Study Testing Radium-223 Dichloride in Relapsed Multiple Myeloma

• ClinicalTrials.gov Identifier: NCT02928029
• Recruitment Status: Terminated
• First Posted: October 7, 2016
• Results First Posted: February 26, 2020
• Last Update Posted: February 26, 2020
• Sponsor: Bayer
• Information provided by (Responsible Party): Bayer

Tracking Information

• First Submitted Date: October 6, 2016
• First Posted Date: October 7, 2016
• Results First Submitted Date: January 19, 2020
• Results First Posted Date: February 26, 2020
• Last Update Posted Date: February 26, 2020
• Actual Study Start Date: February 10, 2017
• Actual Primary Completion Date: March 20, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 25, 2020)

• Phase 1: MTD/RP2D Determined by the Incidence of DLTs [ Time Frame: From the start of study medication through 3 weeks after administration of the second dose of radium-223 dichloride, assessed up to 9 weeks ]
  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
• Phase 1: The Number of Subjects With Treatment-emergent Adverse Events (TEAEs), Drug-related TEAEs, and Treatment-emergent Serious AE [ Time Frame: 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 ]
  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

Original Primary Outcome Measures (submitted: October 6, 2016)

• Joint positive adjudication of safety summary in Phase 1b by steering committee, investigator and sponsor (Yes/No) [ Time Frame: At approximately 13 months ]
• Progression-free survival (PFS) in Phase 2, defined as the time (in days) from date of randomization to disease progression [ Time Frame: Up to 50 months ]

Current Secondary Outcome Measures (submitted: February 25, 2020)

Phase 1: The Number of Subjects With Complete Response (CR) and Very Good Partial Response (VGPR) [ Time Frame: Up to approximately 2 years ]

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

Original Secondary Outcome Measures (submitted: October 6, 2016)

• Objective response rate (ORR) in Phase 1b, in the proportion of subjects in the analysis population who have complete response (CR), stringent complete response (sCR), very good partial response (VGPR), partial response (PR), or stable disease (SD) [ Time Frame: Approximately 12 months ]
• Duration of response in Phase 1b, defined as the time (in days) from the date of first response to treatment (CR, sCR, VGPR, PR) to the date of disease progression or death [ Time Frame: Approximately 12 months ]
• Number of participants with adverse events in phase 2 [ Time Frame: Up to 25 months ]
• Overall survival (OS) in Phase 2, defined as the time (in days) from date of randomization until death from any cause [ Time Frame: Up to 25 months ]
• Time to Symptomatic Skeletal Event (SSE) in Phase 2, defined as the time (days) from the date of randomization to the date of the first on-study SSE [ Time Frame: Up to 25 months ]
• Symptomatic skeletal event free survival in Phase 2, defined as the time from randomization to the occurrence of 1 of the following: First on-study SSE or Death from any cause if death occurs before a documented SSE [ Time Frame: Up to 25 months ]
• Time to pain progression in Phase 2 [ Time Frame: Up to 25 months ]
• Duration of response in Phase 2 [ Time Frame: Up to 25 months ]
• Objective Response Rate (ORR) in Phase 2 [ Time Frame: Up to 25 months ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study Testing Radium-223 Dichloride in Relapsed Multiple Myeloma
• Official Title: 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

Brief Summary

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.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Sequential Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Multiple Myeloma

Intervention

• Drug: Radium-223 dichloride (Xofigo, BAY88-8223)
  Sequential dose escalation in Intravenous (IV) injection
• Drug: Placebo
  Matching placebo
• Drug: Bortezomib
  Bortezomib is administered subcutaneous (SC) (per Investigator choice ) at 1.3 mg/m2/dose
• Drug: Dexamethasone
  Dexamethasone is administered orally at 40 mg

Study Arms

• Experimental: Phase1, arm1: 33 kBq/kg Radium-223 dichloride+SOC
  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.
  Interventions:

  • Drug: Radium-223 dichloride (Xofigo, BAY88-8223)
  • Drug: Bortezomib
  • Drug: Dexamethasone
• Experimental: Phase1, arm2: 55 kBq/kg Radium-223 dichloride+SOC
  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.
  Interventions:

  • Drug: Radium-223 dichloride (Xofigo, BAY88-8223)
  • Drug: Bortezomib
  • Drug: Dexamethasone
• Placebo Comparator: Phase2, arm1: Placebo+SOC
  Phase 2: Matching placebo (isotonic saline) every 6 weeks for a total of 6 doses plus SOC bortezomib/dexamethasone.
  Interventions:

  • Drug: Placebo
  • Drug: Bortezomib
  • Drug: Dexamethasone
• Experimental: Phase2, arm2: Radium-223 dichloride+SOC
  Phase 2: Phase 1b-selected dose of radium-223 dichloride every 6 weeks for 6 doses plus SOC bortezomib/dexamethasone
  Interventions:

  • Drug: Radium-223 dichloride (Xofigo, BAY88-8223)
  • Drug: Bortezomib
  • Drug: Dexamethasone

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: December 19, 2018): 7
• Original Estimated Enrollment (submitted: October 6, 2016): 226
• Actual Study Completion Date: March 20, 2019
• Actual Primary Completion Date: March 20, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Korea, Republic of, Spain, United States

Administrative Information

• NCT Number: NCT02928029
• Other Study ID Numbers: 18987; 2016-002438-58 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Responsible Party: Bayer
• Study Sponsor: Bayer
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Bayer
• Verification Date: February 2020