Clinical trial NCT03158688: Study of Carfilzomib, Daratumumab and Dexamethasone for Patients With Relapsed and/or Refractory Multiple Myeloma.
Official title: A Randomized, Open-label, Phase 3 Study Comparing Carfilzomib, Dexamethasone, and Daratumumab to Carfilzomib and Dexamethasone for the Treatment of Patients With Relapsed or Refractory Multiple Myeloma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Relapsed Multiple Myeloma
Refractory Multiple Myeloma
Keywords: Carfilzomib
Dexamethasone
Daratumumab
Lead sponsor: Amgen
Sponsor class: INDUSTRY
First posted: 2017-05-18
Enrollment: 466
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Compare carfizomib, dexamethasone, and daratumumab (KdD) to Carfilzomib and dexamethasone (Kd) in terms of progression free survival (PFS) in participants with multiple myeloma who have relapsed after 1 to 3 prior therapies.

Detailed description: This is a phase 3 multicenter, open-label, randomized study in participants with relapsed or refractory multiple myeloma (RRMM) who have received 1 to 3 prior therapies.

Participants receive the treatment determined by randomization for a maximum of approximately 5 years, up to 30 days prior to the final analysis data cutoff (DCO) date or until confirmed disease progression, unacceptable toxicity, withdrawal of consent, or death (whichever occurs first). No crossover between the treatment arms is allowed.

This was an open-label study. However, the assessment of response and disease progression for the primary analysis was determined by an Independent Review Committee (IRC) in a blinded manner. Sensitivity analyses of response and disease progression were determined centrally by the sponsor using a validated computer algorithm (Onyx Response Computational Assessment \[ORCA\]) in a blinded manner.

Following progression or discontinuation of study drug(s), participants will have 1 follow-up visit (30 days \[+3} after last dose of all study drug\[s\]). After disease progression, data on survival status and subsequent antimyeloma therapy will be gathered at long-term follow-up (LTFU) visits every 12 weeks (+/-2 weeks) until the Final Analysis DCO.

Eligibility criteria: Inclusion Criteria:

* Criteria 1 Relapsed or progressive multiple myeloma after last treatment
* Criteria 2 Males or females ≥ 18 years of age
* Criteria 3 Measurable disease with at least 1 of the following assessed within 21 days prior to randomization:
* IgG multiple myeloma: serum monoclonal paraprotein (M-protein) level ≥ 1.0 g/dL,
* IgA, IgD, IgE multiple myeloma: serum M-protein level ≥ 0.5 g/dL,
* urine M-protein ≥ 200 mg/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
* Criteria 4 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
* Criteria 5 Prior therapy with carfilzomib is allowed as long as the patient had at least a partial response (PR) to most recent therapy with carfilzomib, was not removed due to toxicity, did not relapse within 60 days from discontinuation of carfilzomib, and will have at least a 6-month carfilzomib treatment-free interval from last dose received until first study treatment. (Patients may receive maintenance therapy with drugs that are not proteasome inhibitors or CD38 antibodies during this 6-month carfilzomib treatment free interval)
* Criteria 6 Prior therapy with anti-CD38 antibodies is allowed as long as the patient had at least a PR to most recent therapy with CD38 antibody, was not removed due to toxicity, did not relapse within 60 days from intensive treatment (at least every other week) of CD38 antibody therapy, and will have at least a 6 month CD38 antibody treatment-free interval from last dose received until first study treatment
* Other inclusion criteria may apply

Exclusion Criteria:

* Criteria 1 Waldenström macroglobulinemia
* Criteria 2 Multiple myeloma of IgM subtype
* Criteria 3 POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
* Criteria 4 Plasma cell leukemia (\> 2.0 \* 10\^9/L circulating plasma cells by standard differential)
* Criteria 5 Myelodysplastic syndrome
* Criteria 6 Known moderate or severe persistent asthma within the past 2 years
* Criteria 7 Known chronic obstructive pulmonary disease (COPD) with a FEV1 \< 50% of predicted normal
* Criteria 8 Active congestive heart failure (New York Heart Association \[NYHA\] Class III to IV), symptomatic ischemia, uncontrolled arrhythmias, clinically significant electrocardiogram (ECG) abnormalities, screening ECG with corrected QT interval (QTc) of \> 470 msec, pericardial disease, or myocardial infarction within 4 months prior to randomization
* Other exclusion criteria may apply

Primary outcomes:
measure: Progression-free Survival (PFS) as Assessed by the Independent Review Committee (PA DCO Only)
timeFrame: From randomization until the PA DCO date of 14 July 2019; the longest treatment duration as of the DCO was 102.3 weeks
Secondary outcomes:
measure: Overall Response (OR) as Assessed by the Independent Review Committee (PA DCO Only)
timeFrame: From randomization until the PA DCO date of 14 July 2019; the longest treatment duration as of the DCO was 102.3 weeks
measure: Minimal Residual Disease Negative Complete Response Rate (MRD[-]CR) at 12 Months as Assessed by the Independent Review Committee
timeFrame: 12 Months (8- to 13-month window)
measure: Overall Survival
timeFrame: Up to 58 months after the first participant was enrolled (at FA DCO, a median of 40.29 weeks of treatment [any study drug] in the Kd group and 79.29 weeks of treatment [any study drug] in the KdD group; FA DCO was 15 Apr 2022)
measure: Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
timeFrame: PA DCO: the longest treatment duration as of the PA DCO was 102.3 weeks; FA DCO: the longest treatment duration as of the FA DCO was 236.3 weeks
measure: Kaplan-Meier Estimate for Duration of Response (DOR) (PA DCO Only)
timeFrame: From Day 1 until the PA DCO date of 14 July 2019; the longest treatment duration as of the DCO was 102.3 weeks
measure: Kaplan-Meier Estimate for Time to Next Treatment (TTNT)
timeFrame: PA DCO: the longest treatment duration as of the PA DCO was 102.3 weeks; FA DCO: the longest treatment duration as of the FA DCO was 236.3 weeks
measure: Kaplan-Meier Estimates for Time to Progression (TTP) as Assessed by the Independent Review Committee (PA DCO Only)
timeFrame: From randomization until the PA DCO date of 14 July 2019; the longest treatment duration as of the DCO was 102.3 weeks
measure: Time to Progression (TTP): Percentage of Participants Who Had Not Had Disease Progression as Assessed by the Independent Review Committee at Months 3, 6, 12, and 18 (PA DCO Only)
timeFrame: Randomization to Months 3, 6, 12, and 18
measure: Time to Overall Response as Assessed by the Independent Review Committee (PA DCO Only)
timeFrame: From randomization until the PA DCO date of 14 July 2019; the longest treatment duration as of the DCO was 102.3 weeks
measure: Percentage of Participants Who Achieved and Maintained a Minimal Residual Disease Negative Complete Response (MRD[-]CR) for 12 Months or More
timeFrame: PA DCO: the longest treatment duration as of the PA DCO was 102.3 weeks; FA DCO: the longest treatment duration as of the FA DCO was 236.3 weeks
measure: Percentage of Participants With a Complete Response (CR) as Assessed by the Independent Review Committee (PA DCO Only)
timeFrame: From randomization until the PA DCO date of 14 July 2019; the longest treatment duration as of the DCO was 102.3 weeks
measure: Percentage of Participants Who Achieved Minimal Residual Disease Negative (MRD[-]) Status as Assessed by Next Generation Sequencing at 12 Months
timeFrame: 12 Months (8- to 13-month window)
measure: Quality of Life Core Module (QLQ-C30) Global Health Status/Quality of Life Scores For Baseline Up to the First Follow-Up Visit After the Last Dose
timeFrame: Baseline (Day 1 pre-dose) up to 236.3 weeks (longest treatment duration as of the FA DCO)
Other outcomes:
Locations:
city: Boca Raton
country: United States
facility: Lynn Cancer Center Boca Raton Regional Hospital, Lynn Cancer Institute
state: Florida
city: Atlanta
country: United States
facility: Emory University Winship Cancer Institute
state: Georgia
city: Chicago
country: United States
facility: University of Chicago Medical Center - Multiple Myeloma Research Consortium
state: Illinois
city: Fort Wayne
country: United States
facility: Fort Wayne Medical Oncology and Hematology
state: Indiana
city: Hattiesburg
country: United States
facility: Hattiesburg Clinic Hematology/Oncology
state: Mississippi
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: New York
country: United States
facility: New York Presbyterian Hospital, Weill Cornell Medical College
state: New York
city: Charlotte
country: United States
facility: Levine Cancer Institute
state: North Carolina
city: Dover
country: United States
facility: Gabrail Cancer Center, LLC
state: Ohio
city: Charleston
country: United States
facility: Charleston Oncology
state: South Carolina
city: Dallas
country: United States
facility: Baylor Charles A Sammons Cancer Center at Dallas
state: Texas
city: Liverpool
country: Australia
facility: Liverpool Hospital
state: New South Wales
city: St Leonards
country: Australia
facility: St Vincents Hospital Sydney
state: New South Wales
city: Westmead
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Herston
country: Australia
facility: Royal Brisbane and Womens Hospital
state: Queensland
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: East Melbourne
country: Australia
facility: Epworth Healthcare
state: Victoria
city: Fitzroy, VIC
country: Australia
facility: St Vincents Hospital Melbourne
state: Victoria
city: Geelong
country: Australia
facility: Barwon Health, University Hospital Geelong
state: Victoria
city: Melbourne
country: Australia
facility: The Alfred Hospital
state: Victoria
city: Graz
country: Austria
facility: Medizinische Universitaet Graz
city: Salzburg
country: Austria
facility: Landeskrankenhaus Salzburg
city: Antwerpen
country: Belgium
facility: Ziekenhuis Netwerk Antwerpen Stuivenberg
city: Brussel
country: Belgium
facility: Universitair Ziekenhuis Brussel
city: Charleroi
country: Belgium
facility: Grand HÃ´pital de Charleroi
city: Gent
country: Belgium
facility: Universitair Ziekenhuis Gent
city: Leuven
country: Belgium
facility: Universitair Ziekenhuis Leuven - Campus Gasthuisberg
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: Calgary
country: Canada
facility: Tom Baker Cancer Centre
state: Alberta
city: Edmonton
country: Canada
facility: Cross Cancer Institute
state: Alberta
city: Ottawa
country: Canada
facility: Ottawa Hospital Research Institute
state: Ontario
city: Toronto
country: Canada
facility: Princess Margaret Cancer Centre
state: Ontario
city: Montreal
country: Canada
facility: Hopital Maisonneuve-Rosemont
state: Quebec
city: Brno
country: Czechia
facility: Fakultni nemocnice Brno
city: Hradec Kralove
country: Czechia
facility: Fakultni nemocnice Hradec Kralove
city: Ostrava-Poruba
country: Czechia
facility: Fakultni nemocnice Ostrava
city: Plzen
country: Czechia
facility: Fakultni nemocnice Plzen
city: Praha 2
country: Czechia
facility: Vseobecna fakultni nemocnice v Praze
city: La Roche Sur Yon Cedex 9
country: France
facility: Centre Hospitalier DÃ©partemental les Oudairies
city: Le Chesnay cedex
country: France
facility: Centre Hospitalier de Versailles - Hopital Andre Mignot
city: Lille Cedex
country: France
facility: Centre Hospitalier RÃ©gional Universitaire de Lille - HÃ´pital Claude Huriez
city: Nantes Cedex 1
country: France
facility: Centre Hospitalier Universitaire de Nantes
city: Pessac Cedex
country: France
facility: Centre Hospitalier Universitaire de Bordeaux - Hopital Haut Leveque
city: Pierre-Benite cedex
country: France
facility: Centre Hospitalier Lyon Sud
city: Poitiers Cedex
country: France
facility: Centre Hospitalier Universitaire de Poitiers - Hopital la Miletrie
city: Vandoeuvre les Nancy Cedex
country: France
facility: Centre Hospitalier Universitaire de Nancy - Hopital de Brabois
city: Athens
country: Greece
facility: General Hospital Evangelismos
city: Athens
country: Greece
facility: Alexandra 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: Bekescsaba
country: Hungary
facility: Bekes Megyei Kozponti Korhaz Dr Rethy Pal Tagkorhaz
city: Budapest
country: Hungary
facility: Semmelweis Egyetem
city: Budapest
country: Hungary
facility: Del-pesti Centrumkorhaz - Orszagos Hematologiai es Infektologiai Intezet
city: Debrecen
country: Hungary
facility: Debreceni Egyetem Klinikai Kozpont
city: Szeged
country: Hungary
facility: Szegedi Tudomanyegyetem Szent-Gyorgyi Albert Klinikai Kozpont Altalanos Orvostudomanyi Kar
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: Fukuoka-shi
country: Japan
facility: Kyushu University Hospital
state: Fukuoka
city: Ogaki-shi
country: Japan
facility: Ogaki Municipal Hospital
state: Gifu
city: Maebashi-shi
country: Japan
facility: Gunma University Hospital
state: Gunma
city: Shibukawa-shi
country: Japan
facility: National Hospital Organization Shibukawa Medical Center
state: Gunma
city: Kyoto-shi
country: Japan
facility: University Hospital Kyoto Prefectural University of Medicine
state: Kyoto
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: 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: Tokushima-shi
country: Japan
facility: Tokushima Prefectural Central Hospital
state: Tokushima
city: Koto-ku
country: Japan
facility: 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: Goyang-si, Gyeonggi-do
country: Korea, Republic of
facility: National Cancer Center
city: Hwasun, Jeollanam-do
country: Korea, Republic of
facility: Chonnam National University Hwasun Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital Yonsei University Health System
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: The Catholic University of Korea Seoul St Marys Hospital
city: Bialystok
country: Poland
facility: InterHem
city: Chorzow
country: Poland
facility: Samodzielny Publiczny Zaklad Opieki Zdrowotnej Zespol Szpitali Miejskich w Chorzowie
city: Lublin
country: Poland
facility: Centrum Onkologii Ziemi Lubelskiej im Swietego Jana z Dukli
city: Poznan
country: Poland
facility: Szpital Kliniczny Przemienienia Panskiego Uniwersytetu Medycznego im K Marcinkowskiego w Poznaniu
city: Warszawa
country: Poland
facility: Instytut Hematologii i Transfuzjologii
city: Wroclaw
country: Poland
facility: Uniwersytecki Szpital Kliniczny im Jana Mikulicza-Radeckiego we Wroclawiu
city: Brasov
country: Romania
facility: Policlinica de Diagnostic Rapid
city: Bucharest
country: Romania
facility: Fundeni Clinical Institute
city: Bucharest
country: Romania
facility: Coltea Clinical Hospital
city: Bucuresti
country: Romania
facility: Spitalul Clinic Colentina
city: Bucuresti
country: Romania
facility: Bucharest Emergency University Hospital
city: Cluj-Napoca
country: Romania
facility: Profesor Dr Ion Chiricuta Institut of Oncology
city: Craiova
country: Romania
facility: Spitalul Clinic Municipal Filantropia Craiova
city: Nizhny Novgorod
country: Russian Federation
facility: SBHI of Nizhny Novgorod region Regional Clinical Hospital of Nizhny Novgorod na N A Semashko
city: Petrozavodsk
country: Russian Federation
facility: SBHI of Republic of Karelia Republic Hosiptal n a V A Baranov
city: Samara
country: Russian Federation
facility: State Budget Educational Institution of High Professional Skills Samara State Medical University
city: Saratov
country: Russian Federation
facility: Clinic of professional pathology and hematology
city: Salamanca
country: Spain
facility: Hospital Clinico Universitario de Salamanca
state: Castilla LeÃ³n
city: Badalona
country: Spain
facility: Hospital Universitari Germans Trias i Pujol
state: CataluÃ±a
city: Barcelona
country: Spain
facility: Hospital Clinic i Provincial de Barcelona
state: CataluÃ±a
city: Pamplona
country: Spain
facility: Clinica Universidad de Navarra
state: Navarra
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Taipei
country: Taiwan
facility: Taipei Veterans General Hospital
city: Ankara
country: Turkey
facility: Hacettepe Universitesi Tip Fakultesi
city: Ankara
country: Turkey
facility: Ankara Universitesi Tip Fakultesi Cebeci Hastanesi
city: Izmir
country: Turkey
facility: Ege University Faculty of Medicine
city: Samsun
country: Turkey
facility: Ondokuz Mayis Universitesi Tip Fakultesi
city: Leeds
country: United Kingdom
facility: St James University Hospital
city: London
country: United Kingdom
facility: University College London Hospital
city: Manchester
country: United Kingdom
facility: Christie Hospital
Study officials:
affiliation: Amgen
name: MD
role: STUDY_DIRECTOR
References:
citation: Quach H, Nooka A, Samoylova O, Venner CP, Kim K, Facon T, Spencer A, Usmani SZ, Grosicki S, Suzuki K, Delimpasi S, Weisel K, Obreja M, Zahlten-Kumeli A, Mateos MV. Carfilzomib, dexamethasone and daratumumab in relapsed or refractory multiple myeloma: results of the phase III study CANDOR by prior lines of therapy. Br J Haematol. 2021 Aug;194(4):784-788. doi: 10.1111/bjh.17541. Epub 2021 May 28. No abstract available.
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citation: Suzuki K, Min CK, Kim K, Lee JJ, Shibayama H, Ko PS, Huang SY, Li SS, Ding B, Khurana M, Iida S. Carfilzomib, dexamethasone, and daratumumab in Asian patients with relapsed or refractory multiple myeloma: post hoc subgroup analysis of the phase 3 CANDOR trial. Int J Hematol. 2021 Dec;114(6):653-663. doi: 10.1007/s12185-021-03204-9. Epub 2021 Aug 19.
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citation: Dimopoulos M, Quach H, Mateos MV, Landgren O, Leleu X, Siegel D, Weisel K, Yang H, Klippel Z, Zahlten-Kumeli A, Usmani SZ. Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): results from a randomised, multicentre, open-label, phase 3 study. Lancet. 2020 Jul 18;396(10245):186-197. doi: 10.1016/S0140-6736(20)30734-0.
citation: Leleu X, Beksac M, Chou T, Dimopoulos M, Yoon SS, Prince HM, Pour L, Shelekhova T, Chari A, Khurana M, Zhang J, Obreja M, Qi M, Oriol A, Siegel D. Efficacy and safety of weekly carfilzomib (70 mg/m2), dexamethasone, and daratumumab (KdD70) is comparable to twice-weekly KdD56 while being a more convenient dosing option: a cross-study comparison of the CANDOR and EQUULEUS studies. Leuk Lymphoma. 2021 Feb;62(2):358-367. doi: 10.1080/10428194.2020.1832672. Epub 2020 Oct 28.
citation: Usmani SZ, Quach H, Mateos MV, Landgren O, Leleu X, Siegel D, Weisel K, Shu X, Li C, Dimopoulos M. Final analysis of carfilzomib, dexamethasone, and daratumumab vs carfilzomib and dexamethasone in the CANDOR study. Blood Adv. 2023 Jul 25;7(14):3739-3748. doi: 10.1182/bloodadvances.2023010026.
citation: Weisel K, Mateos MV, Landgren O, Leleu X, Quach H, Bennett L, Talpes M, Majer I, Patel S, Usmani SZ. Health-Related Quality of Life in Patients With Relapsed/Refractory Multiple Myeloma Treated With Carfilzomib, Dexamethasone, and Daratumumab Versus Carfilzomib and Dexamethasone: An Analysis of Patient-Reported Outcomes From the Phase 3 CANDOR Trial. Clin Lymphoma Myeloma Leuk. 2025 Feb 19:S2152-2650(25)00067-9. doi: 10.1016/j.clml.2025.02.005. Online ahead of print.