The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT02412878




Registration number
NCT02412878
Ethics application status
Date submitted
6/04/2015
Date registered
8/04/2015
Date last updated
9/01/2019

Titles & IDs
Public title
Once-weekly Versus Twice-weekly Carfilzomib in Combination With Dexamethasone in Adults With Relapsed and Refractory Multiple Myeloma
Scientific 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
Secondary ID [1] 0 0
2014-005325-12
Secondary ID [2] 0 0
CFZ014
Universal Trial Number (UTN)
Trial acronym
ARROW
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Multiple Myeloma 0 0
Condition category
Condition code
Cancer 0 0 0 0
Other cancer types

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Carfilzomib
Treatment: Drugs - Dexamethasone

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.

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.


Treatment: Drugs: Carfilzomib
Carfilzomib was administered as an IV infusion

Treatment: Drugs: Dexamethasone
Commercially available dexamethasone was obtained by the investigational site.

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
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.
Timepoint [1] 0 0
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 [1] 0 0
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.
Timepoint [1] 0 0
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 outcome [2] 0 0
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.
Timepoint [2] 0 0
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 outcome [3] 0 0
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.
Timepoint [3] 0 0
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.
Secondary outcome [4] 0 0
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.
Timepoint [4] 0 0
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

Eligibility
Key inclusion criteria
Key

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
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
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
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,VIC
Recruitment hospital [1] 0 0
Research Site - Darlinghurst
Recruitment hospital [2] 0 0
Research Site - Tweed Heads
Recruitment hospital [3] 0 0
Research Site - Waratah
Recruitment hospital [4] 0 0
Research Site - Box Hill
Recruitment postcode(s) [1] 0 0
2010 - Darlinghurst
Recruitment postcode(s) [2] 0 0
2485 - Tweed Heads
Recruitment postcode(s) [3] 0 0
2298 - Waratah
Recruitment postcode(s) [4] 0 0
3128 - Box Hill
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Arizona
Country [2] 0 0
United States of America
State/province [2] 0 0
Maryland
Country [3] 0 0
United States of America
State/province [3] 0 0
New Jersey
Country [4] 0 0
United States of America
State/province [4] 0 0
New York
Country [5] 0 0
United States of America
State/province [5] 0 0
Pennsylvania
Country [6] 0 0
United States of America
State/province [6] 0 0
Texas
Country [7] 0 0
Belgium
State/province [7] 0 0
Antwerpen
Country [8] 0 0
Belgium
State/province [8] 0 0
Brugge
Country [9] 0 0
Belgium
State/province [9] 0 0
Brussel
Country [10] 0 0
Belgium
State/province [10] 0 0
Bruxelles
Country [11] 0 0
Belgium
State/province [11] 0 0
Ghent
Country [12] 0 0
Belgium
State/province [12] 0 0
Leuven
Country [13] 0 0
Canada
State/province [13] 0 0
Alberta
Country [14] 0 0
Canada
State/province [14] 0 0
British Columbia
Country [15] 0 0
Canada
State/province [15] 0 0
Newfoundland and Labrador
Country [16] 0 0
Canada
State/province [16] 0 0
Nova Scotia
Country [17] 0 0
Canada
State/province [17] 0 0
Ontario
Country [18] 0 0
Canada
State/province [18] 0 0
Quebec
Country [19] 0 0
Czechia
State/province [19] 0 0
Brno
Country [20] 0 0
Czechia
State/province [20] 0 0
Hradec Kralove
Country [21] 0 0
Czechia
State/province [21] 0 0
Olomouc
Country [22] 0 0
Czechia
State/province [22] 0 0
Ostrava-Poruba
Country [23] 0 0
Czechia
State/province [23] 0 0
Praha 10
Country [24] 0 0
Czechia
State/province [24] 0 0
Praha
Country [25] 0 0
Denmark
State/province [25] 0 0
Aalborg
Country [26] 0 0
Denmark
State/province [26] 0 0
Copenhagen
Country [27] 0 0
Denmark
State/province [27] 0 0
Odense C
Country [28] 0 0
Denmark
State/province [28] 0 0
Vejle
Country [29] 0 0
Finland
State/province [29] 0 0
Helsinki
Country [30] 0 0
Finland
State/province [30] 0 0
Tampere
Country [31] 0 0
Finland
State/province [31] 0 0
Turku
Country [32] 0 0
France
State/province [32] 0 0
Bayonne
Country [33] 0 0
France
State/province [33] 0 0
Brest
Country [34] 0 0
France
State/province [34] 0 0
Dijon
Country [35] 0 0
France
State/province [35] 0 0
Nantes Cedex 1
Country [36] 0 0
France
State/province [36] 0 0
Nimes cedex 09
Country [37] 0 0
France
State/province [37] 0 0
Paris
Country [38] 0 0
France
State/province [38] 0 0
Pierre-Benite cedex
Country [39] 0 0
France
State/province [39] 0 0
Rennes
Country [40] 0 0
France
State/province [40] 0 0
Tours Cedex 1
Country [41] 0 0
Germany
State/province [41] 0 0
Köln
Country [42] 0 0
Germany
State/province [42] 0 0
Leipzig
Country [43] 0 0
Germany
State/province [43] 0 0
München
Country [44] 0 0
Germany
State/province [44] 0 0
Rostock
Country [45] 0 0
Germany
State/province [45] 0 0
Tubingen
Country [46] 0 0
Greece
State/province [46] 0 0
Athens
Country [47] 0 0
Greece
State/province [47] 0 0
Patra
Country [48] 0 0
Hungary
State/province [48] 0 0
Budapest
Country [49] 0 0
Hungary
State/province [49] 0 0
Debrecen
Country [50] 0 0
Hungary
State/province [50] 0 0
Gyula
Country [51] 0 0
Hungary
State/province [51] 0 0
Kaposvar
Country [52] 0 0
Italy
State/province [52] 0 0
Ancona
Country [53] 0 0
Italy
State/province [53] 0 0
Bologna
Country [54] 0 0
Italy
State/province [54] 0 0
Brescia
Country [55] 0 0
Italy
State/province [55] 0 0
Cagliari
Country [56] 0 0
Italy
State/province [56] 0 0
Catania
Country [57] 0 0
Italy
State/province [57] 0 0
Firenze
Country [58] 0 0
Italy
State/province [58] 0 0
Genova
Country [59] 0 0
Italy
State/province [59] 0 0
Napoli
Country [60] 0 0
Italy
State/province [60] 0 0
Pavia
Country [61] 0 0
Italy
State/province [61] 0 0
Piacenza
Country [62] 0 0
Italy
State/province [62] 0 0
Pisa
Country [63] 0 0
Italy
State/province [63] 0 0
Roma
Country [64] 0 0
Italy
State/province [64] 0 0
Torino
Country [65] 0 0
Japan
State/province [65] 0 0
Aichi
Country [66] 0 0
Japan
State/province [66] 0 0
Fukuoka
Country [67] 0 0
Japan
State/province [67] 0 0
Gifu
Country [68] 0 0
Japan
State/province [68] 0 0
Gunma
Country [69] 0 0
Japan
State/province [69] 0 0
Hokkaido
Country [70] 0 0
Japan
State/province [70] 0 0
Kanagawa
Country [71] 0 0
Japan
State/province [71] 0 0
Kyoto
Country [72] 0 0
Japan
State/province [72] 0 0
Miyagi
Country [73] 0 0
Japan
State/province [73] 0 0
Okayama
Country [74] 0 0
Japan
State/province [74] 0 0
Osaka
Country [75] 0 0
Japan
State/province [75] 0 0
Saitama
Country [76] 0 0
Japan
State/province [76] 0 0
Tochigi
Country [77] 0 0
Japan
State/province [77] 0 0
Tokyo
Country [78] 0 0
Japan
State/province [78] 0 0
Fukuoka-shi
Country [79] 0 0
Japan
State/province [79] 0 0
Nagoya-shi
Country [80] 0 0
Japan
State/province [80] 0 0
Niigata-shi
Country [81] 0 0
Japan
State/province [81] 0 0
Tokushima-shi
Country [82] 0 0
New Zealand
State/province [82] 0 0
Christchurch
Country [83] 0 0
New Zealand
State/province [83] 0 0
Otahuhu, Auckland
Country [84] 0 0
Norway
State/province [84] 0 0
Oslo
Country [85] 0 0
Norway
State/province [85] 0 0
Trondheim
Country [86] 0 0
Poland
State/province [86] 0 0
Brzozow
Country [87] 0 0
Poland
State/province [87] 0 0
Chorzow
Country [88] 0 0
Poland
State/province [88] 0 0
Katowice
Country [89] 0 0
Poland
State/province [89] 0 0
Krakow
Country [90] 0 0
Poland
State/province [90] 0 0
Lodz
Country [91] 0 0
Poland
State/province [91] 0 0
Olsztyn
Country [92] 0 0
Poland
State/province [92] 0 0
Poznan
Country [93] 0 0
Poland
State/province [93] 0 0
Torun
Country [94] 0 0
Poland
State/province [94] 0 0
Warszawa
Country [95] 0 0
Poland
State/province [95] 0 0
Wroclaw
Country [96] 0 0
Romania
State/province [96] 0 0
Brazov
Country [97] 0 0
Romania
State/province [97] 0 0
Bucharest
Country [98] 0 0
Spain
State/province [98] 0 0
Andalucía
Country [99] 0 0
Spain
State/province [99] 0 0
Aragón
Country [100] 0 0
Spain
State/province [100] 0 0
Baleares
Country [101] 0 0
Spain
State/province [101] 0 0
Castilla León
Country [102] 0 0
Spain
State/province [102] 0 0
Cataluña
Country [103] 0 0
Spain
State/province [103] 0 0
Navarra
Country [104] 0 0
Spain
State/province [104] 0 0
Madrid
Country [105] 0 0
Sweden
State/province [105] 0 0
Goteborg
Country [106] 0 0
Sweden
State/province [106] 0 0
Helsingborg
Country [107] 0 0
Sweden
State/province [107] 0 0
Lund
Country [108] 0 0
Sweden
State/province [108] 0 0
Stockholm
Country [109] 0 0
Sweden
State/province [109] 0 0
Uddevalla
Country [110] 0 0
United Kingdom
State/province [110] 0 0
Bournemouth
Country [111] 0 0
United Kingdom
State/province [111] 0 0
London
Country [112] 0 0
United Kingdom
State/province [112] 0 0
Manchester
Country [113] 0 0
United Kingdom
State/province [113] 0 0
Nottingham
Country [114] 0 0
United Kingdom
State/province [114] 0 0
Sheffield
Country [115] 0 0
United Kingdom
State/province [115] 0 0
Wolverhampton

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Amgen
Address
Country

Ethics approval
Ethics application status

Summary
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).
Trial website
https://clinicaltrials.gov/show/NCT02412878
Trial related presentations / 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.
Public notes

Contacts
Principal investigator
Name 0 0
MD
Address 0 0
Amgen
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

No data has been provided for results reporting
Summary results
Other publications