A Study of Aplidin (Plitidepsin) 3 h iv in Subjects With Relapsing or Refractory Multiple Myeloma

"Phase II Multicenter, Open-Label, Clinical and Pharmacokinetic Study of Aplidin® As A 3-Hour Infusion Every 2 Weeks Alone or in Combination With Dexamethasone, in Pre-Treated Patients With Relapsing or Refractory Multiple Myeloma."

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).

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

• Additional pharmacokinetic information for Aplidin® given as 3-hour IV infusion every 2 weeks in patients with MM.
• To obtain additional genomic and pharmacodynamics information on MM and Aplidin.
• To assess the safety and tolerability of Aplidin® given as 3-hour IV infusion every 2 weeks in patients with MM alone or in combination with dexamethasone given orally as a 20 mg daily for 4 days
• To determine the response rate in the second cohort of patients following treatment with Aplidin®, given as a 3 hour infusion every 2 weeks, plus dexamethasone given orally as a 20 mg daily for 4 days, starting the same day of Aplidin® administration, as a second treatment stage in patients with suboptimal response to Aplidin® as single agent (progressive disease after three cycles or stable disease after four cycles).

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.