Once-weekly Versus Twice-weekly Carfilzomib in Combination With Dexamethasone in Adults With Relapsed and Refractory Multiple Myeloma (ARROW)

September 9, 2022 updated by: Amgen

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

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).

Study Overview

Status

Completed

Conditions

Study Type

Interventional

Enrollment (Actual)

478

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

    • New South Wales
      • Darlinghurst, New South Wales, Australia, 2010
        • Research Site
      • Tweed Heads, New South Wales, Australia, 2485
        • Research Site
      • Waratah, New South Wales, Australia, 2298
        • Research Site
    • Victoria
      • Box Hill, Victoria, Australia, 3128
        • Research Site
      • Antwerpen, Belgium, 2060
        • Research Site
      • Brugge, Belgium, 8000
        • Research Site
      • Brussel, Belgium, 1090
        • Research Site
      • Bruxelles, Belgium, 1200
        • Research Site
      • Ghent, Belgium, 9000
        • Research Site
      • Leuven, Belgium, 3000
        • Research Site
      • Quebec, Canada, G1J 1Z4
        • Research Site
    • Alberta
      • Calgary, Alberta, Canada, T2N 2T9
        • Research Site
    • British Columbia
      • Kelowna, British Columbia, Canada, V1Y 5L3
        • Research Site
      • Vancouver, British Columbia, Canada, V5Z 1M9
        • Research Site
    • Newfoundland and Labrador
      • St. Johns, Newfoundland and Labrador, Canada, A1B 3V6
        • Research Site
    • Nova Scotia
      • Halifax, Nova Scotia, Canada, B3H 2Y9
        • Research Site
    • Ontario
      • Ottawa, Ontario, Canada, K1H 8L6
        • Research Site
      • Toronto, Ontario, Canada, M5G 2M9
        • Research Site
    • Quebec
      • Montreal, Quebec, Canada, H4J 1C5
        • Research Site
      • Brno, Czechia, 625 00
        • Research Site
      • Hradec Kralove, Czechia, 500 05
        • Research Site
      • Olomouc, Czechia, 775 20
        • Research Site
      • Ostrava-Poruba, Czechia, 708 52
        • Research Site
      • Praha, Czechia, 128 08
        • Research Site
      • Praha 10, Czechia, 100 34
        • Research Site
      • Aalborg, Denmark, 9000
        • Research Site
      • Copenhagen, Denmark, 2100
        • Research Site
      • Odense C, Denmark, 5000
        • Research Site
      • Vejle, Denmark, 7100
        • Research Site
      • Helsinki, Finland, 00290
        • Research Site
      • Tampere, Finland, 33521
        • Research Site
      • Turku, Finland, 20520
        • Research Site
      • Bayonne, France, 64109
        • Research Site
      • Brest, France, 29609
        • Research Site
      • Dijon, France, 21000
        • Research Site
      • Nantes Cedex 1, France, 44093
        • Research Site
      • Nimes cedex 09, France, 30029
        • Research Site
      • Paris, France, 75012
        • Research Site
      • Pierre-Benite cedex, France, 69495
        • Research Site
      • Rennes, France, 35033
        • Research Site
      • Tours Cedex 1, France, 37044
        • Research Site
      • Köln, Germany, 50937
        • Research Site
      • Leipzig, Germany, 04103
        • Research Site
      • München, Germany, 81241
        • Research Site
      • Rostock, Germany, 18057
        • Research Site
      • Tubingen, Germany, 72076
        • Research Site
      • Athens, Greece, 11528
        • Research Site
      • Athens, Greece, 10676
        • Research Site
      • Patra, Greece, 26504
        • Research Site
      • Budapest, Hungary, 1097
        • Research Site
      • Debrecen, Hungary, 4032
        • Research Site
      • Gyula, Hungary, 5700
        • Research Site
      • Kaposvar, Hungary, 7400
        • Research Site
      • Ancona, Italy, 60126
        • Research Site
      • Bologna, Italy, 40138
        • Research Site
      • Brescia, Italy, 25123
        • Research Site
      • Cagliari, Italy, 09121
        • Research Site
      • Catania, Italy, 95124
        • Research Site
      • Firenze, Italy, 50134
        • Research Site
      • Genova, Italy, 16132
        • Research Site
      • Napoli, Italy, 80131
        • Research Site
      • Pavia, Italy, 27100
        • Research Site
      • Piacenza, Italy, 29100
        • Research Site
      • Pisa, Italy, 56100
        • Research Site
      • Roma, Italy, 00168
        • Research Site
      • Roma, Italy, 00161
        • Research Site
      • Torino, Italy, 10126
        • Research Site
      • Fukuoka-shi, Japan, 811-1395
        • Research Site
      • Nagoya-shi, Japan, 467-8602
        • Research Site
      • Niigata-shi, Japan, 951-8566
        • Research Site
      • Tokushima-shi, Japan, 770-8539
        • Research Site
    • Aichi
      • Toyohashi-shi, Aichi, Japan, 441-8570
        • Research Site
    • Fukuoka
      • Fukuoka-shi, Fukuoka, Japan, 812-8582
        • Research Site
    • Gifu
      • Ogaki-shi, Gifu, Japan, 503-8502
        • Research Site
    • Gunma
      • Maebashi-shi, Gunma, Japan, 371-8511
        • Research Site
      • Shibukawa-shi, Gunma, Japan, 377-8511
        • Research Site
    • Hokkaido
      • Sapporo-shi, Hokkaido, Japan, 060-8543
        • Research Site
    • Kanagawa
      • Isehara-shi, Kanagawa, Japan, 259-1193
        • Research Site
    • Kyoto
      • Kyoto-shi, Kyoto, Japan, 602-8566
        • Research Site
    • Miyagi
      • Sendai-shi, Miyagi, Japan, 980-8574
        • Research Site
    • Okayama
      • Okayama-shi, Okayama, Japan, 701-1192
        • Research Site
    • Osaka
      • Suita-shi, Osaka, Japan, 565-0871
        • Research Site
    • Saitama
      • Kawagoe-shi, Saitama, Japan, 350-8550
        • Research Site
    • Tochigi
      • Utsunomiya-shi, Tochigi, Japan, 320-0834
        • Research Site
    • Tokyo
      • Chuo-ku, Tokyo, Japan, 104-0045
        • Research Site
      • Koto-ku, Tokyo, Japan, 135-8550
        • Research Site
      • Shibuya-ku, Tokyo, Japan, 150-8935
        • Research Site
      • Tachikawa-shi, Tokyo, Japan, 190-0014
        • Research Site
      • Christchurch, New Zealand, 8011
        • Research Site
      • Otahuhu, Auckland, New Zealand, 1640
        • Research Site
      • Oslo, Norway, 0372
        • Research Site
      • Trondheim, Norway, 7006
        • Research Site
      • Brzozow, Poland, 36-200
        • Research Site
      • Chorzow, Poland, 41-500
        • Research Site
      • Katowice, Poland, 40-032
        • Research Site
      • Krakow, Poland, 31-501
        • Research Site
      • Lodz, Poland, 93-510
        • Research Site
      • Olsztyn, Poland, 10-228
        • Research Site
      • Poznan, Poland, 60-569
        • Research Site
      • Torun, Poland, 87-100
        • Research Site
      • Warszawa, Poland, 02-106
        • Research Site
      • Wroclaw, Poland, 50-367
        • Research Site
      • Brazov, Romania, 500152
        • Research Site
      • Bucharest, Romania, 022328
        • Research Site
      • Madrid, Spain, 28034
        • Research Site
      • Madrid, Spain, 28041
        • Research Site
      • Madrid, Spain, 28040
        • Research Site
    • Andalucía
      • Sevilla, Andalucía, Spain, 41013
        • Research Site
    • Aragón
      • Zaragoza, Aragón, Spain, 50012
        • Research Site
    • Baleares
      • Palma de Mallorca, Baleares, Spain, 07010
        • Research Site
    • Castilla León
      • Salamanca, Castilla León, Spain, 37007
        • Research Site
    • Cataluña
      • Badalona, Cataluña, Spain, 08916
        • Research Site
      • Barcelona, Cataluña, Spain, 08036
        • Research Site
      • Girona, Cataluña, Spain, 17007
        • Research Site
    • Navarra
      • Pamplona, Navarra, Spain, 31008
        • Research Site
      • Goteborg, Sweden, 413 45
        • Research Site
      • Helsingborg, Sweden, 251 87
        • Research Site
      • Lund, Sweden, 221 85
        • Research Site
      • Stockholm, Sweden, 141 86
        • Research Site
      • Stockholm, Sweden, 171 76
        • Research Site
      • Uddevalla, Sweden, 451 80
        • Research Site
      • Bournemouth, United Kingdom, BH7 7DW
        • Research Site
      • London, United Kingdom, EC1A 7BE
        • Research Site
      • London, United Kingdom, NW1 2PG
        • Research Site
      • Manchester, United Kingdom, M13 9WL
        • Research Site
      • Nottingham, United Kingdom, NG5 1PB
        • Research Site
      • Sheffield, United Kingdom, S10 2JF
        • Research Site
      • Wolverhampton, United Kingdom, WV10 0QP
        • Research Site
    • Arizona
      • Scottsdale, Arizona, United States
        • Mayo Clinic
      • Scottsdale, Arizona, United States, 85259-5499
        • Research Site
    • Maryland
      • Bethesda, Maryland, United States, 20817
        • Research Site
      • Bethesda, Maryland, United States
        • Center for Cancer and Blood Disorders
      • Rockville, Maryland, United States, 20850
        • Research Site
      • Rockville, Maryland, United States
        • Maryland Oncology Hematology, P.A
    • New Jersey
      • Hackensack, New Jersey, United States, 07601
        • Research Site
      • Hackensack, New Jersey, United States
        • John Theurer Cancer Center at Hackensack University Medical Center
    • New York
      • New York, New York, United States, 10021
        • Research Site
    • Pennsylvania
      • Pittsburgh, Pennsylvania, United States, 15224
        • Research Site
    • Texas
      • Tyler, Texas, United States, 75701
        • Research Site
      • Tyler, Texas, United States
        • Blood and Cancer Center of East Texas

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

14 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
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.

Carfilzomib was administered as an IV infusion
Other Names:
  • PR-171
  • PR171
  • Kyprolis® (carfilzomib) for Injection
Commercially available dexamethasone was obtained by the investigational site.
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.

Carfilzomib was administered as an IV infusion
Other Names:
  • PR-171
  • PR171
  • Kyprolis® (carfilzomib) for Injection
Commercially available dexamethasone was obtained by the investigational site.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.

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.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.

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.
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.

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.
Number of Participants With Adverse Events (AEs)
Time Frame: From first dose of study drug up to 30 days after last dose, up to the end of study; median (minimum, maximum) duration of treatment was 29.1 (0.1, 156.3) weeks and 38.0 (0.1, 158.3) 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.

From first dose of study drug up to 30 days after last dose, up to the end of study; median (minimum, maximum) duration of treatment was 29.1 (0.1, 156.3) weeks and 38.0 (0.1, 158.3) weeks in each treatment group respectively.
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.
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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 9, 2015

Primary Completion (Actual)

June 15, 2017

Study Completion (Actual)

January 7, 2019

Study Registration Dates

First Submitted

April 6, 2015

First Submitted That Met QC Criteria

April 8, 2015

First Posted (Estimate)

April 9, 2015

Study Record Updates

Last Update Posted (Actual)

September 23, 2022

Last Update Submitted That Met QC Criteria

September 9, 2022

Last Verified

September 1, 2022

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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