Trial in Patients With Metastatic or Locally Advanced Leiomyosarcoma

Study is aimed at evaluating the activity of Trabectedin (arm A) in advanced leiomyosarcomas, having Gemcitabine (arm B) as the comparator.

In addition to the randomized cohort, the study has also an observational prospective cohort which include patients who will refuse the randomization or for whom the investigator will not judge the randomization as an appropriate option.

In order to allow the participation of sites only to the prospective-observational (non randomized) cohort, it was introduced the possibility to participate to the study and receive the ethical approval only to the Observational Prospective Cohort In parallel an optional translational study will be performed, in both cohorts, to identify factors predictive of the activity of Trabectedin or Gemcitabine in this specific histotype.

The management of patients with leiomyosarcomas determines many difficulties. Despite patients with metastatic disease at diagnosis or who recur after initial treatment have a dismal prognosis and, except for a subset of selected patients with completely resectable disease, the median survival is less than two years.

At the advanced-disease stage, the main aim of treatment is to improve patient's quality of life, possibly survival, with the best compromise between toxicity and symptoms. Trabectedin (T) is a marine-derived cytotoxic approved by European MEdicine Agency (EMEA) and FDA.

It is indicated for the treatment of patients with advanced soft tissue sarcoma, after failure of anthracyclines-based chemotherapy or who are unsuitable to receive these agents.

Among Soft Tissue Sarcoma (STS), activity has been mainly detected in synovial sarcoma, liposarcoma and leiomyosarcoma. Although the response rate did not exceed 10%, T was demonstrated to provide disease control, with progression arrest rates exceeding 50% and progression-free survival rates exceeding 20% at 6 months. So far no phase II or III studies have been addressed to test the activity of T in leiomyosarcoma specifically (without differentiation between site of primary localization) in comparison with Gemcitabine.

This study is aimed at evaluating the activity of Trabectedin (arm A) in advanced leiomyosarcomas, having Gemcitabine (arm B) as the comparator. In parallel an optional translational study will be performed to identify factors predictive of the activity of Trabectedin or Gemcitabine in this specific histotype.

In addition to the randomized cohort, the study has also an observational prospective cohort which include patients who will refuse the randomization or for whom the investigator will not judge the randomization as an appropriate option.

In order to allow the participation of sites only to the prospective-observational (non randomized) cohort, it was introduced the possibility to participate to the study and receive the ethical approval only to the Observational Prospective Cohort In parallel an optional translational study will be performed, in both cohorts, to identify factors predictive of the activity of Trabectedin or Gemcitabine in this specific histotype.

Eligibility Criteria:
Inclusion Criteria:

1. Patients with histologically documented diagnosis of leiomyosarcoma
2. Patients with diagnosis of unresectable or metastatic leiomyosarcoma
3. Patients who received at least on previous systemic treatment with anthracycline-based chemotherapy.
4. Patients suitable to receive gemcitabine or trabectedin therapy.
5. Measurable or evaluable disease with RECIST 1.1 criteria.
6. Evidence of progression according RECIST 1.1 during the 6 months before study entry.
7. Age ≥18 years
8. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2
9. All previous anticancer treatments must have completed ≥ 3 weeks prior to first dose of study drug.
10. The patient has resolution of adverse events, with the exception of alopecia, and of all clinically significant toxic effects of prior loco-regional therapy, surgery, radiotherapy or systemic anticancer therapy to ≤ Grade 1, by National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0
11. Adequate bone marrow, liver and renal function
12. Left Ventricular Ejection Fraction ≥ 50% and/or above lower institutional limit of normality.
13. Female patients of child-bearing potential must have negative pregnancy test within 7 days before initiation each cycle of chemotherapy.
14. No history of arterial and/or venous thromboembolic event within the previous 12 months.
15. The patient or legal representative must be able to read and understand the informed consent form and must have been willing to give written informed consent prior to any study specific procedure. The subject may also provide an optional consent for the biological/translational sub-study associated.

Exclusion Criteria:

1. Prior treatment with Trabectedin and/or Gemcitabine
2. Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation of the study drugs
3. History of other malignancies (except basal cell carcinoma or cervical carcinoma in situ, adequately treated), unless in remission from 5 years or more and judged of negligible potential of relapse.
4. Persistent toxicities with the exception of alopecia, caused by previous anticancer therapies
5. Metastatic brain or meningeal tumors
6. Active viral hepatitis
7. Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus
8. Patients with any severe and/or uncontrolled medical conditions
9. Medical history of hemorrhage or a bleeding event ≥ Grade 3 (NCI-CTCAE v 5.0) within 4 weeks prior to the initiation of study treatment
10. Active clinically serious infections
11. Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus
12. Previous treatment with radiation therapy within 14 days of first day of study drug dosing,
13. Major surgery within 4 weeks prior to study entry
14. Concomitant use of known strong CYP3A inhibitors or moderate CYP3A inhibitors
15. Concomitant use of known strong or moderate CYP3A inducers
16. Patients undergoing renal dialysis or with Creatinin Clearance \<30 ml/min or Creatinine \>1,5 mg/dL
17. Pregnant or breast feeding patients
18. Patients with severe and/or uncontrolled concurrent medical disease that in the opinion of the investigator could cause unacceptable safety risks or compromise compliance with the protocol