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

Multiple Myeloma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02100657
• Other study ID #: APL-A-012-13
• Status: Completed
• Phase: Phase 1
• Start date: June 2014
• Est. completion date: June 2018

Study information

• Verified date: September 2020
• Source: PharmaMar
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 39
• Est. completion date: June 2018
• Est. primary completion date: June 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Multiple Myeloma
• Neoplasms, Plasma Cell

Intervention

Drug:
• Plitidepsin

• Bortezomib

• Dexamethasone

Locations

Country	Name	City	State
France	Institut Gustave Roussy	Villejuif
Spain	Hospital Universitario Germans Trias I Pujol	Badalona	Barcelona
Spain	MD Anderson Cancer Center Madrid	Madrid
Spain	Clínica Universidad de Navarra	Pamplona	Navarra
Spain	Hospital Universitario Salamanca	Salamanca
Spain	Hospital Universitario Virgen del Rocío	Sevilla
Spain	Hospital Universitari i Politècnic la Fe	Valencia

Sponsors (1)

Lead Sponsor	Collaborator
PharmaMar

Countries where clinical trial is conducted

France,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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