Study Testing Radium-223 Dichloride in Relapsed Multiple Myeloma

Study Overview
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Brief Summary
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This study will be conducted in 2 parts. The phase 1b part will be an international, phase 1b, open-label, dose-escalation assessment of radium-223 dichloride administered with bortezomib and dexamethasone in subjects with relapsed multiple myeloma. The primary endpoint is to determine the optimal dose of radium-223 dichloride in combination with bortezomib/dexamethasone for the Phase 2 portion of the study. The phase 2 part will be an international, phase 2, double-blind, randomized, placebo-controlled assessment of radium-223 dichloride versus placebo administered with bortezomib and dexamethasone, in subjects with relapsed multiple myeloma. Up to 12 subjects in all dose cohorts combined will be treated in the phase 1b part of the study. Up to approximately 100 subjects will be enrolled in the phase 2 part of the study.

Official Title
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A Phase 1b/2 Trial to Evaluate the Safety and Efficacy of Radium-223 Dichloride (BAY88-8223) in Combination With Bortezomib and Dexamethasone in Early Relapsed Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Radium-223 dichloride (Xofigo, BAY88-8223)
* Drug: Placebo
* Drug: Bortezomib
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject must have documented monoclonal plasma cells in the bone marrow of ≥10%, as defined by their institutional standard at some point in their disease history or the presence of a biopsy proven plasmacytoma. Subjects must have received at least 1 and not more than 3 previous lines of treatment and have had a response to at least 1 prior Treatment in the past (i.e., achieved a minimal response [MR] or better) according to the IMWG uniform response criteria. Subject must be non-refractory to bortezomib (Refractory is defined: progression of disease while receiving bortezomib therapy or within 60 days of ending bortezomib therapy). Subjects must have documented evidence of progressive disease according to the IMWG uniform response criteria following the last multiple myeloma treatment. Subjects must have measurable disease defined as at least 1 of the following: Serum M-protein defined by the following: IgG multiple myeloma: Serum monoclonal paraprotein (M-protein) level ≥1.0 g/dL (measured by protein electrophoresis [PEP]); IgA, IgD, IgE, IgM multiple myeloma: serum M-protein level ≥0.5 g/dL (measured by PEP). Urine M-protein ≥200 mg/24 hours (any immunoglobulin heavy chain type measured by PEP). Serum free light chain (FLC) ≥10 mg/dL with abnormal ratio in subjects with unmeasurable disease by serum or urine PEP. ≥1 bone lesion identifiable by radiograph, computed tomography (CT), positron emission tomography - computed tomography (PET-CT), or magnetic resonance imaging (MRI). Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 to 2. Adequate hepatic function, with total bilirubin ≤1.5 x upper limit of normal (ULN) (except for Gilbert Syndrome: total bilirubin < 3.0 x ULN), and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3.0 x ULN. Absolute neutrophil count (ANC) ≥1.5 × 10e9/L, hemoglobin (Hb) ≥9.0 g/dL, and platelet count ≥75.0 × 10e9/L independent of transfusion of red blood cells (RBC) or platelet concentrates and independent of granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF). International normalized ratio (INR) ≤ 1.5 and partial thromboplastin time (PTT) ≤ 1.5 x ULN. Prothrombin time (PT) may be used instead of INR if ≤ 1.5 x ULN. Exclusion Criteria: Systemic glucocorticoid therapy (prednisone >10 mg/day orally or equivalent) within the last 4 weeks prior to first dose, unless tapered and on a stable dose (prednisone ≤10 mg/day orally or equivalent) for at least 1 week. Subjects with known POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) or light-chain (AL) amyloidosis. Plasma cell leukemia (defined by plasma cell >20%, and/or an absolute plasma cell count of >2 x 10e9/L in peripheral blood). Subject has received anti-myeloma treatment within 2 weeks or 5 pharmacokinetic (PK) half-lives (t1/2) of the treatment, whichever is longer, before the date of start of treatment. Radiation therapy in the previous 4 weeks prior to first dose. Prior treatment with radium-223 dichloride or any experimental radiopharmaceutical. Congestive heart failure (New York Heart Association [NYHA] class III to IV), symptomatic cardiac ischemia, unstable angina or myocardial infarction in the previous 6 months prior to first dose, or with a known left ventricular ejection fraction (LVEF) <40%, cardiomyopathy, pericardial disease, clinically relevant cardiac arrhythmia (CTCAE version 4.03 Grade 2 or higher), clinically significant ECG abnormalities, or screening 12-lead ECG showing a baseline prolonged QT interval (baseline QT interval as corrected by Fridericia's formula > 470 msec). Neuropathy ≥ Grade 2.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase1, arm1: 33 kBq/kg Radium-223 dichloride+SOC<br>Phase 1: Radium-223 dichloride; 33 kiloBecquerel (kBq)/kg body weight every 6 weeks for a total of 6 radium-223 dichloride doses plus SOC (standard of care) bortezomib/ dexamethasone. | Drug: Radium-223 dichloride (Xofigo, BAY88-8223)<br>* Sequential dose escalation in Intravenous (IV) injection<br>Drug: Bortezomib<br>* Bortezomib is administered subcutaneous (SC) (per Investigator choice ) at 1.3 mg/m2/dose<br>Drug: Dexamethasone<br>* Dexamethasone is administered orally at 40 mg<br>|
| Experimental: Phase1, arm2: 55 kBq/kg Radium-223 dichloride+SOC<br>Phase 1: Radium-223 dichloride; 55 kBq/kg body weight every 6 weeks for a total of 6 radium-223 dichloride doses plus SOC bortezomib/ dexamethasone. | Drug: Radium-223 dichloride (Xofigo, BAY88-8223)<br>* Sequential dose escalation in Intravenous (IV) injection<br>Drug: Bortezomib<br>* Bortezomib is administered subcutaneous (SC) (per Investigator choice ) at 1.3 mg/m2/dose<br>Drug: Dexamethasone<br>* Dexamethasone is administered orally at 40 mg<br>|
| Placebo Comparator: Phase2, arm1: Placebo+SOC<br>Phase 2: Matching placebo (isotonic saline) every 6 weeks for a total of 6 doses plus SOC bortezomib/dexamethasone. | Drug: Placebo<br>* Matching placebo<br>Drug: Bortezomib<br>* Bortezomib is administered subcutaneous (SC) (per Investigator choice ) at 1.3 mg/m2/dose<br>Drug: Dexamethasone<br>* Dexamethasone is administered orally at 40 mg<br>|
| Experimental: Phase2, arm2: Radium-223 dichloride+SOC<br>Phase 2: Phase 1b-selected dose of radium-223 dichloride every 6 weeks for 6 doses plus SOC bortezomib/dexamethasone | Drug: Radium-223 dichloride (Xofigo, BAY88-8223)<br>* Sequential dose escalation in Intravenous (IV) injection<br>Drug: Bortezomib<br>* Bortezomib is administered subcutaneous (SC) (per Investigator choice ) at 1.3 mg/m2/dose<br>Drug: Dexamethasone<br>* Dexamethasone is administered orally at 40 mg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: MTD/RP2D Determined by the Incidence of DLTs | Maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) determined by incidence of dose limiting toxicity (DLT) using Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 for the severity grade | From the start of study medication through 3 weeks after administration of the second dose of radium-223 dichloride, assessed up to 9 weeks | 
| Phase 1: The Number of Subjects With Treatment-emergent Adverse Events (TEAEs), Drug-related TEAEs, and Treatment-emergent Serious AE | A treatment-emergent adverse event (TEAE) is defined as any event arising or worsening after start of study drug administration until the end of the treatment period | From the start of study drug (radium-223 dichloride) to 30 days after last dose of study treatment (radium-223 dichloride, BOR, or DEX, whichever is last), assessed up to approximately 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: The Number of Subjects With Complete Response (CR) and Very Good Partial Response (VGPR) | Determined by International Myeloma Working Group (IMWG) uniform response criteria. CR: Negative immunofixation of serum and urine, disappearance of any soft-tissue plasmacytomas, and <5% plasma cells in bone marrow; in patients for whom only measurable disease is by serum free light chain (FLC) level, normal FLC ratio of 0.26 to 1.65 in addition to CR criteria is required; 2 consecutive assessments are needed. VGPR: Serum and urine M-component detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-component plus urine M-component <100 mg/24 hours (hrs); in patients for whom only measurable disease is by serum FLC level, >90% decrease in difference between involved and uninvolved FLC levels, in addition to VGPR criteria, is required; 2 consecutive assessments are needed | Up to approximately 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Radium-223 dichloride, Bortezomib, Dexamethasone, Relapsed multiple myeloma, Combination therapy multiple myeloma