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

Multiple Myeloma Clinical Trial

Official title:

A Multicenter Phase 2 Study to Evaluate Subcutaneous Daratumumab in Combination With Standard Multiple Myeloma Treatment Regimens

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03412565
• Other study ID #: CR108435
• Secondary ID: 2017-004203-4154
• Status: Completed
• Phase: Phase 2
• Start date: April 26, 2018
• Est. completion date: April 18, 2024

Study information

• Verified date: May 2024
• Source: Janssen Research & Development, LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 265
• Est. completion date: April 18, 2024
• Est. primary completion date: August 12, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Multiple Myeloma
• Neoplasms, Plasma Cell

Intervention

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.
• 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.
• 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.
• 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.
• Melphalan
Melphalan will be administered as 9 mg/m^2 orally in Cycles 1 to 9.
• Prednisone
Prednisone will be administered as 60 mg/m^2 orally in cycles 1 to 9.
• 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.

Locations

Country	Name	City	State
Brazil	Liga Norte Riograndense Contra O Cancer	Natal
Brazil	Associacao Hospitalar Beneficente Sao Vicente de Paulo - Hospital Sao Vicente de Paulo	Passo Fundo
Brazil	Ministerio da Saude - Instituto Nacional do Cancer	Rio de Janeiro
Brazil	Instituto de Assistencia Medica ao Servidor Publico Estadual IAMSPE	Sao Paulo
Brazil	SPDM - Associacao Paulista para o Desenvolvimento da Medicina - Hospital Sao Paulo	Sao Paulo
Brazil	Clinica Sao Germano	São Paulo
Czechia	Fakultni nemocnice Brno	Brno
Czechia	Fakultni nemocnice Hradec Kralove	Hradec Kralove
Czechia	Fakultni nemocnice Ostrava	Ostrava
Czechia	Vseobecna fakultni nemocnice v Praze - I. interni klinika - klinika hematologie	Praha 2
France	CHU de Nantes hotel Dieu	Nantes Cedex 1
France	CHU de Bordeaux - Hospital Haut-Leveque	Pessac cedex
France	Centre hospitalier Lyon-Sud	Pierre-Bénite
France	CHU Bretonneau	Tours Cedex 9
France	CHU Nancy Brabois	Vandoeuvre Les Nancy
Germany	Klinikum Chemnitz gGmbH	Chemnitz
Germany	Asklepios Klinik Altona	Hamburg
Germany	Universitaetsklinikum Hamburg Eppendorf	Hamburg
Germany	Universitaetsklinikum Heidelberg	Heidelberg
Germany	Universitaetsklinikum Tuebingen der Eberhard-Karls-Universitaet, Abteilung fuer Innere Medizin II,	Tübingen
Israel	Carmel Medical Center	Haifa
Israel	Rambam Medical Center	Haifa
Israel	Hadassah Medical Center	Jerusalem
Israel	Galilee Medical Center	Nahariya
Israel	Sheba Medical Center	Ramat Gan
Israel	Tel-Aviv Sourasky Medical Center	Tel-Aviv
Japan	Kanazawa University Hospital	Kanazawa
Japan	Matsuyama Red Cross Hospital	Matsuyama
Japan	Nagoya City University Hospital	Nagoya
Japan	Japanese Red Cross Medical Center	Shibuya
Spain	Inst. Cat. D'Oncologia-Badalona	Badalona
Spain	Hosp. Clinic de Barcelona	Barcelona
Spain	Hosp. Univ. Vall D Hebron	Barcelona
Spain	Inst. Cat. Doncologia-H Duran I Reynals	Barcelona
Spain	Clinica Univ. de Navarra	Madrid
Spain	Hosp. Gral. Univ. Gregorio Maranon	Madrid
Spain	Hosp. Univ. 12 de Octubre	Madrid
Spain	Hosp. Univ. Ramon Y Cajal	Madrid
Spain	Hosp. Son Llatzer	Mallorca
Spain	Clinica Univ. de Navarra	Pamplona
Spain	Hosp. Clinico Univ. de Salamanca	Salamanca
Spain	Hosp. Univ. Dr. Peset	Valencia
United Kingdom	Heart of England NHS Foundation Trust	Birmingham
United Kingdom	Royal Bournemouth Hospital	Bournemouth
United Kingdom	Kent and Canterbury Hospital	Canterbury
United Kingdom	Manchester Royal Infirmary	Manchester
United Kingdom	Derriford Hospital	Plymouth
United Kingdom	Royal Stoke University Hospital	Stoke on Trent
United States	Billings Clinic	Billings	Montana
United States	University of Virginia Cancer Center - Emily Couric Clinical Cancer Center - Women's Oncology Clinic	Charlottesville	Virginia
United States	Karmonos Cancer Institute	Detroit	Michigan
United States	San Juan Oncology Associates	Farmington	New Mexico
United States	Mayo Clinic in Florida	Jacksonville	Florida
United States	Nebraska Hematology and Oncology	Lincoln	Nebraska
United States	Southeast Nebraska Cancer Center	Lincoln	Nebraska
United States	NYU Winthrop	Mineola	New York
United States	Mt. Sinai School of Medicine	New York	New York
United States	Nebraska Cancer Specialists	Omaha	Nebraska
United States	UF Health Cancer Center at Orlando Health	Orlando	Florida
United States	Utah Cancer Specialists	Salt Lake City	Utah
United States	Avera Medical Group - Oncology & Hematology	Sioux Falls	South Dakota
United States	Providence Cancer Center	Southfield	Michigan
United States	Cancer Center of Central Connecticut - Southington	Southington	Connecticut
United States	Wake Forest University Baptist Medical Center (WFUBMC) - Comprehensive Cancer Center	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Janssen Research & Development, LLC

Countries where clinical trial is conducted

United States,  Brazil,  Czechia,  France,  Germany,  Israel,  Japan,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	D-VMP, D-Rd, and D-Kd Cohorts: Overall Response Rate (ORR)	ORR was defined as the percentage of participants who achieved partial response (PR) or better according to international myeloma working group (IMWG) criteria. 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 milligrams (mg) per 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.	Up to 2 years 3 months
Primary	D-VRd Cohort: Percentage of Participants With Very Good Partial Response (VGPR) or Better Response	VGPR or better rate was defined as the percentage of participants who achieved VGPR or complete response (CR) (including stringent complete response [sCR]) according to the IMWG criteria during or after the study treatment. VGPR: Serum and urine component detectable by immunofixation but not on electrophoresis, or >= 90% reduction in serum M-protein plus urine M-protein level <100 mg/24 hour; CR: negative immunofixation on the serum and urine, Disappearance of any soft tissue plasmacytomas and <5% PCs in bone marrow; sCR: CR in addition to having a normal FLC ratio and an absence of clonal cells in bone marrow by immunohistochemistry, immunofluorescence, 2-4 color flow cytometry.	Up to 2 years and 3 months
Secondary	Maximum Observed Serum Concentration (Cmax) of Daratumumab	Cmax was defined as maximum serum concentration observed following daratumumab administration. Each cycle for: D-VRd cohort is of 21 days, D-VMP cohort is of 42 days and D-Rd and D-Kd cohorts is of 28 days. Each cohort have a treatment period of 84 days.	D-VRd: Day 4 of Cycles 1 and 4 and post treatment at Week 8; D-VMP: Day 4 of Cycles 1 and 2 and post treatment at Week 8; D-Rd and D-Kd: Day 4 of Cycles 1 and 3 and post treatment at Week 8
Secondary	Percentage of Participants With Infusion-Related Reactions (IRRs)	Percentage of Participants with IRRs were reported. The administration-related systemic reactions are referred to as IRRs.	For D-VRD Arm: Baseline up to 2 years 3 months; For D-VMP, D-Rd and D-Kd Arms: Baseline up to 2 years 7 months
Secondary	D-VMP, D-Rd, and D-Kd Cohorts: Percentage of Participants With VGPR or Better Response	VGPR or better rate was defined as the percentage of participants who achieved VGPR or CR (including sCR) according to the IMWG criteria during or after the study treatment. VGPR: Serum and urine component detectable by immunofixation but not on electrophoresis, or >= 90% reduction in serum M-protein plus urine M-protein level <100 mg per 24 hour; CR: negative immunofixation on the serum and urine, Disappearance of any soft tissue plasmacytomas and <5% PCs in bone marrow; sCR: CR in addition to having a normal FLC ratio and an absence of clonal cells in bone marrow by immunohistochemistry, immunofluorescence, 2-4 color flow cytometry.	From baseline up to 2 years 7 months
Secondary	D-VRd Cohort: Overall Response Rate (ORR)	ORR was defined as the percentage of participants who achieved a PR or better, IMWG criteria, during the study or during follow up. 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 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 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.	Up to 2 years and 3 months
Secondary	Percentage of Participants With CR or Better Response	CR or better rate was defined as the percentage of participants with a CR or better response (that is, CR and sCR) as per IMWG criteria. CR: as negative immunofixation on the serum and urine and disappearance of soft tissue plasmacytomas and less than (<) 5 percent plasma cells in bone marrow; sCR: CR plus normal FLC ratio and absence of clonal PCs by immunohistochemistry, immunofluorescence or 2- to 4-color flow cytometry.	For D-VRD Arm: Baseline up to 2 years 3 months; For D-VMP, D-Rd and D-Kd Arms: Baseline up to 2 years 7 months
Secondary	D-VMP, D-Rd and D-Kd Cohorts: Duration of Response (DOR)	DOR was defined as the time from the date of initial documented response (PR or better response) to the date of first documented evidence of progressive disease (PD) or death due to PD. PD is defined as an increase of 25% from the lowest response value in one of the following: serum and urine M-component (absolute increase must be >=0.5 gram per deciliter [g/dL] and >=200 mg/24 hours respectively); only in participants without measurable serum and urine M-protein levels the difference between involved and uninvolved FLC levels (absolute increase must be >10 mg/dL); definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas; development of hypercalcemia (corrected serum calcium >11.5 mg/dL) that can be attributed solely to PC proliferative disorder.	From baseline up to 2 years 7 months
Secondary	Percentage of Participants With Anti-Daratumumab Antibodies	Percentage of participants with antibodies to daratumumab were reported.	For D-VRD Arm: Baseline up to 2 years 3 months; For D-VMP, D-Rd and D-Kd Arms: Baseline up to 2 years 7 months
Secondary	Percentage of Participants With Anti-rHuPH20 Antibodies	Percentage of participants with antibodies to rHuPH20 were reported.	For D-VRD Arm: Baseline up to 2 years 3 months; For D-VMP, D-Rd and D-Kd Arms: Baseline up to 2 years 7 months
Secondary	D-VMP, D-Rd, and D-Kd Cohorts: Percentage of Participants With Minimal Residual Disease (MRD) Negative Rate	MRD negativity rate was defined as the percentage of participants who were considered MRD negative after MRD testing at any timepoint after the first dose by bone marrow aspirate. MRD negativity rate was assessed by next-generation sequencing at a threshold of <10^5.	Up to 2 years and 3 months