Clinical trial NCT02412878: Once-weekly Versus Twice-weekly Carfilzomib in Combination With Dexamethasone in Adults With Relapsed and Refractory Multiple Myeloma
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Multiple Myeloma
Lead sponsor: Amgen
Sponsor class: INDUSTRY
First posted: 2015-04-09
Enrollment: 478
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).


Eligibility criteria: 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

Primary outcomes:
measure: Progression Free Survival
timeFrame: 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 outcomes:
measure: Overall Response Rate
timeFrame: 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.
measure: Overall Survival
timeFrame: 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.
measure: Number of Participants With Adverse Events (AEs)
timeFrame: 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.
measure: Plasma Carfilzomib Concentration During Cycle 2
timeFrame: 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
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Research Site
state: Arizona
city: Scottsdale
country: United States
facility: Mayo Clinic
state: Arizona
city: Bethesda
country: United States
facility: Research Site
state: Maryland
city: Bethesda
country: United States
facility: Center for Cancer and Blood Disorders
state: Maryland
city: Rockville
country: United States
facility: Research Site
state: Maryland
city: Rockville
country: United States
facility: Maryland Oncology Hematology, P.A
state: Maryland
city: Hackensack
country: United States
facility: Research Site
state: New Jersey
city: Hackensack
country: United States
facility: John Theurer Cancer Center at Hackensack University Medical Center
state: New Jersey
city: New York
country: United States
facility: Research Site
state: New York
city: Pittsburgh
country: United States
facility: Research Site
state: Pennsylvania
city: Tyler
country: United States
facility: Research Site
state: Texas
city: Tyler
country: United States
facility: Blood and Cancer Center of East Texas
state: Texas
city: Darlinghurst
country: Australia
facility: Research Site
state: New South Wales
city: Tweed Heads
country: Australia
facility: Research Site
state: New South Wales
city: Waratah
country: Australia
facility: Research Site
state: New South Wales
city: Box Hill
country: Australia
facility: Research Site
state: Victoria
city: Antwerpen
country: Belgium
facility: Research Site
city: Brugge
country: Belgium
facility: Research Site
city: Brussel
country: Belgium
facility: Research Site
city: Bruxelles
country: Belgium
facility: Research Site
city: Ghent
country: Belgium
facility: Research Site
city: Leuven
country: Belgium
facility: Research Site
city: Calgary
country: Canada
facility: Research Site
state: Alberta
city: Kelowna
country: Canada
facility: Research Site
state: British Columbia
city: Vancouver
country: Canada
facility: Research Site
state: British Columbia
city: St. Johns
country: Canada
facility: Research Site
state: Newfoundland and Labrador
city: Halifax
country: Canada
facility: Research Site
state: Nova Scotia
city: Ottawa
country: Canada
facility: Research Site
state: Ontario
city: Toronto
country: Canada
facility: Research Site
state: Ontario
city: Montreal
country: Canada
facility: Research Site
state: Quebec
city: Quebec
country: Canada
facility: Research Site
city: Brno
country: Czechia
facility: Research Site
city: Hradec Kralove
country: Czechia
facility: Research Site
city: Olomouc
country: Czechia
facility: Research Site
city: Ostrava-Poruba
country: Czechia
facility: Research Site
city: Praha 10
country: Czechia
facility: Research Site
city: Praha
country: Czechia
facility: Research Site
city: Aalborg
country: Denmark
facility: Research Site
city: Copenhagen
country: Denmark
facility: Research Site
city: Odense C
country: Denmark
facility: Research Site
city: Vejle
country: Denmark
facility: Research Site
city: Helsinki
country: Finland
facility: Research Site
city: Tampere
country: Finland
facility: Research Site
city: Turku
country: Finland
facility: Research Site
city: Bayonne
country: France
facility: Research Site
city: Brest
country: France
facility: Research Site
city: Dijon
country: France
facility: Research Site
city: Nantes Cedex 1
country: France
facility: Research Site
city: Nimes cedex 09
country: France
facility: Research Site
city: Paris
country: France
facility: Research Site
city: Pierre-Benite cedex
country: France
facility: Research Site
city: Rennes
country: France
facility: Research Site
city: Tours Cedex 1
country: France
facility: Research Site
city: Köln
country: Germany
facility: Research Site
city: Leipzig
country: Germany
facility: Research Site
city: München
country: Germany
facility: Research Site
city: Rostock
country: Germany
facility: Research Site
city: Tubingen
country: Germany
facility: Research Site
city: Athens
country: Greece
facility: Research Site
city: Athens
country: Greece
facility: Research Site
city: Patra
country: Greece
facility: Research Site
city: Budapest
country: Hungary
facility: Research Site
city: Debrecen
country: Hungary
facility: Research Site
city: Gyula
country: Hungary
facility: Research Site
city: Kaposvar
country: Hungary
facility: Research Site
city: Ancona
country: Italy
facility: Research Site
city: Bologna
country: Italy
facility: Research Site
city: Brescia
country: Italy
facility: Research Site
city: Cagliari
country: Italy
facility: Research Site
city: Catania
country: Italy
facility: Research Site
city: Firenze
country: Italy
facility: Research Site
city: Genova
country: Italy
facility: Research Site
city: Napoli
country: Italy
facility: Research Site
city: Pavia
country: Italy
facility: Research Site
city: Piacenza
country: Italy
facility: Research Site
city: Pisa
country: Italy
facility: Research Site
city: Roma
country: Italy
facility: Research Site
city: Roma
country: Italy
facility: Research Site
city: Torino
country: Italy
facility: Research Site
city: Toyohashi-shi
country: Japan
facility: Research Site
state: Aichi
city: Fukuoka-shi
country: Japan
facility: Research Site
state: Fukuoka
city: Ogaki-shi
country: Japan
facility: Research Site
state: Gifu
city: Maebashi-shi
country: Japan
facility: Research Site
state: Gunma
city: Shibukawa-shi
country: Japan
facility: Research Site
state: Gunma
city: Sapporo-shi
country: Japan
facility: Research Site
state: Hokkaido
city: Isehara-shi
country: Japan
facility: Research Site
state: Kanagawa
city: Kyoto-shi
country: Japan
facility: Research Site
state: Kyoto
city: Sendai-shi
country: Japan
facility: Research Site
state: Miyagi
city: Okayama-shi
country: Japan
facility: Research Site
state: Okayama
city: Suita-shi
country: Japan
facility: Research Site
state: Osaka
city: Kawagoe-shi
country: Japan
facility: Research Site
state: Saitama
city: Utsunomiya-shi
country: Japan
facility: Research Site
state: Tochigi
city: Chuo-ku
country: Japan
facility: Research Site
state: Tokyo
city: Koto-ku
country: Japan
facility: Research Site
state: Tokyo
city: Shibuya-ku
country: Japan
facility: Research Site
state: Tokyo
city: Tachikawa-shi
country: Japan
facility: Research Site
state: Tokyo
city: Fukuoka-shi
country: Japan
facility: Research Site
city: Nagoya-shi
country: Japan
facility: Research Site
city: Niigata-shi
country: Japan
facility: Research Site
city: Tokushima-shi
country: Japan
facility: Research Site
city: Christchurch
country: New Zealand
facility: Research Site
city: Otahuhu, Auckland
country: New Zealand
facility: Research Site
city: Oslo
country: Norway
facility: Research Site
city: Trondheim
country: Norway
facility: Research Site
city: Brzozow
country: Poland
facility: Research Site
city: Chorzow
country: Poland
facility: Research Site
city: Katowice
country: Poland
facility: Research Site
city: Krakow
country: Poland
facility: Research Site
city: Lodz
country: Poland
facility: Research Site
city: Olsztyn
country: Poland
facility: Research Site
city: Poznan
country: Poland
facility: Research Site
city: Torun
country: Poland
facility: Research Site
city: Warszawa
country: Poland
facility: Research Site
city: Wroclaw
country: Poland
facility: Research Site
city: Brazov
country: Romania
facility: Research Site
city: Bucharest
country: Romania
facility: Research Site
city: Sevilla
country: Spain
facility: Research Site
state: Andalucía
city: Zaragoza
country: Spain
facility: Research Site
state: Aragón
city: Palma de Mallorca
country: Spain
facility: Research Site
state: Baleares
city: Salamanca
country: Spain
facility: Research Site
state: Castilla León
city: Badalona
country: Spain
facility: Research Site
state: Cataluña
city: Barcelona
country: Spain
facility: Research Site
state: Cataluña
city: Girona
country: Spain
facility: Research Site
state: Cataluña
city: Pamplona
country: Spain
facility: Research Site
state: Navarra
city: Madrid
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Goteborg
country: Sweden
facility: Research Site
city: Helsingborg
country: Sweden
facility: Research Site
city: Lund
country: Sweden
facility: Research Site
city: Stockholm
country: Sweden
facility: Research Site
city: Stockholm
country: Sweden
facility: Research Site
city: Uddevalla
country: Sweden
facility: Research Site
city: Bournemouth
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: Manchester
country: United Kingdom
facility: Research Site
city: Nottingham
country: United Kingdom
facility: Research Site
city: Sheffield
country: United Kingdom
facility: Research Site
city: Wolverhampton
country: United Kingdom
facility: Research Site
Study officials:
affiliation: Amgen
name: MD
role: STUDY_DIRECTOR
References:
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.
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.
citation: 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.
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/m2 ) vs twice-weekly (56 mg/m2 ) 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.
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/m2 vs. twice-weekly 27 mg/m2 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.
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.
citation: Dimopoulos MA, Moreau P, Iida S, Huang SY, Takezako N, Chng WJ, Zahlten-Kumeli A, Sersch MA, Li J, Huang M, Lee JH. Outcomes for Asian patients with multiple myeloma receiving once- or twice-weekly carfilzomib-based therapy: a subgroup analysis of the randomized phase 3 ENDEAVOR and A.R.R.O.W. Trials. Int J Hematol. 2019 Oct;110(4):466-473. doi: 10.1007/s12185-019-02704-z. Epub 2019 Aug 6.