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

• Sponsor: Institut Bergonié (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01876043
• Collaborator: Ministry of Health, France (Other), PharmaMar (Industry)
• Enrollment: 24
• Locations: 6
• Arm: 1
• Duration (Months): 37.9
• Patients Per Site: 4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Adult Patients With Unresectable Locally Advanced or Metastatic, Relapsed/Refractory Dedifferentiated Liposarcoma	Drug: plitidepsin	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 24 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Study Start Date: Feb 1, 2012
• Actual Primary Completion Date: Apr 1, 2015
• Actual Study Completion Date: Apr 1, 2015

Arms and Interventions

Arm

Intervention/Treatment

Experimental: plitidepsin plitidepsin

Drug: plitidepsin; 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.

Outcome Measures

Primary Outcome Measures

1. Percentage of Patients Remaining Alive and Progression Free at 3 Months (i.e. Week 12 ± 1) as Per RECIST1.1 (PFS3). [3 months]

   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.

Secondary Outcome Measures

1. Percentage of Patients With Objective Response at Six Months (as Per RECIST v1.1) [6 months]

   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.

2. Percentage of Patients Remaining Alive and Progression Free at 6 Months as Per RECIST1.1. [6 months]

   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. Progression-free Survival [from start of study treatment to the end of the study (up to 10 months)]

   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.

4. 1-year Overall Survival (OS) Rate [1 year]

5. Treatment Safety (AEs, SAEs and Laboratory Abnormalities) Graded According to the NCI-CTCAE Version 4.0. [through study completion, an average of 1 year]

   Toxicity were graded according to the NCI-CTCAE version 4.0.

6. Number of Participants With a Biomarker Amplification [through study completion, an average of 1 year]

   Genomic status of biomarkers obtained by using array-comparative genomic hybridization.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Voluntarily signed and dated written informed consent prior to any study specific procedure.

2. Histologically confirmed DLPS by central review.

3. Metastatic or unresectable locally advanced disease

4. 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

5. At least one prior anthracycline-containing chemotherapy regimen

6. Age ≥ 18 years.

7. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1.

8. Measurable disease according to RECIST v1.1 outside any previously irradiated field.

9. Adequate hematological, renal, metabolic and hepatic function.

10. 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.

11. 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).

12. Total bilirubin 1.5 x ULN.

13. Albumin > 25 g/l.

14. Calculated creatinine clearance (CrCl) ≥ 40 ml/min (according to cockroft and Gault formula).

15. Creatine phosphokinase (CPK) ≤ 2.5 x ULN.

16. Troponin I ≤ ULN

17. 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.

18. 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.

19. 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).

20. Left ventricular ejection fraction (LVEF) by echocardiogram (ECHO) or multiple gated acquisition (MUGA) within normal limits.

21. 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.

22. Patients with a french social security in compliance with the French law relating to biomedical research

Exclusion Criteria:

1. Previous treatment with plitidepsin.

2. More than three prior lines of therapy for advanced disease.

3. Concomitant diseases/conditions:

4. 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.

5. Previous mediastinal radiotherapy.

6. Previous treatment with anthracyclines at cumulative doses in excess of 450 mg/m2 doxorubicin equivalent.

7. Symptomatic arrhythmia or any arrhythmia requiring ongoing treatment, and/or prolonged QT-QTc grade > 1.

8. Active uncontrolled infection.

9. Myopathy or persistent CPK elevations > 2.5 x ULN in two different determinations performed with one week apart.

10. Any other major illness that, in the Investigator's judgment, will substantially increase the risk associated with the patient's participation in this study.

11. Evidence of progressive or symptomatic central nervous system (CNS) or leptomeningeal metastases.

12. 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.

13. Tumor tissue sample not available for pathological review and/or JNK immunochemistry testing.

14. Participation in a clinical study and / or receipt of an investigational drug during the last 30 days.

15. Previous enrolment in the present study.

16. Patient unable to follow and comply with the study procedures because of any geographical, social or psychological reasons.

17. Known hypersensitivity to any involved study drug or any of its formulation components

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Centre Oscar Lambret	Lille		France	59020
2	Centre Léon Bérard	Lyon		France	69373
3	Hôpital de la Timone	Marseille		France	13385
4	Institut Curie	Paris		France	75005
5	Institut Claudius Regaud	Toulouse		France	31052
6	Institut Gustave Roussy	Villejuif		France	94800

Sponsors and Collaborators

• Institut Bergonié
• Ministry of Health, France
• PharmaMar

Investigators

• Study Chair: Antoine Italiano, MD, Institut Bergonié

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Institut Bergonié
• ClinicalTrials.gov Identifier: NCT01876043
• Other Study ID Numbers: IB2011-02
• First Posted: Jun 12, 2013
• Last Update Posted: Jan 25, 2021
• Last Verified: Dec 1, 2020

• Additional relevant MeSH terms: Liposarcoma

Study Results

Participant Flow

Arm/Group Title	Plitidepsin
Arm/Group Description	Patients received Aplidin® as an i.v. 3-h infusion of 5 mg/m2/day on days 1 and 15 every 4 weeks (q4wk).Patients discontinued Aplidin 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.
Period Title: Overall Study
STARTED	24
Interim Analysis Population	17
COMPLETED	22
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Plitidepsin
Arm/Group Description	plitidepsin plitidepsin
Overall Participants	24
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	14 58.3%
>=65 years	10 41.7%
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	63.3
Sex: Female, Male (Count of Participants)
Female	12 50%
Male	12 50%
Region of Enrollment (participants) [Number]
France	24 100%

Outcome Measures

1. Primary Outcome

Title	Percentage of Patients Remaining Alive and Progression Free at 3 Months (i.e. Week 12 ± 1) as Per RECIST1.1 (PFS3).
Description	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.
Time Frame	3 months

Outcome Measure Data

Analysis Population Description

22 patients who completed study i.e who completed one cycle or two incomplete cycles of treatment were analyzed for final efficacy analysis. Out of these 22 patients who completed study, the first 17 patients (first stage of the 2-stage Simon's optimal design ) were analyzed for interim efficacy analysis based on primary endpoint.

Arm/Group Title	Plitidepsin
Arm/Group Description	plitidepsin plitidepsin
Measure Participants	22
Final efficacy analysis	9.1 37.9%
Interim analysis population	5.9 24.6%

2. Secondary Outcome

Title	Percentage of Patients With Objective Response at Six Months (as Per RECIST v1.1)
Description	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.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Plitidepsin
Arm/Group Description	plitidepsin plitidepsin
Measure Participants	22
Number (95% Confidence Interval) [percentage of participants]	0 0%

3. Secondary Outcome

Title	Percentage of Patients Remaining Alive and Progression Free at 6 Months as Per RECIST1.1.
Description	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.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Plitidepsin
Arm/Group Description	plitidepsin plitidepsin
Measure Participants	22
Number (95% Confidence Interval) [percentage of participants]	0 0%

4. Secondary Outcome

Title	Progression-free Survival
Description	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.
Time Frame	from start of study treatment to the end of the study (up to 10 months)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Plitidepsin
Arm/Group Description	plitidepsin plitidepsin
Measure Participants	22
Median (95% Confidence Interval) [months]	1.6

5. Secondary Outcome

Title	1-year Overall Survival (OS) Rate
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Plitidepsin
Arm/Group Description	plitidepsin plitidepsin
Measure Participants	22
Number (95% Confidence Interval) [percentage of overall survival]	40.9

6. Secondary Outcome

Title	Treatment Safety (AEs, SAEs and Laboratory Abnormalities) Graded According to the NCI-CTCAE Version 4.0.
Description	Toxicity were graded according to the NCI-CTCAE version 4.0.
Time Frame	through study completion, an average of 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Plitidepsin
Arm/Group Description	plitidepsin plitidepsin
Measure Participants	24
Number [adverse events]	232

7. Secondary Outcome

Title	Number of Participants With a Biomarker Amplification
Description	Genomic status of biomarkers obtained by using array-comparative genomic hybridization.
Time Frame	through study completion, an average of 1 year

Outcome Measure Data

Analysis Population Description

19 patients (out of the 22 patients) for whom translational research have been performed.

Arm/Group Title	Plitidepsin
Arm/Group Description	plitidepsin plitidepsin
Measure Participants	19
Number [participants]	2 8.3%

Adverse Events

Arm/Group Title	Plitidepsin
Arm/Group Description	plitidepsin plitidepsin
All Cause Mortality
	Plitidepsin
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Plitidepsin
	Affected / at Risk (%)	# Events
Total	12/24 (50%)
Blood and lymphatic system disorders
ANEMIA	1/24 (4.2%)
Gastrointestinal disorders
NAUSEA	2/24 (8.3%)
FEVER VOMITING	1/24 (4.2%)
ABDOMINAL PAIN DIARRHEA NAUSEA VOMITING	1/24 (4.2%)
NAUSEA VOMITING DYSPNEA	1/24 (4.2%)
General disorders
SUDDEN DEATH	1/24 (4.2%)
WORSENING OF GENERAL STATUS	1/24 (4.2%)
Immune system disorders
HYPERSENSITIVITY	1/24 (4.2%)
Infections and infestations
PNEUMONIA	1/24 (4.2%)
SEPSIS	1/24 (4.2%)
Injury, poisoning and procedural complications
LEFT FOREARM FRACTURE	1/24 (4.2%)
Investigations
CPK increased	1/24 (4.2%)
CHEST PAIN / TROPONIN INCREASED	1/24 (4.2%)
Metabolism and nutrition disorders
ASTHENIA, ANOREXIA, NAUSEA	1/24 (4.2%)
Diabetic decompensation	1/24 (4.2%)
Vascular disorders
Inferior vena cava thrombosis	1/24 (4.2%)
BILATERAL PULMONARY EMBOLISM	1/24 (4.2%)
Other (Not Including Serious) Adverse Events
	Plitidepsin
	Affected / at Risk (%)	# Events
Total	24/24 (100%)
Blood and lymphatic system disorders
ANEMIA	7/24 (29.2%)
Gastrointestinal disorders
Abdominal distension	3/24 (12.5%)
Abdominal pain	3/24 (12.5%)
CONSTIPATION	4/24 (16.7%)
DIARRHEA	10/24 (41.7%)
NAUSEA	19/24 (79.2%)
VOMITING	7/24 (29.2%)
General disorders
EDEMA LIMBS	6/24 (25%)
FATIGUE	22/24 (91.7%)
FEVER	5/24 (20.8%)
INFUSION RELATED REACTION	2/24 (8.3%)
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - OTHER	2/24 (8.3%)
Infections and infestations
LUNG INFECTION	2/24 (8.3%)
Injury, poisoning and procedural complications
FRACTURE	2/24 (8.3%)
Investigations
ALANINE AMINOTRANSFERASE INCREASED	2/24 (8.3%)
ALKALINE PHOSPHATASE INCREASED	2/24 (8.3%)
ASPARTATE AMINOTRANSFERASE INCREASED	2/24 (8.3%)
CARDIAC TROPONINE T INCREASED	3/24 (12.5%)
CPK INCREASED	2/24 (8.3%)
GGT INCREASED	3/24 (12.5%)
WEIGHT LOSS	4/24 (16.7%)
INVESTIGATIONS OTHER	2/24 (8.3%)
Metabolism and nutrition disorders
ANOREXIA	13/24 (54.2%)
DEHYDRATATION	2/24 (8.3%)
HYPOALBUMINEMIA	3/24 (12.5%)
HYPOCALCEMIA	2/24 (8.3%)
Musculoskeletal and connective tissue disorders
BACK PAIN	2/24 (8.3%)
MYALGIA	5/24 (20.8%)
Nervous system disorders
HEADACHE	3/24 (12.5%)
NERVOUS SYSTEM DISORDERS OTHER	2/24 (8.3%)
Psychiatric disorders
INSOMNIA	2/24 (8.3%)
Respiratory, thoracic and mediastinal disorders
DYSPNEA	5/24 (20.8%)
RESPIRATORY THORACIC AND MEDIASTINAL DISORDERS OTHER	2/24 (8.3%)
Vascular disorders
THROMBOEMBOLIC EVENT	2/24 (8.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.