Daratumumab Retreatment in Participants With Multiple Myeloma Who Have Been Previously Treated With Daratumumab

Sponsor
Janssen Research & Development, LLC (Industry)
Overall Status
Recruiting
CT.gov ID
NCT03871829
Collaborator
(none)
230
Enrollment
113
Locations
2
Arms
80.6
Anticipated Duration (Months)
2
Patients Per Site
0
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to compare the efficacy (rate of very good partial response [VGPR] or better as best response as defined by the International Myeloma Working Group [IMWG] criteria) of daratumumab subcutaneous (Dara-SC) in combination with carfilzomib and dexamethasone (Kd) with the efficacy of Kd in participants with relapsed refractory multiple myeloma who were previously exposed to daratumumab to evaluate daratumumab retreatment.

Condition or DiseaseIntervention/TreatmentPhase
  • Drug: Carfilzomib 20 mg/m^2
  • Drug: Carfilzomib 70 mg/m^2
  • Drug: Dexamethasone 40 mg
  • Drug: Dara-SC 1800 mg
  • Drug: Dexamethasone 20 mg
Phase 2

Detailed Description

For relapsed or refractory multiple myeloma, the treatment is determined on an individual basis. Common standard of care regimens use either a proteasome inhibitor (PI) or an immunomodulatory agent (IMiD) in combination with dexamethasone with or without a monoclonal antibody (mAb) such as daratumumab. After relapse from PIs or IMiDs, patients are often retreated with drugs that have same mechanism of action to which they have been sensitive. The disease becomes refractory and all effective treatment options are exhausted. Daratumumab is a human IgG1 mAb that binds with high affinity to unique epitope on cluster of differentiation 38 (CD38) and attacks tumor cells that overexpress CD38. Study is to determine the efficacy of Dara-SC in combination with carfilzomib and dexamethasone (DKd) in adult participants with relapsed refractory MM who had 1 to 3 prior line(s) of treatment including a line containing daratumumab to evaluate daratumumab retreatment. The MM treatment is determined on an individual basis where patient's age, prior therapy, bone marrow function, co-morbidities, patient preference and time to relapse are considered. Common standard of care regimens use either PI or an IMiD in combination with dexamethasone with or without a mAb. It is a targeted immunotherapy that attacks tumor cells that overexpress CD38, a transmembrane glycoprotein, in a variety of hematological malignancies including multiple myeloma. The study will be conducted in 3 phases: Screening (28 days), Treatment, and Follow-Up. Assessments like chest X-ray, spirometry test, electrocardiogram (ECG), will be performed during Screening phase. During the Treatment Phase, participants will be randomized to receive Kd or DKd. Efficacy assessments like bone marrow examination will be performed. Follow-up will continue until the end of study.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
230 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase 2 Study of Daratumumab Subcutaneous (Dara-SC) Administration in Combination With Carfilzomib and Dexamethasone (DKd) Compared With Carfilzomib and Dexamethasone (Kd) in Participants With Multiple Myeloma Who Have Been Previously Treated With Daratumumab to Evaluate Daratumumab Retreatment
Actual Study Start Date :
May 31, 2019
Anticipated Primary Completion Date :
Jan 6, 2023
Anticipated Study Completion Date :
Feb 15, 2026

Arms and Interventions

ArmIntervention/Treatment
Active Comparator: Arm A: Carfilzomib+Dexamethasone (Kd)

Participants will receive carfilzomib 20 milligram per square meter (mg/m^2) intravenously (IV) on Day 1 of Cycle 1 and then 70 mg/m^2 on Days 8 and 15 of Cycle 1 and thereafter on Days 1, 8, 15 of Cycle 2 onwards. Participants will receive dexamethasone 20 mg on Cycle 1 Day 1, a second dose of 20 milligram (mg) will be given on Cycle 1 Day 2 and 40 mg IV or orally on Days 8, 15, 22 for Cycle 1. Patients will then receive dexamethasone 40mg on days 1, 8, 15 and 22 for cycles 2-9, then on Days 1, 8, 15 for Cycle 10 onwards, until death, intolerable toxicity, start of a new treatment for multiple myeloma, withdrawal of consent, or end of the study. The total duration of each cycle is 28 Days.

Drug: Carfilzomib 20 mg/m^2
Carfilzomib 20 mg/m^2 will be administered intravenously (IV).

Drug: Carfilzomib 70 mg/m^2
Carfilzomib 70 mg/m^2 will be administered IV.

Drug: Dexamethasone 40 mg
Dexamethasone 40 mg will be administered as IV infusion or orally.

Drug: Dexamethasone 20 mg
Dexamethasone 20 mg will be administered as IV infusion or orally.

Experimental: Arm B: Dara-SC in combination with Kd (DKd)

Participants will receive daratumumab subcutaneous (Dara-SC) 1800 mg by SC injection on Days 1, 8, 15, 22 for Cycle 1 and 2, Days 1 and 15 for Cycle 3-6, Day 1 for Cycle 7 onwards. Participants will receive carfilzomib 20 mg/m^2 IV on Cycle 1 Day 1 and then 70 mg/m^2 on Day 8 and 15 of Cycle 1 and Days 1, 8 and 15 of Cycle 2. Participants will receive dexamethasone 20 mg on Cycle 1 Day 1, a second dose of 20 milligram (mg) will be given on Cycle 1 Day 2 and 40 mg IV or orally on Days 8, 15, 22 for Cycle 1. Patients will then receive dexamethasone 40mg on days 1, 8, 15 and 22 for cycles 2-9, then on Days 1, 8, 15 for Cycle 10 onwards, until death, intolerable toxicity, start of a new treatment for multiple myeloma, withdrawal of consent, or end of the study. The total duration of each cycle is 28 Days.

Drug: Carfilzomib 20 mg/m^2
Carfilzomib 20 mg/m^2 will be administered intravenously (IV).

Drug: Carfilzomib 70 mg/m^2
Carfilzomib 70 mg/m^2 will be administered IV.

Drug: Dexamethasone 40 mg
Dexamethasone 40 mg will be administered as IV infusion or orally.

Drug: Dara-SC 1800 mg
Dara-SC 1800 mg will be administered by SC injection.

Drug: Dexamethasone 20 mg
Dexamethasone 20 mg will be administered as IV infusion or orally.

Outcome Measures

Primary Outcome Measures

  1. Percentage of Participants Achieving Very Good Partial Response (VGPR) or Better Response [Up to 6 years and 9 months]

    Percentage of participants achieving VGPR or better response according IMWG criteria for VGPR will be reported. IMWG criteria for VGPR: Serum and urine M-component detectable by immunofixation but not on electrophoresis, or greater than or equal to (>=) 90 percent (%) reduction in serum M-protein plus urine M-protein less than (<) 100 milligram (mg)/24 hours.

Secondary Outcome Measures

  1. Overall Response Rate (ORR) [Up to 6 years and 9 months]

    ORR is defined as percentage of participants who achieve partial response (PR) or better (including VGPR, CR, sCR) responses prior to subsequent anti-myeloma therapy. IMWG criteria for PR: >=50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by >=90% or to <200 mg/24 hours; If the serum and urine M-protein are not measurable, a decrease of >=50% in the difference between involved and uninvolved free light chain (FLC) levels is required in place of the M-protein criteria; If serum and urine M-protein are not measurable, and serum free light assay is also not measurable, >=50% reduction in bone marrow plasma cells (PCs) is required in place of M-protein, provided baseline bone marrow plasma cell percentage was >=30%; additionally, if present at baseline, a >=50% reduction in the size of soft tissue PCs is also required.

  2. Percentage of Participants Achieving Complete Response (CR) or Stringent Complete Response (sCR) [Up to 6 years and 9 months]

    Complete response is based on serum M-Protein assessments. IMWG criteria for CR: Negative immunofixation on the serum and urine, and Disappearance of any soft tissue plasmacytomas (PCs), and <5% PCs in bone marrow. IMWG criteria for sCR defined as, CR plus normal free light chain (FLC) ratio, and Absence of clonal PCs by immunohistochemistry, immunofluorescence or 2- to 4- color flow cytometry.

  3. Progression Free Survival (PFS) [Up to 6 years and 9 months]

    PFS is time from date of randomization to date of documented progressive disease (PD) on first line treatment given for multiple myeloma (MM) or death, whichever comes first. IMWG criteria for PD: >=25% from lowest response level in serum M-component (the absolute increase must be >=0.5 gram per deciliter [g/dL]) and/or in urine M-component (the absolute increase must be >=200 mg/24 hour); only in participants without measurable serum and urine M-protein levels: increase of >=25% in the difference between involved and uninvolved free light chain levels and the absolute increase must be >10 mg/dL. BMPC%: the absolute % must be >=10%; definite increase in size of existing bone lesions or soft tissue plasmacytomas; definite development of new bone lesions or soft tissue plasmacytomas; development of hypercalcemia (corrected serum calcium >11.5 milligrams per deciliter (mg/dL) or 2.65 millimoles per liter [mmol/L]) that can be attributed solely to PC proliferative disorder.

  4. Overall Survival (OS) [Up to 6 years and 9 months]

    OS is defined as the time from the date of first dose of study drug to date of death due to any cause. If the participant is alive or the vital status is unknown, the participant will be censored at the date the participant will be last known to be alive.

  5. Percentage of Participants With Negative Minimal Residual Disease (MRD) [Up to 6 years and 9 months]

    Percentage of participants who have achieved MRD negative status will be assessed.

  6. Time to Next Treatment [Up to 6 years and 9 months]

    Time to next treatment is defined as the time from randomization to the start of the next-line treatment.

  7. Serum Concentrations of Daratumumab [Arm A: Cycle 1 (each cycle of 28 days) Day 1 (Cycle 1 Day 1), Cycle 3 Day 1; Arm B: Cycle 1 Day1, Cycle 3 Day 1, Cycle 7 Day 1 and Follow Up (post treatment Week 8)]

    Serum concentrations of daratumumab will be assessed.

  8. Number of Participants with Anti-Daratumumab Antibodies [Arm A: Cycle 1 (each cycle of 28 days) Day 1 (Cycle 1 Day 1), Cycle 3 Day 1; Arm B: Cycle 1 Day1, Cycle 3 Day 1, Cycle 7 Day 1 and Follow Up (post treatment Week 8)]

    Number of participants who test positive for anti-daratumumab antibodies will be reported.

  9. Number of Participants with Anti-recombinant Human Hyaluronidase (rHuPH20) Antibodies [Arm A: Cycle 1 (each cycle of 28 days) Day 1 (Cycle 1 Day 1), Cycle 3 Day 1; Arm B: Cycle 1 Day1, Cycle 3 Day 1, Cycle 7 Day 1 and Follow Up (post treatment Week 8)]

    Number of participants who test positive for anti-rHuPH20 antibodies will be reported.

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
  • Evidence of a response (partial response or better based on investigator's determination of response by International Myeloma Working Group [IMWG] criteria) to daratumumab-containing therapy with response duration of at least 4 months

  • Participants must have progressed from or be refractory to their last line of treatment. Relapsed or refractory disease as defined as: a) Relapsed disease is defined as an initial response to previous treatment, followed by confirmed progressive disease (PD) by IMWG criteria greater than (>) 60 days after cessation of treatment. b) Refractory disease is defined as less than (<) 25 percent (%) reduction in M-protein or confirmed PD by IMWG criteria during previous treatment or >60 days after cessation of treatment

  • Received 1 to 3 prior line(s) of treatment of which one contained daratumumab, and completed daratumumab at least 3 months prior to randomization. A single line of therapy may consist of 1 or more agents, and may include induction, hematopoietic stem cell transplantation, and maintenance therapy. Radiotherapy, bisphosphonate, or a single short course of corticosteroids (no more than the equivalent of dexamethasone 40 milligram per day [mg/day] for 4 days) would not be considered prior lines of therapy

  • Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0, 1, or 2

  • Women of childbearing potential must have a negative urine or serum pregnancy test at screening within 14 days prior to randomization

Exclusion Criteria:
  • Previous treatment with daratumumab within the last 3 months prior to randomization

  • Discontinuation of daratumumab due to a daratumumab-related adverse event (AE)

  • History of malignancy (other than multiple myeloma) unless all treatment of that malignancy was completed at least 2 years before consent and the patient has no evidence of disease. Further exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or breast, or other non-invasive lesion, that in the opinion of the investigator, with concurrence with the sponsor's medical monitor, is considered cured with minimal risk of recurrence within 3 years

  • Allergies, hypersensitivity, or intolerance to daratumumab, hyaluronidase, monoclonal antibodies (mAbs), human proteins, or their excipients, or known sensitivity to mammalian-derived products. Known history of allergy to Captisol (a cyclodextrin derivative used to solubilize carfilzomib)

  • Participant is: a) Known to be seropositive for human immunodeficiency virus (HIV) with one or more of the following: not receiving highly active antiretroviral therapy (ART), had a change in ART within 6 months of the start of screening, receiving ART that may interfere with study treatment, cluster of differentiation (CD)4 count <350 (unit: cells per cubic millimeter of blood) at screening, acquired immunodeficiency syndrome (AIDS)-defining opportunistic infection within 6 months of start of screening, and not agreeing to start ART and be on ART >4 weeks plus having HIV viral load <400 copies/milliliters (mL) at end of 4-week period (to ensure ART is tolerated and HIV controlled. b) Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Participants with resolved infection (example: participants who are HBsAg negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) deoxyribonucleic acid (DNA) levels. Those who are PCR positive will be excluded. c) Known to be seropositive for hepatitis C (except in the setting of a sustained virologic response [SVR], defined as aviremia at least 12 weeks after completion of antiviral therapy)

Contacts and Locations

Locations

SiteCityStateCountryPostal Code
1Banner MD Anderson Cancer CenterGilbertArizonaUnited States85234
2Oncology Institute of Hope and InnovationTucsonArizonaUnited States85745
3American Institute of Research (AIR)WhittierCaliforniaUnited States90603
4Fort Wayne Medical Oncology and Hematology, Inc.Fort WayneIndianaUnited States46804
5Karmanos Cancer Institute - Wayne State UniversityDetroitMichiganUnited States48201
6Mayo Clinic - RochesterRochesterMinnesotaUnited States55905
7Washington University School of MedicineSaint LouisMissouriUnited States63110-1032
8Columbia University Medical CenterNew YorkNew YorkUnited States10032
9Weill Medical College of Cornell UniversityNew YorkNew YorkUnited States10065
10Cleveland Clinic Main CampusClevelandOhioUnited States44195
11Baylor Scott and White HealthDallasTexasUnited States75246
12Millennium OncologyHoustonTexasUnited States77090
13Medical College Of WisconsinMilwaukeeWisconsinUnited States53226
14ZNA StuivenbergAntwerpenBelgium2060
15UZ GentGentBelgium9000
16Universidade Estadual de Campinas (UNICAMP) - Centro De Hematologia e HemoterapiaCampinasBrazil13083-878
17Hospital Erasto Gaertner- Liga Paranaense de Combate ao CâncerCuritibaBrazil81520-060
18Hospital Das Clinicas Da Universidade Federal De GoiasGoiâniaBrazil
19Liga Norte Riograndense Contra O CancerNatalBrazil59062-000
20NTC Santa Casa Porto AlegrePorto AlegreBrazil90050-170
21Centro Gaucho Integrado De OncologiaPorto AlegreBrazil90110-270
22INCA - Instituto Nacional Do CancerRio De JaneiroBrazil20230-130
23Instituto COI de Educacao e PesquisaRio De JaneiroBrazil22793-080
24Hospital Sao RafaelSalvadorBrazil41253-190
25CEHONSalvadorBrazil45995-000
26Instituto de Ensino E Pesquisa Sao LucasSao PauloBrazil01236-030
27IBCC Instituto Brasileiro de Controle do CancerSao PauloBrazil03102-002
28Hospital Beneficencia PortuguesaSão PauloBrazil01321-001
29Clinica Sao GermanoSão PauloBrazil01455-010
30Ac Camargo Cancer CenterSão PauloBrazil01509-010
31Tom Baker Cancer CentreCalgaryAlbertaCanadaT2N 4N2
32Aarhus University HospitalAarhus NDenmarkDK-8200
33Regionshospitalet i HolstebroHolstebroDenmark7500
34Haematological Research unit HFE-X OUH.OdenseDenmark5000
35Vejle HospitalVejleDenmarkDK-7100
36Hopital Claude HuriezLilleFrance59037
37CHU de Montpellier, Hopital Saint-EloiMontpellierFrance34295
38Centre Hospitalier Emile MullerMulhouseFrance68100
39Hotel DieuNantesFrance44035
40Hopitaux Universitaires Est Parisien Hopital Saint AntoineParisFrance75012
41Hopital de la Pitie SalpetriereParisFrance75013
42Hôpital Necker-Enfants MaladesParisFrance75743
43Fentre F Magendie, Hôpital Haut Leveque, CHU BordeauxPessacFrance33600
44Centre Hospitalier Lyon-Sud Service d'hematologiePierre BeniteFrance69310
45CHU Poitiers - Hôpital la MilétriePoitiersFrance86021
46Chu Rennes - Hopital PontchaillouRennes CedexFrance35033
47Institut Claudius RegaudToulouseFrance31052
48CHU BretonneauToursFrance37044
49CHU Nancy BraboisVandoeuvre Les NancyFrance54511
50Universitätsklinik Carl Gustav Carus, Med. Klinik u. Poliklinik IDresdenGermany1307
51Evangelisches Krankenhaus Essen-WerdenEssenGermany45239
52Universitatsklinikum EssenEssenGermanyD-45147
53Universitätsklinik Hamburg-Eppendorf UKEHamburgGermany20246
54St. Barbara-Klinik Hamm GmbHHammGermany59075
55Universitaetsklinikum HeidelbergHeidelbergGermany69120
56Praxisklinik für Haematologie und Onkologie KoblenzKoblenzGermany56068
57Universitaetsklinikum KoelnKoelnGermany50397
58Universitätsmedizin der Johannes gutenberg-Universität; III. Med. Klinik - GermanyMainzGermany55101
59Onkologische Schwerpunkt PraxisSaarbruckenGermany
60Klinikum der Eberhard-Karls-Universität/Abt. für innere Med. II/Hämatologie/Onkologie-GermanyTubingenGermany72076
61Schwarzwald-Baar KlinikumVillingen-SchwenningenGermany78052
62Universitätsklinikum Würzburg Med. Klinik U. Poliklinik IiWürzburgGermany97080
63Alexandra General Hospital of AthensAthens AtticaGreece115 28
64University of Athens - Evaggelismos Hospital (Evangelismos Hospital)AthensGreece106 76
65University Hospital Of LarissaLarisaGreece41110
66University General Hospital of RioPatraGreece26500
67Anticancer Hospital of Thessaloniki 'Theageneio'ThessalonikiGreece546 39
68Azienda Ospedaliera Papa Giovanni XXIIIBergamoItaly24127
69Istituto di Ematologia Seràgnoli azienda ospedaliera univeristaria Policlinico S.Orsola-MalpighiBolognaItaly40138
70Azienda Ospedaliera Universitaria CareggiFirenzeItaly50139
71IRCCS Azienda Ospedaliera San Martino - ISTGenovaItaly16132
72San Martino HospitalGenovaItaly16132
73Asst Ovest Milanese - Ospedale Di LegnanoLegnanoItaly20025
74Istituto Scientifico Romagnolo per lo Studio e la Cura dei TumoriMeldolaItaly47014
75ASST Grande Ospedale Metropolitano NiguardaMilanoItaly20162
76Ospedale Maggiore della CaritàNovaraItaly28100
77Casa di Cura La MaddalenaPalermoItaly90146
78Ospedale Villa Sofia-CervelloPalermoItaly90146
79Fondazione IRCCS Policlinico San MatteoPaviaItaly27100
80Universita Degli Studi di Roma 'Tor Vergata'RomaItaly00133
81Sapienza University of RomeRomaItaly00161
82ASL ROMARomaItaly30 - 00153
83Fondazione Policlinico Universitario A. Gemelli IRCCSRomeItaly00168
84IRCCS Ospedale Casa Sollievo della SofferenzaSan Giovanni RotondoItaly71013
85Azienda Ospedaliera Santa MariaTerniItaly5100
86VUMCAmsterdamNetherlands1081
87Albert Schweitzer ziekenhuis-lokatie DordwijkDordrechtNetherlands3318 AT
88Zuyderland Medical CenterSittardNetherlands6130 MB
89Szpital Uniwersytecki nr 2 im. Jana Biziela w BydgoszczyBydgoszczPoland85-168
90Szpital Wojewodzki w OpoluOpolePoland45-061
91Szpital MagodentWarszawaPoland01-748
92Uniwersytecki Szpital Kliniczny im. Jana Mikulicza-Radeckiego we WroclawiuWroclawPoland50-367
93Emergency Hospital of DzerzhinskDzerzhinskRussian Federation606019
94Nizhniy Novgorod Region Clinical HospitalNizhny NovgorodRussian Federation603126
95Ryazan Regional Clinical HospitalRyazanRussian Federation390003
96Samara Region Clinical HospitalSamaraRussian Federation443095
97Oncological dispensary #2SochiRussian Federation354057
98Clinical Research Institute of Hematology and TransfusiologySt-PetersburgRussian Federation191024
99Oncology Dispensary of Komi RepublicSyktyvkarRussian Federation167904
100Hosp. Clinic I Provincial de BarcelonaBarcelonaSpain08036
101Inst. Cat. Doncologia-H Duran I ReynalsBarcelonaSpain08908
102Hosp. de Jerez de La FronteraJerez de la FronteraSpain11407
103Hosp. de LeonLeonSpain24080
104Hosp. Univ. Ramon Y CajalMadridSpain28034
105Hosp. Univ. 12 de OctubreMadridSpain28041
106Hosp. Univ. de La PazMadridSpain28046
107Hosp. Costa Del SolMalagaSpain29603
108Hosp. Univ. Son EspasesPalmaSpain7120
109Clinica Univ. de NavarraPamplonaSpain31008
110Hosp. Clinico Univ. de SalamancaSalamancaSpain37007
111Hosp. Univ. de CanariasSan Cristóbal de La LagunaSpain38320
112Hosp. Virgen Del RocioSevillaSpain41013
113Hosp. Virgen de La SaludToledoSpain45071

Sponsors and Collaborators

  • Janssen Research & Development, LLC

Investigators

  • Study Director: Janssen Research & Development, LLC Clinical Trial, Janssen Research & Development, LLC

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

Publications

None provided.
Responsible Party:
Janssen Research & Development, LLC
ClinicalTrials.gov Identifier:
NCT03871829
Other Study ID Numbers:
  • CR108598
  • 2018-004185-34
  • 54767414MMY2065
First Posted:
Mar 12, 2019
Last Update Posted:
Oct 8, 2021
Last Verified:
Oct 1, 2021
Individual Participant Data (IPD) Sharing Statement:
Yes
Plan to Share IPD:
Yes
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Additional relevant MeSH terms:

Study Results

No Results Posted as of Oct 8, 2021