Study of Plitidepsin (Aplidin®) in Combination With Bortezomib and Dexamethasone in Patients With Multiple Myeloma

Study Overview
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Brief Summary
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Study of Plitidepsin (Aplidin®) to determine the recommended dose (RD) of plitidepsin in Combination with Bortezomib and Dexamethasone in Patients with Relapsed and/or Refractory Multiple Myeloma.

Detailed Description
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Phase I Multicenter, Open-label, Dose-escalating Clinical and Pharmacokinetic Trial of Plitidepsin (Aplidin®) to determine the recommended dose (RD) of plitidepsin in combination with bortezomib and dexamethasone in patients with relapsed and/or refractory multiple myeloma (MM), to determine the efficacy of the combination plitidepsin/bortezomib/dexamethasone, to evaluate the safety and tolerability of the combination in patients with relapsing and/or refractory MM and to study the pharmacokinetics (PK) and pharmacodynamics (PDy) of plitidepsin in combination with bortezomib and dexamethasone.

Official Title
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Phase I Study of Plitidepsin (Aplidin®) in Combination With Bortezomib and Dexamethasone in Patients With Relapsed and/or Refractory Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Plitidepsin
* Drug: Bortezomib
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years. Prior autologous transplantation (HSCT) patients are allowed. Patients must have received at least one previous treatment line of induction, chemotherapy, chemotherapy and transplantation or previous treatment with bortezomib or another proteasome drug Exclusion Criteria: Previous treatment with plitidepsin. Active or metastatic primary malignancy other than MM. Serious concomitant systemic disorders History of hypersensitivity reactions to bortezomib, polyoxyl 35 castor oil or mannitol Neuropathy Pregnant and/or lactating women HIV infection Active hepatitis B or C virus infection. Treatment with any Investigational Medicinal Product (IMP) in the 30 days before inclusion in the study Plasma cell leukemia at the time of study entry Contraindication for the use of steroids

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: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: plitidepsin + bortezomib + dexamethasone<br>Plitidepsin will be administered as a 3-hour (h) intravenous (i.v.) infusion on Day (D) 1 and 15, every four weeks (q4wk). Bortezomib will be administered as a subcutaneous (s.c.) injection on D1, 4, 8 and 11, q4wk, for a maximum of eight cycles. Dexamethasone will be taken orally on D1, 8, 15 and 22, q4wk | Drug: Plitidepsin<br> <br> Drug: Bortezomib<br> <br> Drug: Dexamethasone<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recommended Dose of Plitidepsin in Combination With Bortezomib and Dexamethasone | To determine the recommended dose (RD) of plitidepsin in combination with bortezomib and dexamethasone in patients with relapsed and/or refractory multiple myeloma (MM). To define the RD, patients will be evaluated for DLTs during the first 28-day cycle. The RD will be the highest DL at which fewer than two out of six (33%) of evaluable patients experience a DLT during the first 28-day cycle. | After 28-day cycle | 
| Recommended Dose of Bortezomib in Combination With Plitidepsin and Dexamethasone | To determine the recommended dose (RD) of plitidepsin in combination with bortezomib and dexamethasone in patients with relapsed and/or refractory multiple myeloma (MM). To define the RD, patients will be evaluated for DLTs during the first 28-day cycle. The RD will be the highest DL at which fewer than two out of six (33%) of evaluable patients experience a DLT during the first 28-day cycle. | After 28-day cycle | 
| Recommended Dose of Dexamethasone in Combination With Plitidepsin and Bortezomib | To determine the recommended dose (RD) of plitidepsin in combination with bortezomib and dexamethasone in patients with relapsed and/or refractory multiple myeloma (MM). To define the RD, patients will be evaluated for DLTs during the first 28-day cycle. The RD will be the highest DL at which fewer than two out of six (33%) of evaluable patients experience a DLT during the first 28-day cycle. | After 28-day cycle | 
| Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs) | DLTs were defined as: Hematological Toxicity Grade 3/4 neutropenia associated with fever or lasting>7 days related to the study treatment Grade 3/4 thrombocytopenia accompanied by grade 3/4 hemorrhage Extensive bone marrow (BM) infiltration, DLT was defined as grade 4 thrombocytopenia with grade 3/4 hemorrhage or grade 4 neutropenia lasting >7 days or with fever Non-hematological Toxicity Grade 3/4 nausea and vomiting refractory to antiemetic therapy Grade≥3 muscular Adverse events (AE) (myalgia, muscular weakness, muscle cramps, myopathy) Grade≥3 alanine aminotransferase (ALT)/Aspartate aminotransferase (AST) lasting more than 1 week Grade≥3 bilirubin increase Grade≥3 creatine phosphokinase (CPK) increase Cardiac toxicity Symptomatic or treatment-requiring grade ≥1 cardiac arrhythmia related to plitidepsin Grade≥1 left ventricular systolic dysfunction related to plitidepsin Neuropathic pain and peripheral sensory neuropathy related to BTZ | After 28-day cycle | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response According to International Myeloma Working Group Criteria | Stringent complete response (sCR) normal Free Light Chains (FLC) ratio. No clonal cells Complete response (CR) no serum/urine M-protein, no evidence of soft tissue plasmacytoma. <5% clonal plasma cells 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 | Response or disease progression was assessed on Day 1 of each cycle, assessed up to 4 years | 
| Overall Response Rate | Overall response rate (ORR), including stringent complete response (sCR), complete response (CR), very good partial response (VGPR) and partial response (PR) according to the International Myeloma Working Group (IMWG) criteria | Response or disease progression was assessed on Day 1 of each cycle, assessed up to 4 years | 
| Duration of Response | Duration of response (DR) was analyzed for all patients in whom a response had been observed and was calculated from the date of the first documentation of response to the date of PD or further therapy or death | From the date of the first documentation of response to the date of PD or further therapy or death, up to 4 years | 
| Time to Progression | Time to progression (TTP) was calculated from the date of the first infusion to the date of documented PD or death due to PD. | From the date of the first infusion to the date of documented PD or death due to PD, up to 4 years | 
| Time to Progression Rates | Time to progression (TTP) was calculated from the date of the first infusion to the date of documented PD or death due to PD. | From the date of the first infusion to the date of documented PD or death due to PD, up to 4 years | 
| Progression-free Survival | Progression-free survival (PFS) was calculated from the date of the first infusion to the date of documented PD or death (regardless of the reason), whichever comes first | from the date of the first infusion to the date of documented PD or death, up to 4 years | 
| Progression-free Survival Rates | Progression-free survival (PFS) was calculated from the date of the first infusion to the date of documented PD or death (regardless of the reason), whichever comes first | From the date of the first infusion to the date of documented PD or death, up to 4 years | 
| Event-free Survival | Event-free survival (EFS) was calculated from the date of first infusion to the date of documented PD or death, but could include additional events besides death and PD that were considered of importance | From the date of first infusion to the date of documented PD or death, up to 4 years | 
| Event-free Survival Rates | Event-free survival (EFS) was calculated from the date of first infusion to the date of documented PD or death, but could include additional events besides death and PD that were considered of importance | from the date of first infusion to the date of documented PD or death, up to 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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multiple myeloma, plitidepsin, APLIDIN