Clinical Trial Results:
A Phase II Study of Plitidepsin in Patients with Relapsed or Refractory Angioimmunoblastic T-cell Lymphoma.
Summary
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EudraCT number |
2015-001909-14 |
Trial protocol |
ES CZ IT |
Global end of trial date |
02 Jul 2018
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Results information
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Results version number |
v1(current) |
This version publication date |
10 Aug 2019
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First version publication date |
10 Aug 2019
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
APL-B-021-13
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03070964 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Pharma Mar, S.A.
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Sponsor organisation address |
Avenida de los Reyes, 1 Polígono Industrial "La Mina", Colmenar Viejo, Madrid, Spain, 28770
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Public contact |
Clinical Developtment, Department of PharmaMar´s Oncology., Business Unit., Pharmamar, S.A., 34 91846 60 00, clinicaltrials@pharmamar.com
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Scientific contact |
Clinical Developtment, Department of PharmaMar´s Oncology., Business Unit., Pharmamar, S.A., 34 91846 60 00, clinicaltrials@pharmamar.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
11 Feb 2019
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
02 Jul 2018
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Global end of trial reached? |
Yes
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Global end of trial date |
02 Jul 2018
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
To evaluate the efficacy of plitidepsin on the basis of overall response rate (ORR) in patients with relapsing/refractory angioimmunoblastic T-cell lymphoma (AITL).
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Protection of trial subjects |
The study was in compliance with ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local
requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
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Background therapy |
All patients had to receive the following prophylactic medication 30-60 min before infusion of plitidepsin. • Dexamethasone (8 mg i.v. or equivalent). • Ondansetron (8 mg i.v.) or equivalent (granisetron 3 mg i.v. preferred when available), and • Diphenhydramine hydrochloride (25 mg i.v.) or equivalent, and • Ranitidine (50 mg i.v.) or equivalent. Oral metoclopramide and/or extended oral ondansetron (or their equivalents) could be used as per Investigator’s criteria/institutional guidelines. Additional dexamethasone only could be used as an antiemetic in the event that alternative antiemetics could not be used; and only if the Investigator had considered the options above as insufficient. | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
25 Oct 2016
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Italy: 3
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Country: Number of subjects enrolled |
United States: 1
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Country: Number of subjects enrolled |
Spain: 9
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Country: Number of subjects enrolled |
Czech Republic: 1
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Worldwide total number of subjects |
14
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EEA total number of subjects |
13
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
9
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From 65 to 84 years |
5
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85 years and over |
0
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Recruitment
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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
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Screening details |
Age≥18 years;signed IC;ECOG PS≤2;Life expectancy≥3 months;Histologically confirmed diagnosis of R/R AITL;At least a two-week washout period;Adequate bone marrow (BM), renal, hepatic, and metabolic function;LVEF within normal range | ||||||||||||||||||||
Period 1
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Period 1 title |
Overall period
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Is this the baseline period? |
Yes | ||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||||
Blinding implementation details |
Not applicable
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Arms
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Arm title
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Plitidepsin | ||||||||||||||||||||
Arm 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 four-week period. A 1-day window was allowed for plitidepsin administration. | ||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||
Investigational medicinal product name |
Plitidepsin
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Investigational medicinal product code |
Plitidepsin
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Other name |
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Pharmaceutical forms |
Powder for concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
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 four-week period. A 1-day window was allowed for plitidepsin administration.
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Baseline characteristics reporting groups
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Reporting group title |
Plitidepsin
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Reporting 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 four-week period. A 1-day window was allowed for plitidepsin administration. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Plitidepsin
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Reporting 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 four-week period. A 1-day window was allowed for plitidepsin administration. |
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End point title |
Overall Response Rate by the Lugano Classification per Independent Review Assessment [1] | ||||||
End point 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 (see Section 9.5.1.5). 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.
Overall Response Rate by the Lugano Classification per Independent Review Assessment.
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End point type |
Primary
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End point timeframe |
Overall period
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Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. 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. |
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No statistical analyses for this end point |
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End point title |
Overall Response Rate by Investigator’s Assessment - Per Protocol Patients Population | ||||||||||||||||
End point description |
CI, confidence interval; CR, complete response; NE, not evaluable; ORR, overall response rate; PD, disease progression; PR, partial response; SD, stable disease.
ORR (95% CI) = 16.7% (2.1-48.4%)
Clinical benefit rate (CR+PR+SD ≥ 6 months) (95% CI) = 25.0% (5.5-57.2%)
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End point type |
Secondary
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End point timeframe |
Overall period
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Notes [2] - A patient was never treated with plitidepsin A patient due to lack of AITL diagnosis confirmation |
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No statistical analyses for this end point |
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End point title |
Overall Response Rate by Investigator’s Assessment - All Evaluable Patients Population | ||||||||||||||
End point description |
CI, confidence interval; CR, complete response; ORR, overall response rate; PD, disease progression; PR, partial response; SD, stable disease.
ORR (95% CI) = 20.0% (2.5-55.6%)
Clinical benefit rate (CR+PR+SD ≥ 6 months) (95% CI) = 30.0% (6.7-65.2%)
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End point type |
Secondary
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End point timeframe |
Overall period
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Notes [3] - Four patients were not evaluable for efficacy in the “All Evaluable Patients” population |
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No statistical analyses for this end point |
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End point title |
Overall Response Rate by Investigator’s Assessment - All Treated Patients Population | ||||||||||||||||
End point description |
CI, confidence interval; CR, complete response; NE, not evaluable; ORR, overall response rate; PD, disease progression; PR, partial response; SD, stable disease.
ORR (95% CI) = 15.4% (1.9-45.4%)
Clinical benefit rate (CR+PR+SD ≥ 6 months) (95% CI) = 23.1% (5.0-53.8%)
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End point type |
Secondary
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End point timeframe |
Overall period
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Notes [4] - 1 patient was never treated |
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No statistical analyses for this end point |
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End point title |
Complete Remission Rate by Investigator’s Assessment | ||||||||
End point description |
CR rate in the “All Evaluable Patients” population was 10.0% (95% CI, 0.3-44.5%)
CR rate in the “All Treated Patients” population was 7.7% (95% CI, 0.2-36%)
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End point type |
Secondary
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End point timeframe |
Overall period
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Notes [5] - A patient was never treated with plitidepsin A patient due to lack of AITL diagnosis confirmation |
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No statistical analyses for this end point |
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End point title |
Duration of Response by Investigator’s Assessment | ||||||||
End point description |
CI, confidence interval; DoR, duration of response
DoR (months) at 3 months (95% CI) = 100% (100-100%)
DoR (months) at 6 months (95% CI) = 50% (0-100%)
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End point type |
Secondary
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End point timeframe |
Overall period
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Notes [6] - the two responders to plitidepsin |
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No statistical analyses for this end point |
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End point title |
Time to Response by Investigator’s Assessment | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Overall period
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No statistical analyses for this end point |
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End point title |
Progression-free Survival by Investigator’s Assessment - Per Protocol Patients Population | ||||||||
End point description |
CI, confidence interval; PFS, progression-free survival
Events = 10 (83.3%)
PFS at 6 months (95% CI) = 30.0% (1.6-58.4%)
PFS at 12 months (95% CI) = 10.0% (0-28.6%)
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End point type |
Secondary
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End point timeframe |
Overall period
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Notes [7] - A patient was never treated with plitidepsin A patient due to lack of AITL diagnosis confirmation |
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No statistical analyses for this end point |
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End point title |
Progression-free Survival by Investigator’s Assessment - All Evaluable Patients Population | ||||||||
End point description |
CI, confidence interval; PFS, progression-free survival.
Events 10 (100%)
PFS at 6 months (95% CI) 30.0% (1.6-58.4%)
PFS at 12 months (95% CI) 10.0% (0-28.6%)
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End point type |
Secondary
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End point timeframe |
Overall period
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Notes [8] - Four patients were not evaluable for efficacy in the “All Evaluable Patients” population |
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No statistical analyses for this end point |
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End point title |
Progression-free Survival by Investigator’s Assessment - All Treated Patients population | ||||||||
End point description |
CI, confidence interval; PFS, progression-free survival.
Events 11 (84.6%)
PFS at 6 months (95% CI) 27.3% (1.0-53.6%)
PFS at 12 months (95% CI) 9.1% (0-26.1%)
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End point type |
Secondary
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End point timeframe |
Overall period
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Notes [9] - 1 patient was never treated |
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No statistical analyses for this end point |
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End point title |
Overall survival - Per Protocol Patients population | ||||||||
End point description |
CI, confidence interval; 999, not reached; OS, overall survival
Events 7 (58.3%)
OS at 6 months (95% CI) 65.6% (38.1-93.1%)
OS at 12 months (95% CI) 29.2% (0-60.2%)
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End point type |
Secondary
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End point timeframe |
Overall period
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Notes [10] - A patient was never treated with plitidepsin A patient due to lack of AITL diagnosis confirmation |
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No statistical analyses for this end point |
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End point title |
Overall Survival - All Evaluable Patients Population | ||||||||
End point description |
CI, confidence interval; 999, not reached; OS, overall survival
Events 5 (50.0%)
OS at 6 months (95% CI) 68.6% (38.9-98.3%)
OS at 12 months (95% CI) 36.6% (0-73.5%)
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End point type |
Secondary
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End point timeframe |
Overall period
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Notes [11] - Four patients were not evaluable for efficacy in the “All Evaluable Patients” population |
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No statistical analyses for this end point |
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End point title |
Overall Survival - All Treated Patients Population | ||||||||
End point description |
CI, confidence interval; 999, not reached; OS, overall survival
Events 7 (53.8%)
OS at 6 months (95% CI) 68.4% (42.6-94.1%)
OS at 12 months (95% CI) 32.6% (0-65.1%)
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End point type |
Secondary
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End point timeframe |
Overall period
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Notes [12] - 1 patient was never treated |
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
Overall period
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
21.1
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Reporting groups
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Reporting group title |
Plitidepsin
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Reporting 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 four-week period. A 1-day window was allowed for plitidepsin administration. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||||||
Date |
Amendment |
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06 Jul 2016 |
This substantial amendment was generated to include dexamethasone as prophylactic medication required before infusion with plitidepsin. Therefore, standard premedication for hypersensitivity reactions with anti H1 and H2 receptor antagonists and glucocorticoids had to be given intravenously before each plitidepsin infusion; this is mandatory in all ongoing studies with plitidepsin as stated in the Investigator Brochure. In v.1.0 of this protocol, dexamethasone was not part of the premedication regimen due to an omission at the time of writing the document.
Additionally, the following changes, corrections, and clarifications were also included in this substantial amendment:
- Clarifications to some of the parts of the text regarding the prior treatment, LVEF and hypersensitivity eligibility criteria were included to ensure patient safety
- Muscular toxicity criteria for treatment continuation and dose reduction were revised to ensure patient safety
- The list of excipients of plitidepsin was added to the study drug formulation information
- Clarifications to some assessments and procedures windows were included as follow: tumor assessment timing after Cycle 3 was changed to avoid delays in starting Cycle 4; the frequency of follow-up until disease progression during the first year of follow-up was corrected in line with standard clinical practice; laboratory analyses required in the event of grade 3/4 nausea/vomiting or a treatment-related SAE were corrected to require only biochemistry-A laboratory tests.
- The use of National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade 5 was revised to align with current Pharmacovigilance Department standard practice.
- ICH Topic E6 Guideline for Good Clinical Practice reference to R1 was removed in anticipation of a revised version (R2).
- Study contact details were updated and some minor typographical errors were corrected |
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09 Jun 2017 |
This substantial amendment was generated to:
- Implement additional information on imaging requirements and periods for radiological tumor assessment with PET-CT in combination with diagnostic quality CT.
- Modify the exclusion criterion #5 to allow the inclusion of patients concurrently treated with low doses of corticosteroids (an equivalent prednisone dose of ≤10 mg daily) for controlling symptoms derived from the disease.
- Modify section referred to prohibited medications/therapies to clarify that patients were allowed to receive hydrocortisone treatment by any administration, not only by single bolus, and also to be consistent with the amended Exclusion criterion #5 (see above).
- Simplify the follow-up procedures and periods for patients discontinuing treatment with or without disease progression, to be similar to the procedures used in clinical practice for monitoring these patients. Therefore, both groups of patients would be followed up ‘every four months during the first two years and then once every six months’.
- Update the study contacts and correct some minor typographical errors. |
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07 May 2018 |
Additionally, according to an FDA request, a new Substantial Amendment No. 3 (7 May 2018) was issued to include several changes as additional precautionary measures to mitigate any likely rhythm abnormality. This amendment was based on the occurrence of one episode of grade 4 cardiac arrest due to Torsades de pointes (TdP) reported in one patient during Cycle 4 that resolved but led to treatment discontinuation. Precautionary measures to avoid TdP risk were to be implemented in this ongoing phase II study, including more stringent eligibility criteria, continuation of treatment criteria, prohibited medications (excluding prophylactic antiemetic ondansetron), and more extensive cardiac monitoring.
Furthermore, as preliminary data from the APL-C-001-09 ADMYRE study showed that the greatest increases in QTcF, although being below the safety threshold of 20 milliseconds (ms), occurred 30 and 60 min after the end of infusion, thus the FDA requested that protocol of APL-B-021-13 study had to be modified to check ECGs 30 and 60 min post-infusion, timed with pharmacokinetic sample collections.
Nevertheless, the study APL-B-021-13 was closed before this new substantial amendment was implemented. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? Yes | |||||||
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Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||||||
None reported |