A Study Comparing Once-weekly vs Twice-weekly Carfilzomib in Combination With Lenalidomide and Dexamethasone in Subjects With Relapsed or Refractory Multiple Myeloma

Relapsed or Refractory Multiple Myeloma Clinical Trial

— ARROW2  

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03859427
• Other study ID #: 20180015
• Status: Completed
• Phase: Phase 3
• Start date: May 8, 2019
• Est. completion date: March 31, 2023

Study information

• Verified date: February 2024
• Source: Amgen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 454
• Est. completion date: March 31, 2023
• Est. primary completion date: March 31, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 99 Years

Eligibility

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

Related Conditions & MeSH terms

• Multiple Myeloma
• Neoplasms, Plasma Cell
• Relapsed or Refractory Multiple Myeloma

Intervention

Drug:
• Carfilzomib
Once weekly IV over 30 minutes on day 1, 8 and 15 of each 28 day cycle. The dose will be 20 mg/m2 on cycle 1 day 1 and 56 mg/m2 beginning with cycle 1 day 8 and thereafter. 12 cycles or until progression, unacceptable toxicity, death, loss to follow up or withdrawal of consent.
• Carfilzomib
Twice weekly IV over 10 minutes on day 1, 2, 8, 9, 15 and 16 of each 28 day cycle. The dose will be 20 mg/m2 on cycle 1 days 1 and 2 and 27 mg/m2 beginning with cycle 1 day 8 and thereafter. 12 cycles or until progression, unacceptable toxicity, death, loss to follow up or withdrawal of consent.
• Lenalidomide
Once daily orally 25 mg days 1 to 21 of each cycle. 12 cycles or until progression, unacceptable toxicity, death, loss to follow up or withdrawal of consent
• Dexamethasone
Once daily orally or by IV 40 mg days 1, 8 and 15 of each cycle. Also day 22 of cycles 1 to 9. 12 cycles or until progression, unacceptable toxicity, death, loss to follow up or withdrawal of consent

Locations

Country	Name	City	State
Austria	Universitaetsklinikum Salzburg	Salzburg
Bulgaria	University Multiprofile Hospital for Active Treatment Sveti Georgi EAD	Plovdiv
Bulgaria	Specialized Hospital for Active Treatment of Hematology Diseases EAD	Sofia
Bulgaria	University Multiprofile Hospital for Active Treatment Sveti Ivan Rilski EAD	Sofia
Czechia	Fakultni nemocnice Brno	Brno
Czechia	Fakultni nemocnice Hradec Kralove	Hradec Kralove
Czechia	Fakultni nemocnice Olomouc	Olomouc
Czechia	Vseobecna fakultni nemocnice v Praze	Praha 2
Finland	Helsingin Yliopistollinen Keskussairaala	Helsinki
Finland	Oulun Yliopistollinen Sairaala	Oulu
Finland	Turun Yliopistollinen Keskussairaala	Turku
France	Centre Hospitalier Universitaire de Nantes	Nantes
France	Centre Hospitalier Universitaire Archet 2	Nice cedex 3
France	Hopital Pitie-Salpetriere	Paris
France	Hopital Saint Louis	Paris
France	Centre Hospitalier Lyon Sud	Pierre-Benite
France	Centre Hospitalier Universitaire de Poitiers - Hopital la Miletrie	Poitiers Cedex
France	Centre Hospitalier Universitaire de Rennes	Rennes
France	Institut de Cancerologie Strasbourg	Strasbourg
France	Institut Universitaire du Cancer Toulouse Oncopole	Toulouse cedex 9
France	Centre Hospitalier Universitaire de Nancy - Hopital de Brabois	Vandoeuvre les Nancy Cedex
Germany	Charité, Universitätsklinikum Berlin, Campus Benjamin Franklin	Berlin
Germany	Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden	Dresden
Germany	Universitatsklinikum Hamburg-Eppendorf	Hamburg
Germany	Universitatsklinikum Koln	Köln
Germany	Johannes Gutenberg Universitaet Mainz	Mainz
Greece	University Hospital of Alexandroupolis	Alexandroupoli
Greece	251 General Airforce Hospital	Athens
Greece	Agios Savvas Anticancer Hospital	Athens
Greece	Alexandra Hospital	Athens
Greece	General Hospital Evangelismos	Athens
Greece	Metropolitan Hospital	Athens
Greece	General University Hospital of Patras Panagia i Voithia	Patra
Greece	General Hospital of Thessaloniki Georgios Papanikolaou	Thessaloniki
Greece	Theagenion Cancer Hospital of Thessaloniki	Thessaloniki
Japan	Juntendo University Hospital	Bunkyo-ku	Tokyo
Japan	National Hospital Organization Kyushu Cancer Center	Fukuoka-shi	Fukuoka
Japan	Japanese Red Cross Society Himeji Hospital	Himeji-shi	Hyogo
Japan	Hitachi Ltd Hitachi General Hospital	Hitachi-shi	Ibaraki
Japan	Tesshokai Kameda General Hospital	Kamogawa-shi	Chiba
Japan	Saitama Medical Center	Kawagoe-shi	Saitama
Japan	The Cancer Institute Hospital of Japanese Foundation for Cancer Research	Koto-ku	Tokyo
Japan	University Hospital Kyoto Prefectural University of Medicine	Kyoto-shi	Kyoto
Japan	Nagoya City University Hospital	Nagoya-shi	Aichi
Japan	Niigata Cancer Center Hospital	Niigata-shi	Niigata
Japan	Hyogo College of Medicine Hospital	Nishinomiya-shi	Hyogo
Japan	Ogaki Municipal Hospital	Ogaki-shi	Gifu
Japan	National Hospital Organization Okayama Medical Center	Okayama-shi	Okayama
Japan	Japanese Red Cross Osaka Hospital	Osaka-shi	Osaka
Japan	Kindai University Hospital	Osakasayama-shi	Osaka
Japan	National Hospital Organization Sendai Medical Center	Sendai-shi	Miyagi
Japan	National Hospital Organization Shibukawa Medical Center	Shibukawa-shi	Gunma
Japan	Japanese Red Cross Medical Center	Shibuya-ku	Tokyo
Japan	Osaka University Hospital	Suita-shi	Osaka
Japan	Toyohashi Municipal Hospital	Toyohashi-shi	Aichi
Japan	Tochigi Cancer Center	Utsunomiya-shi	Tochigi
Lithuania	Hospital of Lithuanian University of Health Sciences Kaunas Clinics Public Institution	Kaunas
Lithuania	Vilnius University Hospital Santaros Clinic Public Institution	Vilnius
Netherlands	VU Medisch Centrum	Amsterdam
Netherlands	Gelre Ziekenhuizen	Apeldoorn
Netherlands	Spaarne Gasthuis	Hoofddorp
Romania	Fundeni Clinical Institute	Bucharest
Romania	Institutul Clinic Fundeni	Bucharest
Romania	Spitalul Clinic Coltea	Bucharest
Romania	Spitalul Universitar de Urgenta Bucuresti	Bucharest
Romania	Spitalul Clinic Colentina	Bucuresti
Romania	Institutul Oncologic Prof Dr Ion Chiricuta	Cluj-Napoca
Romania	Institutul Regional de Oncologie Iasi	Iasi
Romania	Spitalul Clinic Dr Gavril Curteanu Oradea	Oradea
Romania	Spitalul Clinic Judetean de Urgenta Sibiu	Sibiu
Romania	Spitalul Clinic Municipal de Urgenta Timisoara	Timisoara
Russian Federation	Regional Clinical Hospital	Krasnoyarsk
Russian Federation	Moscow State Budget Healthcare Institution City clinical Hospital 52 of Moscow Healthcare Department	Moscow
Russian Federation	SBHI of Moscow city City clinical hospital na S P Botkin of Moscow city Healthcare department	Moscow
Russian Federation	SBHI of Republic of Karelia Republic Hosiptal n a V A Baranov	Petrozavodsk
Russian Federation	Federal centre of heart, blood and endocrinology Almazova	Saint Petersburg
Russian Federation	State Budget Educational Institution of High Professional Skills Samara State Medical University	Samara
Slovakia	Univerzitna nemocnica Bratislava, Nemocnica sv Cyrila a Metoda	Bratislava
Spain	Hospital Universitari Germans Trias i Pujol	Badalona	Cataluña
Spain	Hospital Clinic i Provincial de Barcelona	Barcelona	Cataluña
Spain	Hospital Universitari Son Espases	Palma de Mallorca	Baleares
Spain	Clinica Universidad de Navarra	Pamplona	Navarra
Spain	Hospital Universitario Quironsalud Madrid	Pozuelo de Alarcon	Madrid
Spain	Hospital Clinico Universitario de Salamanca	Salamanca	Castilla León
Sweden	Falu Lasarett	Falun
Sweden	Sahlgrenska Universitetssjukhuset	Goteborg
Sweden	Hallands Sjukhus Halmstad	Halmstad
Sweden	Sunderby Sjukhus	Lulea
Sweden	Skanes Universitetssjukhus	Lund
Turkey	Ankara Universitesi Tip Fakultesi Cebeci Arastirma ve Uygulama Hastanesi	Ankara
Turkey	Gazi Universitesi Saglik Arastirma ve Uygulama Merkezi Gazi Hastanesi	Ankara
Turkey	Bagcilar Medipol Mega Universite Hastanesi	Istanbul
Turkey	Istanbul Florence Nightingale Hastanesi	Istanbul
Turkey	Istanbul Universitesi Istanbul Tip Fakultesi	Istanbul
Turkey	Dokuz Eylul Universitesi Arastirma Uygulama Hastanesi	Izmir
Turkey	Erciyes Universitesi Tip Fakultesi Mehmet Kemal Dedeman Hematoloji-Onkoloji Hastanesi	Kayseri
United States	New York Oncology Hematology, PC	Albany	New York
United States	Oncology Hematology Care Inc	Cincinnati	Ohio
United States	Texas Oncology-Denton	Denton	Texas
United States	Rocky Mountain Cancer Centers Denver Midtown	Denver	Colorado
United States	US Oncology Research Investigational Products Center	Fort Worth	Texas
United States	Robert A Moss Oncology	Fountain Valley	California
United States	Oncology Consultants PA	Houston	Texas
United States	Baptist MD Anderson Cancer Center	Jacksonville	Florida
United States	Advocate Lutheran General Hospital	Park Ridge	Illinois
United States	Hartford HealthCare Cancer Institute at The Hospital of Central Connecticut	Plainville	Connecticut
United States	Texas Oncology	San Antonio	Texas
United States	United States Oncology Regulatory Affairs Corporate Office	The Woodlands	Texas

Sponsors (1)

Lead Sponsor	Collaborator
Amgen

Countries where clinical trial is conducted

United States,  Austria,  Bulgaria,  Czechia,  Finland,  France,  Germany,  Greece,  Japan,  Lithuania,  Netherlands,  Romania,  Russian Federation,  Slovakia,  Spain,  Sweden,  Turkey, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Response Rate (ORR) Per International Myeloma Working Group Uniform Response Criteria (IMWG-URC)	ORR 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) per IMWG-URC. CR: negative immunofixation on serum and urine, soft tissue plasmacytomas disappearance, < 5% plasma cells in bone marrow (BM). sCR: CR and normal serum free light chain ratio and no clonal cells in BM by immunohistochemistry. VGPR: Serum and urine M-protein detectable by immunofixation or = 90% reduction in serum M-protein (urine M-protein level < 100 mg/24-hours). PR: = 50% reduction of serum M-protein and reduction in 24-hours urinary M-protein by = 90% or to < 200 mg/24-hours. The ORR 95% confidence intervals (CIs) were estimated using the Clopper-Pearson method.	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	Kaplan-Meier Estimate of Progression-free Survival (PFS) Rate at 12 Months	PFS rate was defined as the percentage of participants without disease progression or death due to any cause at 12 months. The PFS rate at 12 months was estimated using the Kaplan-Meier method by Klein and Moeschberger (1997). 95% CIs were estimated using the method by Kalbfleisch and Prentice (1980). PFS data was censored for participants who met any one of the following: 1. no baseline/no post-baseline disease assessments; 2. starting new anti-myeloma therapy before documentation of progressive disease (PD) or death; 3. PD or death immediately after more than 1 consecutively missed disease assessment visit (PD or death immediately after > 63 days without disease assessment visit); 4. alive without documentation of PD; 5. lost to follow-up or withdrawn consent.	12 months
Secondary	Percentage of Participants Who Reported Convenience as Measured by the Patient-reported Convenience With Carfilzomib-dosing Schedule Question	Patient-reported convenience was measured by the Patient-reported Convenience with Carfilzomib-dosing Schedule Question. The items in the questionnaire were categorized as 'Convenient', which included responses of 'Very Convenient' and 'Convenient', and 'Inconvenient' which included responses of 'Inconvenient' and 'Very Inconvenient'. The 95% CIs were estimated using the Clopper-Pearson method.	Day 28 of Cycle 4
Secondary	Number of Participants With Treatment-emergent Adverse Events (TEAEs)	An adverse event (AE) was any untoward medical occurrence in a clinical study participant irrespective of a causal relationship with the study treatment. TEAEs were AEs starting on or after the first dose of any study drug, and up to 30 days of the last dose of any study drug, excluding AEs reported after End of Study date.	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
Secondary	Time to Response (TTR)	TTR was defined as the time from randomization to the earliest date when confirmed sCR, CR, VGPR, or PR per IMWG-URC was first achieved.	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	Kaplan-Meier Estimate of Duration of Response (DOR)	For participants who achieved a PR or better, i.e., sCR, CR, VGPR, or PR per IMWG-URC, the DOR was defined as the time from the earliest date when a PR or better was first achieved, and subsequently confirmed, to the earliest date of confirmed PD or death due to any cause. Median DOR was estimated using the Kaplan-Meier method. 95% CIs were estimated using the method by Klein and Moeschberger (1997) with log-log transformation. For those alive and who had not experienced PD by analysis time, DOR was censored for participants who met any one of the following: 1. no baseline/no post-baseline disease assessments; 2. starting new anti-myeloma therapy before documentation of PD or death; 3. PD or death immediately after more than 1 consecutively missed disease assessment visit (PD or death immediately after > 63 days without disease assessment visit); 4. alive without documentation of PD; 5. lost to follow-up or withdrawn consent.	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	Kaplan-Meier Estimate of Time to Progression (TTP)	TTP was defined as the duration from randomization for the first documented disease progression per IMWG-UCR. Median TTP was estimated using the Kaplan-Meier method. 95% CIs were estimated using the method by Klein and Moeschberger (1997) with log-log transformation. TTP was censored for participants who had no confirmed PD at the last non non-evaluable (non-NE), post-baseline disease assessment or the earlier of the following, where applicable: 1. the last non-NE, post-baseline disease assessment prior to start of a new anti-myeloma treatment, or 2. the last non-NE, post-baseline assessment followed > 63 days later by disease progression; otherwise, at randomization.	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	Kaplan-Meier Estimate of Overall Survival (OS)	OS was defined as the time from randomization to the date of death due to any cause. Median OS was estimated using the Kaplan-Meier method. 95% CIs were estimated using the method by Klein and Moeschberger (1997) with log-log transformation. Participants still alive or lost to follow-up or withdrawn consent from study by the analysis time were censored at the date on which the participant was last known to be alive.	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	Percentage of Participants Who Achieved Minimal Residual Disease Negative Complete Response (MRD[-]CR) by Independent Review Committee (IRC) Per IMWG-URC	MRD[-]CR was defined as achievement of CR or better by IRC per IMWG-URC and achievement of MRD negativity as assessed by next generation sequencing method at a 10^-5 threshold over the duration of the study. The 95% CIs for percentages were estimated using the Clopper-Pearson method.	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	Percentage of Participants With Minimal Residual Disease Negativity (MRD[-]) by IRC Per IMWG-URC at 12 Months	The percentage of participants with achievement of MRD[-] at 12 months (± 4 weeks) from randomization, as assessed by next generation sequencing method at a 10^-5 threshold. MRD negativity results from BM samples obtained at 8 to 13 months from randomization and prior to new anti-myeloma therapy or disease progression were considered in the calculation. The 95% CIs for percentages were estimated using the Clopper-Pearson method.	Cycle 1 Day 1 up to 12 months (cycle = 28 days)
Secondary	Change From Baseline in European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ)-Core 30 (C30) Physical Functioning Scale	The QLQ-C30 physical function is one of the functional domains of the EORTC QLQ-C30 self-reported instrument and the physical functioning score score ranges from 0-100 points, with 100 points indicating the best possible functioning. A positive change from baseline indicated an improvement in functioning.	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)
Secondary	Change From Baseline in EORTC QLQ-C30 Role Functioning Scale	The QLQ-C30 role function is one of the functional domains of the EORTC QLQ-C30 self-reported instrument and the role functioning score ranges from 0-100 points, with 100 points indicating the best possible functioning. A positive change from baseline indicated an improvement in functioning.	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)
Secondary	Patient-reported Treatment Satisfaction as Measured by the Cancer Therapy Satisfaction Questionnaire (CTSQ)	The CTSQ measures treatment satisfaction in individuals with cancer and includes a domain for satisfaction with therapy. The satisfaction with therapy scores ranges from 0 to 100 points, with 100 points indicating greatest satisfaction.; Analysis was based on ANCOVA model. The dependent variable of the models were the scale scores measured at each visit. The model included effects of intercept, scale score measured at cycle 2 day 1 visit, treatment arm, and randomization stratification factors.	Cycle 5 Day 1, Cycle 12 Day 1, and safety follow-up (30 days after last dose)

External Links

•   AmgenTrials clinical trials website