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Trial record 1 of 1 for:    NCT02412878
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Once-weekly Versus Twice-weekly Carfilzomib in Combination With Dexamethasone in Adults With Relapsed and Refractory Multiple Myeloma (ARROW)

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ClinicalTrials.gov Identifier: NCT02412878
Recruitment Status : Completed
First Posted : April 9, 2015
Results First Posted : December 13, 2018
Last Update Posted : January 30, 2019
Sponsor:
Information provided by (Responsible Party):
Amgen

Tracking Information
First Submitted Date  ICMJE April 6, 2015
First Posted Date  ICMJE April 9, 2015
Results First Submitted Date  ICMJE October 24, 2018
Results First Posted Date  ICMJE December 13, 2018
Last Update Posted Date January 30, 2019
Actual Study Start Date  ICMJE September 9, 2015
Actual Primary Completion Date June 15, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 12, 2018)
Progression Free Survival [ Time Frame: From randomization until the data cut-off date of 15 June 2017; median (minimum, maximum) follow-up time for PFS was 12.0 (0, 20) and 12.6 (0, 19) months in each treatment group respectively. ]
Progression-free survival (PFS) was defined as the time from randomization to the earlier of disease progression or death due to any cause. Disease status was assessed at a central laboratory with serum and urine protein electrophoresis, immunofixation, serum-free light chain (SFLC) assay, bone marrow sample evaluation, serum calcium, plasmacytoma evaluation, and skeletal survey. Response and disease progression were determined using a validated computer algorithm based on the International Myeloma Working Group—Uniform Response Criteria (IMWG-URC). Median PFS was derived using the Kaplan-Meier method; participants still alive with no disease progression were censored at the time of their last disease assessment.
Original Primary Outcome Measures  ICMJE
 (submitted: April 8, 2015)
Overall Response Rate (ORR) [ Time Frame: 19 months ]
Overall Response Rate (ORR) is defined as the proportion of subjects who achieve a best overall response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR) in accordance with International Myeloma Working Group-Uniform Response Criteria (IMWG-URC).
Change History Complete list of historical versions of study NCT02412878 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: December 12, 2018)
  • Overall Response Rate [ Time Frame: Disease response was assessed every 28 days until progressive disease, up to the data cut-off date of 15 June 2017; median time on follow-up was 12.0 and 12.6 months in each treatment group respectively. ]
    Disease response was evaluated according to the IMWG-URC using a validated computer algorithm. Overall response rate 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.
  • Overall Survival [ Time Frame: From randomization until the data cut-off date of 15 June 2017; median (minimum, maximum) follow-up time for OS was 12.6 (0, 20) and 13.2 (0, 19) months in each treatment group respectively. ]
    Overall Survival (OS) was defined as the time from randomization to death due to any cause. Median overall survival was derived using the Kaplan-Meier method; participants still alive were censored at the date last known to be alive.
  • Number of Participants With Adverse Events (AEs) [ Time Frame: From first dose of study drug up to 30 days after last dose, as of the data cutoff of 15 June 2017; median (minimum, maximum) duration of treatment was 29.1 (0.1, 84.3) weeks and 38.0 (0.1, 84.1) weeks in each treatment group respectively. ]
    The severity of adverse events was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03, where where Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Life-threatening; Grade 5 = Fatal. Treatment-related adverse events are adverse events considered related to at least 1 investigational product by the investigator, including those with unknown relationship.
  • Plasma Carfilzomib Concentration During Cycle 2 [ Time Frame: Cycle 2 day 1 predose, 15 minutes after the start of infusion (once-weekly carfilzomib only), end of infusion, and 30 minutes after the end of infusion ]
    Concentrations of carfilzomib in plasma were measured using a validated assay method. The lower limit of quantification was 0.100 ng/mL.
Original Secondary Outcome Measures  ICMJE
 (submitted: April 8, 2015)
  • Progression-Free Survival (PFS) [ Time Frame: 25 months ]
    Progression-free survival (PFS) is defined as the time from randomization to the earlier of disease progression or death due to any cause.
  • Overall Survival (OS) [ Time Frame: 25 months ]
    Overall Survival (OS) is defined as the time from randomization to death due to any cause.
  • Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: 25 months ]
    Safety and tolerability will be assessed by the incidence and severity of Adverse Events (AEs).
  • Laboratory Values [ Time Frame: 25 months ]
    For laboratory values, the baseline values and changes from baseline to the minimum, maximum, and last observed values will be summarized descriptively by visit. Laboratory test results will be graded using the NCI-CTCAE (version 4.03).
  • Vital Signs [ Time Frame: 25 months ]
    Vital sign results will be summarized descriptively for baseline values and changes from baseline to the minimum, maximum, and last observed values.
  • Electrocardiogram (ECG) QT-interval [ Time Frame: 25 months ]
    Twelve-lead electrocardiograms (ECGs) including corrected QT-interval (QTc; representing the corrected duration of ventricular electrical activity) will be performed locally.
  • Pharmacokinetics (PK) Plasma Samples (Concentrations of carfilzomib) [ Time Frame: 17 months ]
    Concentrations of carfilzomib will be measured in plasma with a validated assay method.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Once-weekly Versus Twice-weekly Carfilzomib in Combination With Dexamethasone in Adults With Relapsed and Refractory Multiple Myeloma
Official Title  ICMJE A Randomized, Open-label, Phase 3 Study in Subjects With Relapsed and Refractory Multiple Myeloma Receiving Carfilzomib in Combination With Dexamethasone, Comparing Once-weekly Versus Twice-weekly Carfilzomib Dosing
Brief Summary The purpose of the study is to compare the progression-free survival (PFS) of once-weekly carfilzomib dosing in combination with dexamethasone to twice-weekly carfilzomib dosing in combination with dexamethasone in adults with relapsed and refractory multiple myeloma, previously treated with bortezomib and an immunomodulatory agent (IMiD).
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Multiple Myeloma
Intervention  ICMJE
  • Drug: Carfilzomib
    Carfilzomib was administered as an IV infusion
    Other Names:
    • PR-171
    • PR171
    • Kyprolis® (carfilzomib) for Injection
  • Drug: Dexamethasone
    Commercially available dexamethasone was obtained by the investigational site.
Study Arms  ICMJE
  • Experimental: Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone

    Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8, and 15 of each 28-day cycle (20 mg/m² on day 1 of cycle 1 and 70 mg/m² thereafter).

    Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15.

    Interventions:
    • Drug: Carfilzomib
    • Drug: Dexamethasone
  • Experimental: Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone

    Participants received carfilzomib administered by IV infusion on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle (20 mg/m² on days 1 and 2 of cycle 1 and 27 mg/m² thereafter).

    Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15.

    Interventions:
    • Drug: Carfilzomib
    • Drug: Dexamethasone
Publications * Moreau P, Mateos MV, Berenson JR, Weisel K, Lazzaro A, Song K, Dimopoulos MA, Huang M, Zahlten-Kumeli A, Stewart AK. Once weekly versus twice weekly carfilzomib dosing in patients with relapsed and refractory multiple myeloma (A.R.R.O.W.): interim analysis results of a randomised, phase 3 study. Lancet Oncol. 2018 Jul;19(7):953-964. doi: 10.1016/S1470-2045(18)30354-1. Epub 2018 Jun 1. Erratum in: Lancet Oncol. 2018 Aug;19(8):e382.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: November 10, 2016)
478
Original Estimated Enrollment  ICMJE
 (submitted: April 8, 2015)
460
Actual Study Completion Date  ICMJE January 7, 2019
Actual Primary Completion Date June 15, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Key Inclusion Criteria:

  1. Relapsed multiple myeloma
  2. Refractory multiple myeloma defined as meeting 1 or more of the following:

    • Nonresponsive to most recent therapy (stable disease only or PD while on treatment), or
    • Disease progression within 60 days of discontinuation from most recent therapy
  3. At least 2 but no more than 3 prior therapies for multiple myeloma
  4. Prior exposure to an immunomodulatory agent (IMiD)
  5. Prior exposure to a proteasome inhibitor (PI)
  6. Documented response of at least partial response (PR) to 1 line of prior therapy
  7. Measurable disease with at least 1 of the following assessed within the 21 days prior to randomization:

    • Serum M-protein ≥ 0.5 g/dL
    • Urine M-protein ≥ 200 mg/24 hours
    • In subjects without detectable serum or urine M-protein, serum free light chain (SFLC) > 100 mg/L (involved light chain) and an abnormal serum kappa lambda ratio
  8. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1
  9. Left ventricular ejection fraction (LVEF) ≥ 40% within the 21 days prior to randomization
  10. Adequate organ and bone marrow function within the 21 days prior to randomization defined by:

    • Bilirubin < 1.5 times the upper limit of normal (ULN)
    • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 times the ULN
    • Absolute neutrophil count (ANC) ≥ 1000/mm³ (screening ANC should be independent of growth factor support for ≥ 1 week)
    • Hemoglobin ≥ 8.0 g/dL (Use of erythropoietic stimulating factors and red blood cell [RBC] transfusion per institutional guidelines is allowed, however the most recent RBC transfusion may not have been done within 7 days prior to obtaining screening hemoglobin.)
    • Platelet count ≥ 50,000/mm³ (≥ 30,000/mm³ if myeloma involvement in the bone marrow is > 50%. Subjects should not have received platelet transfusions for at least 1 week prior to obtaining the screening platelet count.)
    • Calculated or measured creatinine clearance (CrCl) of ≥ 30 mL/min

Key Exclusion Criteria:

  1. Waldenström macroglobulinemia
  2. Multiple myeloma of Immunoglobin M (IgM) subtype
  3. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
  4. Plasma cell leukemia (> 2.0 × 10⁹/L circulating plasma cells by standard differential)
  5. Myelodysplastic syndrome
  6. Second malignancy within the past 5 years except:

    • Adequately treated basal cell or squamous cell skin cancer
    • Carcinoma in situ of the cervix
    • Prostate cancer < Gleason score 6 with stable prostate-specific antigen (PSA) over 12 months
    • Ductal breast carcinoma in situ with full surgical resection (i.e., negative margins)
    • Treated medullary or papillary thyroid cancer
    • Similar condition with an expectation of > 95% five-year disease-free survival
  7. History of or current amyloidosis
  8. Cytotoxic chemotherapy within the 28 days prior to randomization
  9. Immunotherapy within the 21 days prior to randomization
  10. Glucocorticoid therapy within the 14 days prior to randomization that exceeds a cumulative dose of 160 mg of dexamethasone or 1000 mg prednisone
  11. Radiation therapy:

    • Focal therapy within the 7 days prior to randomization
    • Extended field therapy within the 21 days prior to randomization
  12. Prior treatment with either carfilzomib or oprozomib
  13. Known history of allergy to Captisol (a cyclodextrin derivative used to solubilize carfilzomib)
  14. Contraindication to dexamethasone or any of the required concomitant drugs or supportive treatments, including hypersensitivity to antiviral drugs, or intolerance to hydration due to pre-existing pulmonary or cardiac impairment
  15. Active congestive heart failure (New York Heart Association [NYHA] Class III or IV), symptomatic ischemia, conduction abnormalities uncontrolled by conventional intervention, acute diffuse infiltrative pulmonary disease, pericardial disease, or myocardial infarction within 6 months prior to enrollment
  16. Active infection within the 14 days prior to randomization requiring systemic antibiotics
  17. Pleural effusions requiring thoracentesis within the 14 days prior to randomization
  18. Ascites requiring paracentesis within the 14 days prior to randomization
  19. Ongoing graft-versus-host disease
  20. Uncontrolled hypertension or uncontrolled diabetes despite medication
  21. Significant neuropathy (≥ Grade 3) within the 14 days prior to randomization
  22. Known cirrhosis
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Belgium,   Canada,   Czechia,   Denmark,   Finland,   France,   Germany,   Greece,   Hungary,   Italy,   Japan,   New Zealand,   Norway,   Poland,   Romania,   Spain,   Sweden,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02412878
Other Study ID Numbers  ICMJE CFZ014
2014-005325-12 ( EudraCT Number )
20140355 ( Other Identifier: Amgen Study ID )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Amgen
Study Sponsor  ICMJE Amgen
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: MD Amgen
PRS Account Amgen
Verification Date January 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP