Adult Patients With Unresectable Locally Advanced or Metastatic, Relapsed/Refractory Dedifferentiated LiposarcomaPhase 2APLIPONCT01876043

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

A Phase 2 study testing plitidepsin in people with Adult Patients With Unresectable Locally Advanced or Metastatic, Relapsed/Refractory Dedifferentiated Liposarcoma, run by Institut Bergonié at 6 sites in France.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record

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Trial summary

Who is it for?: Ages 18 years and older
Conditions the study is for: Adult Patients With Unresectable Locally Advanced or Metastatic, Relapsed/Refractory Dedifferentiated Liposarcoma
What is being tested?: plitidepsin
Type of treatment: Injection or infusion
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 24 participants
Where: 6 sitesFrance
Study dates: Feb 2012to Apr 2015
Phase: Phase 2

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 years and older
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

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.

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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

Who cannot join

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.

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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

Trial locations and contacts

6 sites in 1 country.

City, postcode or hospital

6 sites in 1 country

France6 sites

Centre Oscar Lambret
Lille, 59020
Centre Léon Bérard
Lyon, 69373
Hôpital de la Timone
Marseille, 13385
Institut Curie
Paris, 75005
Institut Claudius Regaud
Toulouse, 31052
Institut Gustave Roussy
Villejuif, 94800

Other trials in France

About this study

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
Being tested: plitidepsin
Medical subject headings: Neoplasm Metastasis, Recurrence, Liposarcoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

plitidepsinDrug
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.

Study groups in NCT01876043
Study group	Role	What they receive
plitidepsin	Experimental	plitidepsin Receives: Drug: plitidepsin

What is being measured

The primary outcome is the main question the study is designed to answer.

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.
Measured: 3 months

Secondary outcomes (6)

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.
Measured: 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.
Measured: 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.
Measured: from start of study treatment to the end of the study (up to 10 months)
1-year Overall Survival (OS) Rate
Measured: 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.
Measured: 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.
Measured: through study completion, an average of 1 year

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

Feb 2012Apr 2015

First posted12 Jun 2013 (estimated)
Study startFeb 2012
Primary completionApr 2015
Study completionApr 2015

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (1)Papers the sponsor has linked to this study.
Other trials for Adult Patients With Unresectable Locally Advanced or Metastatic, Relapsed/Refractory Dedifferentiated LiposarcomaStudies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 2
Primary purpose: Treatment
Allocation: Not applicable
Intervention model: Single group
Masking: None (open label)
Enrolment: 24 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT01876043
Sponsor's protocol ID: IB2011-02
Acronym: APLIPO
Status last verified: Dec 2020
First submitted: 29 Oct 2012
Last updated: 25 Jan 2021
Results posted: Yes, on ClinicalTrials.gov

Publications

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.
PubMed 26041763