Aplidin - Dexamethasone in Relapsed/Refractory Myeloma

Study Overview
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Brief Summary
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Study of Plitidepsin in combination with dexamethasone versus dexamethasone alone in patients with relapsed/refractory multiple myeloma.

Detailed Description
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Phase III Study in Patients with Relapsed/Refractory Multiple Myeloma to compare the efficacy of plitidepsin in combination with dexamethasone vs. dexamethasone alone measured by progression-free survival (PFS) and to evaluate tumor response, duration of response (DR), overall survival (OS) and to rule out any effect of plitidepsin on the duration of the QT/QTc interval (time corresponding to the beginning of depolarization to re-polarization of the ventricles).

Official Title
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Randomized, Multicenter, Open-label, Phase III Study of Plitidepsin in Combination With Dexamethasone vs. Dexamethasone Alone in Patients With Relapsed/Refractory Multiple Myeloma

Conditions
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Relapsed/Refractory Multiple Myeloma

Intervention / Treatment
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* Drug: Plitidepsin
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤ 2 Life expectancy ≥ 3 months. Patients previously diagnosed with multiple myeloma Patients must have relapsed or relapsed and refractory multiple myeloma (MM) after at least three but not more than six prior therapeutic regimens for MM, including induction therapy and stem cell transplant in candidate patients, which will be considered as only one regimen. Patients must have received previous bortezomib-containing and lenalidomide-containing regimens (or thalidomide where lenalidomide is not available) Women must have a negative serum pregnancy test Voluntarily signed and dated written informed consent Exclusion Criteria: Concomitant diseases/conditions Women who are pregnant or breast feeding. Concomitant medications that include corticosteroids, chemotherapy, or other therapy that is or may be active against MM Known hypersensitivity to any involved study drug or any of its formulation components

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Plitidepsin+Dexamethasone<br>plitidepsin + dexamethasone combination | Drug: Plitidepsin<br>* plitidepsin: powder and solvent for concentrate for solution for infusion. 2 mg vial + 4 ml ampoule. 5 mg/m2 intravenously (i.v.) over three hours on Day 1 and 15 every 4 weeks. dexamethasone: 4 mg tablet. 40 mg orally on Day 1, 8, 15 and 22 every four weeks at least one hour before plitidepsin infusion.<br>* Other names: APLIDIN (plitidepsin);Drug: Dexamethasone<br>* 4 mg tablet. 40 mg orally on Day 1, 8, 15 and 22 every four weeks.<br>* Other names: DXN;|
| Active Comparator: Dexamethasone<br>dexamethasone single agent | Drug: Dexamethasone<br>* 4 mg tablet. 40 mg orally on Day 1, 8, 15 and 22 every four weeks.<br>* Other names: DXN;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) as Per Intention-to-treat (ITT) | To compare the efficacy of plitidepsin in combination with dexamethasone vs. dexamethasone alone as measured by progression-free survival (PFS) in patients with relapsed/refractory multiple myeloma (MM). Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 5 years | 
| Percentage of Participants With Progression Free Survival (PFS) as Per Intention-to-treat (ITT) at 6 Months | To compare the efficacy of plitidepsin in combination with dexamethasone vs. dexamethasone alone as measured by progression-free survival (PFS) in patients with relapsed/refractory multiple myeloma (MM). Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (Investigator Assessment) | The secondary study analysis was based on Investigator's assessment PFS data in the ITT efficacy population, defined as all patients randomized to either treatment arm. PFS was calculated from randomization to the first evidence of PD or death due to any cause. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions If the patient received further antitumor therapy before PD and within the timeframe expected for first follow-up, PFS was censored on the date of the last disease assessment prior to the administration of this antitumor therapy. | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 5 years | 
| Percentage of Participants With Progression-free Survival (Investigator Assessment) at 6 Months | The secondary study analysis was based on Investigator's assessment PFS data in the ITT efficacy population, defined as all patients randomized to either treatment arm. PFS was calculated from randomization to the first evidence of PD or death due to any cause. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions If the patient received further antitumor therapy before PD and within the timeframe expected for first follow-up, PFS was censored on the date of the last disease assessment prior to the administration of this antitumor therapy. | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 6 months | 
| Overall Survival | Overall Survival (OS) is defined as the time from the date of randomization to the date of death or last contact | From randomization to the death due to any cause,assessed up to 5 years | 
| Percentage of Participants With Overall Survival at 12 Months | Overall Survival (OS) is defined as the time from the date of randomization to the date of death or last contact | From randomization to the death due to any cause,assessed up to 12 months | 
| Percentage of Participants With Overall Survival at 24 Months | Overall Survival (OS) is defined as the time from the date of randomization to the date of death or last contact | From randomization to the death due to any cause,assessed up to 24 months | 
| Duration of Response (Independent Review Committee) | DR was calculated from the date of first documentation of response to the date of disease progression or death. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions | From the date of first documentation of response to the date of disease progression or death, assessed up to 5 years | 
| Percentage of Participants With Duration of Response (Independent Review Committee) at 6 Months | DR was calculated from the date of first documentation of response to the date of disease progression or death. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions | From the date of first documentation of response to the date of disease progression or death, assessed up to 6 months | 
| Duration of Response (Investigator Assessment) | DR was calculated from the date of first documentation of response to the date of disease progression or death. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions | From the date of first documentation of response to the date of disease progression or death, assessed up to 5 years | 
| Percentage of Participants With Duration of Response (Investigator Assessment) at 6 Months | DR was calculated from the date of first documentation of response to the date of disease progression or death. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions | From the date of first documentation of response to the date of disease progression or death, assessed up to 6 months | 
| Best Overall Response (Independent Review Committee) | Very good partial response (VGPR) serum and urine M-protein detectable but not electrophoresis or >90% reduction in serum M-protein and urine M-protein <100 mg/24h Partial response (PR) ≥50% reduction in serum M-protein and 90% reduction in 24h urine M-protein or to <200 mg/24h. 50% reduction in size of any soft tissue plasmacytomas Minor response (MR) 25%-49% reduction of serum M-protein and 50-89% reduction of 24h urine M-protein. 25-49% reduction in size of soft tissue plasmacytomas. No increase in size or number of bone lesions Stable disease (SD) No sCR, CR, VGPR, PR, MR or PD Progressive disease (PD) 25% increase from the lowest value: serum M-protein, urine M-protein, BM plasma cell. Increase in size, new bone lesions, soft tissue plasmacytomas or serum calcium >11.5 mg/dL; NE, not evaluable | From the date of first documentation of response to the date of disease progression or death, assessed up to 5 years | 
| Overall Response Rate (Independent Review Committee) | Overall response rate including sCR, CR, VGPR, PR and MR. Very good partial response (VGPR) serum and urine M-protein detectable but not electrophoresis or >90% reduction in serum M-protein and urine M-protein <100 mg/24h Partial response (PR) ≥50% reduction in serum M-protein and 90% reduction in 24h urine M-protein or to <200 mg/24h. 50% reduction in size of any soft tissue plasmacytomas Minor response (MR) 25%-49% reduction of serum M-protein and 50-89% reduction of 24h urine M-protein. 25-49% reduction in size of soft tissue plasmacytomas. No increase in size or number of bone lesions | From the date of first documentation of response to the date of disease progression or death, assessed up to 5 years | 
| Overall Response Rate (Independent Review Committee) Excluding MR | Includes sCR, CR, VGPR and PR (excludes MR). Very good partial response (VGPR) serum and urine M-protein detectable but not electrophoresis or >90% reduction in serum M-protein and urine M-protein <100 mg/24h Partial response (PR) ≥50% reduction in serum M-protein and 90% reduction in 24h urine M-protein or to <200 mg/24h. 50% reduction in size of any soft tissue plasmacytomas | From the date of first documentation of response to the date of disease progression or death, assessed up to 5 years | 
| Best Overall Response (Investigator Assessment) | Very good partial response (VGPR) serum and urine M-protein detectable but not electrophoresis or >90% reduction in serum M-protein and urine M-protein <100 mg/24h Partial response (PR) ≥50% reduction in serum M-protein and 90% reduction in 24h urine M-protein or to <200 mg/24h. 50% reduction in size of any soft tissue plasmacytomas Minor response (MR) 25%-49% reduction of serum M-protein and 50-89% reduction of 24h urine M-protein. 25-49% reduction in size of soft tissue plasmacytomas. No increase in size or number of bone lesions Stable disease (SD) No sCR, CR, VGPR, PR, MR or PD Progressive disease (PD) 25% increase from the lowest value: serum M-protein, urine M-protein, BM plasma cell. Increase in size, new bone lesions, soft tissue plasmacytomas or serum calcium >11.5 mg/dL; NE, not evaluable | From the date of first documentation of response to the date of disease progression or death, assessed up to 5 years | 
| Overall Response Rate (Investigator Assessment) | Includes sCR, CR, VGPR, PR and MR. Very good partial response (VGPR) serum and urine M-protein detectable but not electrophoresis or >90% reduction in serum M-protein and urine M-protein <100 mg/24h Partial response (PR) ≥50% reduction in serum M-protein and 90% reduction in 24h urine M-protein or to <200 mg/24h. 50% reduction in size of any soft tissue plasmacytomas Minor response (MR) 25%-49% reduction of serum M-protein and 50-89% reduction of 24h urine M-protein. 25-49% reduction in size of soft tissue plasmacytomas. No increase in size or number of bone lesions | From the date of first documentation of response to the date of disease progression or death, assessed up to 5 years | 
| Overall Response Rate (Investigator Assessment) Excluding MR | Very good partial response (VGPR) serum and urine M-protein detectable but not electrophoresis or >90% reduction in serum M-protein and urine M-protein <100 mg/24h Partial response (PR) ≥50% reduction in serum M-protein and 90% reduction in 24h urine M-protein or to <200 mg/24h. 50% reduction in size of any soft tissue plasmacytomas | From the date of first documentation of response to the date of disease progression or death, assessed up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple Myeloma, Aplidin, plitidepsin, dexamethasone