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

NCT01876043 | Terminated Phase 2 Results

• 1 other identifier: IB2011-02
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 6

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.

Conditions

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

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (6)

• Percentage of Patients With Objective Response at Six Months (as Per RECIST v1.1)

  6 months

• Percentage of Patients Remaining Alive and Progression Free at 6 Months as Per RECIST1.1.

  6 months

• Progression-free Survival

  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.

  through study completion, an average of 1 year

Study Arms (1)

plitidepsin

EXPERIMENTAL

plitidepsin

Drug: plitidepsin

Interventions

plitidepsin DRUG

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.

plitidepsin

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Institut Bergonié: lead
• Ministry of Health, France: collaborator
• PharmaMar: collaborator

Study Sites (6)

Centre Oscar Lambret

Lille, 59020, France

Location

Centre Léon Bérard

Lyon, 69373, France

Location

Hôpital de la Timone

Marseille, 13385, France

Location

Institut Curie

Paris, 75005, France

Location

Institut Claudius Regaud

Toulouse, 31052, France

Location

Institut Gustave Roussy

Villejuif, 94800, France

Location

Related Publications (1)

• Toulmonde M, Le Cesne A, Piperno-Neumann S, Penel N, Chevreau C, Duffaud F, Bellera C, Italiano A. Aplidin in patients with advanced dedifferentiated liposarcomas: a French Sarcoma Group Single-Arm Phase II study. Ann Oncol. 2015 Jul;26(7):1465-70. doi: 10.1093/annonc/mdv195. Epub 2015 Jun 3.

  PMID: 26041763 RESULT

MeSH Terms

Conditions

Neoplasm Metastasis; Recurrence; Liposarcoma

Interventions

plitidepsin

Condition Hierarchy (Ancestors)

Neoplastic Processes; Neoplasms; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Disease Attributes; Neoplasms, Adipose Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Sarcoma

Results Point of Contact

• Title: Dr Antoine ITALIANO
• Organization: Institut Bergonié

a.italiano@bordeaux.unicancer.fr

+33556333333

Study Officials

• Antoine Italiano, MD

  Institut Bergonié

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 29, 2012
• First Posted: June 12, 2013
• Study Start: February 1, 2012
• Primary Completion: April 1, 2015
• Study Completion: April 1, 2015
• Last Updated: January 25, 2021
• Results First Posted: November 12, 2019

Record last verified: 2020-12

Locations

FR (6)