Efficacy and Safety of Plitidepsin in Patients With Advanced Unresectable or Metastatic, Relapsed/Refractory, Dedifferentiated Liposarcoma (DLPS): an Exploratory Phase II Multicenter Trial

Study Overview
=================
Brief Summary
-----------------
Liposarcomas are soft tissue sarcomas most frequent. We distinguish three subtypes on the basis of their histological and cytogenetic characteristics: well-differentiated liposarcoma / dedifferentiated, myxoid liposarcoma and / or round cell liposarcoma and pleomorphic. Dedifferentiated liposarcomas (LDD) represent 20% of liposarcomas and are characterized by well-differentiated component associated with a contingent sarcomatous differentiation and fat-usually high grade. The LDD are most often rétropértionéal seat. Thus, their development is very long asymptomatic. At diagnosis, tumor volume is often very important making surgical removal impossible in a high proportion of cases. Operable tumors have also a risk of local recurrence by about 50% and about 20% metastatic. Chemotherapy is the only treatment of these advanced forms. However, the currently available drugs (adriamycin, ifosfamide) have only very limited effectiveness. Progression-free survival of patients does not exceed 2 months. The LDD is characterized cytogenetically by the constant presence of two amplicons (1p32 and 6q23) respectively targeting genes MAP3K5 and JUN. These two genes encode proteins involved in the signaling pathway Jun N-terminal kinase (JNK). Activation of JNK is involved in the loss of adipose differentiation and tumor aggressiveness of LDD. The plitidepsin is a drug capable of inducing apoptosis of tumor cells carrying a functional activation of the JNK pathway. This drug has such a pro-apoptotic and anti-proliferative in vitro models of LDD. plitidepsin could represent the treatment of choice for patients with advanced LDD. The objective of this study is to evaluate the anti-tumor activity of plitidepsin patients with locally advanced dedifferentiated liposarcomas and / or metastatic.

Official Title
-----------------
Efficacy and Safety of Plitidepsin in Patients With Advanced Unresectable or Metastatic, Relapsed/Refractory, Dedifferentiated Liposarcoma (DLPS): an Exploratory Phase II Multicenter Trial

Conditions
-----------------
Adult Patients With Unresectable Locally Advanced or Metastatic, Relapsed/Refractory Dedifferentiated Liposarcoma

Intervention / Treatment
-----------------
* Drug: plitidepsin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Voluntarily signed and dated written informed consent prior to any study specific procedure. Histologically confirmed DLPS by central review. Metastatic or unresectable locally advanced disease Progressive disease according to RECIST v1.1 criteria diagnosed on the basis of two CT scan obtained at an interval less than 3 months and confirmed by central review At least one prior anthracycline-containing chemotherapy regimen Age ≥ 18 years. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1. Measurable disease according to RECIST v1.1 outside any previously irradiated field. Adequate hematological, renal, metabolic and hepatic function. Hemoglobin ≥ 9 g/dl (patients may have received prior red blood cell [RBC] transfusion, if clinically indicated); absolute neutrophil count (ANC) ≥ 1.2 x 109/l, and platelet count ≥ 100 x 109/l. Alkaline phosphatase (AP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) 2.5 x upper limit of normality (ULN) (5 in case of extensive skeletal involvement for AP exclusively). Total bilirubin 1.5 x ULN. Albumin > 25 g/l. Calculated creatinine clearance (CrCl) ≥ 40 ml/min (according to cockroft and Gault formula). Creatine phosphokinase (CPK) ≤ 2.5 x ULN. Troponin I ≤ ULN No prior or concurrent malignant disease in the last 5 years except for adequately treated in situ carcinoma of the cervix, basal or squamous skin cell carcinoma, or in situ transitional bladder cell carcinoma. At least three weeks since last chemotherapy (six weeks in case of nitrosoureas and mitomycin C), immunotherapy or any other pharmacological treatment and/or radiotherapy. Recovery to grade ≤ 1 from any adverse event (AE) derived from previous treatment (excluding alopecia of any grade and non-painful peripheral neuropathy grade ≤ 2) according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE, version 4.0). Left ventricular ejection fraction (LVEF) by echocardiogram (ECHO) or multiple gated acquisition (MUGA) within normal limits. Women of childbearing potential must have a negative serum pregnancy test before study entry. Both women and men must agree to use a medically acceptable method of contraception throughout the treatment period and for six months after discontinuation of treatment. Acceptable methods of contraception include intrauterine device (IUD), oral contraceptive, subdermal implant and double barrier. Patients with a french social security in compliance with the French law relating to biomedical research Exclusion Criteria: Previous treatment with plitidepsin. More than three prior lines of therapy for advanced disease. Concomitant diseases/conditions: History or presence of unstable angina, myocardial infarction, congestive heart failure or clinically significant valvular heart disease. Symptomatic arrhythmia or any arrhythmia requiring ongoing treatment, and/or prolonged QT-QTc grade > 1. Previous mediastinal radiotherapy. Previous treatment with anthracyclines at cumulative doses in excess of 450 mg/m2 doxorubicin equivalent. Symptomatic arrhythmia or any arrhythmia requiring ongoing treatment, and/or prolonged QT-QTc grade > 1. Active uncontrolled infection. Myopathy or persistent CPK elevations > 2.5 x ULN in two different determinations performed with one week apart. Any other major illness that, in the Investigator's judgment, will substantially increase the risk associated with the patient's participation in this study. Evidence of progressive or symptomatic central nervous system (CNS) or leptomeningeal metastases. Men or women of childbearing potential who are not using an effective method of contraception as previously described; women who are pregnant or breast feeding. Tumor tissue sample not available for pathological review and/or JNK immunochemistry testing. Participation in a clinical study and / or receipt of an investigational drug during the last 30 days. Previous enrolment in the present study. Patient unable to follow and comply with the study procedures because of any geographical, social or psychological reasons. Known hypersensitivity to any involved study drug or any of its formulation components

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: plitidepsin<br>plitidepsin | Drug: plitidepsin<br>* Patients received plitidepsin as an i.v. 3-h infusion of 5 mg/m2/day on days 1 and 15 every 4 weeks. Patients discontinued plitidepsin if one of the following occurred: consent withdrawal, unacceptable toxicity, disease progression (RECIST v1.1), intercurrent illness or investigator's decision. Single-arm phase II clinical trial based on a two-stage optimal Simon's design with 37 evaluable patients (first stage: 17 patients) used to distinguish a favorable true non-progression rate of 40% from a null rate of 20% (90% power and 10% type I error). Stage 1(17 participants): if <=3 non-progressions at 3 months, the study was stopped early. Otherwise, the second group of 20 participants was recruited. Stage 2 (37 participants): if >= 11 non-progressions, Aplidin was considered promising.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients Remaining Alive and Progression Free at 3 Months (i.e. Week 12 ± 1) as Per RECIST1.1 (PFS3). | Progression is defined using New Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of diameters of target lesions (taking as reference the smallest sum on study), or a unequivocal progression of existing non-target lesions, or the appearance of one or more new lesions. | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients With Objective Response at Six Months (as Per RECIST v1.1) | Objective response assessed as per New Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) : Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.; Overall Response (OR) = CR + PR. | 6 months | 
| Percentage of Patients Remaining Alive and Progression Free at 6 Months as Per RECIST1.1. | Progression is defined using New Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of diameters of target lesions (taking as reference the smallest sum on study), or a unequivocal progression of existing non-target lesions, or the appearance of one or more new lesions. | 6 months | 
| Progression-free Survival | Progression-free survival is defined as the delay between the start date of treatment and the date of progression or death (from any cause), whichever occurs first. Patients alive and progression free were censored at the date of last follow-up, death, or last patient contact. Progression is assessed as per RECIST v1.1. | from start of study treatment to the end of the study (up to 10 months) | 
| 1-year Overall Survival (OS) Rate |  | 1 year | 
| Treatment Safety (AEs, SAEs and Laboratory Abnormalities) Graded According to the NCI-CTCAE Version 4.0. | Toxicity were graded according to the NCI-CTCAE version 4.0. | through study completion, an average of 1 year | 
| Number of Participants With a Biomarker Amplification | Genomic status of biomarkers obtained by using array-comparative genomic hybridization. | through study completion, an average of 1 year |