Study on Trabectedin in Combination With Pioglitazone in Patients Myxoid Liposarcomas With Stable Disease After T Alone.

In the specific the first stage will be an Italian mono-institutional, single arm, pilot study exploring the activity of the combination of T and P in myxoid liposarcoma patients who achieved a stable disease after a minimum of 4 cycles of T alone. If a minimum required activity will be demonstrated from the first stage, the second stage of the study will be conducted; otherwise, the study will be stopped.

The second stage will be an Italian multicenter, open-label, randomized, double arm, phase II trial, aimed at evaluating the combination of T and P in myxoid liposarcoma and G1 or G2 dedifferentiated liposarcomas compared to the standard treatment. Patients will be randomized by a centralized computer system with a 1:1 ratio to one of the following two arms:

* Control arm (A): T alone
* Experimental arm (B): T in combination with P The pilot study will be conducted in Italy at Istituto Nazionale Tumori Milano in order to recruit 10 evaluable patients. The second stage will be conducted in approximately 10 italian centers in order to recruit 80 evaluable patients.

• Trabectedin (Drug), also known as Trabectedine: Patients will be treated with Trabectedin administered at a dose of 1.5 mg/m2-1.3 mg/m2 (according to investigator's choice, with a top-dose of 2.6 total mg per cycle) as a 24-hour continuous infusion via a central venous access every 3 weeks and pioglitazone given continuously at the daily dose of 45 mg by oral route.
• Pioglitazone Oral Product (Drug), also known as Pioglitazone: Patients will be treated with Trabectedin administered at a dose of 1.5 mg/m2-1.3 mg/m2 (according to investigator's choice, with a top-dose of 2.6 total mg per cycle) as a 24-hour continuous infusion via a central venous access every 3 weeks and pioglitazone given continuously at the daily dose of 45 mg by oral route.

Primary outcomes

• Objective response (OR) in patients with myxoid liposarcomas according to RECIST criteria or CHOI criteria [From the date of the enrollment up to 24 months]: The primary activity endpoint is the number of responders. Patients will be considered as responders if they reach a CR or PR as best response during treatment according to RECIST criteria or according to Choi criteria.

Secondary outcomes

• Number and severity of Adverse Events [up to 24 months]: The safety profile of T+P is assessed by the frequency and type of treatment emergent adverse events, graded according to NCI-CTCAE v5.0, frequency and nature of SAEs.
• Maximum Plasma Concentration [Cmax] [up to 24 months]: The analysis of \[Cmax\] will be performed on the first four enrolled patients within the safety analysis set 1.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. Diagnosis of myxoid/round cell liposarcomas
2. Histological diagnosis confirmation by a reference centre
3. Age ≥ 18 years
4. ECOG PS ≤2
5. One or more previous systemic treatments employing anthracyclines +/- ifosfamide (unless one or both are clinically contraindicated)
6. Four or more previous cycles of T with a stable disease as defined by RECIST criteria
7. Recovery from toxic effects of prior therapies to NCI CTC Grade 1 or higher
8. Provision of signed informed consent

Exclusion Criteria:

1. Pregnant or breast-feeding women
2. Partial response or progression disease as per RECIST criteria to the previous treatment with T
3. Inadequate haematological, renal and liver functions
4. 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
5. Known central nervous system (CNS) metastases
6. Active viral hepatitis or chronic liver disease
7. Unstable cardiac condition, including congestive heart failure or angina pectoris, myocardial infarction within one year before enrolment, uncontrolled arterial hypertension or arrhythmias
8. Active major infection
9. Other serious concomitant illnesses

• Maurizio D'Incalci, MD, Study chair, Humanitas University
• Irene De Simone, Study chair, Istituto Di Ricerche Farmacologiche Mario Negri