Clinical trial NCT03859427: A Study Comparing Once-weekly vs Twice-weekly Carfilzomib in Combination With Lenalidomide and Dexamethasone in Subjects With Relapsed or Refractory Multiple Myeloma
Official title: A Randomized, Open-label, Phase 3 Study Comparing Once-weekly vs Twice-weekly Carfilzomib in Combination With Lenalidomide and Dexamethasone in Subjects With Relapsed or Refractory Multiple Myeloma (A.R.R.O.W.2)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Relapsed or Refractory Multiple Myeloma
Keywords: Bone Marrow Cancer
Lead sponsor: Amgen
Sponsor class: INDUSTRY
First posted: 2019-03-01
Enrollment: 454
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Compare efficacy of 56 mg/m2 carfilzomib administered once-weekly in combination with lenalidomide and dexamethasone (KRd 56 mg/m2) to 27 mg/m2 carfilzomib administered twice-weekly in combination with lenalidomide and dexamethasone (KRd 27 mg/m2) in subjects with relapsed or refractory multiple myeloma (RRMM) with 1 to 3 prior lines of therapy.


Eligibility criteria: Inclusion Criteria:

Multiple myeloma with documented relapse or progression after most recent myeloma treatment. Subjects refractory to the most recent line of therapy are eligible, unless last treatment contained proteasome inhibitor (PI) or lenalidomide and dexamethasone. Refractory is defined as disease that is nonresponsive or progresses within 60 days of last therapy.

Subjects must have at least PR to at least 1 line of prior therapy.

Subjects must have received at least 1 but not more than 3 prior lines of therapy for multiple myeloma (induction therapy followed by stem cell transplant and consolidation maintenance therapy will be considered as 1 line of therapy).

Prior therapy with a PI or the combination of lenalidomide and dexamethasone are allowed if the patient had at least a PR to the most recent treatment with a PI or lenalidomide and dexamethasone, neither PI or lenalidomide and dexamethasone containing treatment were ceased due to toxicity, the patient has not relapsed within 60 days of discontinuation of the PI or lenalidomide and dexamethasone containing treatment. A history of prior neuropathy is permitted if this was not grade 3, grade 4 or grade 2 with pain and if not resolved within the 14 days before enrollment, is less than or equal to grade 2 without pain. Patients are permitted to have received single agent lenalidomide as maintenance therapy within 60 days of enrollment.

Previous treatment with a lenalidomide and dexamethasone containing regimen is allowed, as long as the subject did not progress during the first 3 months after initiating lenalidomide and dexamethasone containing therapy.

Measurable disease with at least 1 of the following assessed within 21 days prior to randomization:

* Immunoglobulin G (IgG) multiple myeloma: serum monoclonal protein (M-protein) level ≥ 1.0 g/dL
* Immunoglobulin A (IgA), Immunoglobulin D (IgD), Immunoglobulin E (IgE) multiple myeloma: serum M-protein level ≥ 0.5 g/dL
* Urine M-protein ≥ 200 mg per 24 hours
* In subjects without measurable serum or urine M-protein, serum-free light chain (SFLC) ≥ 100 mg/L (involved light chain) and an abnormal serum kappa lambda ratio

Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 ≤ 2

Other inclusion criteria may apply

Exclusion Criteria:

Waldenström macroglobulinemia.

Multiple myeloma of Immunoglobulin M (IgM) subtype.

Plasma cell leukemia (\> 2.0 × 10\^9 /L circulating plasma cells by standard differential).

Uncontrolled hypertension, defined as a subject whose blood pressure is greater than or equal to 160 mmHg systolic or greater than or equal to 100 mmHg diastolic when taken in accordance with the European Society of Hypertension/European Society of Cardiology 2018 guidelines (Section 12.10; Williams et al, 2018).

Active congestive heart failure (New York Heart Association Class III to IV), symptomatic ischemia, uncontrolled arrhythmias, screening ECG with corrected QT interval (QTc) of \> 470 msec, pericardial disease, or myocardial infarction within 4 months prior to randomization.

Calculated or measured creatinine clearance \< 30 mL/min (calculation must be based on the Cockcroft and Gault formula) within 28 days prior to randomization.

Other exclusion criteria may apply

Primary outcomes:
measure: Overall Response Rate (ORR) Per International Myeloma Working Group Uniform Response Criteria (IMWG-URC)
timeFrame: Cycle 1 Day 1 up to approximately 12 months (cycle = 28 days); median treatment duration for the twice-weekly arm was 47.00 weeks and for the once-weekly arm was 47.14 weeks.
Secondary outcomes:
measure: Kaplan-Meier Estimate of Progression-free Survival (PFS) Rate at 12 Months
timeFrame: 12 months
measure: Percentage of Participants Who Reported Convenience as Measured by the Patient-reported Convenience With Carfilzomib-dosing Schedule Question
timeFrame: Day 28 of Cycle 4
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs)
timeFrame: Cycle 1 Day 1 up to end of Cycle 12 + 30 days, where each cycle was 28 days; median treatment duration (any study treatment) was 47.00 weeks in the twice-weekly KRd group and 47.14 weeks in the once-weekly KRd group
measure: Time to Response (TTR)
timeFrame: Cycle 1 Day 1 up to approximately 12 months (cycle = 28 days); median treatment duration for the twice-weekly arm was 47.00 weeks and for the once-weekly arm was 47.14 weeks.
measure: Kaplan-Meier Estimate of Duration of Response (DOR)
timeFrame: Cycle 1 Day 1 up to approximately 12 months (cycle = 28 days); median treatment duration for the twice-weekly arm was 47.00 weeks and for the once-weekly arm was 47.14 weeks.
measure: Kaplan-Meier Estimate of Time to Progression (TTP)
timeFrame: Cycle 1 Day 1 up to approximately 12 months (cycle = 28 days); median treatment duration for the twice-weekly arm was 47.00 weeks and for the once-weekly arm was 47.14 weeks.
measure: Kaplan-Meier Estimate of Overall Survival (OS)
timeFrame: Cycle 1 Day 1 up to approximately 12 months (cycle = 28 days); median treatment duration for the twice-weekly arm was 47.00 weeks and for the once-weekly arm was 47.14 weeks.
measure: Percentage of Participants Who Achieved Minimal Residual Disease Negative Complete Response (MRD[-]CR) by Independent Review Committee (IRC) Per IMWG-URC
timeFrame: Cycle 1 Day 1 up to approximately 12 months (cycle = 28 days); median treatment duration for the twice-weekly arm was 47.00 weeks and for the once-weekly arm was 47.14 weeks.
measure: Percentage of Participants With Minimal Residual Disease Negativity (MRD[-]) by IRC Per IMWG-URC at 12 Months
timeFrame: Cycle 1 Day 1 up to 12 months (cycle = 28 days)
measure: Change From Baseline in European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ)-Core 30 (C30) Physical Functioning Scale
timeFrame: Baseline (Cycle 1 Day 1), Cycle 3 Day 1, Cycle 5 Day 1, Cycle 7 Day 1, Cycle 9 Day 1, Cycle 12 Day 1, and safety follow-up (30 days after last dose)
measure: Change From Baseline in EORTC QLQ-C30 Role Functioning Scale
timeFrame: Baseline (Cycle 1 Day 1), Cycle 3 Day 1, Cycle 5 Day 1, Cycle 7 Day 1, Cycle 9 Day 1, Cycle 12 Day 1, and safety follow-up (30 days after last dose)
measure: Patient-reported Treatment Satisfaction as Measured by the Cancer Therapy Satisfaction Questionnaire (CTSQ)
timeFrame: Cycle 5 Day 1, Cycle 12 Day 1, and safety follow-up (30 days after last dose)
Other outcomes:
Locations:
city: Fountain Valley
country: United States
facility: Robert A Moss Oncology
state: California
city: Denver
country: United States
facility: Rocky Mountain Cancer Centers Denver Midtown
state: Colorado
city: Plainville
country: United States
facility: Hartford HealthCare Cancer Institute at The Hospital of Central Connecticut
state: Connecticut
city: Jacksonville
country: United States
facility: Baptist MD Anderson Cancer Center
state: Florida
city: Park Ridge
country: United States
facility: Advocate Lutheran General Hospital
state: Illinois
city: Albany
country: United States
facility: New York Oncology Hematology, PC
state: New York
city: Cincinnati
country: United States
facility: Oncology Hematology Care Inc
state: Ohio
city: Denton
country: United States
facility: Texas Oncology-Denton
state: Texas
city: Fort Worth
country: United States
facility: US Oncology Research Investigational Products Center
state: Texas
city: Houston
country: United States
facility: Oncology Consultants PA
state: Texas
city: San Antonio
country: United States
facility: Texas Oncology
state: Texas
city: The Woodlands
country: United States
facility: United States Oncology Regulatory Affairs Corporate Office
state: Texas
city: Salzburg
country: Austria
facility: Universitaetsklinikum Salzburg
city: Plovdiv
country: Bulgaria
facility: University Multiprofile Hospital for Active Treatment Sveti Georgi EAD
city: Sofia
country: Bulgaria
facility: University Multiprofile Hospital for Active Treatment Sveti Ivan Rilski EAD
city: Sofia
country: Bulgaria
facility: Specialized Hospital for Active Treatment of Hematology Diseases EAD
city: Brno
country: Czechia
facility: Fakultni nemocnice Brno
city: Hradec Kralove
country: Czechia
facility: Fakultni nemocnice Hradec Kralove
city: Olomouc
country: Czechia
facility: Fakultni nemocnice Olomouc
city: Praha 2
country: Czechia
facility: Vseobecna fakultni nemocnice v Praze
city: Helsinki
country: Finland
facility: Helsingin Yliopistollinen Keskussairaala
city: Oulu
country: Finland
facility: Oulun Yliopistollinen Sairaala
city: Turku
country: Finland
facility: Turun Yliopistollinen Keskussairaala
city: Nantes
country: France
facility: Centre Hospitalier Universitaire de Nantes
city: Nice cedex 3
country: France
facility: Centre Hospitalier Universitaire Archet 2
city: Paris
country: France
facility: Hopital Saint Louis
city: Paris
country: France
facility: Hopital Pitie-Salpetriere
city: Pierre-Benite
country: France
facility: Centre Hospitalier Lyon Sud
city: Poitiers Cedex
country: France
facility: Centre Hospitalier Universitaire de Poitiers - Hopital la Miletrie
city: Rennes
country: France
facility: Centre Hospitalier Universitaire de Rennes
city: Strasbourg
country: France
facility: Institut de Cancerologie Strasbourg
city: Toulouse cedex 9
country: France
facility: Institut Universitaire du Cancer Toulouse Oncopole
city: Vandoeuvre les Nancy Cedex
country: France
facility: Centre Hospitalier Universitaire de Nancy - Hopital de Brabois
city: Berlin
country: Germany
facility: Charité, Universitätsklinikum Berlin, Campus Benjamin Franklin
city: Dresden
country: Germany
facility: Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden
city: Hamburg
country: Germany
facility: Universitatsklinikum Hamburg-Eppendorf
city: Köln
country: Germany
facility: Universitatsklinikum Koln
city: Mainz
country: Germany
facility: Johannes Gutenberg Universitaet Mainz
city: Alexandroupoli
country: Greece
facility: University Hospital of Alexandroupolis
city: Athens
country: Greece
facility: General Hospital Evangelismos
city: Athens
country: Greece
facility: Agios Savvas Anticancer Hospital
city: Athens
country: Greece
facility: 251 General Airforce Hospital
city: Athens
country: Greece
facility: Alexandra Hospital
city: Athens
country: Greece
facility: Metropolitan Hospital
city: Patra
country: Greece
facility: General University Hospital of Patras Panagia i Voithia
city: Thessaloniki
country: Greece
facility: Theagenion Cancer Hospital of Thessaloniki
city: Thessaloniki
country: Greece
facility: General Hospital of Thessaloniki Georgios Papanikolaou
city: Nagoya-shi
country: Japan
facility: Nagoya City University Hospital
state: Aichi
city: Toyohashi-shi
country: Japan
facility: Toyohashi Municipal Hospital
state: Aichi
city: Kamogawa-shi
country: Japan
facility: Tesshokai Kameda General Hospital
state: Chiba
city: Fukuoka-shi
country: Japan
facility: National Hospital Organization Kyushu Cancer Center
state: Fukuoka
city: Ogaki-shi
country: Japan
facility: Ogaki Municipal Hospital
state: Gifu
city: Shibukawa-shi
country: Japan
facility: National Hospital Organization Shibukawa Medical Center
state: Gunma
city: Himeji-shi
country: Japan
facility: Japanese Red Cross Society Himeji Hospital
state: Hyogo
city: Nishinomiya-shi
country: Japan
facility: Hyogo College of Medicine Hospital
state: Hyogo
city: Hitachi-shi
country: Japan
facility: Hitachi Ltd Hitachi General Hospital
state: Ibaraki
city: Kyoto-shi
country: Japan
facility: University Hospital Kyoto Prefectural University of Medicine
state: Kyoto
city: Sendai-shi
country: Japan
facility: National Hospital Organization Sendai Medical Center
state: Miyagi
city: Niigata-shi
country: Japan
facility: Niigata Cancer Center Hospital
state: Niigata
city: Okayama-shi
country: Japan
facility: National Hospital Organization Okayama Medical Center
state: Okayama
city: Osaka-shi
country: Japan
facility: Japanese Red Cross Osaka Hospital
state: Osaka
city: Osakasayama-shi
country: Japan
facility: Kindai University Hospital
state: Osaka
city: Suita-shi
country: Japan
facility: Osaka University Hospital
state: Osaka
city: Kawagoe-shi
country: Japan
facility: Saitama Medical Center
state: Saitama
city: Utsunomiya-shi
country: Japan
facility: Tochigi Cancer Center
state: Tochigi
city: Bunkyo-ku
country: Japan
facility: Juntendo University Hospital
state: Tokyo
city: Koto-ku
country: Japan
facility: The Cancer Institute Hospital of Japanese Foundation for Cancer Research
state: Tokyo
city: Shibuya-ku
country: Japan
facility: Japanese Red Cross Medical Center
state: Tokyo
city: Kaunas
country: Lithuania
facility: Hospital of Lithuanian University of Health Sciences Kaunas Clinics Public Institution
city: Vilnius
country: Lithuania
facility: Vilnius University Hospital Santaros Clinic Public Institution
city: Amsterdam
country: Netherlands
facility: VU Medisch Centrum
city: Apeldoorn
country: Netherlands
facility: Gelre Ziekenhuizen
city: Hoofddorp
country: Netherlands
facility: Spaarne Gasthuis
city: Bucharest
country: Romania
facility: Fundeni Clinical Institute
city: Bucharest
country: Romania
facility: Institutul Clinic Fundeni
city: Bucharest
country: Romania
facility: Spitalul Clinic Coltea
city: Bucharest
country: Romania
facility: Spitalul Universitar de Urgenta Bucuresti
city: Bucuresti
country: Romania
facility: Spitalul Clinic Colentina
city: Cluj-Napoca
country: Romania
facility: Institutul Oncologic Prof Dr Ion Chiricuta
city: Iasi
country: Romania
facility: Institutul Regional de Oncologie Iasi
city: Oradea
country: Romania
facility: Spitalul Clinic Dr Gavril Curteanu Oradea
city: Sibiu
country: Romania
facility: Spitalul Clinic Judetean de Urgenta Sibiu
city: Timisoara
country: Romania
facility: Spitalul Clinic Municipal de Urgenta Timisoara
city: Krasnoyarsk
country: Russian Federation
facility: Regional Clinical Hospital
city: Moscow
country: Russian Federation
facility: Moscow State Budget Healthcare Institution City clinical Hospital 52 of Moscow Healthcare Department
city: Moscow
country: Russian Federation
facility: SBHI of Moscow city City clinical hospital na S P Botkin of Moscow city Healthcare department
city: Petrozavodsk
country: Russian Federation
facility: SBHI of Republic of Karelia Republic Hosiptal n a V A Baranov
city: Saint Petersburg
country: Russian Federation
facility: Federal centre of heart, blood and endocrinology Almazova
city: Samara
country: Russian Federation
facility: State Budget Educational Institution of High Professional Skills Samara State Medical University
city: Bratislava
country: Slovakia
facility: Univerzitna nemocnica Bratislava, Nemocnica sv Cyrila a Metoda
city: Palma de Mallorca
country: Spain
facility: Hospital Universitari Son Espases
state: Baleares
city: Salamanca
country: Spain
facility: Hospital Clinico Universitario de Salamanca
state: Castilla León
city: Badalona
country: Spain
facility: Hospital Universitari Germans Trias i Pujol
state: Cataluña
city: Barcelona
country: Spain
facility: Hospital Clinic i Provincial de Barcelona
state: Cataluña
city: Pozuelo de Alarcon
country: Spain
facility: Hospital Universitario Quironsalud Madrid
state: Madrid
city: Pamplona
country: Spain
facility: Clinica Universidad de Navarra
state: Navarra
city: Falun
country: Sweden
facility: Falu Lasarett
city: Goteborg
country: Sweden
facility: Sahlgrenska Universitetssjukhuset
city: Halmstad
country: Sweden
facility: Hallands Sjukhus Halmstad
city: Lulea
country: Sweden
facility: Sunderby Sjukhus
city: Lund
country: Sweden
facility: Skanes Universitetssjukhus
city: Ankara
country: Turkey
facility: Gazi Universitesi Saglik Arastirma ve Uygulama Merkezi Gazi Hastanesi
city: Ankara
country: Turkey
facility: Ankara Universitesi Tip Fakultesi Cebeci Arastirma ve Uygulama Hastanesi
city: Istanbul
country: Turkey
facility: Istanbul Universitesi Istanbul Tip Fakultesi
city: Istanbul
country: Turkey
facility: Bagcilar Medipol Mega Universite Hastanesi
city: Istanbul
country: Turkey
facility: Istanbul Florence Nightingale Hastanesi
city: Izmir
country: Turkey
facility: Dokuz Eylul Universitesi Arastirma Uygulama Hastanesi
city: Kayseri
country: Turkey
facility: Erciyes Universitesi Tip Fakultesi Mehmet Kemal Dedeman Hematoloji-Onkoloji Hastanesi
Study officials:
affiliation: Amgen
name: MD
role: STUDY_DIRECTOR
References: