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

• ClinicalTrials.gov Identifier: NCT02100657
• Recruitment Status: Completed
• First Posted: April 1, 2014
• Results First Posted: October 12, 2020
• Last Update Posted: October 12, 2020
• Sponsor: PharmaMar
• Information provided by (Responsible Party): PharmaMar

Tracking Information

• First Submitted Date: March 21, 2014
• First Posted Date: April 1, 2014
• Results First Submitted Date: July 22, 2020
• Results First Posted Date: October 12, 2020
• Last Update Posted Date: October 12, 2020
• Study Start Date: June 2014
• Actual Primary Completion Date: June 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 17, 2020)

• Recommended Dose of Plitidepsin in Combination With Bortezomib and Dexamethasone [ Time Frame: After 28-day cycle ]
  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.
• Recommended Dose of Bortezomib in Combination With Plitidepsin and Dexamethasone [ Time Frame: After 28-day cycle ]
  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.
• Recommended Dose of Dexamethasone in Combination With Plitidepsin and Bortezomib [ Time Frame: After 28-day cycle ]
  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.
• Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs) [ Time Frame: After 28-day cycle ]
  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

Original Primary Outcome Measures (submitted: March 27, 2014)

Recommended dose of plitidepsin in combinatio with bortezomib and dexamethasone [ Time Frame: After 28-day cycle ]

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.

Current Secondary Outcome Measures (submitted: September 17, 2020)

• Response According to International Myeloma Working Group Criteria [ Time Frame: Response or disease progression was assessed on Day 1 of each cycle, assessed up to 4 years ]
  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
• Overall Response Rate [ Time Frame: Response or disease progression was assessed on Day 1 of each cycle, assessed up to 4 years ]
  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
• Duration of Response [ Time Frame: From the date of the first documentation of response to the date of PD or further therapy or death, up to 4 years ]
  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
• Time to Progression [ Time Frame: 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 (TTP) was calculated from the date of the first infusion to the date of documented PD or death due to PD.
• Time to Progression Rates [ Time Frame: 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 (TTP) was calculated from the date of the first infusion to the date of documented PD or death due to PD.
• Progression-free Survival [ Time Frame: from the date of the first infusion to the date of documented PD or death, up to 4 years ]
  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
• Progression-free Survival Rates [ Time Frame: From the date of the first infusion to the date of documented PD or death, up to 4 years ]
  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
• Event-free Survival [ Time Frame: From the date of first infusion to the date of documented PD or death, up to 4 years ]
  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
• Event-free Survival Rates [ Time Frame: from the date of first infusion to the date of documented PD or death, up to 4 years ]
  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

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study of Plitidepsin (Aplidin®) in Combination With Bortezomib and Dexamethasone in Patients With Multiple Myeloma
• Official Title: Phase I Study of Plitidepsin (Aplidin®) in Combination With Bortezomib and Dexamethasone in Patients With Relapsed and/or Refractory Multiple Myeloma
• Brief 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.
• Detailed 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.
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Other
• Condition: Multiple Myeloma

Intervention

• Drug: Plitidepsin
• Drug: Bortezomib
• Drug: Dexamethasone

Study Arms

Experimental: plitidepsin + bortezomib + dexamethasone

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

Interventions:

• Drug: Plitidepsin
• Drug: Bortezomib
• Drug: Dexamethasone

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 17, 2020): 39
• Original Estimated Enrollment (submitted: March 27, 2014): 25
• Actual Study Completion Date: June 2018
• Actual Primary Completion Date: June 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: France, Spain

Administrative Information

• NCT Number: NCT02100657
• Other Study ID Numbers: APL-A-012-13
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: PharmaMar
• Study Sponsor: PharmaMar
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: PharmaMar
• Verification Date: September 2020