Efficacité et Tolérance de la Plitidepsine chez les patients souffrant d’un liposarcome dédifférencié (DLPS) avancé, non opérable ou métastatique, en rechute/réfractaire : Une étude exploratoire multicentrique de phase II.

• Register: EUCTR
• Last refreshed on: 19 March 2012
• Main ID: EUCTR2009-010980-18-FR
• Date of registration: 19/05/2009
• Prospective Registration: Yes
• Primary sponsor: Pharma Mar, S.A.
• Public title: Efficacité et Tolérance de la Plitidepsine chez les patients souffrant d’un liposarcome dédifférencié (DLPS) avancé, non opérable ou métastatique, en rechute/réfractaire : Une étude exploratoire multicentrique de phase II.
• Scientific title: Efficacité et Tolérance de la Plitidepsine chez les patients souffrant d’un liposarcome dédifférencié (DLPS) avancé, non opérable ou métastatique, en rechute/réfractaire : Une étude exploratoire multicentrique de phase II.
• Date of first enrolment: 29/06/2009
• Target sample size: 37
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2009-010980-18
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no Randomised: Open: Single blind: Double blind: Parallel group: Cross over: Other: If controlled, specify comparator, Other Medicinial Product: Placebo: Other:

Countries of recruitment

France

Key inclusion & exclusion criteria

Inclusion criteria:
1. Histologically confirmed DLPS.
2. Metastatic or unresectable locally advanced disease with progression or relapse after standard therapy (at least one prior anthracycline-containing chemotherapy regimen).
3. Age = 18 years.
4. Eastern Cooperative Oncology Group (ECOG) performance status (PS) = 1.
5. Documented disease progression (as per RECIST) before study entry.
6. Measurable disease according to RECIST outside any previously irradiated field.
7. Adequate hematological, renal, metabolic and hepatic function.
a. 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.
b. 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).
c. Total bilirubin = 1.5 x ULN. d. Albumin > 25 g/l.
e. Calculated creatinine clearance (CrCl) = 40 ml/min (according to Cockroft and Gault formula).
f. Creatine phosphokinase (CPK) = 2.5 x ULN.
8. Troponin I = ULN.
9. No prior or concurrent malignant disease except for adequately treated in situ carcinoma of the cervix, basal or squamous skin cell carcinoma, or in situ transitional bladder cell carcinoma.
10. Life expectancy > 3 months.
11. 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.
12. 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 3.0).
13. Left ventricular ejection fraction (LVEF) by echocardiogram (ECHO) or multiple gated acquisition (MUGA) within normal limits.
14. 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.
15. Voluntarily signed and dated written informed consents prior to any study specific procedure.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
1. Previous treatment with plitidepsin.
2. Pathological diagnosis different from DLPS.
3. More than three prior lines of therapy for advanced disease.
4. Concomitant diseases/conditions:
a. History or presence of unstable angina, myocardial infarction, congestive heart failure or clinically significant valvular heart disease.
b. Previous mediastinal radiotherapy.
c. Previous treatment with anthracyclines at cumulative doses in excess of 450 mg/m2 doxorubicin equivalent.
d. Symptomatic arrhythmia or any arrhythmia requiring ongoing treatment, and/or prolonged QT-QTc grade > 1.
e. Active uncontrolled infection.
f. Myopathy or persistent CPK elevations > 2.5 x ULN in two different determinations performed with one week apart.
g. Limitation of the patient’s ability to comply with the treatment or to follow-up the protocol.
h. Any other major illness that, in the Investigator’s judgment, will substantially increase the risk associated with the patient’s participation in this study.
5. Evidence of progressive or symptomatic central nervous system (CNS) or leptomeningeal metastases.
6. 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. 7. Treatment with any investigational product within the period = 5 half-lives prior to the first infusion of plitidepsin.
8. Tumor tissue sample not available for pathological review and/or JNK immunochemistry testing.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

DEDIFFERENTIATED LIPOSARCOMA (DLPS)
MedDRA version: 9.1 Level: PT Classification code 10024627 Term: Liposarcoma

Intervention(s)

Product Name: APLIDIN (plitidepsin)
Pharmaceutical Form: Powder and solvent for solution for injection
INN or Proposed INN: plitidepsin
CAS Number: 137219-37-5
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 2-

Primary Outcome(s)

Secondary Objective: • Response rate as per the Response Evaluation Criteria in Solid Tumors (RECIST).
• Correlation of clinical benefit (as per RECIST: complete response [CR] + partial response [PR] + stable disease [SD] = 3 months) according to c-Jun N-terminal (JUN)-kinase (JNK) immunohistochemistry (IHC) expression status.
• Progression-free survival (PFS) and progression-free survival rate at six months (PFS6).
• Overall survival (OS).
• Safety evaluation in this patient population.
• Pharmacogenomic (PGx) analysis of :
?????? Potential biomarkers of sensitivity or resistance to plitidepsin and predictive markers of treatment outcome from pre-treatment available paraffin-embedded tumor tissue samples, and
?????? Changes of gene expression profile (GEP) in peripheral white blood cells (PWBC) before and after plitidepsin exposure and in fresh/frozen tissue samples (when available) in consenting patients.

Main Objective: To evaluate the antitumor activity of plitidepsin in terms of progression-free survival rate at three months (PFS3).

Primary end point(s): Primary endpoint:
PFS3, defined as the percentage of patients remaining alive and progression free at three months (i.e., Week 12 ± 1) after the first infusion as per RECIST.
Secondary endpoints:
-Efficacy:
• Overall response rate (ORR), defined as the percentage of patients with CR or PR response according to RECIST
• PFS, defined as the time between the date of the first infusion and the date of disease progression defined as per RECIST or death of any cause.
• PFS6, defined as the percentage of patients remaining alive and progression free at six months from first infusion as per RECIST.
• Clinical benefit, defined as the percentage of patients with CR, PR or SD according to RECIST. Correlation of clinical benefit and the JNK status of the patients, as assessed by IHC, will be performed.
• OS, defined as the time from first infusion to death (of any cause).
-Safety profile:
• Treatment safety (AEs, SAEs and laboratory abnormalities) graded according to the NCI-CTCAE version 3.0 (25).
-Others:
• PGx analysis

Secondary ID(s)

APL-B-019-08