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A Study of Plitidepsin in Patients With Relapsed or Refractory Angioimmunoblastic T-cell Lymphoma

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ClinicalTrials.gov Identifier: NCT03070964
Recruitment Status : Terminated (The main reason that motivated the study termination was the slow recruitment of the trial.)
First Posted : March 6, 2017
Results First Posted : October 14, 2020
Last Update Posted : October 14, 2020
Sponsor:
Information provided by (Responsible Party):
PharmaMar

Study Type Interventional
Study Design Allocation: N/A;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Lymphoma
Intervention Drug: plitidepsin
Enrollment 14
Recruitment Details

The first IC was signed on 25Oct2016 and the first study treatment administration was on 9Nov2016.

The cutoff date was 2Jul2018 (date of last follow-up, clinical cutoff). At cutoff date, 14 patients had been included, of whom 13 were treated and evaluable for safety, and 12 were evaluable for the primary efficacy endpoint

Pre-assignment Details  
Arm/Group Title Plitidepsin
Hide Arm/Group Description Plitidepsin was administered i.v. as a 1-hour infusion (fixed rate) via central or peripheral venous catheter. Patients received plitidepsin at a starting dose of 3.2 mg/m2 on Day 1, 8 and 15 every four weeks (q4wk). A 1-day window is allowed for plitidepsin administration. A cycle is defined as a fourweek period. A 1-day window was allowed for plitidepsin administration.
Period Title: Overall Study
Started 14
Completed 0
Not Completed 14
Reason Not Completed
Progressive disease             8
Treatment-unrelated adverse event             2
Never treated             1
Physician Decision             1
Withdrawal by Subject             1
Adverse Event             1
Arm/Group Title Plitidepsin
Hide Arm/Group Description Plitidepsin was administered i.v. as a 1-hour infusion (fixed rate) via central or peripheral venous catheter. Patients received plitidepsin at a starting dose of 3.2 mg/m2 on Day 1, 8 and 15 every four weeks (q4wk). A 1-day window is allowed for plitidepsin administration. A cycle is defined as a fourweek period. A 1-day window was allowed for plitidepsin administration.
Overall Number of Baseline Participants 14
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 14 participants
<=18 years
0
   0.0%
Between 18 and 65 years
9
  64.3%
>=65 years
5
  35.7%
Age, Continuous  
Median (Full Range)
Unit of measure:  Years
Number Analyzed 14 participants
61
(40 to 75)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 14 participants
Female
6
  42.9%
Male
8
  57.1%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 14 participants
White
13
  92.9%
Hispanolatin
1
   7.1%
ECOG PS   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 14 participants
PS 0
8
  57.1%
PS 1
5
  35.7%
PS 2
1
   7.1%
[1]
Measure Description: ECOG PS, Eastern Cooperative Oncology Group performance status PS 0 Fully active able to carry on all pre-disease performance without restriction PS 1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature PS 2 Ambulatory and capable of all selfcare but unable to carry out any work activities up and about more than 50% of waking hours PS 3 Capable of only limited selfcare confined to bed or chair more than 50% of waking hours PS 4 Completely disabled cannot carry on any selfcare; totally confined to bed or chair PS 5 Dead
Ann Arbor stage   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 14 participants
III
1
   7.1%
III-A
3
  21.4%
III-B
3
  21.4%
IV-A
3
  21.4%
IV-B
4
  28.6%
[1]
Measure Description:

Stages:

I cancer in a single region, usually one lymph node and the surrounding area. No outward symptoms II cancer in 2 separate regions, an affected lymph node or lymphatic organ and a 2nd affected area. Both affected areas are confined to one side of the diaphragm III cancer has spread to both sides of the diaphragm, including one organ or area near the lymph nodes or the spleen IV disseminated involvement of one/more extralymphatic organs A/B the absence of constitutional B-type symptoms is denoted by adding an A to stage; the presence adding a B

Extranodal disease at diagnosis  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 14 participants
Yes
5
  35.7%
No
9
  64.3%
Bulky lesion at diagnosis  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 14 participants
Yes
1
   7.1%
No
13
  92.9%
International Prognostic Index score at diagnosis  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 14 participants
Low risk (0-1 risk factors)
2
  14.3%
Low-intermediate risk (2 risk factors)
2
  14.3%
High-intermediate risk (3 risk factors)
2
  14.3%
High risk (4-5 risk factors)
4
  28.6%
NA
4
  28.6%
Prognostic index for peripheral T-cell lymphoma at diagnosis  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 14 participants
Group 1 (no adverse factors)
1
   7.1%
Group 2 (1 risk factor)
1
   7.1%
Group 4 (3-4 risk factors)
2
  14.3%
NA
10
  71.4%
Prognostic index for angioimmunoblastic T-cell lymphoma score at diagnosis  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 14 participants
Low-risk group
3
  21.4%
High-risk group
3
  21.4%
NA
8
  57.1%
International prognostic index score at current disease  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 14 participants
Low risk (0-1 risk factors)
3
  21.4%
Low-intermediate risk (2 risk factors)
3
  21.4%
High-intermediate risk (3 risk factors)
4
  28.6%
High risk (4-5 risk factors)
4
  28.6%
Prognostic index for peripheral T-cell lymphoma at current disease  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 14 participants
Group 1 (no adverse factors)
2
  14.3%
Group 2 (1 risk factor)
3
  21.4%
Group 3 (2 risk factors)
1
   7.1%
Group 4 (3-4 risk factors)
1
   7.1%
NA
7
  50.0%
Prognostic index for angioimmunoblastic T-cell lymphoma score at current disease  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 14 participants
Low-risk group
5
  35.7%
High-risk group
4
  28.6%
NA
5
  35.7%
Prior anticancer therapy lines  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 14 participants
1 line
2
  14.3%
2 lines
5
  35.7%
3 lines
5
  35.7%
4 lines
1
   7.1%
5 lines
1
   7.1%
Best response to last prior therapy   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 14 participants
CR
4
  28.6%
PR
4
  28.6%
SD
1
   7.1%
PD
3
  21.4%
UK
2
  14.3%
[1]
Measure Description: CR, complete response; PD, disease progression; PR, partial response; SD, stable disease; UK, unknown
Prior stem cell transplantation  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 14 participants
NO
8
  57.1%
Allogenic stem cell transplantation
1
   7.1%
Autologous stem cell transplantation
5
  35.7%
Weight  
Median (Full Range)
Unit of measure:  Kg
Number Analyzed 14 participants
72.5
(44.7 to 145.0)
Height  
Median (Full Range)
Unit of measure:  Cm
Number Analyzed 14 participants
166.5
(152 to 190)
Body Surface Area  
Median (Full Range)
Unit of measure:  M^2
Number Analyzed 14 participants
1.8
(1.4 to 2.8)
Time from diagnosis to first plitidepsin infusion  
Median (Full Range)
Unit of measure:  Months
Number Analyzed 14 participants
24.1
(8.5 to 200.5)
Time from last progressive disease to infusion  
Median (Full Range)
Unit of measure:  Weeks
Number Analyzed 14 participants
6.9
(0.9 to 54.0)
Prior anticancer therapy lines  
Median (Full Range)
Unit of measure:  Therapy lines
Number Analyzed 14 participants
2.5
(1 to 5)
Time to progressions to last anticancer therapy  
Median (Full Range)
Unit of measure:  Months
Number Analyzed 14 participants
4.6
(1.5 to 92.5)
1.Primary Outcome
Title Overall Response Rate by the Lugano Classification Per Independent Review Assessment
Hide Description The study protocol established that the analysis of the primary endpoint should have been done once a total of 60 patients have received plitidepsin, with two futility analyses planned after the inclusion of approximately 15 and 30 patients, respectively. However, only a total of 14 patients were included, of whom 13 were treated, and 12 were evaluable for the primary efficacy endpoint (ORR per IRC in the "Per Protocol Patients" population). As a result of slow patient accrual, the study was closed before reaching the target enrollment of 15 patients for the first futility analysis, and the primary endpoint (ORR according to the Lugano classification criteria and per IRC) was not assessed.
Time Frame Change from Baseline to assessments at: 1/2 weeks after cycle 3 and 4-8 weeks after cycle 6 (1cycle =28days), follow-up every 4 months +/- 2 weeks until progression disease or end of study (expected: 42 months)
Hide Outcome Measure Data
Hide Analysis Population Description
Justification: The study was closed before reaching the target enrollment of 15 patients for the first futility analysis, and the primary endpoint (ORR according to the Lugano classification criteria and per IRC) was not assessed.
Arm/Group Title Plitidepsin
Hide Arm/Group Description:
Plitidepsin was administered i.v. as a 1-hour infusion (fixed rate) via central or peripheral venous catheter. Patients received plitidepsin at a starting dose of 3.2 mg/m2 on Day 1, 8 and 15 every four weeks (q4wk). A 1-day window is allowed for plitidepsin administration. A cycle is defined as a fourweek period. A 1-day window was allowed for plitidepsin administration.
Overall Number of Participants Analyzed 12
Measure Type: Count of Participants
Unit of Measure: Participants
NA [1] 
[1]
ORR according to the Lugano classification criteria per IRC was not assessed
2.Secondary Outcome
Title Overall Response Rate by Investigator's Assessment - Per Protocol Patients Population
Hide Description

CI, confidence interval; CR, complete response; NE, not evaluable; ORR, overall response rate; PD, disease progression; PR, partial response; SD, stable disease.

Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

Time Frame From the date when the remission criteria are fulfilled to the first date when progressive disease, recurrence or death (due to any cause)is documented, expected at a maximum of 42 months
Hide Outcome Measure Data
Hide Analysis Population Description
A patient was never treated with plitidepsin. A patient due to lack of AITL diagnosis confirmation
Arm/Group Title Plitidepsin
Hide Arm/Group Description:
Plitidepsin was administered i.v. as a 1-hour infusion (fixed rate) via central or peripheral venous catheter. Patients received plitidepsin at a starting dose of 3.2 mg/m2 on Day 1, 8 and 15 every four weeks (q4wk). A 1-day window is allowed for plitidepsin administration. A cycle is defined as a fourweek period. A 1-day window was allowed for plitidepsin administration.
Overall Number of Participants Analyzed 12
Measure Type: Count of Participants
Unit of Measure: Participants
CR
1
   8.3%
PR
1
   8.3%
SD
1
   8.3%
PD
7
  58.3%
NE
2
  16.7%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Plitidepsin
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Exact binomial estimator
Estimated Value 16.7
Confidence Interval (2-Sided) 95%
2.1 to 48.4
Estimation Comments [Not Specified]
Time Frame Participants were assessed through study completion, approximately 2 years
Adverse Event Reporting Description One patient was never treated with plitidepsin and was excluded from the analysis of safety.
 
Arm/Group Title Plitidepsin
Hide Arm/Group Description Plitidepsin was administered i.v. as a 1-hour infusion (fixed rate) via central or peripheral venous catheter. Patients received plitidepsin at a starting dose of 3.2 mg/m2 on Day 1, 8 and 15 every four weeks (q4wk). A 1-day window is allowed for plitidepsin administration. A cycle is defined as a fourweek period. A 1-day window was allowed for plitidepsin administration.
All-Cause Mortality
Plitidepsin
Affected / at Risk (%)
Total   7/13 (53.85%)    
Hide Serious Adverse Events
Plitidepsin
Affected / at Risk (%) # Events
Total   9/13 (69.23%)    
Blood and lymphatic system disorders   
Febrile neutropenia  1  1/13 (7.69%)  1
Cardiac disorders   
Cardiac arrest  1  1/13 (7.69%)  1
Cardiac failure  1  1/13 (7.69%)  1
General disorders   
Pyrexia  1  1/13 (7.69%)  1
Immune system disorders   
Anaphylactic reaction  1  1/13 (7.69%)  1
Infections and infestations   
Pneumonia  1  1/13 (7.69%)  2
Rhinovirus infection  1  1/13 (7.69%)  1
Septic shock  1  1/13 (7.69%)  1
Skin infection  1  1/13 (7.69%)  1
Investigations   
Alanine aminotransferase increased  1  1/13 (7.69%)  1
Aspartate aminotransferase increased  1  1/13 (7.69%)  1
Respiratory, thoracic and mediastinal disorders   
Dyspnoea  1  1/13 (7.69%)  1
Pulmonary embolism  1  1/13 (7.69%)  1
Skin and subcutaneous tissue disorders   
Rash  1  1/13 (7.69%)  1
Vascular disorders   
Peripheral embolism  1  1/13 (7.69%)  2
1
Term from vocabulary, MedDRA (21.1)
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Plitidepsin
Affected / at Risk (%) # Events
Total   13/13 (100.00%)    
Gastrointestinal disorders   
Abdominal pain  1  2/13 (15.38%)  2
Abdominal pain upper  1  1/13 (7.69%)  1
Diarrhoea  1  5/13 (38.46%)  7
Dysphagia  1  1/13 (7.69%)  1
Epigastric discomfort  1  1/13 (7.69%)  1
Flatulence  1  1/13 (7.69%)  1
Gastric mucosa erythema  1  1/13 (7.69%)  1
Melaena  1  1/13 (7.69%)  1
Nausea  1  6/13 (46.15%)  7
Rectal haemorrhage  1  1/13 (7.69%)  1
Vomiting  1  3/13 (23.08%)  4
General disorders   
Asthenia/Fatigue  1  4/13 (30.77%)  6
Chills  1  1/13 (7.69%)  2
Malaise  1  1/13 (7.69%)  1
Oedema peripheral  1  3/13 (23.08%)  3
Pyrexia  1  6/13 (46.15%)  17
Infections and infestations   
Candida infection  1  1/13 (7.69%)  1
Cytomegalovirus infection  1  1/13 (7.69%)  1
Herpes zoster  1  2/13 (15.38%)  2
Influenza  1  1/13 (7.69%)  1
Nasopharyngitis  1  2/13 (15.38%)  2
Pharyngitis  1  1/13 (7.69%)  1
Respiratory tract infection  1  2/13 (15.38%)  2
Rhinovirus infection  1  1/13 (7.69%)  1
Upper respiratory tract infection  1  1/13 (7.69%)  1
Injury, poisoning and procedural complications   
Limb injury  1  1/13 (7.69%)  1
Investigations   
Alanine aminotransferase increased  1  4/13 (30.77%)  15
Aspartate aminotransferase increased  1  1/13 (7.69%)  2
Blood creatine phosphokinase increased  1  1/13 (7.69%)  2
Electrocardiogram QT prolonged  1  1/13 (7.69%)  6
Weight decreased  1  1/13 (7.69%)  1
Anaemia  1  3/13 (23.08%)  13
Eosinophilia  1  1/13 (7.69%)  1
Lymphadenopathy  1  1/13 (7.69%)  1
Neutropenia  1  2/13 (15.38%)  2
Thrombocytopenia  1  2/13 (15.38%)  2
Metabolism and nutrition disorders   
Decreased appetite  1  1/13 (7.69%)  1
Hypokalaemia  1  2/13 (15.38%)  2
Hypomagnesaemia  1  2/13 (15.38%)  3
Hyponatraemia  1  1/13 (7.69%)  1
Musculoskeletal and connective tissue disorders   
Joint swelling  1  1/13 (7.69%)  1
Musculoskeletal pain  1  2/13 (15.38%)  2
Myalgia  1  1/13 (7.69%)  3
Myopathy  1  1/13 (7.69%)  1
Nervous system disorders   
Dizziness  1  2/13 (15.38%)  2
Dysaesthesia  1  1/13 (7.69%)  1
Headache  1  1/13 (7.69%)  1
Neuropathy peripheral  1  1/13 (7.69%)  1
Paraesthesia  1  2/13 (15.38%)  2
Transient ischaemic attack  1  1/13 (7.69%)  1
Psychiatric disorders   
Insomnia  1  1/13 (7.69%)  1
Renal and urinary disorders   
Renal failure  1  1/13 (7.69%)  1
Renal impairment  1  2/13 (15.38%)  2
Respiratory, thoracic and mediastinal disorders   
Cough  1  3/13 (23.08%)  3
Dyspnoea  1  2/13 (15.38%)  3
Nasal congestion  1  1/13 (7.69%)  1
Oropharyngeal pain  1  1/13 (7.69%)  1
Rhinorrhoea  1  1/13 (7.69%)  1
Skin and subcutaneous tissue disorders   
Night sweats  1  1/13 (7.69%)  1
Pruritus  1  4/13 (30.77%)  5
Rash  1  3/13 (23.08%)  8
Rash macular  1  1/13 (7.69%)  1
Vascular disorders   
Subclavian vein thrombosis  1  1/13 (7.69%)  1
1
Term from vocabulary, MedDRA (21.1)
Indicates events were collected by systematic assessment
On 14May18, Sponsor informed to the sites and IPs its decision to close the recruitment. Study was terminated before reaching the target enrollment due to slow patient accrual and the negative opinion of the EMA-refusal of the mark. auth. plitidepsin
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
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 more than 60 days but less than or equal to 180 days from the time submitted to the sponsor for review.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Clinical Developtment, Department of PharmaMar´s Oncology., Business Unit.
Organization: Pharma Mar, S.A.
Phone: +34 918466000
EMail: clinicaltrials@pharmamar.com
Layout table for additonal information
Responsible Party: PharmaMar
ClinicalTrials.gov Identifier: NCT03070964    
Other Study ID Numbers: APL-B-021-13
First Submitted: January 16, 2017
First Posted: March 6, 2017
Results First Submitted: June 19, 2020
Results First Posted: October 14, 2020
Last Update Posted: October 14, 2020