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Phase 3 Study of Carfilzomib, Melphalan, Prednisone vs Bortezomib, Melphalan, Prednisone in Newly Diagnosed Multiple Myeloma (CLARION)

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ClinicalTrials.gov Identifier: NCT01818752
Recruitment Status : Completed
First Posted : March 26, 2013
Results First Posted : August 1, 2017
Last Update Posted : August 26, 2019
Sponsor:
Information provided by (Responsible Party):
Amgen

Study Description
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Brief Summary:
The primary objective was to compare the progression-free survival of transplant ineligible patients newly diagnosed with multiple myeloma who were treated with carfilzomib, melphalan and prednisone (CMP) or with Velcade® (bortezomib), melphalan and prednisone (VMP).

Condition or disease Intervention/treatment Phase
Multiple Myeloma Drug: Carfilzomib Drug: Bortezomib Drug: Melphalan Drug: Prednisone Phase 3

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 955 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized, Open-label Phase 3 Study of Carfilzomib, Melphalan, and Prednisone Versus Bortezomib, Melphalan, and Prednisone in Transplant-ineligible Patients With Newly Diagnosed Multiple Myeloma
Actual Study Start Date : July 8, 2013
Actual Primary Completion Date : July 15, 2016
Actual Study Completion Date : November 4, 2016

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Arms and Interventions
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Arm Intervention/treatment
Experimental: Carfilzomib, Melphalan, Prednisone
Participants received carfilzomib administered in combination with melphalan and prednisone for nine 42-day cycles. Carfilzomib was administered as an intravenous (IV) infusion on days 1, 2, 8, 9, 22, 23, 29, and 30 of each 42-day cycle. The carfilzomib dose was at 20 mg/m² on cycle 1, days 1 and 2 followed by 36 mg/m² thereafter. On days 1 to 4, melphalan was administered at 9 mg/m² and prednisone was administered at 60 mg/m².
 Drug: Carfilzomib
Carfilzomib was administered over 30 minutes on days 1, 2, 8, 9, 22, 23, 29, and 30 for nine 42-day cycles. Carfilzomib 20 mg/m² IV was administered on days 1 and 2 of cycle 1, followed by escalation to 36 mg/m² IV starting on day 8 of cycle 1.
Other Name: Krypolis®

Drug: Melphalan
Melphalan 9 mg/m² was taken orally on days 1 to 4 of all cycles.

Drug: Prednisone
Prednisone 60 mg/m² was taken orally on days 1 to 4 of all cycles.
Active Comparator: Bortezomib, Melphalan, Prednisone
Participants received bortezomib in combination with melphalan and prednisone for nine 42-day cycles. Bortezomib was administered either IV or subcutaneously at 1.3 mg/m² during cycles 1 to 4 on days 1, 4, 8, 11, 22, 25, 29, and 32 followed by 1.3 mg/m² during cycles 5 to 9 on days 1, 8, 22, and 29. On days 1 to 4 of each cycle, melphalan was administered at 9 mg/m² and prednisone was administered at 60 mg/m².
 Drug: Bortezomib
Bortezomib 1.3 mg/m² was administered as a bolus IV injection or as a subcutaneous injection (per investigator's choice, dose modification, or regulatory approval) on days 1, 4, 8, 11, 22, 25, 29, and 32 of cycles 1 to 4, and on days 1, 8, 22, and 29 of cycles 5 to 9.
Other Name: Velcade®

Drug: Melphalan
Melphalan 9 mg/m² was taken orally on days 1 to 4 of all cycles.

Drug: Prednisone
Prednisone 60 mg/m² was taken orally on days 1 to 4 of all cycles.


Outcome Measures
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Primary Outcome Measures :
  1. Progression-Free Survival (PFS) [ Time Frame: From randomization until the data cut-off date of 15 July 2016; median follow-up time for PFS was 21.6.and 22.2 months in the bortezomib and carfilzomib arms respectively. ]

    Progression-free survival was defined as the time from randomization to the earlier of documented disease progression or death due to any cause. PFS was analyzed using Kaplan-Meier methods. The duration of PFS was censored for participants with no baseline and/or post-baseline disease assessments, who started a new anti-cancer therapy before documentation of disease progression or death, death or disease progression after missed disease assessment of 100 consecutive days or longer, or who were alive without documentation of disease progression before the data cutoff date, including lost to follow-up prior to disease progression.

    Participants were evaluated for disease response and progression according to the International Myeloma Working Group Uniform Response Criteria (IMWG-URC), determined centrally using a validated computer algorithm in a blinded manner.



Secondary Outcome Measures :
  1. Overall Survival (OS) [ Time Frame: From randomization until the data cut-off date of 15 July 2016; median follow-up time for OS was 22.2 and 22.5 months in the bortezomib and carfilzomib arms respectively. ]

    Overall survival (OS) was defined as the time from randomization to the date of death (whatever the cause). Participants who were alive or lost to follow-up as of the data analysis cut-off date were censored on the date the patient was last known to be alive.

    Median overall survival was estimated using the Kaplan-Meier method.


  2. Overall Response Rate [ Time Frame: Disease response was assessed every 3 weeks during the first 54 weeks and every 6 weeks thereafter until PD or the data cut-off date of 15 July 2016; median follow-up time was 21.6.and 22.2 months in the bortezomib and carfilzomib arms respectively. ]

    Disease response was evaluated according to the IMWG-URC using a validated computer algorithm. Overall response was defined as the percentage of participants with a best overall response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR).

    sCR: As for CR, normal serum free light chain (SFLC) ratio and no clonal cells in bone marrow (BM).

    CR: No immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas and < 5% plasma cells in BM biopsy; VGPR: Serum and urine M-protein detectable by immunofixation but not electrophoresis or ≥ 90% reduction in serum M-protein with urine M-protein <100 mg/24 hours. A ≥ 50% reduction in the size of soft tissue plasmacytomas if present at baseline.

    PR: ≥ 50% reduction of serum M-protein and reduction in urine M-protein by ≥ 90% or to < 200 mg/24 hours. A ≥ 50% reduction in the size of soft tissue plasmacytomas if present at baseline.


  3. Complete Response Rate [ Time Frame: Disease response was assessed every 3 weeks during the first 54 weeks and every 6 weeks thereafter until PD or the data cut-off date of 15 July 2016; median follow-up time was 21.6.and 22.2 months in the bortezomib and carfilzomib arms respectively. ]

    Complete response rate was defined as the percentage of participants in each treatment group who achieved a sCR or CR per the IMWG-URC as their best response.

    sCR: As for CR, normal serum free light chain (SFLC) ratio and no clonal cells in bone marrow (BM).

    CR: No immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas and < 5% plasma cells in BM biopsy.


  4. Percentage of Participants With ≥ Grade 2 Peripheral Neuropathy [ Time Frame: From the first dose of any study drug up to 30 days after the last dose of any study drug as of the data cut-off date of 15 July 2016; median duration of treatment was 52 weeks in both treatment groups. ]

    Neuropathy events were defined as Grade 2 or higher peripheral neuropathy as specified by peripheral neuropathy Standardised Medical Dictionary for Regulatory Activities (MedDRA) Query, narrow (scope) (SMQN) terms.

    Peripheral neuropathy was assessed by neurologic exam and graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03:

    Grade 1: Asymptomatic; Grade 2: Moderate symptoms, limiting instrumental activities of daily living (ADL) Grade 3: Severe symptoms; limiting self-care ADL; Grade 4: Life-threatening consequences, urgent intervention indicated; Grade 5: Death.


  5. European Organisation for Research and Treatment of Cancer Quality of Life Core Module (EORTC QLQ-C30) Global Health Status/Quality of Life (QOL) Scores [ Time Frame: Baseline, weeks 6, 12, 18, 24, 30, 36, 42 and 48 ]

    The EORTC QLQ-C30 is a validated self-rating questionnaire including 30 items used to assess the overall quality of life in cancer patients.

    It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact).

    The EORTC QLQ-C30 Global Health Status/QOL scale was scored between 0 and 100, with higher scores indicating better Global Health Status/QOL.


  6. Number of Participants With Adverse Events [ Time Frame: From the first dose of any study drug up to 30 days after the last dose of any study drug as of the data cut-off date of 15 July 2016; median duration of treatment was 52 weeks in both treatment groups. ]

    Adverse events (AEs)were graded using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 4.03, where GRADE 1 = Mild; GRADE 2 = Moderate; GRADE 3 = Severe; GRADE 4 = Life-threatening; GRADE 5 = Fatal.

    A serious adverse event is an adverse event that met 1 or more of the following criteria:

    • Death
    • Life-threatening
    • Required inpatient hospitalization or prolongation of an existing hospitalization
    • Resulted in persistent or significant disability/incapacity
    • Congenital anomaly/birth defect
    • Important medical event that jeopardized the participant and may have required medical or surgical intervention to prevent 1 of the outcomes listed above.

    Treatment-related adverse events are adverse events considered related to at least 1 investigational product by the investigator, including those with unknown relationship.



Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Newly diagnosed symptomatic multiple myeloma (per International Myeloma Working Group [IMWG] diagnostic criteria)
  2. Transplant ineligibility

  3. Measurable disease, as defined by 1 or more of the following (assessed within 21 days prior to randomization):

    • Serum M-protein ≥ 0.5 g/dL, or
    • Urine M-protein ≥ 200 mg/24 hours, or
    • In subjects without detectable serum or urine M-protein, serum free light chain (SFLC) > 100 mg/L (involved light chain) and an abnormal kappa lambda ratio (SFLC kappa lambda ratio < 0.26 or > 1.65)
  4. No prior treatment for multiple myeloma
  5. Eastern Cooperative Oncology Group (ECOG) performance status 0-2

Exclusion Criteria:

  1. Multiple myeloma of IgM (immunoglobulin M) subtype
  2. Glucocorticoid therapy within 14 days prior to randomization that equals or exceeds a cumulative dose of 160 mg of dexamethasone
  3. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
  4. Plasma cell leukemia (> 2.0 × 10^9/L circulating plasma cells by standard differential)
  5. Waldenström macroglobulinemia (WM)
  6. Known amyloidosis
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01818752


Locations
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Sponsors and Collaborators
Amgen
Investigators
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Study Director: MD Amgen
More Information
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Additional Information:

Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Amgen
ClinicalTrials.gov Identifier: NCT01818752    
Other Study ID Numbers: 2012-005
2012-005283-97 ( EudraCT Number )
20130397 ( Other Identifier: Amgen Inc. )
First Posted: March 26, 2013    Key Record Dates
Results First Posted: August 1, 2017
Last Update Posted: August 26, 2019
Last Verified: August 2019
Additional relevant MeSH terms:
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Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Prednisone
 Bortezomib
Melphalan
Anti-Inflammatory Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Myeloablative Agonists
Immunosuppressive Agents
Immunologic Factors