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

• ClinicalTrials.gov Identifier: NCT02412878
• Recruitment Status: Completed
• First Posted: April 9, 2015
• Results First Posted: December 13, 2018
• Last Update Posted: September 23, 2022
• Sponsor: Amgen
• Information provided by (Responsible Party): Amgen

Tracking Information

• First Submitted Date: April 6, 2015
• First Posted Date: April 9, 2015
• Results First Submitted Date: October 24, 2018
• Results First Posted Date: December 13, 2018
• Last Update Posted Date: September 23, 2022
• Actual Study Start Date: September 9, 2015
• Actual Primary Completion Date: June 15, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 12, 2018)

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.

Original Primary Outcome Measures (submitted: April 8, 2015)

Overall Response Rate (ORR) [ Time Frame: 19 months ]

Overall Response Rate (ORR) is defined as the proportion of subjects who achieve a best overall response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR) in accordance with International Myeloma Working Group-Uniform Response Criteria (IMWG-URC).

Current Secondary Outcome Measures (submitted: December 3, 2019)

• 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.
• 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.
• 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.
• 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.

Original Secondary Outcome Measures (submitted: April 8, 2015)

• Progression-Free Survival (PFS) [ Time Frame: 25 months ]
  Progression-free survival (PFS) is defined as the time from randomization to the earlier of disease progression or death due to any cause.
• Overall Survival (OS) [ Time Frame: 25 months ]
  Overall Survival (OS) is defined as the time from randomization to death due to any cause.
• Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: 25 months ]
  Safety and tolerability will be assessed by the incidence and severity of Adverse Events (AEs).
• Laboratory Values [ Time Frame: 25 months ]
  For laboratory values, the baseline values and changes from baseline to the minimum, maximum, and last observed values will be summarized descriptively by visit. Laboratory test results will be graded using the NCI-CTCAE (version 4.03).
• Vital Signs [ Time Frame: 25 months ]
  Vital sign results will be summarized descriptively for baseline values and changes from baseline to the minimum, maximum, and last observed values.
• Electrocardiogram (ECG) QT-interval [ Time Frame: 25 months ]
  Twelve-lead electrocardiograms (ECGs) including corrected QT-interval (QTc; representing the corrected duration of ventricular electrical activity) will be performed locally.
• Pharmacokinetics (PK) Plasma Samples (Concentrations of carfilzomib) [ Time Frame: 17 months ]
  Concentrations of carfilzomib will be measured in plasma with a validated assay method.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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).
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Multiple Myeloma

Intervention

• Drug: Carfilzomib
  Carfilzomib was administered as an IV infusion
  Other Names:

  • PR-171
  • PR171
  • Kyprolis® (carfilzomib) for Injection
• Drug: Dexamethasone
  Commercially available dexamethasone was obtained by the investigational site.

Study Arms

• 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.

  Interventions:

  • Drug: Carfilzomib
  • Drug: Dexamethasone
• 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.

  Interventions:

  • Drug: Carfilzomib
  • Drug: Dexamethasone

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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: November 10, 2016): 478
• Original Estimated Enrollment (submitted: April 8, 2015): 460
• Actual Study Completion Date: January 7, 2019
• Actual Primary Completion Date: June 15, 2017 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Belgium, Canada, Czechia, Denmark, Finland, France, Germany, Greece, Hungary, Italy, Japan, New Zealand, Norway, Poland, Romania, Spain, Sweden, United Kingdom, United States

Administrative Information

• NCT Number: NCT02412878
• Other Study ID Numbers: CFZ014; 2014-005325-12 ( EudraCT Number ); 20140355 ( Other Identifier: Amgen Study ID )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Amgen
• Original Responsible Party: Onyx Therapeutics, Inc.
• Current Study Sponsor: Amgen
• Original Study Sponsor: Onyx Therapeutics, Inc.
• Collaborators: Not Provided

Investigators

• Study Director: MD; Amgen

• PRS Account: Amgen
• Verification Date: September 2022