A Study to Evaluate Subcutaneous Daratumumab in Combination With Standard Multiple Myeloma Treatment Regimens

Sponsor
Janssen Research & Development, LLC (Industry)
Overall Status
Active, not recruiting
CT.gov ID
NCT03412565
Collaborator
(none)
265
Enrollment
64
Locations
4
Arms
49.4
Anticipated Duration (Months)
4.1
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the clinical benefit of subcutaneous (SC) daratumumab administered in combination with standard multiple myeloma (MM) regimens in participants with MM as measured by overall response rate (ORR) or very good partial response (VGPR) or better rate.

Detailed Description

The hypothesis is that the addition of daratumumab administered SC to standard MM regimens will improve responses compared to response data observed in completed phase 3 studies without daratumumab. Disease evaluations will include measurements of myeloma proteins, bone marrow examinations, skeletal surveys, assessment of extramedullary plasmacytomas, and measurements of serum calcium corrected for albumin. Safety will be measured by adverse events, laboratory test results, electrocardiogram (ECGs), vital sign measurements, physical examination findings, SC injection-site assessments, and assessment of Eastern Cooperative Oncology Group (ECOG) performance status score. Study will consist of 3 phases (screening, treatment and follow-up) and duration of study is approximately 3 years.

Study Design

Study Type:
Interventional
Actual Enrollment :
265 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Multicenter Phase 2 Study to Evaluate Subcutaneous Daratumumab in Combination With Standard Multiple Myeloma Treatment Regimens
Actual Study Start Date :
Apr 26, 2018
Actual Primary Completion Date :
Aug 12, 2020
Anticipated Study Completion Date :
Jun 7, 2022

Arms and Interventions

ArmIntervention/Treatment
Experimental: Daratumumab(D)+Bortezomib+Lenalidomide+Dexamethasone (D-VRd)

Participants will receive daratumumab 1800 milligram (mg) by subcutaneous (SC) injection on Days 1, 8 and 15 of Cycles 1 to 3 (each cycle of 21 days) and on Day 1 of Cycle 4; bortezomib 1.3 milligram per square meter (mg/m^2) SC injection on Days 1, 4, 8 and 11 of Cycles 1 to 4; lenalidomide 25 mg orally on Day 1 through Day 14 of Cycles 1 to 4 and dexamethasone 20 mg orally or intravenously on Days 1, 2 ,8, 9, 15 and 16 of Cycle 1 to 4.

Drug: Daratumumab
Daratumumab will be administered at a dose of 1800 mg by SC injection in Cycles 1 to 4 in D-VRd cohort and until documented progression of disease, unacceptable toxicity, or end of study for D-VMP, D-Rd and D-Kd cohorts.

Drug: Bortezomib
Bortezomib will be administered as 1.3 mg/m^2 SC injection in Cycles 1 to 4 in D-VRd cohort and in Cycles 1 to 9 in D-VMP cohort.

Drug: Lenalidomide
Lenalidomide will be administered as 25 mg capsule orally in Cycles 1 to 4 in D-VRd cohort and in all Cycles until documented progression of disease, unacceptable toxicity, or end of study in D-Rd cohort.

Drug: Dexamethasone
Dexamethasone will be administered as 20 mg orally or intravenously in Cycles 1 to 4 in D-VRd cohort; 40 mg orally or intravenously in all cycles and thereafter until documented progression of disease, unacceptable toxicity, or end of study in D-Rd and D-Kd cohort.

Experimental: D + Bortezomib + Melphalan + Prednisone (D-VMP)

Participants will receive daratumumab 1800 mg by SC injection on Days 1, 8, 15, 22, 29 and 36 of Cycle 1 then on Days 1 and 22 in Cycles 2 to 9 and Day 1 of Cycle 10 and thereafter until documented progression of disease, unacceptable toxicity, or end of study; bortezomib 1.3 mg/m^2 SC injection on Day 1, 4, 8, 11, 22, 25, 29 and 32 of Cycle 1 and on Days 1, 8, 22 and 29 of Cycles 2 to 9; melphalan 9 mg/m^2 orally on Day 1 through Day 4 of Cycles 1 to 9; prednisone 60 mg/m^2 orally on Days 1 to 4 of cycles 1 to 9.

Drug: Daratumumab
Daratumumab will be administered at a dose of 1800 mg by SC injection in Cycles 1 to 4 in D-VRd cohort and until documented progression of disease, unacceptable toxicity, or end of study for D-VMP, D-Rd and D-Kd cohorts.

Drug: Bortezomib
Bortezomib will be administered as 1.3 mg/m^2 SC injection in Cycles 1 to 4 in D-VRd cohort and in Cycles 1 to 9 in D-VMP cohort.

Drug: Melphalan
Melphalan will be administered as 9 mg/m^2 orally in Cycles 1 to 9.

Drug: Prednisone
Prednisone will be administered as 60 mg/m^2 orally in cycles 1 to 9.

Experimental: Daratumumab + Lenalidomide + Dexamethasone (D-Rd)

Participants will receive daratumumab 1800 mg by SC injection on Days 1, 8, 15 and 22 of Cycles 1 and 2 then on Day 1 and 15 of Cycles 3 to 6 and on Day 1 of Cycle 7 and thereafter until documented progression of disease, unacceptable toxicity, or end of study; lenalidomide 25 mg orally on Day 1 through Day 21 of each cycle until documented progression of disease, unacceptable toxicity, or end of study and dexamethasone 40 mg orally or intravenously weekly until documented progression of disease, unacceptable toxicity, or end of study.

Drug: Daratumumab
Daratumumab will be administered at a dose of 1800 mg by SC injection in Cycles 1 to 4 in D-VRd cohort and until documented progression of disease, unacceptable toxicity, or end of study for D-VMP, D-Rd and D-Kd cohorts.

Drug: Lenalidomide
Lenalidomide will be administered as 25 mg capsule orally in Cycles 1 to 4 in D-VRd cohort and in all Cycles until documented progression of disease, unacceptable toxicity, or end of study in D-Rd cohort.

Drug: Dexamethasone
Dexamethasone will be administered as 20 mg orally or intravenously in Cycles 1 to 4 in D-VRd cohort; 40 mg orally or intravenously in all cycles and thereafter until documented progression of disease, unacceptable toxicity, or end of study in D-Rd and D-Kd cohort.

Experimental: Daratumumab + Carfilzomib + Dexamethasone (D-Kd)

Participants will receive daratumumab 1800 mg by SC injection on Days 1, 8, 15 and 22 of Cycles 1 and 2 (each cycle is of 28 days) then on Day 1 and 15 of Cycles 3 to 6 and on Day 1 of Cycle 7 and thereafter until documented progression of disease, unacceptable toxicity, or end of study; Carfilzomib 20 mg/m^2 intravenously (IV) on Day 1 of Cycle 1 only then 70 mg/m^2 IV on Days 8 and 15 of Cycle 1 and Days 1, 8 and 15 of Cycle 2 and thereafter until documented progression of disease, unacceptable toxicity, or end of study and dexamethasone 40 mg orally or IV weekly for Cycles 1-9 then on Days 1, 8, 15 of each cycle for Cycles 10 and thereafter until documented progression of disease, unacceptable toxicity, or end of study.

Drug: Daratumumab
Daratumumab will be administered at a dose of 1800 mg by SC injection in Cycles 1 to 4 in D-VRd cohort and until documented progression of disease, unacceptable toxicity, or end of study for D-VMP, D-Rd and D-Kd cohorts.

Drug: Dexamethasone
Dexamethasone will be administered as 20 mg orally or intravenously in Cycles 1 to 4 in D-VRd cohort; 40 mg orally or intravenously in all cycles and thereafter until documented progression of disease, unacceptable toxicity, or end of study in D-Rd and D-Kd cohort.

Drug: Carfilzomib
Carfilzomib will be administered as 20 mg/m^2 IV on Day 1 of Cycle 1 only then 70 mg/m^2 IV on Days 8 and 15 of Cycle 1 and Days 1, 8 and 15 of Cycle 2 and thereafter until documented progression of disease, unacceptable toxicity, or end of study in D-Kd cohort.

Outcome Measures

Primary Outcome Measures

  1. D-VMP, D-Kd, and D-Rd Cohort: Overall Response Rate (ORR) [10 months after the last participant enrolled (up to 10 months)]

    The ORR is defined as the percentage of participants who achieve partial response (PR) or better according to international myeloma working group (IMWG) criteria, during or after study treatment for D-VMP, D-Kd and D-Rd cohorts. IMWG criteria for PR: greater than or equal to (>=) 50 percent (%) reduction of serum M-protein and reduction in 24-hour urinary M-protein by >=90% or to less than (<) 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%. In addition to the above criteria, if present at baseline, a >=50% reduction in the size of soft tissue plasmacytomas is also required.

  2. D-VRd Cohort: Very Good Partial Response (VGPR) or Better Rate [10 months after the last participant enrolled (up to 10 months)]

    The VGPR or better rate, defined as the percentage of participants achieving VGPR or better according IMWG criteria during or after the study treatment in Daratumumab + Bortezomib + Lenalidomide + Dexamethasone (D-VRd) cohort. IMWG criteria for VGPR: Serum and urine M-component detectable by immunofixation but not on electrophoresis, or >= 90 percent (%) reduction in serum M-protein plus urine M-protein <100 milligram per 24 hours (mg/24 hours).

Secondary Outcome Measures

  1. Maximum Observed Serum Concentrations (Cmax) of Daratumumab [D-VRd: Day 4 of Cycles 1 and 4 and post treatment 4 weeks and at week 8; D-VMP and D-Rd: Day 4 of Cycles 1 and 2 and post treatment 4 weeks and at week 8; D-Kd: Day 4 of Cycles 1 and 3 and post treatment 4 weeks and at week 8]

    Cmax is defined as maximum concentration observed following daratumumab administration.

  2. Minimum Observed Serum Concentrations (Cmin) of Daratumumab [D-VRd: predose on Day 1 of Cycles 1, 3, and 4; D-VMP: predose on Day 1 of Cycles 1, 2, 3, 6 and 9; D-Rd: predose on Day 1 of Cycles 1, 3, 6, 9 and 12 and D-Kd: predose on Day 1 of Cycles 1, 3, 6, 9, and 12]

    Cmin is defined as the minimum concentration observed immediately before daratumumab administration.

  3. Percentage of Participants with Infusion-Related Reactions (IRR) [10 months after the last participant enrolled (up to 10 months)]

    The Percentage of Participants with infusion reactions will be reported.

  4. D-Kd, D-VMP, and D-Rd Cohort: Very Good Partial Response (VGPR) or Better Rate [10 months after the last participant enrolled (up to 10 months)]

    The VGPR or better rate, defined as the percentage of participants achieving VGPR or better rate according IMWG criteria during or after the study treatment for Daratumumab + Carfilzomib + Dexamethasone (D-Kd), Daratumumab + Bortezomib + Melphalan + Prednisone (D-VMP), and Daratumumab + Lenalidomide + Dexamethasone (D-Rd) cohorts. IMWG criteria for VGPR: Serum and urine M-component detectable by immunofixation but not on electrophoresis, or greater than equal to (>=) 90 percent (%) reduction in serum M-protein plus urine M-protein <100 milligram (mg)/24 hours.

  5. D-VRd Cohort: Overall Response Rate (ORR) [10 months after the last participant enrolled (up to 10 months)]

    The ORR is defined as the proportion of participants who achieve partial response (PR) or better according to IMWG criteria, during or after study treatment for D-VRd cohort. IMWG criteria for PR: greater than or equal to (>=) 50 percent (%) reduction of serum M-protein and reduction in 24-hour urinary M-protein by >=90% or to less than (<) 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%. In addition to the above criteria, if present at baseline, a >=50% reduction in the size of soft tissue plasmacytomas is also required.

  6. Complete Response or Better Rate [10 months after the last participant enrolled (up to 10 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, and <5% PCs in bone marrow. Stringent complete response (sCR): CR plus normal FLC ratio, and absence of clonal PCs by immunohistochemistry, immunofluorescence or 2- to 4 color flow cytometry.

  7. Duration of Response (DOR) [10 months after the last participant enrolled (up to 10 months)]

    Duration of response is defined as the time from the date of initial documented response (PR or better for D-Kd, D-VMP, D-Rd cohorts) to the date of first documented evidence of progressive disease or death due to progressive disease (PD).

  8. Number of Participants with Anti-Drug Antibodies Against Daratumumab or Recombinant Human Hyaluronidase (rHuPH20) [Up to 8 weeks after the last dose of study drug (approximately 1 year)]

    Participants with anti-drug antibodies against daratumumab or rHuPH20 will be analyzed.

  9. D-Kd, D-VMP, and D-Rd Cohorts: Percentage of Participants who are Minimal Residual Disease (MRD) Negative [10 months after the last participant enrolled (up to 10 months)]

    Percentage of participants who are MRD negative will be assessed for D-Kd, D-VMP, and D-Rd cohorts. MRD negative is defined as less than (<) 0.01% abnormal population counts to total event counts when measured by flow.

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
  • Multiple myeloma diagnosed according to the International Myeloma Working Group (IMWG) diagnostic criteria

  • Measurable, secretory disease as defined by any of the following:

  1. Serum monoclonal paraprotein (M-protein) level greater than or equal to (>=) 1.0 gram per deciliter (g/dL); or

  2. Urine M-protein level >= 200 milligram per 24 hours (mg/24 hours); or

  3. Light chain multiple myeloma (MM), for participants without measurable disease in the serum or urine: serum Immunoglobulin (Ig) free light chain (FLC) >= 10 mg/dL and abnormal FLC ratio

  • Meets one of the sets of the following criteria:
  1. For Daratumumab + bortezomib + lenalidomide + dexamethasone (D-VRd) and Daratumumab + bortezomib + melphalan + prednisone + dexamethasone (D-VMP) regimen: newly diagnosed myeloma

  2. For Daratumumab + lenalidomide + dexamethasone (D-Rd) and Daratumumab + Carfilzomib + Dexamethasone (D-Kd) regimen: relapsed or refractory disease

  3. D-Kd cohort: Participants must have received only 1 prior line of therapy for MM which included at least 2 consecutive cycles of lenalidomide therapy

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

  • During the study, during dose interruptions, and for 3 months after receiving the last dose of any component of the study treatment, a female participant must agree not to donate eggs (ova, oocytes) and male participants of reproductive potential must not donate semen or sperm during the study, during dose interruptions, or for 3 months after the last dose of any study drug

Exclusion Criteria:
  • History of malignancy (other than MM) unless all treatment of that malignancy was completed at least 2 years before consent and the participant 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

  • Exhibits clinical signs of meningeal involvement of MM

  • Either of the following: a) Chronic obstructive pulmonary disease with a forced expiratory volume in 1 second (FEV1) is less than (<) 50 percentage (%) of predicted normal b) Moderate or severe persistent asthma, or a history of asthma within the last 2 years, or currently has uncontrolled asthma of any classification c) For D-Kd cohort: Known infiltrative pulmonary disease or known pulmonary hypertension

  • Any of the following: a) Known to be seropositive for human immunodeficiency virus; b) Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Participants with resolved infection (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) DNA levels. Those who are polymerase chain reaction (PCR) positive will be excluded

  • Known to be seropositive for hepatitis C (Anti-HCV antibody positive or HCV-RNA quantitation positive) except in the setting of a sustained virologic response [SVR], defined as aviremia at least 12 weeks after completion of antiviral therapy

  • For D-Kd cohort only: Transthoracic echocardiogram showing left ventricular ejection fraction (LVEF) <40%; uncontrolled hypertension, defined as an average systolic blood pressure greater than (>)159 millimeters of mercury (mmHg) or diastolic >99 mmHg despite optimal treatment

Contacts and Locations

Locations

SiteCityStateCountryPostal Code
1Cancer Center of Central Connecticut - SouthingtonSouthingtonConnecticutUnited States06489-3237
2Mayo Clinic in FloridaJacksonvilleFloridaUnited States32224
3UF Health Cancer Center at Orlando HealthOrlandoFloridaUnited States32806
4Karmonos Cancer InstituteDetroitMichiganUnited States48201
5Providence Cancer CenterSouthfieldMichiganUnited States48075
6Billings ClinicBillingsMontanaUnited States59101
7Nebraska Hematology and OncologyLincolnNebraskaUnited States68506
8Southeast Nebraska Cancer CenterLincolnNebraskaUnited States68510
9Nebraska Cancer SpecialistsOmahaNebraskaUnited States68130
10San Juan Oncology AssociatesFarmingtonNew MexicoUnited States87401
11NYU WinthropMineolaNew YorkUnited States11501
12Mt. Sinai School of MedicineNew YorkNew YorkUnited States10029
13Wake Forest University Baptist Medical Center (WFUBMC) - Comprehensive Cancer CenterWinston-SalemNorth CarolinaUnited States27157
14Avera Medical Group - Oncology & HematologySioux FallsSouth DakotaUnited States57105
15Utah Cancer SpecialistsSalt Lake CityUtahUnited States84121
16University of Virginia Cancer Center - Emily Couric Clinical Cancer Center - Women's Oncology ClinicCharlottesvilleVirginiaUnited States22903
17Liga Norte Riograndense Contra O CancerNatalBrazil59062-000
18Centro de Pesquisa do Instituto do Câncer- Hospital São Vicente de PauloPasso FundoBrazil99010-090
19Instituto Nacional do Cancer - INCARio de JaneiroBrazil20230-130
20Universidade Federal de Sao PauloSao PauloBrazil04037-002
21Hospital do Servidor Publico Estadual - IAMSPESao PauloBrazil
22Clinica Sao GermanoSão PauloBrazil01455-010
23Fakultni nemocnice BrnoBrnoCzechia625 00
24Fakultni nemocnice Hradec KraloveHradec KraloveCzechia500 05
25Fakultni nemocnice OstravaOstravaCzechia70852
26Vseobecna fakultni nemocnice v Praze - I. interni klinika - klinika hematologiePraha 2Czechia128 08
27CHU de Nantes hôtel-DieuNantes Cedex 1France44093
28CHU de Bordeaux - Hôpital Haut-LévêquePessac cedexFrance33604
29Centre hospitalier Lyon-SudPierre-BéniteFrance69495
30CHU BretonneauTours Cedex 9France37044
31CHU Nancy BraboisVandoeuvre Les NancyFrance54511
32Klinikum Chemnitz gGmbHChemnitzGermany09113
33Universitaetsklinikum Hamburg EppendorfHamburgGermany20246
34Asklepios Klinik AltonaHamburgGermany22763
35Universitaetsklinikum HeidelbergHeidelbergGermany69120
36Universitaetsklinikum Tuebingen der Eberhard-Karls-Universitaet, Abteilung fuer Innere Medizin II,TübingenGermany72076
37Rambam Medical CenterHaifaIsrael31096
38Carmel Medical CenterHaifaIsrael3436212
39Hadassah Medical CenterJerusalemIsrael9112001
40Galilee Medical CenterNahariyaIsrael22100
41Sheba Medical CenterRamat GanIsrael52621
42Tel-Aviv Sourasky Medical CenterTel-AvivIsrael64239
43Kanazawa University HospitalKanazawaJapan920-8641
44Matsuyama Red Cross HospitalMatsuyamaJapan790-8524
45Nagoya City University HospitalNagoyaJapan467-8602
46Japanese Red Cross Medical CenterShibuyaJapan150-8935
47Inst. Cat. D'Oncologia-BadalonaBadalonaSpain08916
48Hosp. Clinic I Provincial de BarcelonaBarcelonaSpain08036
49Inst. Cat. Doncologia-H Duran I ReynalsBarcelonaSpain08908
50Hosp. Univ. Vall D HebronBarcelonaSpain8035
51Hosp. Gral. Univ. Gregorio MarañonMadridSpain28007
52Clinica Univ. de NavarraMadridSpain28027
53Hosp. Univ. Ramon Y CajalMadridSpain28034
54Hosp. Univ. 12 de OctubreMadridSpain28041
55Hosp. Son LlatzerMallorcaSpain07198
56Clinica Univ. de NavarraPamplonaSpain31008
57Hosp. Clinico Univ. de SalamancaSalamancaSpain37007
58Hosp. Univ. Dr. PesetValenciaSpain46017
59Heart of England NHS Foundation TrustBirminghamUnited KingdomB9 5SS
60Royal Bournemouth HospitalBournemouthUnited KingdomBH7 7DW
61Kent and Canterbury HospitalCanterburyUnited KingdomCT1 3NG
62Manchester Royal InfirmaryManchesterUnited KingdomM13 9WL
63Derriford HospitalPlymouthUnited KingdomPL6 8DH
64Royal Stoke University HospitalStoke on TrentUnited KingdomST4 6QG

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

Publications

None provided.
Responsible Party:
Janssen Research & Development, LLC
ClinicalTrials.gov Identifier:
NCT03412565
Other Study ID Numbers:
  • CR108435
  • 2017-004203-41
  • 54767414MMY2040
First Posted:
Jan 26, 2018
Last Update Posted:
Oct 8, 2021
Last Verified:
Oct 1, 2021
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