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

NCT03117361 | Terminated Phase 2 Results

• 1 other identifier: APL-B-022-15
• Study Type: interventional
• Target: 10
• Locations: 3 countries
• Sites: 13

Brief Summary

This is a multi-center, open-label, single arm, non-comparative phase II trial, designed to evaluate the efficacy of plitidepsin in combination with bortezomib and dexamethasone in patients with Multiple Myeloma (MM) double refractory to bortezomib and lenalidomide.

Conditions

Multiple Myeloma

Keywords

multiple myeloma; plitidepsin; Aplidin

Outcome Measures

Primary Outcomes (2)

• Overall Response

  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

  From the date of first drug administration to the date of at least one disease assessment, up to 100 weeks

• Overall Response Rate

  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.

  From the date of first drug administration to the date of at least one disease assessment, up to 100 weeks

Secondary Outcomes (18)

• Clinical Benefit Rate

  From the date of first drug administration to the date of at least one disease assessment, up to 100 weeks

• Disease Control Rate

  From the date of first drug administration to the date of at least one disease assessment, up to 100 weeks

• Duration of Response

  From the date of first documentation of response to the date of disease progression, up to 100 weeks

• Time to Progression

  From the date of the first infusion to the date of documented PD or death due to PD, up to 100 weeks

• Percentage of Participants With Progression Disease at 3 Months

  From the date of the first infusion to the date of documented PD or death due to PD, up to 3 months

Study Arms (1)

Experimental

EXPERIMENTAL

Plitidepsin + bortezomib + dexamethasone Plitidepsin will be administered as a 3-hour intravenous (i.v.) infusion on Day(D) 1 and 15 , every four weeks (q4wk) Bortezomib will be administered as a bolus subcutaneous (s.c.) injection on D 1, 4, 8 and 11,q4wk Dexamethasone will be taken orally on D1,8,15 and 22, q4wk

Drug: plitidepsin; Drug: Bortezomib; Drug: Dexamethasone

Interventions

plitidepsin DRUG

Patients received plitidepsin as a 3-hour i.v. infusion at a dose of 5 mg/m2 on Days 1 and 15 every Four Weeks.

Experimental

Bortezomib DRUG

BTZ as a 3-5 second bolus s.c. injection at a dose of 1.3 mg/m2 on Days 1, 4, 8 and 11 every four weeks

Experimental

Dexamethasone DRUG

DXM orally at a dose of 40 mg/day on Days 1, 8, 15 and 22 every four weeks

Experimental

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must give written informed consent (IC) in accordance with institutional and local guidelines.
• Age ≥ 18 years.
• Patients must have a confirmed diagnosis of MM according to the Durie and Salmon criteria.
• Patients must have measurable disease defined as any of the following:
• Serum M-protein ≥ 0.5 g/dL or ≥ 0.2 g/24-h urine light chain (UFLC) excretion.
• In patients who lack measureable M-protein in serum or urine, i.e., serum M-protein \< 0.5 g/dL and urine M-protein \< 0.2 g/24 h, serum free light chain (SFLC) levels are most informative. SFLC levels can be used only if the baseline SFLC ratio is abnormal (\<0.26 or \>1.65), indicating clonality. In addition, the baseline SFLC level must be ≥10 mg/dl of the appropriate involved light chain isotype.
• When applicable, measurable soft tissue plasmacytoma ≥ 2 cm, by either physical examination and/or applicable radiological evaluation (i.e., magnetic resonance imaging \[MRI\], computed tomography \[CT\]-scan).
• Prior autologous and/or allogeneic hematopoietic stem cell transplantation (HSCT) patients are allowed. Patients must not have acute/chronic graft-versus-host disease (GVHD) or be receiving immunosuppressive therapy at least 90 days before the onset of treatment with the trial drug(s).
• Patients must have received previous treatment with bortezomib and lenalidomide and be refractory to both.
• Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2.
• Recovery to grade ≤ 1 from any non-hematological adverse event (AE) derived from previous treatment (if present, alopecia and peripheral neuropathy must be grade \<1).
• Laboratory data:
• Hemoglobin ≥ 8 g/dL.
• Absolute neutrophil count (ANC) ≥ 1,000 cells/mm3 (1.0 x 109/L) (≥ 0.5 x 109/L if due to extensive bone marrow \[BM\] involvement by ≥ 50% of plasma cells in BM biopsy). Screening of ANC should be independent of granulocyte- and granulocyte/macrophage-colony stimulating factor (G-CSF and GM-CSF) support for at least one week and of pegylated G-CSF for at least two weeks.
• Platelet count ≥ 50,000/mm3 (50.0 x 109/L) for patients in whom \< 50% of the BM nucleated cells are plasma cells.

You may not qualify if:

• Previous treatment with plitidepsin.
• Active or metastatic primary malignancy other than MM.
• Serious concomitant systemic disorders that would compromise the safety of the patient or the patient's ability to complete the trial, including the following specific conditions:
• Uncontrolled psychiatric illness or medical illness that the Investigator feels will compromise the patient's tolerance of the trial medication.
• Significant non-neoplastic liver disease.
• Uncontrolled endocrine diseases (i.e., requiring relevant changes in medication within the last month, or hospital admission within the last three months).
• Uncontrolled systemic infection.
• Acute infiltrative pulmonary and pericardial disease.
• Other relevant cardiac conditions:
• History or presence of unstable angina, myocardial infarction, valvular heart disease, cardiac amyloidosis or congestive heart failure within the last 12 months.
• Uncontrolled arterial hypertension (≥ 150/100 mmHg) despite optimal medical therapy.
• Previous treatment with doxorubicin at cumulative doses of \> 400 mg/m², or equivalent.
• History of hypersensitivity reactions and/or intolerance to bortezomib, polyoxyl 35 castor oil, mannitol, boron or dexamethasone.
• Myopathy or any clinical situation that causes significant and persistent elevation of creatine phosphokinase (CPK) (\> 2.5 ULN) in two different determinations performed within one week of each other.
• Grade ≥ 1 neuropathy (either bortezomib-related or not) according to NCI-CTCAE v4.0.

Sponsors & Collaborators

• PharmaMar: lead

Study Sites (13)

CHRU de Lille - Hôpital Claude Huriez

Lille, 59037, France

Location

Institut Gustave Roussy

Villejuif, 94800, France

Location

Policlinico Vittorio Emanuele Hospital

Catania, 95123, Italy

Location

Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori

Meldola, 47014, Italy

Location

Azienda Ospedaliera Città della Salute e della Scienza di Torino

Torino, 00126, Italy

Location

Hospital Universitario Germans Trias i Pujol

Badalona, Barcelona, 08916, Spain

Location

Clinica Universidad de Navarra

Pamplona, Navarre, 31008, Spain

Location

Institut Català d´Oncologia Girona

Girona, 17007, Spain

Location

Institut Català d´Oncologia L´Hospitalet

L'Hospitalet de Llobregat, 08908, Spain

Location

Hospital General Universitario J.M. Morales Meseguer

Murcia, 30008, Spain

Location

Hospital Universitario de Salamanca

Salamanca, 37007, Spain

Location

Complexo Hospitalario Universitario de Santiago

Santiago de Compostela, 15706, Spain

Location

Complejo Hospitalario Regional Virgen Del Rocio

Seville, 41013, Spain

Location

MeSH Terms

Conditions

Multiple Myeloma

Interventions

plitidepsin; Bortezomib; Dexamethasone

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Boronic Acids; Acids, Noncarboxylic; Acids; Inorganic Chemicals; Boron Compounds; Organic Chemicals; Pyrazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated

Limitations and Caveats

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.

Results Point of Contact

• Title: Clinical Developtment, Department of PharmaMar´s Oncology., Business Unit.
• Organization: Pharma Mar, S.A.

clinicaltrials@pharmamar.com

+34 918466000

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 12, 2017
• First Posted: April 17, 2017
• Study Start: May 8, 2017
• Primary Completion: July 30, 2018
• Study Completion: July 30, 2018
• Last Updated: December 2, 2020
• Results First Posted: December 2, 2020

Record last verified: 2020-11

Locations

FR (2); IT (3); ES (8)