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Trial of Plitidepsin (Aplidin®) in Combination With Bortezomib and Dexamethasone in Multiple Myeloma Patients Double Refractory to Bortezomib and Lenalidomide

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ClinicalTrials.gov Identifier: NCT03117361
Recruitment Status : Terminated (PharmaMar has decided to end this study due to the slow recruitment rate of the trial)
First Posted : April 17, 2017
Results First Posted : December 2, 2020
Last Update Posted : December 2, 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 Multiple Myeloma
Interventions Drug: plitidepsin
Drug: Bortezomib
Drug: Dexamethasone
Enrollment 10
Recruitment Details Patients participated between 15May2017 - 30Jul2018 (last follow-up cutoff date). The 1st dose/1st cycle was administered on 15May2017 and the last dose/last cycle on 23Jul2018. At cutoff date 10 patients had been included and treated with plitidepsin+BTZ+DXM and they were evaluable for safety. 8 of these were evaluable for the efficacy endpoint
Pre-assignment Details IC signed;Age≥18 years;confirmed diagnosis of MM,ECOG PS≤2;LVEF≥45%;negative pregnancy test
Arm/Group Title Experimental
Hide Arm/Group Description Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Period Title: Overall Study
Started 10
Completed 0
Not Completed 10
Reason Not Completed
Progressive disease             5
Death             1
Physician Decision             2
On study treatment at the end of study             1
Treatment-related adverse event             1
Arm/Group Title Experimental
Hide Arm/Group Description Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Overall Number of Baseline Participants 10
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 10 participants
<=18 years
0
   0.0%
Between 18 and 65 years
8
  80.0%
>=65 years
2
  20.0%
Age, Continuous  
Median (Full Range)
Unit of measure:  Years
Number Analyzed 10 participants
59
(43 to 72)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 10 participants
Female
5
  50.0%
Male
5
  50.0%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 10 participants
White
7
  70.0%
Other
3
  30.0%
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 10 participants
Italy
4
  40.0%
France
3
  30.0%
Spain
3
  30.0%
ECOG PS   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 10 participants
PS 0
5
  50.0%
PS 1
4
  40.0%
PS 2
1
  10.0%
[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
Multiple myeloma type at diagnosis  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 10 participants
Secretory IgA
2
  20.0%
Secretory IgG
4
  40.0%
Secretory Kappa light-chain disease
2
  20.0%
Secretory Lambda light-chain disease
2
  20.0%
Durie-Salmon stage and subclassification at diagnosis   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 10 participants
IIA
2
  20.0%
IIIA
3
  30.0%
IIIB
1
  10.0%
Missing
4
  40.0%
[1]
Measure Description: 4 patients had missing data in stage and sub-classification Stage I: All of the following: Hemoglobin>10 g/dl,Serum calcium<10.5 mg/dL, normal bone structure,IgG<5 g/dL; IgA<3 g/dL, Urine light chain M-component<4 g/24h Stage II:Fitting neither Stage I nor Stage III Stage III: One or more of the following: Hemoglobin<8.5 g/dL, Serum calcium>12 mg/dL,Advanced lytic bone lesions,IgG>7 g/dL; IgA> 5 g/dL,Urine light chain M-component>12 g/24h Subclassification: A, serum creatinine<2.0 mg/dL;B, serum creatinine>2.0 mg/dL
ISS stage at diagnosis   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 10 participants
ISS I
1
  10.0%
ISS II
1
  10.0%
ISS III
4
  40.0%
Not done
4
  40.0%
[1]
Measure Description: ISS, International Staging System ISS stage I was defined as serum β2-microglobulin level less than 3.5 mg/L and serum albumin level ≥ 3.5 g/dL. ISS stage II included all patients with neither stage I nor stage III disease. ISS stage III was defined as serum β2-microglobulin level ≥ 5.5 mg/L, irrespective of serum albumin level
R-ISS stage at study entry   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 10 participants
Stage II
3
  30.0%
Stage III
3
  30.0%
Non available genetic results
4
  40.0%
[1]
Measure Description: R-ISS, Revised International Staging System Stage I: Serum β2 microglobulin<3.5 mg/l; Serum albumin≥3.5 g/dl;Standard-risk chromosomal abnormalities (CA);Normal LDH Stage II: Not R-ISS stage I or III Stage III: Serum β2 microglobulin≥5.5 mg/L and either High-risk CA by FISH OR High LDH
Cytogenetic at study entry  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 10 participants
High risk
2
  20.0%
Standard risk
4
  40.0%
Non available genetic results
4
  40.0%
Disease status with respect to last prior therapy   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 10 participants
Primary Refractory
7
  70.0%
Relapsed and refractory
3
  30.0%
[1]
Measure Description:

Total refractory MM included 2 categories of refractory:

  • Primary Refractory: disease that was non-responsive in patients who had never achieved a MR or better, with any therapy. It included patients who never achieved MR or better, in whom there was no significant change in M-protein and no evidence of clinical progression, as well as primary, refractory PD where patients met criteria for true PD.
  • Relapsed and refractory: disease that was non-responsive while on salvage therapy, or progressed within 60 days of the last therapy in patients who had achieved MR or better at some point
Best response to last prior anticancer therapy   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 10 participants
PR
2
  20.0%
MR
1
  10.0%
SD
2
  20.0%
PD
5
  50.0%
[1]
Measure Description:

Partial response (PR): had ≥50% reduction in serum M-protein and reduction of 24-hour urine M-protein by 90% or to <200 mg/24h Minimal response (MR): had ≥25% but ≤49% reduction of serum M-protein and reduction of 24h urine M-protein 50-89%.

Progressive disease (PD): had a 25% increase from the lowest response value in any of the following: serum M-protein, urine M-protein, BM plasma cell percentage, or difference in the kappa and lambda FLC. PD also diagnosed when an increase size or new bone lesions Stable disease (SD): not meet the criteria for PR, MR or PD

Prior HSCT   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 10 participants
Autologous
6
  60.0%
Autologous and allogenic
2
  20.0%
No
2
  20.0%
[1]
Measure Description: HSCT, hematopoietic stem cell transplantation
Lines of prior chemotherapy  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 10 participants
3 lines
1
  10.0%
4 lines
2
  20.0%
5 lines
4
  40.0%
8 lines
2
  20.0%
9 lines
1
  10.0%
Weight  
Median (Full Range)
Unit of measure:  Kg
Number Analyzed 10 participants
71.4
(51.0 to 105.3)
Height  
Median (Full Range)
Unit of measure:  Cm
Number Analyzed 10 participants
167.1
(152 to 186)
Body surface area  
Median (Full Range)
Unit of measure:  M^2
Number Analyzed 10 participants
1.8
(1.5 to 2.2)
Time from diagnosis to first plitidepsin infusion  
Median (Full Range)
Unit of measure:  Months
Number Analyzed 10 participants
70.7
(16 to 168)
Time from last progressive disease to first infusion  
Median (Full Range)
Unit of measure:  Weeks
Number Analyzed 10 participants
5.3
(2 to 14)
Lines of prior chemotherapy  
Median (Full Range)
Unit of measure:  Lines
Number Analyzed 10 participants
5
(3 to 9)
Agents of prior chemotherapy  
Median (Full Range)
Unit of measure:  Agents
Number Analyzed 10 participants
9
(5 to 13)
TTP to last anticancer therapy   [1] 
Median (Full Range)
Unit of measure:  Months
Number Analyzed 10 participants
3.4
(1.6 to 10.6)
[1]
Measure Description: Time to progression (TTP) was defined as the time, in months, from the date of the first infusion of last anticancer therapy to the date of documented PD previous study entry.
1.Primary Outcome
Title Overall Response
Hide Description

Partial response (PR): ≥50% reduction in serum M-protein and reduction of 24-hour urine M-protein by 90% or to <200 mg/24h Minimal response (MR): ≥25% but ≤49% reduction of serum M-protein and reduction of 24h urine M-protein 50-89%.

Progressive disease (PD): 25% increase from the lowest response value in any of the following: serum M-protein, urine M-protein, BM plasma cell percentage, or difference in the kappa and lambda FLC. PD also diagnosed when an increase size or new bone lesions Stable disease (SD): not meet the criteria for PR, MR or PD Primary analysis should have been done once a total of 64 patients have received plitidepsin+BTZ+DXM with one futility analysis planned after the inclusion of 20 evaluable patients that had completed two full treatment cycles. Only 10 patients were treatedand 8 evaluable for the primary endpoint (ORR according to IMWG criteria). As a result of slow patient accrual, the study was closed before reaching the target enrollment

Time Frame From the date of first drug administration to the date of at least one disease assessment, up to 100 weeks
Hide Outcome Measure Data
Hide Analysis Population Description

1 died without any valid tumor assessment done

1 discontinued treatment-related AEs

Arm/Group Title Experimental
Hide Arm/Group Description:
Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Overall Number of Participants Analyzed 8
Measure Type: Count of Participants
Unit of Measure: Participants
PR
1
  12.5%
MR
1
  12.5%
SD
5
  62.5%
PD
1
  12.5%
2.Primary Outcome
Title Overall Response Rate
Hide Description The primary endpoint was overall response rate (ORR) (including stringent complete response [sCR], complete response [CR], very good partial response [VGPR] and partial response [PR]), according to the IMWG response criteria.
Time Frame From the date of first drug administration to the date of at least one disease assessment, up to 100 weeks
Hide Outcome Measure Data
Hide Analysis Population Description

1 died without any valid tumor assessment done

1 discontinued treatment-related AEs

Arm/Group Title Experimental
Hide Arm/Group Description:
Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Overall Number of Participants Analyzed 8
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
12.5
(0.3 to 52.7)
3.Secondary Outcome
Title Clinical Benefit Rate
Hide Description Clinical benefit rate defined as minimal response or better
Time Frame From the date of first drug administration to the date of at least one disease assessment, up to 100 weeks
Hide Outcome Measure Data
Hide Analysis Population Description

1 died without any valid tumor assessment done

1 discontinued treatment-related AEs

Arm/Group Title Experimental
Hide Arm/Group Description:
Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Overall Number of Participants Analyzed 8
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
25.0
(3.2 to 65.1)
4.Secondary Outcome
Title Disease Control Rate
Hide Description Disease control rate defined as stable disease [SD] or better
Time Frame From the date of first drug administration to the date of at least one disease assessment, up to 100 weeks
Hide Outcome Measure Data
Hide Analysis Population Description

1 died without any valid tumor assessment done

1 discontinued treatment-related AEs

Arm/Group Title Experimental
Hide Arm/Group Description:
Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Overall Number of Participants Analyzed 8
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
87.5
(47.3 to 99.7)
5.Secondary Outcome
Title Duration of Response
Hide Description Duration of Response defined as the time, in months, from the date of first documentation of response to the date of disease progression. Response was assessed according to the IMWG classification response criteria.
Time Frame From the date of first documentation of response to the date of disease progression, up to 100 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Only one patient achieved a partial response
Arm/Group Title Experimental
Hide Arm/Group Description:
Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Overall Number of Participants Analyzed 1
Measure Type: Number
Unit of Measure: months
9.2
6.Secondary Outcome
Title Time to Progression
Hide Description

Time to progression (TTP) was defined as the time, in months, from the date of the first infusion to the date of documented PD or death due to PD. TTP was to be censored on the date of the last tumor assessment or on the date of the first drug administration if there were no tumor assessments.

Progressive disease (PD): 25% increase from the lowest response value in any of the following: serum M-protein, urine M-protein, BM plasma cell percentage, or difference in the kappa and lambda FLC. PD also diagnosed when an increase size or new bone lesions.

Time Frame From the date of the first infusion to the date of documented PD or death due to PD, up to 100 weeks
Hide Outcome Measure Data
Hide Analysis Population Description

1 died without any valid tumor assessment done

1 discontinued treatment-related AEs

Arm/Group Title Experimental
Hide Arm/Group Description:
Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Overall Number of Participants Analyzed 8
Median (95% Confidence Interval)
Unit of Measure: months
2.7 [1] 
(0.7 to NA)
[1]
upper limit was not estimable due to few participants with events
7.Secondary Outcome
Title Percentage of Participants With Progression Disease at 3 Months
Hide Description Progression disease was defined as documented PD or death due to PD Progressive disease (PD): 25% increase from the lowest response value in any of the following: serum M-protein, urine M-protein, BM plasma cell percentage, or difference in the kappa and lambda FLC. PD also diagnosed when an increase size or new bone lesions.
Time Frame From the date of the first infusion to the date of documented PD or death due to PD, up to 3 months
Hide Outcome Measure Data
Hide Analysis Population Description

1 died without any valid tumor assessment done

1 discontinued treatment-related AEs

Arm/Group Title Experimental
Hide Arm/Group Description:
Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Overall Number of Participants Analyzed 8
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
37.5
(4.0 to 71.0)
8.Secondary Outcome
Title Percentage of Participants With Progression Disease at 6 Months
Hide Description Progression disease was defined as documented PD or death due to PD. Progressive disease (PD): 25% increase from the lowest response value in any of the following: serum M-protein, urine M-protein, BM plasma cell percentage, or difference in the kappa and lambda FLC. PD also diagnosed when an increase size or new bone lesions
Time Frame From the date of the first infusion to the date of documented PD or death due to PD, up to 6 months
Hide Outcome Measure Data
Hide Analysis Population Description

1 died without any valid tumor assessment done

1 discontinued treatment-related AEs

Arm/Group Title Experimental
Hide Arm/Group Description:
Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Overall Number of Participants Analyzed 8
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
25.0
(0.0 to 55.0)
9.Secondary Outcome
Title Percentage of Participants With Progression Disease at 12 Months
Hide Description Progression disease was defined as documented PD or death due to PD. Progressive disease (PD): 25% increase from the lowest response value in any of the following: serum M-protein, urine M-protein, BM plasma cell percentage, or difference in the kappa and lambda FLC. PD also diagnosed when an increase size or new bone lesions.
Time Frame From the date of the first infusion to the date of documented PD or death due to PD, up to 12 months
Hide Outcome Measure Data
Hide Analysis Population Description

1 died without any valid tumor assessment done

1 discontinued treatment-related AEs

Arm/Group Title Experimental
Hide Arm/Group Description:
Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Overall Number of Participants Analyzed 8
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
25.0
(0.0 to 55.0)
10.Secondary Outcome
Title Progression-free Survival
Hide Description

Progression-free survival (PFS) was defined as the time, in months, from the date of first drug administration to the date of documented PD, or death (of any cause). If any patient was lost to follow-up before PD or received another antitumor therapy, PFS was to be censored on the date of the last tumor assessment. If there were no tumor assessments, these parameters were to be censored on the date of the first drug administration.

Progressive disease (PD): 25% increase from the lowest response value in any of the following: serum M-protein, urine M-protein, BM plasma cell percentage, or difference in the kappa and lambda FLC. PD also diagnosed when an increase size or new bone lesions.

Time Frame From the date of first drug administration to the date of documented PD, or death (of any cause), up to 100 weeks
Hide Outcome Measure Data
Hide Analysis Population Description

1 died without any valid tumor assessment done

1 discontinued treatment-related AEs

Arm/Group Title Experimental
Hide Arm/Group Description:
Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Overall Number of Participants Analyzed 8
Median (95% Confidence Interval)
Unit of Measure: months
2.7 [1] 
(0.7 to NA)
[1]
upper limit was not estimable due to few participants with events
11.Secondary Outcome
Title Percentage of Participants With Progression-free Survival at 3 Months
Hide Description Progression-free Survival was defined as documented PD, or death of any cause. Progressive disease (PD): 25% increase from the lowest response value in any of the following: serum M-protein, urine M-protein, BM plasma cell percentage, or difference in the kappa and lambda FLC. PD also diagnosed when an increase size or new bone lesions.
Time Frame From the date of first drug administration to the date of documented PD, or death (of any cause), up to 3 months
Hide Outcome Measure Data
Hide Analysis Population Description

1 died without any valid tumor assessment done

1 discontinued treatment-related AEs

Arm/Group Title Experimental
Hide Arm/Group Description:
Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Overall Number of Participants Analyzed 8
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
37.5
(4.0 to 71.0)
12.Secondary Outcome
Title Percentage of Participants With Progression-free Survival at 6 Months
Hide Description Progression-free Survival was defined as documented PD, or death of any cause. Progressive disease (PD): 25% increase from the lowest response value in any of the following: serum M-protein, urine M-protein, BM plasma cell percentage, or difference in the kappa and lambda FLC. PD also diagnosed when an increase size or new bone lesions.
Time Frame From the date of first drug administration to the date of documented PD, or death (of any cause), up to 6 months
Hide Outcome Measure Data
Hide Analysis Population Description

1 died without any valid tumor assessment done

1 discontinued treatment-related AEs

Arm/Group Title Experimental
Hide Arm/Group Description:
Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Overall Number of Participants Analyzed 8
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
25.0
(0.0 to 55.0)
13.Secondary Outcome
Title Percentage of Participants With Progression-free Survival at 12 Months
Hide Description Progression-free survival (PFS) was defined as the time, in months, from the date of first drug administration to the date of documented PD, or death (of any cause). If any patient was lost to follow-up before PD or received another antitumor therapy, PFS was to be censored on the date of the last tumor assessment. If there were no tumor assessments, these parameters were to be censored on the date of the first drug administration Progressive disease (PD): 25% increase from the lowest response value in any of the following: serum M-protein, urine M-protein, BM plasma cell percentage, or difference in the kappa and lambda FLC. PD also diagnosed when an increase size or new bone lesions.
Time Frame From the date of first drug administration to the date of documented PD, or death (of any cause), up to 12 months
Hide Outcome Measure Data
Hide Analysis Population Description

1 died without any valid tumor assessment done

1 discontinued treatment-related AEs

Arm/Group Title Experimental
Hide Arm/Group Description:
Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Overall Number of Participants Analyzed 8
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
25.0
(0.0 to 55.0)
14.Secondary Outcome
Title Event-free Survival
Hide Description Event-free survival (EFS) was defined as the time, in months, from the date of first drug administration to the date of onset of the first drug-related event leading to treatment discontinuation, documented PD or death. The censoring rules defined above for PFS were used for EFS
Time Frame From the date of first drug administration to the date of onset of the first drug-related event leading to treatment discontinuation, documented PD or death, up to 100 weeks
Hide Outcome Measure Data
Hide Analysis Population Description

1 died without any valid tumor assessment done

1 discontinued treatment-related AEs

Arm/Group Title Experimental
Hide Arm/Group Description:
Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Overall Number of Participants Analyzed 8
Median (95% Confidence Interval)
Unit of Measure: months
2.7 [1] 
(0.7 to NA)
[1]
upper limit was not estimable due to few participants with events
15.Secondary Outcome
Title Percentage of Participants With Event-free Survival at 3 Months
Hide Description

Event-free survival (EFS) was defined as the first drug-related event leading to treatment discontinuation, documented PD or death.

rogressive disease (PD): 25% increase from the lowest response value in any of the following: serum M-protein, urine M-protein, BM plasma cell percentage, or difference in the kappa and lambda FLC. PD also diagnosed when an increase size or new bone lesions.

Time Frame From the date of first drug administration to the date of onset of the first drug-related event leading to treatment discontinuation, documented PD or death, up to 3 months
Hide Outcome Measure Data
Hide Analysis Population Description

1 died without any valid tumor assessment done

1 discontinued treatment-related AEs

Arm/Group Title Experimental
Hide Arm/Group Description:
Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Overall Number of Participants Analyzed 8
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
37.5
(4.0 to 71.0)
16.Secondary Outcome
Title Percentage of Participants With Event-free Survival at 6 Months
Hide Description

Event-free survival (EFS) was defined as the first drug-related event leading to treatment discontinuation, documented PD or death.

Progressive disease (PD): 25% increase from the lowest response value in any of the following: serum M-protein, urine M-protein, BM plasma cell percentage, or difference in the kappa and lambda FLC. PD also diagnosed when an increase size or new bone lesions.

Time Frame From the date of first drug administration to the date of onset of the first drug-related event leading to treatment discontinuation, documented PD or death, up to 6 months
Hide Outcome Measure Data
Hide Analysis Population Description

1 died without any valid tumor assessment done

1 discontinued treatment-related AEs

Arm/Group Title Experimental
Hide Arm/Group Description:
Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Overall Number of Participants Analyzed 8
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
25.0
(0.0 to 55.0)
17.Secondary Outcome
Title Percentage of Participants With Event-free Survival at 12 Months
Hide Description

Event-free survival (EFS) was defined as the first drug-related event leading to treatment discontinuation, documented PD or death.

Progressive disease (PD): 25% increase from the lowest response value in any of the following: serum M-protein, urine M-protein, BM plasma cell percentage, or difference in the kappa and lambda FLC. PD also diagnosed when an increase size or new bone lesions.

Time Frame From the date of first drug administration to the date of onset of the first drug-related event leading to treatment discontinuation, documented PD or death, up to 12 months
Hide Outcome Measure Data
Hide Analysis Population Description

1 died without any valid tumor assessment done

1 discontinued treatment-related AEs

Arm/Group Title Experimental
Hide Arm/Group Description:
Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Overall Number of Participants Analyzed 8
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
25.0
(0.0 to 55.0)
18.Secondary Outcome
Title Overall Survival
Hide Description Overall survival (OS) was defined as the time, in months, from the date of first drug administration to the date of death (of any cause) or last patient contact (in this case, survival was to be censored on that date).
Time Frame From the date of first drug administration to the date of death (of any cause) or last patient contact, up to 100 weeks
Hide Outcome Measure Data
Hide Analysis Population Description

1 died without any valid tumor assessment done

1 discontinued treatment-related AEs

Arm/Group Title Experimental
Hide Arm/Group Description:
Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Overall Number of Participants Analyzed 8
Median (95% Confidence Interval)
Unit of Measure: months
NA [1] 
(2.3 to NA)
[1]
Median and upper limit was not estimable due to few participants with events
19.Secondary Outcome
Title Percentage of Participants With Overall Survival at 6 Months
Hide Description Overall survival (OS) was defined as death of any cause.
Time Frame From the date of first drug administration to the date of death (of any cause) or last patient contact, up to 6 months
Hide Outcome Measure Data
Hide Analysis Population Description

1 died without any valid tumor assessment done

1 discontinued treatment-related AEs

Arm/Group Title Experimental
Hide Arm/Group Description:
Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Overall Number of Participants Analyzed 8
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
55.6
(6.9 to 100.0)
20.Secondary Outcome
Title Percentage of Participants With Overall Survival at 12 Months
Hide Description Overall survival (OS) was defined as death of any cause.
Time Frame From the date of first drug administration to the date of death (of any cause) or last patient contact, up to 12 months
Hide Outcome Measure Data
Hide Analysis Population Description

1 died without any valid tumor assessment done

1 discontinued treatment-related AEs

Arm/Group Title Experimental
Hide Arm/Group Description:
Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Overall Number of Participants Analyzed 8
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
55.6
(6.9 to 100.0)
Time Frame From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Experimental
Hide Arm/Group Description Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
All-Cause Mortality
Experimental
Affected / at Risk (%)
Total   3/10 (30.00%)    
Hide Serious Adverse Events
Experimental
Affected / at Risk (%) # Events
Total   5/10 (50.00%)    
Blood and lymphatic system disorders   
Anaemia  1  1/10 (10.00%)  1
Thrombocytopenia  1  1/10 (10.00%)  1
Gastrointestinal disorders   
Gastrointestinal haemorrhage  1  1/10 (10.00%)  1
General disorders   
Pyrexia  1  1/10 (10.00%)  1
Infections and infestations   
Cellulitis  1  1/10 (10.00%)  2
Respiratory tract infection  1  1/10 (10.00%)  1
Metabolism and nutrition disorders   
Hypercalcaemia  1  1/10 (10.00%)  1
Musculoskeletal and connective tissue disorders   
Rhabdomyolysis  1  1/10 (10.00%)  1
Nervous system disorders   
Sciatica  1  1/10 (10.00%)  1
Renal and urinary disorders   
Acute kidney injury  1  1/10 (10.00%)  1
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%
Experimental
Affected / at Risk (%) # Events
Total   10/10 (100.00%)    
Blood and lymphatic system disorders   
Anaemia  1  6/10 (60.00%)  25
Neutropenia  1  3/10 (30.00%)  5
Thrombocytopenia  1  4/10 (40.00%)  35
Ear and labyrinth disorders   
Vertigo  1  1/10 (10.00%)  1
Eye disorders   
Cataract  1  1/10 (10.00%)  2
Gastrointestinal disorders   
Constipation  1  2/10 (20.00%)  3
Diarrhoea  1  2/10 (20.00%)  7
Gastric disorder  1  1/10 (10.00%)  1
Gingival bleeding  1  1/10 (10.00%)  1
Mouth haemorrhage  1  1/10 (10.00%)  2
Nausea  1  5/10 (50.00%)  8
Vomiting  1  2/10 (20.00%)  2
General disorders   
Asthenia/Fatigue  1  4/10 (40.00%)  22
Extravasation  1  1/10 (10.00%)  1
Malaise  1  1/10 (10.00%)  1
Oedema peripheral  1  1/10 (10.00%)  7
Peripheral swelling  1  1/10 (10.00%)  1
Pyrexia  1  4/10 (40.00%)  6
Infections and infestations   
Folliculitis  1  1/10 (10.00%)  1
Gastroenteritis  1  1/10 (10.00%)  1
Herpes zoster  1  1/10 (10.00%)  2
Influenza  1  1/10 (10.00%)  1
Nasopharyngitis  1  1/10 (10.00%)  1
Respiratory tract infection  1  1/10 (10.00%)  2
Injury, poisoning and procedural complications   
Overdose  1  1/10 (10.00%)  1
Investigations   
Alanine aminotransferase increased  1  4/10 (40.00%)  12
Antithrombin III decreased  1  1/10 (10.00%)  1
Aspartate aminotransferase increased  1  2/10 (20.00%)  2
Blood cholesterol  1  1/10 (10.00%)  1
Blood creatine phosphokinase increased  1  1/10 (10.00%)  1
Blood creatinine increased  1  1/10 (10.00%)  1
Blood lactate dehydrogenase increased  1  1/10 (10.00%)  1
Neutrophil count decreased  1  1/10 (10.00%)  1
Weight decreased  1  2/10 (20.00%)  3
Metabolism and nutrition disorders   
Decreased appetite  1  2/10 (20.00%)  3
Hypercalcaemia  1  1/10 (10.00%)  1
Hyperglycaemia  1  1/10 (10.00%)  1
Hyperuricaemia  1  2/10 (20.00%)  3
Hypocalcaemia  1  1/10 (10.00%)  2
Hypokalaemia  1  2/10 (20.00%)  4
Hypomagnesaemia  1  2/10 (20.00%)  2
Musculoskeletal and connective tissue disorders   
Arthralgia  1  1/10 (10.00%)  7
Back pain  1  1/10 (10.00%)  1
Muscular weakness  1  1/10 (10.00%)  19
Musculoskeletal chest pain  1  1/10 (10.00%)  2
Myalgia  1  2/10 (20.00%)  2
Nervous system disorders   
Headache  1  1/10 (10.00%)  1
Neuropathy peripheral  1  1/10 (10.00%)  1
Peripheral sensory neuropathy  1  2/10 (20.00%)  14
Sciatica  1  1/10 (10.00%)  4
Seizure  1  1/10 (10.00%)  1
Psychiatric disorders   
Depression  1  1/10 (10.00%)  1
Renal and urinary disorders   
Renal failure  1  1/10 (10.00%)  1
Respiratory, thoracic and mediastinal disorders   
Catarrh  1  1/10 (10.00%)  2
Cough  1  1/10 (10.00%)  2
Epistaxis  1  1/10 (10.00%)  1
Respiratory failure  1  1/10 (10.00%)  1
Rhinorrhoea  1  1/10 (10.00%)  1
Surgical and medical procedures   
Intramedullary rod insertion  1  1/10 (10.00%)  1
Vascular disorders   
Haematoma  1  1/10 (10.00%)  2
Hypertension  1  2/10 (20.00%)  3
1
Term from vocabulary, MedDRA (21.1)
Indicates events were collected by systematic assessment
On 29052018 the Sponsor closed the recruitment of the study due to the slow patient accrual. Besides the negative opinion of the EMA recommending the refusal of the marketing authorization for plitidepsin for MM reinforced the decision.
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: NCT03117361    
Other Study ID Numbers: APL-B-022-15
First Submitted: April 12, 2017
First Posted: April 17, 2017
Results First Submitted: July 24, 2020
Results First Posted: December 2, 2020
Last Update Posted: December 2, 2020