Patient case: 78-year-old female with sarcoma; genetic feature: MDM2

Clinical trial: Phase I-II Trial, Multicenter, Open, Exploring Trabectedin Plus Radiotherapy in Soft Tissue Sarcoma Patients

Summary: Phase I-II trial that combines trabectedin plus radiotherapy for tumor reduction response measure in two 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. Phase I: escalating dose of 1.3 or 1.5 mg/m2. Radiotherapy for cohort A: 30Gy in 10 fractions (3Gy/fraction) Radiotherapy for cohort B: 45Gy in 25 fractions (1.8Gy/fraction) A translational substudy is developed to analyse different biomarkers predictive value.

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 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.
  To cohorts are indicated for this trial, A: Patients with diagnosis of non-operable or unresectable or not oncologically recommended metastasectomy of limited to lung metastases soft tissue sarcoma and cohort B: Patients with locally advanced resectable Myxoid Liposarcoma. Unlimited cycles of chemotherapy are considered to be beneficial for cohort A patients, whereas cohort B only 3 cycles are indicated. About radiotherapy treatment, 30Gy will be given to cohort A patients, whereas cohort B will receive 45Gy. TCs and MRI are selected for imaging purposes.
  Several biomarkers are selected to perform FFPE tumor assays in relation to prediction

Eligibility: 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 between 18 and 70.
  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
  4. Patients must have documentation of disease progression within 6 months prior to study entry.
  5. 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.
  6. 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)
  7. Measurable disease, according to RECIST V 1.1 criteria
  8. Performance status ≤1 (ECOG).
  9. Adequate respiratory functions: FEV1 >1L
  10. 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 5' nucleotidase and/or GGT must be ≤ UNL.
  11. 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.
  12. Normal cardiac function with a LVEF ≥ 50% by echocardiogram or MUGA.
  13. Disease distribution in lungs allows meeting with normal tissue constraints of radiation therapy. Radiation oncologist must confirm this point.
  14. 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)
  15. Patient must have a Central Venous Catheter for treatment
  Exclusion Criteria:
  1. Previous treatment with trabectedin or radiotherapy involving any lung field.
  2. Performance status ≥ 2 (ECOG).
  3. Metastases out of those located in lungs.
  4. Plasma bilirubin > UNL.
  5. Creatinine > 1.6 mg/dL.
  6. History of other neoplastic disease with the exception of basal cell carcinoma or in situ cervical cancer adequately treated.
  7. Severe COPD or other severe pulmonary diseases.
  8. Significant cardiovascular disease (for example, dyspnea > 2 NYHA)
  9. 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.
  10. Uncontrolled bacterial, mycotic or viral infections.
  11. Known positive test for infection by human immunodeficiency virus (HIV).
  12. Women who are pregnant or breast-feeding.
  13. Psychological, familial, social or geographic circumstances that limit the patient's ability to comply with the protocol or informed consent.
  14. Patients participating in another clinical trial or receiving any other investigational product.
  15. Patients who had participated in another clinical trial and/or had received any other investigational product in the last 30 days prior to inclusion.
  16. 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. Aged between 18 and 70.
  3. Pathological diagnosis of Myxoid Liposarcoma, deep located and more than 5 cm or superficial more than 10 cm.
  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 5' nucleotidase 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. More than one previous chemotherapy treatment for local disease including trabectedin.
  2. Radiotherapy involving the tumoral bed.
  3. Performance status ≥ 2 (ECOG).
  4. Presence of metastases or lymph node involvement by the tumor.
  5. Location other than limb or superficial trunk wall.
  6. Plasma bilirubin > UNL.
  7. Creatinine > 1.6 mg/dL.
  8. History of other neoplastic disease with the exception of basal cell carcinoma or in situ cervical cancer adequately treated.
  9. Significant cardiovascular disease (for example, dyspnea > 2 NYHA)
  10. 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.
  11. Uncontrolled bacterial, mycotic or viral infections.
  12. Known positive test for infection by human immunodeficiency virus (HIV).
  13. Women who are pregnant or breast-feeding.
  14. Psychological, familial, social or geographic circumstances that limit the patient's ability to comply with the protocol or informed consent.
  15. Patients participating in another clinical trial or receiving any other investigational product.
  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.

Relevance to patient case: not relevant