A Study of Subcutaneous Versus (vs.) Intravenous Administration of Daratumumab in Participants With Relapsed or Refractory Multiple Myeloma

Multiple Myeloma Clinical Trial

Official title:

A Phase 3 Randomized, Multicenter Study of Subcutaneous vs. Intravenous Administration of Daratumumab in Subjects With Relapsed or Refractory Multiple Myeloma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03277105
• Other study ID #: CR108342
• Secondary ID: 2017-000206-3854
• Status: Completed
• Phase: Phase 3
• Start date: October 27, 2017
• Est. completion date: January 12, 2024

Study information

• Verified date: March 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 show that subcutaneous (SC) administration of daratumumab co-formulated with recombinant human hyaluronidase PH20 (Dara SC) is non-inferior to intravenous (IV) administration of daratumumab (Dara IV) in terms of the overall response rate (ORR) and maximum trough concentration (Ctrough).

Description:

The study population will consist of adults diagnosed with multiple myeloma who have received at least 3 prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD), or whose disease is refractory to both a PI and an IMiD. The study consists of 3 phases: a screening phase (up to 28 days), a treatment phase, and a follow-up phase. Efficacy, pharmacokinetics, immunogenicity, biomarkers and safety will be assessed at scheduled time. Follow-up will continue until the end of the data collection period, approximately 24 months after the last participant was randomized or when the median overall survival for both arms has been reached, whichever occurs first. The primary hypotheses is that the ORR and maximum Ctrough for Dara SC 1800 milligram (mg) are not inferior to the ORR and maximum Ctrough, respectively, for Dara IV 16 mg per kilogram (mg/kg) in participants with multiple myeloma who have received at least 3 prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD), or whose disease is refractory to both a PI and an IMiD.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 522
• Est. completion date: January 12, 2024
• Est. primary completion date: June 27, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Evidence of a response (Partial response [PR] or better based on investigator's determination of response by international myeloma working group [IMWG] criteria) to at least 1 prior treatment regimen

• Received at least 3 prior lines of therapy including a proteasome inhibitor (PI) (greater than or equal to [>=] 2 cycles or 2 months of treatment) and an immunomodulatory drug (IMiD) (>=2 cycles or 2 months of treatment) in any order during the course of treatment (except for participants who discontinued either of these treatments due to a severe allergic reaction within the first 2 cycles/months). 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/day [mg/day] for 4 days) would not be considered prior lines of therapy

• Documented multiple myeloma as defined by the criteria below:

1. Multiple myeloma diagnosis according to the IMWG diagnostic criteria

2. Measurable disease at Screening as defined by any of the following:

1. Serum M-protein level >=1.0 gram per deciliter (g/dL) or urine M-protein level >=200 mg/24 hours; or

2. Light chain multiple myeloma without measurable disease in the serum or the urine: Serum immunoglobulin free light chain (FLC) >=10 mg/dL and abnormal serum immunoglobulin kappa lambda FLC ratio

• Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2

• Meet the clinical laboratory criteria as specified in the protocol

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

Exclusion Criteria:

• Received daratumumab or other anti-CD38 therapies previously

• Received anti-myeloma treatment within 2 weeks or 5 pharmacokinetic half-lives of the treatment, whichever is longer, before the date of randomization. The only exception is emergency use of a short course of corticosteroids (equivalent of dexamethasone 40 mg/day for a maximum of 4 days) before treatment

• Received autologous stem cell transplant within 12 weeks before the date of randomization, or the participant has previously received allogeneic stem cell transplant (regardless of timing)

• Plans to undergo a stem cell transplant prior to progression of disease on this study (these participants should not be enrolled to reduce disease burden prior to transplant)

• 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

Related Conditions & MeSH terms

• Multiple Myeloma
• Neoplasms, Plasma Cell

Intervention

Drug:
• Dara SC
Participants will receive a fixed dose of Dara SC as 1800 mg daratumumab with rHuPH20 2000 U/mL, once weekly in Cycle 1 and 2, every 2 weeks in Cycle 3 to 6, every 4 weeks in Cycle 7 and thereafter until disease progression, unacceptable toxicity or the end of study.
• Dara IV
Participants will receive Dara IV 16 mg/kg once weekly in Cycle 1 and 2, every 2 weeks in Cycle 3 to 6, every 4 weeks in Cycle 7 and thereafter until disease progression, unacceptable toxicity or the end of study.

Locations

Country	Name	City	State
Australia	Royal Prince Alfred Hospital	Camperdown
Australia	St. Vincent's Hospital Melbourne	Fitzroy
Australia	Alfred Health	Melbourne
Australia	Fiona Stanley Hospital	Murdoch
Australia	Sir Charles Gairdner Hospital	Nedlands
Australia	Calvary Mater Newcastle Hospital	Waratah
Australia	The Queen Elizabeth Hospital	Woodville South
Australia	Princess Alexandra Hospital	Woolloongabba
Brazil	Fundacao Pio XII	Barretos
Brazil	Centro de Pesquisa e Ensino em Oncologia de Santa Catarina - CEPEN	Florianopolis
Brazil	Fundacao Doutor Amaral Carvalho	Jau
Brazil	Instituto Joinvilense de Hematologia e Oncologia Ltda-Centro de Hematologia e Oncologia	Joinville
Brazil	Associacao Hospitalar Beneficente Sao Vicente de Paulo - Hospital Sao Vicente de Paulo	Passo Fundo
Brazil	Hospital das Clinicas de Porto Alegre	Porto Alegre
Brazil	Instituto de Educacao, Pesquisa e Gestao em Saude	Rio de Janeiro
Brazil	CEHON	Salvador
Brazil	Fundacao Faculdade Regional de Medicina de Sao Jose do Rio Preto - Hospital de Base	Sao Jose do Rio Preto
Brazil	Clinica Sao Germano	São Paulo
Brazil	Hospital Das Clinicas Da Faculdade De Medicina Da USP	São Paulo
Canada	Tom Baker Cancer Centre	Calgary	Alberta
Canada	Cross Cancer Institute	Edmonton	Alberta
Canada	QEII Health Sciences Centre	Halifax	Nova Scotia
Canada	Victoria Hospital	London	Ontario
Canada	CHU de Québec -L'Hôtel-Dieu de Québec	Québec	Quebec
Canada	Princess Margaret Hospital	Toronto	Ontario
Canada	The Gordon & Leslie Diamond Health Care Center	Vancouver	British Columbia
Czechia	Fakultni nemocnice Brno	Brno
Czechia	Fakultni nemocnice Hradec Kralove	Hradec Kralove
Czechia	Fakultní nemocnice Olomouc	Olomouc
Czechia	Fakultni nemocnice Ostrava	Ostrava
Czechia	Fakultni nemocnice Plzen, Hemato-onkologicke oddeleni	Plzen
Czechia	Fakultni nemocnice Kralovske Vinohrady	Praha 10
Czechia	Vseobecna fakultni nemocnice v Praze - I. interni klinika - klinika hematologie	Praha 2
France	CHU Caen - Côte de Nacre	Caen
France	Hopital Claude Huriez	Lille Cedex
France	CHU de Nantes hotel Dieu	Nantes Cedex 1
France	CHU de Boreaux	Pessac
France	Centre hospitalier Lyon-Sud	Pierre-Bénite
France	CHU Poitiers - Hôpital la Milétrie	Poitiers
France	CHU Nancy Brabois	Vandoeuvre Les Nancy
Greece	Alexandra General Hospital of Athens	Athens Attica
Israel	Hillel Yaffe Medical Center - Oncology	Hadera
Israel	Carmel Medical Center	Haifa
Israel	Rambam Med.Center - Hematology Institute	Haifa
Israel	Hadassah Medical Center	Jerusalem
Israel	Rabin Medical Center Beilinson Campus	Petah Tikva
Israel	Sheba Medical Center Tel Hashomer	Ramat Gan
Israel	Tel Aviv Sourasky Medical Center	Tel Aviv
Italy	Policlinico Sant'Orsola Malpighi	Bologna
Italy	Fondazione IRCCS Istituto Nazionale dei Tumori	Milano
Italy	Ospedale Villa Sofia-Cervello	Palermo
Italy	Fondazione IRCCS Policlinico San Matteo	Pavia
Italy	Azienda USL di Piacenza	Piacenza
Italy	Policlinico Universitario Agostino Gemelli	Roma
Italy	Università di Roma La Sapienza	Roma
Italy	A.O.U. Città della Salute e della Scienza	Torino
Japan	Fukuoka University Hospital	Fukuoka
Japan	Chugoku Central Hospital	Fukuyama
Japan	Ogaki Municipal Hospital	Gifu
Japan	Gunma University Hospital	Gunma
Japan	Kobe City Medical Center General Hospital	Hyogo
Japan	Iwate Medical University Hospital	Iwate
Japan	University Hospital Kyoto Perfectural University of Medicine	Kyoto
Japan	Matsuyama Red Cross Hospital	Matsuyama
Japan	Japanese Red Cross Nagoya Daini Hospital	Nagoya
Japan	Nagoya City University Hospital	Nagoya
Japan	Niigata Cancer Center Hospital	Niigata
Japan	National Hospital Organization Okayama Medical Center	Okayama
Japan	Osaka University Hospital	Osaka
Japan	National Hospital Organization Sendai Medical Center	Sendai-City
Japan	National Hospital Organization Shibukawa Medical Center	Shibukawa
Japan	Japanese Red Cross Medical Center	Shibuya
Korea, Republic of	Pusan National University Hospital	Busan
Korea, Republic of	National Cancer Center	Goyang-Si
Korea, Republic of	Gachon University Gil Medical Center	Incheon
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Severance Hospital	Seoul
Korea, Republic of	The Catholic University of Korea Seoul St. Mary's Hospital	Seoul
Korea, Republic of	Ulsan University Hospital	Ulsan
Poland	Szpital Specjalistyczny w Brzozowie Podkarpacki Osrodek Onkologiczny im Ks B Markiewicza	Brzozow
Poland	Szpital Uniwersytecki nr 2 im. Jana Biziela w Bydgoszczy	Bydgoszcz
Poland	Samodzielny Publiczny Zaklad Opieki Zdrowotnej Zespol Szpitali Miejskich	Chorzów
Poland	Szpitale Pomorskie Sp z o o	Gdynia
Poland	Szpital Uniwersytecki w Krakowie	Krakow
Poland	Wojewodzki Szpital Specjalistyczny w Legnicy	Legnica
Poland	Samodzielny Publiczny Szpital Kliniczny nr 1 w Lublinie	Lublin
Poland	Szpital Kliniczny Przemienienia Panskiego Uniwersytetu Medycznego im. Karola Marcinkowskiego	Poznan
Poland	Narodowy Instytut Onkologii im Marii Sklodowskiej Curie Panstwowy Instytut Badawczy	Warszawa
Russian Federation	Emergency Hospital of Dzerzhinsk	Dzerzhinsk
Russian Federation	Ekaterinburg City Clinical Hospital # 7	Ekaterinburg
Russian Federation	City Clinical Hospital # 40	Moscow
Russian Federation	S.P. Botkin Moscow City Clinical Hospital	Moscow
Russian Federation	Nizhniy Novgorod Region Clinical Hospital	Nizny Novgorod
Russian Federation	Penza Regional Oncology Dispensary	Penza
Russian Federation	Ryazan Regional Clinical Hospital	Ryazan
Russian Federation	Saint Petersburg City Hospital #15	Saint-Petersburg
Russian Federation	Samara Region Clinical Hospital	Samara
Russian Federation	Clinical Research Institute of Hematology and Transfusiology	St-Petersburg
Russian Federation	Oncology Dispensary of Komi Republic	Syktyvkar
Spain	Hosp. Univ. Germans Trias I Pujol	Badalona
Spain	Hosp. Clinic de Barcelona	Barcelona
Spain	Hosp. Univ. Dr. Josep Trueta	Girona
Spain	Hosp. Univ. Virgen de Las Nieves	Granada
Spain	Hosp. Univ. de Canarias	La Laguna
Spain	Hosp. de Leon	Leon
Spain	Hosp. Gral. Univ. Gregorio Maranon	Madrid
Spain	Hosp. Univ. 12 de Octubre	Madrid
Spain	Hosp. Univ. Infanta Leonor	Madrid
Spain	Clinica Univ. de Navarra	Pamplona
Spain	Hosp. Quiron Madrid Pozuelo	Pozuelo de Alarcon
Spain	Hosp. Clinico Univ. de Salamanca	Salamanca
Spain	Hosp. Univ. Dr. Peset	Valencia
Sweden	Falu Lasarett	Falun
Sweden	Helsingborgs lasarett	Helsingborg
Sweden	Karolinska University Hospital, Huddinge	Huddinge
Sweden	Skanes universitetssjukhus	Lund
Sweden	Norrlands University Hospital	Umea
Sweden	Akademiska Sjukhuset	Uppsala
Taiwan	Chang-Hua Christian Hospital	Changhua
Taiwan	China Medical University Hospital	Taichung City
Taiwan	Taichung Veterans General Hospital	Taichung,
Taiwan	National Cheng Kung University Hospital	Tainan
Taiwan	National Taiwan University Hospital	Taipei
Taiwan	Chang Gung Memorial Hospital	Taoyuan
Ukraine	Communal Nonprofit Enterprise 'Cherkasy Regional Oncology Dispensary Of Cherkasy Regional Council'	Cherkasy
Ukraine	Dnepropetrovsk City Clinical Hospital #4, Regional Hematology Center	Dnepropetrovsk
Ukraine	Ivano-Frankivsk Regional Clinical Hospital	Ivano-Frankivsk
Ukraine	SI Grigoriev Institute for Medical Radiology National Academy of Medical Science of Ukraine	Kharkiv
Ukraine	Kiev Marrow Transplantation Center, Bone Marrow Transplantation Department	Kiev
Ukraine	National Cancer Institute, Dept. of chemotherapy of hemoblastosis	Kiev
Ukraine	State Institution 'National Scientific Center for Radiation Medicine of NAMS of Ukraine'	Kiev
Ukraine	Institute of Blood Pathology and Transfusion Medicine of AMS of Ukraine	Lviv
Ukraine	Mykolaiv Regional Clinical Hospital	Mykolaiv
Ukraine	Ukrainian Medical Stomatological Academy, Poltava Regional Clinical Hospital	Poltava
United Kingdom	Blackpool Victoria Hospital	Blackpool
United Kingdom	Royal Bournemouth Hospital	Bournemouth
United Kingdom	Leicester Royal Infirmary - Haematology	Leicester
United Kingdom	Guys St Thomas Hospital	London
United Kingdom	St Bartholomew's Hospital	London
United Kingdom	Christie Hospital NHS Trust	Manchester
United Kingdom	Nottingham City Hospital	Nottingham
United Kingdom	Royal Marsden Hospital	Surrey
United Kingdom	New Cross Hospital	Wolverhampton
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Levine Cancer Institute	Charlotte	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Janssen Research & Development, LLC

Countries where clinical trial is conducted

United States,  Australia,  Brazil,  Canada,  Czechia,  France,  Greece,  Israel,  Italy,  Japan,  Korea, Republic of,  Poland,  Russian Federation,  Spain,  Sweden,  Taiwan,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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, during or after study treatment. 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)/24 hours, If the serum and urine M-proteins are not measurable, a decrease of >=50% in the difference between involved and uninvolved free light chain (FLC) levels were required in place of the M-protein criteria, If serum and urine M-protein are not measurable, and serum free light assay was also not measurable, >=50% reduction in bone marrow plasma cells (PCs) was 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 was also required.	Up to 1 year 8 months
Primary	Maximum Trough Concentration (Ctrough) of Daratumumab	Maximum Ctrough was defined as the serum predose concentration of daratumumab on Cycle 3 Day 1.	Predose on Cycle 3 Day 1 (each cycle of 28 days)
Secondary	Percentage of Participants With Treatment-emergent Infusion-related Reactions (IRR)	Percentage of participants with treatment-emergent infusion-related reactions were reported.	Up to 3 years
Secondary	Progression Free Survival (PFS)	PFS was defined as time from date of randomization to either progression of disease (PD), death due to any cause, whichever occurs first. IMWG criteria for PD: Increase of 25% from lowest response value in any one of the following: Serum M component (absolute increase must be >=0.5 gram per deciliter (g/dL), Urine M-component (absolute increase must be >=200 mg/24 hours), Participants without measurable serum and urine Mprotein levels: difference between involved and uninvolved free light chain (FLC) levels (absolute increase must be >10 milligrams per deciliter (mg/dL), participants without measurable serum and urine M-protein levels and without measurable disease by FLC levels, bone marrow PC% (absolute percentage must be >=10%), definite development of new bone lesions or soft tissue plasmacytomas or increase in size of bone lesions or tissue plasmacytomas and development of hypercalcemia (serum calcium >11.5 mg/dL) that can be attributed solely to PC proliferative disorder.	Up to 3 years
Secondary	Percentage of Participants With Very Good Partial Response (VGPR) or Better	VGPR or better was defined as the percentage of participants who achieved VGPR or better (VGPR, complete response (CR) or stringent complete response [sCR]), based on computerized algorithm as per IMWG criteria during or after the study treatment. 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 milligrams (mg)/24 hours, CR: Negative immunofixation on the serum and urine, disappearance of any soft tissue plasmacytomas and <5% plasma cells (PCs) in bone marrow. sCR: CR plus normal FLC ratio, and absence of clonal PCs by immunohistochemistry (IHC), immunofluorescencea or 2- to 4 color flow cytometry.	Up to 3 years
Secondary	Percentage of Participants With Complete Response (Including sCR) or Better	CR or better was defined as percentage of participants with a CR or better (CR or stringent complete response [sCR]) based on computerized algorithm as per IMWG criteria. IMWG criteria for CR- negative immunofixation on the serum and urine, and disappearance of any soft tissue plasmacytomas, and <5% PCs in bone marrow. sCR: CR plus normal FLC ratio, and absence of clonal PCs by IHC, immunofluorescencea or 2- to 4 color flow cytometry.	Up to 3 years
Secondary	Time to Next Therapy	Time to next therapy was defined as the time from randomization to the start of the first subsequent anti-cancer therapy.	Up to 3 years
Secondary	Overall Survival (OS)	OS was defined as the time from the date of randomization to the date of the participant's death due to any cause.	Up to 3 years
Secondary	Patient-Reported Satisfaction With Therapy as Assessed With Cancer Therapy Satisfaction Questionnaire (CTSQ)	Modified-CTSQ contain 9 items (2 items for Thoughts about Cancer Therapy and 7 items in a defined domain of Satisfaction with Therapy) specific to satisfaction with therapy and for comparison of SC and IV administration. Satisfaction with therapy was calculated based on 7-items using 5-point verbal rating scale, where 1= never and 5= always. Scores were averaged and transformed to a 0-100 scale; higher scores represent better health. At least 5 of the 7 items within the Satisfaction with Therapy domain had to be completed to calculate a domain score. No domain score was calculated for Thoughts about Cancer Therapy.	Cycle 1 (Days 8,15 and 22), Cycle 2 (Days 1,8,15 and 22), Cycle 3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21 and 22 (Day 1)
Secondary	Duration of Response	Duration of response was defined as the duration from the date of initial documentation of a response (PR or better) to the date of first documented evidence of progressive disease according to the IMWG criteria. PD was 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 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.	Up to 3 years
Secondary	Time to Partial Response (PR) or Better	Time to PR or better was defined as the time from randomization until onset of first response of PR or better.	Up to 3 years
Secondary	Time to Very Good Partial Response (VGPR) or Better	Time to VGPR or better was defined as the time from randomization until onset of first VGPR or better.	Up to 3 years
Secondary	Time to Complete Response (CR) or Better	Time to CR or better was defined as the time from randomization until onset of first CR or better.	Up to 3 years