor assessment: RECIST response for the combination of trabectedin plus radiation therapy in cohorts A and B. CHOI response for the combination of trabectedin plus radiation therapy in cohort C.
Time Frame
every 6 weeks for 24 months
Title
Relapse-free survival.
Description
In cohort D to improve 5-year relapse-free survival (RFS), decreasing the 5-year relapse percentage from 30% to 10% in patients with well differentiated liposarcoma with cellular component and dedifferentiated G2 retroperitoneal resected liposarcoma (20% increase in RFS).
Time Frame
5 years.
Secondary Outcome Measure Information:
Title
Number and grade of adverse events
Description
CTCAE v4.03 adverse events registration to evaluate safety
Time Frame
every 21 days until 30 days after last dose or during 25 months
Title
Number of months without progression
Description
Progression free survival (PFS)
Time Frame
24 months
Title
Number of months alive
Description
Overall survival (OS)
Time Frame
24 months
Title
Tumor size
Description
Image tumor assessment measured by Choi criteria.
Time Frame
every 6 weeks during 24 months (cohort A) or every 4months during 36 months (cohort B and C)
Title
Questionnaire
Description
QLQ-C30 EORTC questionnaire to evaluate patient quality of life
Time Frame
every 3 months during 24 months
Title
Overall response rate (ORR)
Description
Sum of complete responses, partial responses and stable diseases
Time Frame
every 6 weeks during 24 months
Title
relapse free survival (RFS) at 3 years (cohorts C and D)
Description
percentage of relapses from diagnosis at 3 years
Time Frame
After 3 year since last patient treatment initiation
Title
relapse at 5 years (cohorts C and D)
Description
number of months without relapse from treatment initiation until 5 years.
Time Frame
After 5 years since last patient treatment initiation
Title
Tumor cells response to the treatment
Description
Number of tumor necrotic cells
Time Frame
Week 11, at surgery
Title
Predictive and prognostic biomarker
Description
percentage of protein and RNA expression of FAS, Ca2+ and NER pathways in tumor samples obtained at baseline and at surgery (approx week 11)
Time Frame
Baseline and week 11 (at surgery)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Cohort A: STS Inclusion Criteria: The patient must sign voluntarily the informed consent form before any study test is conducted that is not part of routine patient care. Aged equal or over 18. 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. Disease distribution allows meeting with normal tissue constraints of radiation therapy. Radiation oncologist must confirm this point. Metastatic spread could be present in two organs at maximum (i.e. lungs and pelvic fosa). 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) 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. Patients must have documentation of disease progression 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 as long as trabectedin has not been included. 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) Measurable disease, according to RECIST V 1.1 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, 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. 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. 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 Exclusion Criteria: Previous treatment with trabectedin or previous treatment with radiotherapy (except if previous radiotherapy treatment plus planned study radiotherapy treatment allow tissues constrains) Performance status ≥ 2 (ECOG). Plasma bilirubin > UNL. Creatinine > 1.6 mg/dL. 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. Severe COPD or other severe pulmonary diseases. Significant cardiovascular disease (for example, dyspnea > 2 NYHA) 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. Uncontrolled bacterial, mycotic or viral infections. Known positive test for infection by human immunodeficiency virus (HIV). Women who are pregnant or breast-feeding. Psychological, familial, social or geographic circumstances that limit the patient"s ability to comply with the protocol or informed consent. Patients participating in another clinical trial or receiving any other investigational product Patients who had participated in another clinical trial and/or had received any other investigational product in the last 30 days prior to inclusion. Histologies other than those described in inclusion criteria. Cohort B: ML Inclusion criteria: The patient must sign voluntarily the informed consent form before any study test is conducted that is not part of routine patient care. Age ≥18 years old. 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. 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. Disease distribution allows meeting with normal tissue constraints of radiation therapy. Radiation oncologist must confirm this point. Measurable disease, according to RECIST V 1.1 criteria Performance status 0-1 (ECOG). 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. 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. 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 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). Patient may have had one previous chemotherapy line. Patient must have a Central Venous Catheter for treatment. Exclusion criteria: Unresectable tumors (with limb sparing surgery) More than one previous chemotherapy treatment for local disease including trabectedin. Radiotherapy involving the tumoral bed. Performance status ≥ 2 (ECOG). Presence of metastases or lymph node involvement by the tumor. Location other than limb or superficial trunk wall. Plasma bilirubin > UNL. Creatinine > 1.6 mg/dL. 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. Significant cardiovascular disease (for example, dyspnea > 2 NYHA) 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. Uncontrolled bacterial, mycotic or viral infections. Known positive test for infection by human immunodeficiency virus (HIV). Women who are pregnant or breast-feeding. Psychological, familial, social or geographic circumstances that limit the patient"s ability to comply with the protocol or informed consent. Patients who had participated in another clinical trial and/or had received any other investigational product in the last 30 days prior to inclusion. Cohorts C and D: Retroperitoneum sarcoma Inclusion criteria: 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. Aged between 18 and 75 years. The following histological subtypes may be included in the cohort C: High grade leiomyosarcoma (G2-3), liposarcoma (G2-3), if at least 30% of the tumour is dedifferentiated, pleomorphic liposarcoma. The following histological subtypes may be included in the cohort D: Well differentiated liposarcoma (WD liposarcoma) and G2 dedifferentiated liposarcorcoma, if less than 30% of the tumour is dedifferentiated. A centralised diagnosis will be made to confirm that the patient can be included in the study. 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. This point must be confirmed by the central surgeon reviewer. 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 and the central radiation oncologist reviewer. Measurable disease according to CHOI criteria for cohort C and RECIST V 1.1 criteria for cohort D. ECOG performance status 0-1. 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. 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. Normal cardiac function with LVEF ≥50% by echocardiogram or MUGA. 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). Patient may have had one previous chemotherapy line (cohort D only). The patient must have a central venous catheter for the administration of the treatment. Exclusion criteria Unresectable tumours. Location other than the retroperitoneum. Patients who have previously received systemic treatment with chemotherapy (trabectedin included). For cohort D, patients may have received one previous line of chemotherapy with any other agent. Patients who underwent prior local treatment for retroperitoneal sarcoma: surgery or radiotherapy in the tumour bed. ECOG performance status ≥2. Presence of metastasis or lymph node involvement of the tumour. 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. Significant cardiovascular disease (e.g. dyspnoea >2 NYHA). 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. Uncontrolled viral, mycotic or bacterial infections. Known HIV-positive patients. Pregnant or breast-feeding women. Psychological, familial, social or geographical circumstances that limit the patient's ability to comply with the protocol or informed consent form. 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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Adriana Rojo
Phone
0034912866807
Email
adriana.crc@grupogeis.org
First Name & Middle Initial & Last Name or Official Title & Degree
Elisa Cerezo, MSc
Phone
0034912866807
Email
elisa.crc@grupogeis.org
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Javier Martín-Broto, MD
Organizational Affiliation
Jiménez Díaz Foundation University Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Institut Bergonié
City
Bordeaux
ZIP/Postal Code
33000
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Antoine Italiano, MD
Facility Name
Centre Léon Berard
City
Lyon
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jean Yves Blay, MD
Facility Name
Istituto Clinico Humanitas
City
Rozzano
State/Province
Milan
ZIP/Postal Code
20089
Country
Italy
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Armando Santoro, MD
Facility Name
Centro di Referimento Ocologico
City
Aviano
ZIP/Postal Code
33081
Country
Italy
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Angela Buonadonna, MD
Facility Name
Istituto Ortopedico Rizzoli
City
Bologna
ZIP/Postal Code
40136
Country
Italy
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Stefano Ferrari, MD
Facility Name
Candiolo Cancer Institute
City
Candiolo
ZIP/Postal Code
10060
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Giovanni Grignani, MD
Facility Name
Istituto Nazionale dei Tumori
City
Milan
ZIP/Postal Code
20133
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Alessandro Gronchi, MD
Email
alessandro.gronchi@istitutotumori.mi.it
Facility Name
Hospital Miguel Servet
City
Zaragoza
State/Province
Aragón
ZIP/Postal Code
50009
Country
Spain
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Javier Martínez-Trufero, MD
Facility Name
Hospital Sant Pau
City
Barcelona
State/Province
Cataluña
ZIP/Postal Code
08041
Country
Spain
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Antonio Lopez-Posa, MD
Facility Name
Hospital Son Espases
City
Palma de Mallorca
State/Province
Mallorca
ZIP/Postal Code
07010
Country
Spain
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Pablo Luna, MD
Facility Name
Hospital Universitario Canarias
City
San Cristobal de la Laguna
State/Province
Tenerife
ZIP/Postal Code
38320
Country
Spain
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Josefina Cruz, MD
Facility Name
Hospital Vall d'Hebrón
City
Barcelona
ZIP/Postal Code
08035
Country
Spain
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Claudia Valverde, MD
Facility Name
Hospital Puerta de Hierro
City
Madrid
ZIP/Postal Code
28006
Country
Spain
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Ricardo Cubedo, MD
Facility Name
Hospital Universitario Gregorio Marañón
City
Madrid
ZIP/Postal Code
28007
Country
Spain
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Rosa Álvarez, MD
Email
rosa.alvarez.al@gmail.com
Facility Name
Hospital Uniersitario La Paz
City
Madrid
ZIP/Postal Code
28046
Country
Spain
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Andres Redondo, MD
Facility Name
Jiménez Díaz Foundation University Hospital
City
Madrid
Country
Spain
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Javier Martín-Broto, MD
Email
jmartin@atbsarc.org
Facility Name
Hospital Virgen del Rocío
City
Sevilla
ZIP/Postal Code
41013
Country
Spain
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Irene Carrasco, MD
Email
irenecg1990@gmail.com

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
32827353
Citation
Vatner R, James CD, Sathiaseelan V, Bondra KM, Kalapurakal JA, Houghton PJ. Radiation therapy and molecular-targeted agents in preclinical testing for immunotherapy, brain tumors, and sarcomas: Opportunities and challenges. Pediatr Blood Cancer. 2021 May;68 Suppl 2:e28439. doi: 10.1002/pbc.28439. Epub 2020 Aug 22.
Results Reference
derived
PubMed Identifier
32077895
Citation
Martin-Broto J, Hindi N, Lopez-Pousa A, Peinado-Serrano J, Alvarez R, Alvarez-Gonzalez A, Italiano A, Sargos P, Cruz-Jurado J, Isern-Verdum J, Dolado MC, Rincon-Perez I, Sanchez-Bustos P, Gutierrez A, Romagosa C, Morosi C, Grignani G, Gatti M, Luna P, Alastuey I, Redondo A, Belinchon B, Martinez-Serra J, Sunyach MP, Coindre JM, Dei Tos AP, Romero J, Gronchi A, Blay JY, Moura DS. Assessment of Safety and Efficacy of Combined Trabectedin and Low-Dose Radiotherapy for Patients With Metastatic Soft-Tissue Sarcomas: A Nonrandomized Phase 1/2 Clinical Trial. JAMA Oncol. 2020 Apr 1;6(4):535-541. doi: 10.1001/jamaoncol.2019.6584. Erratum In: JAMA Oncol. 2020 Oct 1;6(10):1641.
Results Reference
derived
PubMed Identifier
31143880
Citation
Gronchi A, Hindi N, Cruz J, Blay JY, Lopez-Pousa A, Italiano A, Alvarez R, Gutierrez A, Rincon I, Sangalli C, Perez Aguiar JL, Romero J, Morosi C, Sunyach MP, Sanfilippo R, Romagosa C, Ranchere-Vince D, Dei Tos AP, Casali PG, Martin-Broto J. Trabectedin and RAdiotherapy in Soft Tissue Sarcoma (TRASTS): Results of a Phase I Study in Myxoid Liposarcoma from Spanish (GEIS), Italian (ISG), French (FSG) Sarcoma Groups. EClinicalMedicine. 2019 Mar 11;9:35-43. doi: 10.1016/j.eclinm.2019.03.007. eCollection 2019 Mar.
Results Reference
derived

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Trabectedin Plus Radiotherapy in Soft Tissue Sarcoma Patients

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