Trial of Plitidepsin (Aplidin®) in Combination With Bortezomib and Dexamethasone in Multiple Myeloma Patients Double Refractory to Bortezomib and Lenalidomide
Condition: Multiple Myeloma
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell
Intervention: plitidepsin; Bortezomib; Dexamethasone
Intervention description: 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.; 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; DXM orally at a dose of 40 mg/day on Days 1, 8, 15 and 22 every four weeks
Intervention MeSH terms: Dexamethasone; Bortezomib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 10.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: multiple myeloma; plitidepsin; Aplidin

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.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Patients must give written informed consent (IC) in accordance with institutional and
             local guidelines.

          2. Age ≥ 18 years.

          3. Patients must have a confirmed diagnosis of MM according to the Durie and Salmon
             criteria.

          4. Patients must have measurable disease defined as any of the following:

               1. Serum M-protein ≥ 0.5 g/dL or ≥ 0.2 g/24-h urine light chain (UFLC) excretion.

               2. 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.

               3. 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).

          5. 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).

          6. Patients must have received previous treatment with bortezomib and lenalidomide and be
             refractory to both.

          7. Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status
             (PS) ≤ 2.

          8. 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).

          9. Laboratory data:

               1. Hemoglobin ≥ 8 g/dL.

               2. 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.

               3. Platelet count ≥ 50,000/mm3 (50.0 x 109/L) for patients in whom < 50% of the BM
                  nucleated cells are plasma cells.

               4. Platelet count ≥ 25,000/mm3 (25.0 x 109/L) for patients in whom ≥ 50% of BM
                  nucleated cells are plasma cells.

               5. Serum total bilirubin < 1.5 x institutional upper limit of normal (ULN) (except
                  when Gilbert syndrome is clearly documented and other liver function tests are
                  within normal levels).

               6. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 x
                  institutional ULN and alkaline phosphatase (AP) ≤ 2.5 x institutional ULN.

               7. Creatinine clearance (CrCl) > 30 mL/min, measured or calculated according to
                  Cockcroft and Gault's formula.

               8. Albumin ≥ 2.5 g/dl.

         10. Evidence of non-childbearing status for women of childbearing potential (WOCBP): WOCBP
             must have a negative serum or urine pregnancy test within seven days prior to
             enrolment and must agree to use a highly effective contraceptive measure throughout
             the trial and during six months after treatment discontinuation. Male patients
             enrolled in the study should also use contraceptive methods during and after treatment
             discontinuation.

         11. Left ventricular ejection fraction (LVEF) ≥ 45%.

         12. Patients must have a BM assessment within three weeks prior to enrolment.

        Exclusion Criteria:

          1. Previous treatment with plitidepsin.

          2. Active or metastatic primary malignancy other than MM.

          3. 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:

               1. Uncontrolled psychiatric illness or medical illness that the Investigator feels
                  will compromise the patient's tolerance of the trial medication.

               2. Significant non-neoplastic liver disease.

               3. Uncontrolled endocrine diseases (i.e., requiring relevant changes in medication
                  within the last month, or hospital admission within the last three months).

               4. Uncontrolled systemic infection.

               5. Acute infiltrative pulmonary and pericardial disease.

          4. Other relevant cardiac conditions:

               1. Symptomatic arrhythmia (excluding anemia-related grade ≤ 2 sinusal tachycardia)
                  or any arrhythmia requiring ongoing treatment, and/or prolonged grade ≥ 2 QT-QTc;
                  or presence of unstable atrial fibrillation (according to the National Cancer
                  Institute Common Terminology Criteria for the Classification of Adverse Events
                  [NCI-CTCAE] v4.0). Patients on treatment for stable atrial fibrillation are
                  allowed, provided they do not meet any other cardiac or prohibited drug exclusion
                  criterion.

               2. History or presence of unstable angina, myocardial infarction, valvular heart
                  disease, cardiac amyloidosis or congestive heart failure within the last 12
                  months.

               3. Uncontrolled arterial hypertension (≥ 150/100 mmHg) despite optimal medical
                  therapy.

               4. Previous treatment with doxorubicin at cumulative doses of > 400 mg/m², or
                  equivalent.

          5. History of hypersensitivity reactions and/or intolerance to bortezomib, polyoxyl 35
             castor oil, mannitol, boron or dexamethasone.

          6. 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.

          7. Grade ≥ 1 neuropathy (either bortezomib-related or not) according to NCI-CTCAE v4.0.

          8. Any other major illness that, in the Investigator's judgment, will substantially
             increase the risk associated with the patients' participation in this trial.

          9. Pregnant and/or lactating women.

         10. Known active human immunodeficiency virus (HIV) infection (HIV testing is not required
             unless infection is clinically suspected).

         11. Active hepatitis B or C virus (HBV or HCV) infection.

         12. Treatment with any Investigational Medicinal Product (IMP) in the 30 days before
             inclusion in the trial.

         13. Concomitant medications that include corticosteroids, chemotherapy (CT), or other
             therapy that is or may be active against myeloma. Concurrent corticosteroids are
             allowed as an equivalent to a prednisone dose of ≤ 10 mg daily, administered as an
             antiemetic or as premedication for blood products.

         14. Wash-out periods after the end of the previous therapy:

               1. Nitrosoureas must be discontinued six weeks prior to Cycle (C) 1, D1.

               2. Thirty days for other CTs and 15 days for other biological agents prior to C1 D1.

               3. Thirty days after the end of any prior radiation or radionuclide therapy (six
                  weeks in the case of prior extensive external beam radiation, with more than 25%
                  of BM distribution).

         15. Plasma cell leukemia at the time of trial entry.

         16. Disease-related symptomatic hypercalcemia despite optimal medical therapy.

         17. Limitation of the patient's ability to comply with the treatment or follow-up
             protocol.

         18. Contraindication to use steroids.