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Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT02412878
Other study ID # CFZ014
Secondary ID 2014-005325-1220
Status Completed
Phase Phase 3
First received
Last updated
Start date September 9, 2015
Est. completion date January 7, 2019

Study information

Verified date September 2022
Source Amgen
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial 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).


Recruitment information / eligibility

Status Completed
Enrollment 478
Est. completion date January 7, 2019
Est. primary completion date June 15, 2017
Accepts healthy volunteers No
Gender All
Age group 18 Years and older
Eligibility 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 × 10?/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 Design


Related Conditions & MeSH terms


Intervention

Drug:
Carfilzomib
Carfilzomib was administered as an IV infusion
Dexamethasone
Commercially available dexamethasone was obtained by the investigational site.

Locations

Country Name City State
Australia Research Site Box Hill Victoria
Australia Research Site Darlinghurst New South Wales
Australia Research Site Tweed Heads New South Wales
Australia Research Site Waratah New South Wales
Belgium Research Site Antwerpen
Belgium Research Site Brugge
Belgium Research Site Brussel
Belgium Research Site Bruxelles
Belgium Research Site Ghent
Belgium Research Site Leuven
Canada Research Site Calgary Alberta
Canada Research Site Halifax Nova Scotia
Canada Research Site Kelowna British Columbia
Canada Research Site Montreal Quebec
Canada Research Site Ottawa Ontario
Canada Research Site Quebec
Canada Research Site St. Johns Newfoundland and Labrador
Canada Research Site Toronto Ontario
Canada Research Site Vancouver British Columbia
Czechia Research Site Brno
Czechia Research Site Hradec Kralove
Czechia Research Site Olomouc
Czechia Research Site Ostrava-Poruba
Czechia Research Site Praha
Czechia Research Site Praha 10
Denmark Research Site Aalborg
Denmark Research Site Copenhagen
Denmark Research Site Odense C
Denmark Research Site Vejle
Finland Research Site Helsinki
Finland Research Site Tampere
Finland Research Site Turku
France Research Site Bayonne
France Research Site Brest
France Research Site Dijon
France Research Site Nantes Cedex 1
France Research Site Nimes cedex 09
France Research Site Paris
France Research Site Pierre-Benite cedex
France Research Site Rennes
France Research Site Tours Cedex 1
Germany Research Site Köln
Germany Research Site Leipzig
Germany Research Site München
Germany Research Site Rostock
Germany Research Site Tubingen
Greece Research Site Athens
Greece Research Site Athens
Greece Research Site Patra
Hungary Research Site Budapest
Hungary Research Site Debrecen
Hungary Research Site Gyula
Hungary Research Site Kaposvar
Italy Research Site Ancona
Italy Research Site Bologna
Italy Research Site Brescia
Italy Research Site Cagliari
Italy Research Site Catania
Italy Research Site Firenze
Italy Research Site Genova
Italy Research Site Napoli
Italy Research Site Pavia
Italy Research Site Piacenza
Italy Research Site Pisa
Italy Research Site Roma
Italy Research Site Roma
Italy Research Site Torino
Japan Research Site Chuo-ku Tokyo
Japan Research Site Fukuoka-shi
Japan Research Site Fukuoka-shi Fukuoka
Japan Research Site Isehara-shi Kanagawa
Japan Research Site Kawagoe-shi Saitama
Japan Research Site Koto-ku Tokyo
Japan Research Site Kyoto-shi Kyoto
Japan Research Site Maebashi-shi Gunma
Japan Research Site Nagoya-shi
Japan Research Site Niigata-shi
Japan Research Site Ogaki-shi Gifu
Japan Research Site Okayama-shi Okayama
Japan Research Site Sapporo-shi Hokkaido
Japan Research Site Sendai-shi Miyagi
Japan Research Site Shibukawa-shi Gunma
Japan Research Site Shibuya-ku Tokyo
Japan Research Site Suita-shi Osaka
Japan Research Site Tachikawa-shi Tokyo
Japan Research Site Tokushima-shi
Japan Research Site Toyohashi-shi Aichi
Japan Research Site Utsunomiya-shi Tochigi
New Zealand Research Site Christchurch
New Zealand Research Site Otahuhu, Auckland
Norway Research Site Oslo
Norway Research Site Trondheim
Poland Research Site Brzozow
Poland Research Site Chorzow
Poland Research Site Katowice
Poland Research Site Krakow
Poland Research Site Lodz
Poland Research Site Olsztyn
Poland Research Site Poznan
Poland Research Site Torun
Poland Research Site Warszawa
Poland Research Site Wroclaw
Romania Research Site Brazov
Romania Research Site Bucharest
Spain Research Site Badalona Cataluña
Spain Research Site Barcelona Cataluña
Spain Research Site Girona Cataluña
Spain Research Site Madrid
Spain Research Site Madrid
Spain Research Site Madrid
Spain Research Site Palma de Mallorca Baleares
Spain Research Site Pamplona Navarra
Spain Research Site Salamanca Castilla León
Spain Research Site Sevilla Andalucía
Spain Research Site Zaragoza Aragón
Sweden Research Site Goteborg
Sweden Research Site Helsingborg
Sweden Research Site Lund
Sweden Research Site Stockholm
Sweden Research Site Stockholm
Sweden Research Site Uddevalla
United Kingdom Research Site Bournemouth
United Kingdom Research Site London
United Kingdom Research Site London
United Kingdom Research Site Manchester
United Kingdom Research Site Nottingham
United Kingdom Research Site Sheffield
United Kingdom Research Site Wolverhampton
United States Center for Cancer and Blood Disorders Bethesda Maryland
United States Research Site Bethesda Maryland
United States John Theurer Cancer Center at Hackensack University Medical Center Hackensack New Jersey
United States Research Site Hackensack New Jersey
United States Research Site New York New York
United States Research Site Pittsburgh Pennsylvania
United States Maryland Oncology Hematology, P.A Rockville Maryland
United States Research Site Rockville Maryland
United States Mayo Clinic Scottsdale Arizona
United States Research Site Scottsdale Arizona
United States Blood and Cancer Center of East Texas Tyler Texas
United States Research Site Tyler Texas

Sponsors (1)

Lead Sponsor Collaborator
Amgen

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Canada,  Czechia,  Denmark,  Finland,  France,  Germany,  Greece,  Hungary,  Italy,  Japan,  New Zealand,  Norway,  Poland,  Romania,  Spain,  Sweden,  United Kingdom, 

References & Publications (6)

Dimopoulos MA, Niesvizky R, Weisel K, Siegel DS, Hajek R, Mateos MV, Cavo M, Huang M, Zahlten-Kumeli A, Moreau P. Once- versus twice-weekly carfilzomib in relapsed and refractory multiple myeloma by select patient characteristics: phase 3 A.R.R.O.W. study subgroup analysis. Blood Cancer J. 2020 Mar 9;10(3):35. doi: 10.1038/s41408-020-0300-y. — View Citation

Facon T, Niesvizky R, Mateos MV, Siegel D, Rosenbaum C, Bringhen S, Weisel K, Ho PJ, Ludwig H, Kumar S, Wang K, Obreja M, Yang Z, Klippel Z, Mezzi K, Goldrick A, Tekle C, Dimopoulos MA. Efficacy and safety of carfilzomib-based regimens in frail patients with relapsed and/or refractory multiple myeloma. Blood Adv. 2020 Nov 10;4(21):5449-5459. doi: 10.1182/bloodadvances.2020001965. — View Citation

Kumar SK, Majer I, Panjabi S, Medhekar R, Campioni M, Dimopoulos MA. Cost-effectiveness of once weekly carfilzomib 70 mg/m2 plus dexamethasone in patients with relapsed and refractory multiple myeloma in the United States. Expert Rev Hematol. 2020 Jun;13(6):687-696. doi: 10.1080/17474086.2020.1746639. Epub 2020 Apr 6. — View Citation

Moreau P, Kumar S, Boccia R, Iida S, Goldschmidt H, Cocks K, Trigg A, Zahlten-Kumeli A, Yucel E, Panjabi SS, Dimopoulos M. Convenience, satisfaction, health-related quality of life of once-weekly 70 mg/m(2) vs. twice-weekly 27 mg/m(2) carfilzomib (randomized A.R.R.O.W. study). Leukemia. 2019 Dec;33(12):2934-2946. doi: 10.1038/s41375-019-0480-2. Epub 2019 May 15. — View Citation

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. — View Citation

Moreau P, Stewart KA, Dimopoulos M, Siegel D, Facon T, Berenson J, Raje N, Berdeja JG, Orlowski RZ, Yang H, Ma H, Klippel Z, Zahlten-Kumeli A, Mezzi K, Iskander K, Mateos MV. Once-weekly (70 mg/m(2) ) vs twice-weekly (56 mg/m(2) ) dosing of carfilzomib in patients with relapsed or refractory multiple myeloma: A post hoc analysis of the ENDEAVOR, A.R.R.O.W., and CHAMPION-1 trials. Cancer Med. 2020 May;9(9):2989-2996. doi: 10.1002/cam4.2945. Epub 2020 Feb 28. — View Citation

Outcome

Type Measure Description Time frame Safety issue
Primary Progression Free Survival 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 Overall Response Rate 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.
Secondary Overall Survival 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.
Secondary Number of Participants With Adverse Events (AEs) 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.
Secondary Plasma Carfilzomib Concentration During Cycle 2 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
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