Multiple Myeloma Double Refractory. MedDRA version: 19.0 Level: LLT Classification code 10028228 Term: Multiple myeloma System Organ Class: 100000004864
Conditions
Interventions
Product Name: Aplidin
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
Other desc
Sponsors
Pharma Mar, S.A.
Eligibility
Sex/Gender
All
Inclusion 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: a)Serum M-protein = 0.5 g/dL or = 0.2 g/24-h urine light chain (UFLC) excretion. b)In patients who lack measureable M-protein in serum or urine, i.e., serum M-protein 1.65), indicating clonality. In addition, the baseline SFLC level must be =10 mg/dl of the appropriate involved light chain isotype. c)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 30 mL/min, measured or calculated according to Cockcroft and Gault’s formula. h)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. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 12 F.1.3 Elderly (
Exclusion criteria
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: a)Uncontrolled psychiatric illness or medical illness that the Investigator feels will compromise the patient’s tolerance of the trial medication. b)Significant non-neoplastic liver disease. c)Uncontrolled endocrine diseases (i.e., requiring relevant changes in medication within the last month, or hospital admission within the last three months). d)Uncontrolled systemic infection. e)Acute infiltrative pulmonary and pericardial disease. 4)Other relevant cardiac conditions: a)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. b)History or presence of unstable angina, myocardial infarction, valvular heart disease, cardiac amyloidosis or congestive heart failure within the last 12 months. c)Uncontrolled arterial hypertension (= 150/100 mmHg) despite optimal medical therapy. d)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: a)Nitrosoureas must be discontinued six weeks prior to Cycle (C) 1, D1. b)Thirty days for other CTs and 15 days for other biological agents prior to C1 D1. c)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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the efficacy of plitidepsin in combination with bortezomib and dexamethasone in patients with multiple myeloma (MM) double refractory to bortezomib and lenalidomide in terms of overall response rate (ORR), including stringent complete response (sCR), complete response (CR), very good partial response (VGPR) and partial response (PR).;Secondary Objective: •To evaluate time-to-event efficacy endpoints of plitidepsin in combination with bortezomib and dexamethasone, i.e., duration of response (DOR), time to progression (TTP), progression-free survival (PFS) and event-free survival (EFS). •To evaluate overall survival (OS) and OS rate at 6 and 12 months (OS6 and OS12, respectively). •To evaluate the safety and tolerability of plitidepsin in combination with bortezomib and dexamethasone. •To study the pharmacokinetics (PK) and pharmacodynamics (PDy) of plitidepsin in combination with bortezomib and dexamethasone. •To obtain pharmacogenomic information (Pharmacogenomics [PGx]) on markers of response to plitidepsin and bortezomib treatment.;Primary end point(s): Overall response rate (ORR), including Stringent complete response (sCR), complete response (CR), Very good partial response(VGPR) and Partial response (PR). Clinical benefit rate, including Overall response rate (ORR) plus Minimal response (MR) plus Stable disease (SD).;Timepoint(s) of evaluation of this end point: Along the study. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Time-to-event efficacy endpoints of plitidepsin in combination with bortezomib and dexamethasone, i.e., DOR, TTP, PFS and EFS. OS and OS rate at 6 and 12 months (OS6 and OS12). Safety and tolerability of plitidepsin in combination with bortezomib and dexamethasone. PK and PDy of plitidepsin in combination with bortezomib and dexamethasone. PGx information on markers of response to plitidepsin and bortezomib treatment.;Timepoint(s) of evaluation of this end point: Along the study. | — |
Countries
France, Spain
Contacts
Public ContactClinical Trials
Pharma Mar, S.A.
Outcome results
None listed