Study of Plitidepsin in Combination with Dexamethasone vs. Dexamethasone Alone in Patients with Relapsed/Refractory Multiple Myeloma.

• Register: EUCTR
• Last refreshed on: 29 January 2018
• Main ID: EUCTR2009-016138-29-GR
• Date of registration: 05/11/2010
• Prospective Registration: Yes
• Primary sponsor: Pharma Mar, S.A.
• Public title: Study of Plitidepsin in Combination with Dexamethasone vs. Dexamethasone Alone in Patients with Relapsed/Refractory Multiple Myeloma.
• Scientific title: Randomized, Multicenter, Open-label, Phase III Study of Plitidepsin in Combination with Dexamethasone vs. Dexamethasone Alone in Patients with Relapsed/Refractory Multiple Myeloma. - ADMYRE
• Date of first enrolment: 05/11/2010
• Target sample size: 250
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2009-016138-29
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: yes; Single blind: no; Double blind: no; Parallel group: yes; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: yes; Placebo: no; Other: yes; Other specify the comparator: dexamethasone; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Australia, Austria, Belgium, Czech Republic, France, Germany, Greece, Ireland, Italy, Netherlands, Poland, Portugal, Spain, United Kingdom, United States

Contacts

• Name: Ana Belén Irigaray
• Affiliation: Pharma Mar, S.A.

• Name: Ana Belén Irigaray
• Affiliation: Pharma Mar, S.A.

Key inclusion & exclusion criteria

Inclusion criteria:
1. Age = 18 years.
2. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) = 2.
3. Life expectancy = 3 months.
4. Patients previously diagnosed with multiple myeloma based on IMWG diagnostic criteria.
5. 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.
6. Patients must have received previous bortezomib-containing and lenalidomide-containing regimens (or
thalidomide where lenalidomide is not available), unless unable to tolerate either of them.
7. Patients must have measurable disease defined as:
a) For secretory MM: any quantifiable serum monoclonal protein value and, where applicable, urine light-chain
excretion = 200 mg/24 hours.
b) For oligo- or non-secretory MM: presence of soft tissue (not bone) plasmacytomas, as determined by clinical
examination or applicable radiographs [i.e., magnetic resonance imaging (MRI), computed tomography (CT)-
scan], and/or by the presence of abnormal serum free light chains (sFLC): involved FLC level = 10 mg/dl
provided the serum FLC ratio is abnormal.
8. At least two-week washout period since the end of last therapy (six weeks if previous nitrosoureas-containing
regimen), given recovery to grade = 1 from any non-hematological related adverse event (AE) derived from
previous treatment (excluding alopecia).
9. Adequate bone marrow (BM), renal, hepatic, and metabolic function (assessed = 7 days before inclusion in the
study):
a) Absolute neutrophil count (ANC) = 1.0 x 109/l (= 0.5 x 109/l if due to extensive and documented 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.
b) Platelet count = 50 x 109/l (= 25 x 109/l if due to extensive and documented BM disease involvement).
c) Hemoglobin = 8.5 g/dl.
- Patients may receive red blood cells (RBC) and/or erythropoietin (EPO), and/or platelets transfusions in
accordance with institutional guidelines.
d) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) = 3.0 x the upper limit of normal
(ULN).
e) Direct bilirubin = 1.0 x ULN.
f) Calculated creatinine clearance (CrCl) = 30 ml/minute (by means of Cockcroft and Gault´s formula).
g) Creatine phosphokinase (CPK) = 2.5 x ULN.
h) Albumin = 2.5 g/dl.
10. Left ventricular ejection fraction (LVEF) by echocardiogram (ECHO) or multiple-gated acquisition scan
(MUGA) above the lower limit of normal (LLN).
11. Women of childbearing potential must have a negative serum pregnancy test before study entry. Both women
and men must agree to use a medically acceptable method of contraception throughout the treatment period and
for six months after
discontinuation of treatment.
12. Voluntarily signed and dated written informed consent prior to any specific study procedure.
Are the trial subjects under 18? no
Number of subjects for this age range: 0
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 125
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 125

Exclusion criteria:
1. Concomitant diseases/conditions:
a) History or presence of angina, myocardial infarction, clinically relevant valvular heart disease, cardiac
amyloidosis or congestive heart failure within the last 12 months.
b) Symptomatic arrhythmia (excluding anemia-related sinusal tachycardia grade = 2) or any arrhythmia requiring
ongoing treatment, and/or prolonged QT-QTc grade = 2; or presence of unstable atrial fibrilation. Patients with
stable atrial fibrillation on treatment are allowed provided they do not meet any other cardiac or prohibited drug
exclusion criterion.
c) Active uncontrolled infection.
d) Morphological or cytological features of myelodysplasia and/or post-chemotherapy aplasia on BM assessment.
e) Myopathy > grade 2 or any clinical situation that causes significant and persistent elevation of CPK (>2.5 x
ULN in two different determinations performed one week apart).
f) Known human immunodeficiency virus (HIV) infection (HIV testing is not required unless infection is
clinically suspected).
g) Known active hepatitis B or C virus (HBV or HCV) infection.
h) Limitation of the patient’s ability to comply with the treatment or follow-up requirements.
i) Any other major illness that, in the Investigator’s judgment, will substantially increase the risk associated with
the patient’s participation in this study.
j) Peripheral neuropathy > grade 2.
2. Women who are pregnant or breast feeding.
3. Concomitant medications that include corticosteroids, chemotherapy, or other therapy that is or may be active
against MM, within two weeks prior to Cycle 1 Day 1. Concurrent corticosteroids are allowed, provided they are
administered at an equivalent prednisone dose of = 10 mg daily, as premedication for blood products only.
4. Known history of peptic ulcer and/or major upper gastrointestinal bleeding episode occurring during last year
before study entry and/or related to prior steroid-based therapy.
5. Relevant history of mood-disturbances changes associated with previous steroid-based therapy.
6. Disease-related symptomatic hypercalcemia despite optimal medical therapy.
7. Known hypersensitivity to any involved study drug or any of its formulation components.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Relapsed/Refractory Multiple Myeloma
MedDRA version: 13.1 Level: PT Classification code 10028228 Term: Multiple myeloma System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Therapeutic area: Diseases [C] - Cancer [C04]

Intervention(s)

Product Name: APLIDIN (plitidepsin)
Product Code: Not applicable
Pharmaceutical Form: Powder and solvent for concentrate for solution for infusion
INN or Proposed INN: plitidepsin
CAS Number: 137219-37-5
Current Sponsor code: Not applicable
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 2-

Trade Name: FORTECORTIN 4 mg Tabletten
Product Name: FORTECORTIN 4 mg Tabletten
Product Code: Not applicable
Pharmaceutical Form: Tablet
CAS Number: 50-02-2
Other descriptive name: DEXAMETHASONE
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 4-

Primary Outcome(s)

Main Objective: 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).

Primary end point(s): Progression Free Survival (PFS) as per intention-to-treat (ITT)

Secondary Objective: To evaluate tumor response according to the International Myeloma Working Group (IMWG) criteria.
To assess duration of response (DR) and overall survival (OS).
To assess efficacy in patients who undergo crossover from dexamethasone alone to plitidepsin and dexamethasone combination.
To characterize and compare the safety profile on both arms in this population.
To characterize the pharmacokinetics (PK) and pharmacokinetic /pharmacodynamic (PK/PD) relationship.

Timepoint(s) of evaluation of this end point: Estimated average: 5 months. From randomization to the first evidence of progressive disease or death due to any cause

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: Response rate Time points: Every 4 weeks untill progression
Duration of Response Time Points: Estimated average: 3 months. From the date of first documentation of response to the date of disease progression or death.
Overall Survival Time Points: Estimated average: 9 months. From randomization to the first evidence of progressive disease or death due to any cause

Secondary end point(s): Response rate
Duration of Response
Overall Survival

Secondary ID(s)

APL-C-001-09

2009-016138-29-FR

Source(s) of Monetary Support

Pharma Mar, S.A.