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

Multiple Myeloma Clinical Trial

— ARROW  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02412878
• Other study ID #: CFZ014
• Secondary ID: 2014-005325-1220
• Status: Completed
• Phase: Phase 3
• 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
• 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

Related Conditions & MeSH terms

• Multiple Myeloma
• Neoplasms, Plasma Cell

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

External Links

•   AmgenTrials clinical trials website