A Study of Aplidin (Plitidepsin) 3 h iv in Subjects With Relapsing or Refractory Multiple Myeloma
Condition: Multiple Myeloma
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell
Intervention: Plitidepsin
Intervention description: 3-hour infusion every 2 weeks alone or in combination with dexamethasone
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 51.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Myeloma; Aplidin; Plitidepsin; PharmaMar

Summary:

      This is a phase II study to determine the efficacy following treatment with Aplidin® 5 mg/m2,
      given as a 3 hours intravenous infusion every 2 weeks, in patients with relapsed or
      refractory multiple myeloma (MM).
    

Eligibility criteria:

        Inclusion criteria

          1. Written informed consent obtained from the patient before starting any study-specific
             procedure. If any patient is unable to give consent, it may be obtained from the
             patient's legal representative if in accordance with local laws and regulations

          2. Age ≥ 18 years

          3. Performance status Eastern Cooperative Oncology Group (ECOG) ≤ 2

          4. Life expectancy ≥ 3 months.

          5. Patient was previously diagnosed with MM based on standard criteria and currently
             requires treatment because MM relapses following a response to standard chemotherapy
             or high-dose chemotherapy, or MM is refractory (i.e., failure to achieve at least
             complete response (CR), partial response (PR) or stable disease (SD)) to their most
             recent chemotherapy.

          6. Patient has measurable disease, defined as follows:

               -  For secretory multiple myeloma, measurable disease is defined as any quantifiable
                  serum monoclonal protein value and, where applicable, urine light-chain excretion
                  of ≥ 200 mg/24 hours.

               -  For oligo or non-secretory multiple myeloma, measurable disease is defined by the
                  presence of soft tissue (not bone) plasmacytomas as determined by clinical
                  examination or applicable radiographs (i.e. Magnetic resonance imaging (MRI),
                  Computerized Axial Tomography (CT-Scan)).

          7. Recovery from any non-hematological toxicity derived from previous treatments. The
             presence of alopecia and National Cancer Institute Common Toxicity Criteria (NCI-CTC)
             grade < 2 sensitive peripheral neuropathy is allowed.

          8. Patient has the following laboratory values within 14 days before day 1, cycle 1:

               -  Platelet count ≥ 50 x109/L, hemoglobin ≥ 8.0 g/dl and absolute neutrophil count
                  (ANC) ≥ 1.0x109/L; lower values may be accepted if clearly are due to bone marrow
                  involvement by multiple myeloma.

               -  Corrected serum calcium < 14mg/dL.

               -  Aspartate transaminase (AST): ≤ 2.5 x the upper limit of normal.

               -  Alanine transaminase (ALT): ≤ 2.5 x the upper limit of normal.

               -  Total bilirubin: ≤ 1.5 x the upper limit of normal.

               -  Calculated Creatinine clearance: ≥ 40 mL/minute (by means of Crockoft and Gault´s
                  formula).

          9. Left ventricular ejection fraction within normal limits.

        Exclusion criteria

          1. Prior therapy with Aplidin®.

          2. Pregnant or lactating women; men and women of reproductive potential who are not using
             effective contraceptive methods (double barrier method, intrauterine device, oral
             contraception)

          3. History of another neoplastic disease. The exceptions are:

               -  non-melanoma skin cancer,

               -  carcinoma in situ of uterine cervix,

               -  any other cancer curatively treated and no evidence of disease for at least 10
                  years.

          4. Other relevant diseases or adverse clinical conditions:

               -  History or presence of unstable angina, myocardial infarction, valvular heart
                  disease or congestive heart failure.

               -  Previous mediastinal radiotherapy.

               -  Uncontrolled arterial hypertension despite optimal medical therapy.

               -  Previous treatment with doxorubicin at cumulative doses in excess of 400 mg/m².

               -  Symptomatic arrhythmia or any arrhythmia requiring treatment.

               -  History of significant neurological or psychiatric disorders

               -  Active infection

               -  Patient is known to be human immunodeficiency virus (HIV) positive, Hepatitis B
                  surface antigen-positive or active hepatitis C infection.

               -  Myopathy or any clinical situation that causes significant and persistent
                  elevation of creatine kinase (CK)(>2.5 ULN in two different determinations
                  performed with one week apart)

               -  Significant non-neoplastic liver disease (e.g. cirrhosis, active chronic
                  hepatitis)

               -  Uncontrolled endocrine diseases (e.g. diabetes mellitus, hypothyroidism or
                  hyperthyroidism) (i.e. requiring relevant changes in medication within the last
                  month, or hospital admission within the last 3 months)

          5. Limitation of the patient's ability to comply with the treatment or follow-up
             protocol.

          6. Treatment with any investigational product in the 30 days period before inclusion in
             the study or radiotherapy in the 4 weeks before inclusion in the study. Other previous
             treatments should have been completed 3 weeks before inclusion in the study, and in
             case of high dose chemotherapy, 8 weeks.

          7. Known hypersensitivity to Aplidin®, mannitol, cremophor, or ethanol or dexamethasone.