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

Multiple Myeloma Clinical Trial

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03871829
• Other study ID #: CR108598
• Secondary ID: 2018-004185-3454
• Status: Terminated
• Phase: Phase 2
• Start date: May 31, 2019
• Est. completion date: January 10, 2023

Study information

• Verified date: November 2023
• 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 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 88
• Est. completion date: January 10, 2023
• Est. primary completion date: October 24, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Multiple Myeloma
• Neoplasms, Plasma Cell

Intervention

Drug:
• Carfilzomib 20 mg/m^2
Carfilzomib 20 mg/m^2 will be administered intravenously (IV).
• Carfilzomib 70 mg/m^2
Carfilzomib 70 mg/m^2 will be administered IV.
• Dexamethasone 40 mg
Dexamethasone 40 mg will be administered as IV infusion or orally.
• Dara-SC 1800 mg
Dara-SC 1800 mg will be administered by SC injection.
• Dexamethasone 20 mg
Dexamethasone 20 mg will be administered as IV infusion or orally.

Locations

Country	Name	City	State
Belgium	ZNA Stuivenberg	Antwerpen
Belgium	UZ Gent	Gent
Brazil	Universidade Estadual De Campinas	Campinas
Brazil	Liga Paranaense de Combate ao Cancer	Curitiba
Brazil	Universidade Federal de Goias - Hospital das Clinicas da UFG	Goiania
Brazil	Liga Norte Riograndense Contra O Cancer	Natal
Brazil	Irmandade Santa Casa de Misericordia de Porto Alegre	Porto Alegre
Brazil	Instituto de Educacao, Pesquisa e Gestao em Saude Instituto Americas (COI)	Rio de Janeiro
Brazil	Ministerio da Saude - Instituto Nacional do Cancer	Rio de Janeiro
Brazil	CEHON	Salvador
Brazil	Hospital Sao Rafael	Salvador
Brazil	Fundacao Antonio Prudente - A.C. Camargo Cancer Center	Sao Paulo
Brazil	Instituto Brasileiro de Controle do Cancer - Sao Camilo Oncologia	Sao Paulo
Brazil	Instituto de Ensino e Pesquisa São Lucas	Sao Paulo
Brazil	Clinica Sao Germano	São Paulo
Brazil	Real e Benemérita Associação Portuguesa de Beneficência	São Paulo
Canada	Tom Baker Cancer Centre	Calgary	Alberta
Denmark	Aarhus University Hospital	Aarhus N
Denmark	Regionshospitalet i Holstebro	Holstebro
Denmark	Haematological Research unit HFE-X OUH.	Odense
Denmark	Vejle Hospital	Vejle
France	Hopital Claude Huriez	Lille
France	CHU de Montpellier, Hopital Saint-Eloi	Montpellier
France	Centre Hospitalier Emile Muller	Mulhouse
France	Hotel Dieu	Nantes
France	Hopital de la Pitie Salpetriere	Paris
France	Hôpital Necker-Enfants Malades	Paris
France	Hopitaux Universitaires Est Parisien Hopital Saint Antoine	Paris
France	Fentre F Magendie, Hôpital Haut Leveque, CHU Bordeaux	Pessac
France	Centre Hospitalier Lyon-Sud Service d'hematologie	Pierre Benite
France	CHU Poitiers - Hôpital la Milétrie	Poitiers
France	Chu Rennes - Hopital Pontchaillou	Rennes Cedex
France	Institut Claudius Regaud	Toulouse
France	CHU Bretonneau	Tours
France	CHU Nancy Brabois	Vandoeuvre Les Nancy
Germany	Universitätsklinik Carl Gustav Carus, Med. Klinik u. Poliklinik I	Dresden
Germany	Evangelisches Krankenhaus Essen-Werden	Essen
Germany	Universitatsklinikum Essen	Essen
Germany	Universitätsklinik Hamburg-Eppendorf UKE	Hamburg
Germany	St. Barbara-Klinik Hamm GmbH	Hamm
Germany	Praxisklinik für Haematologie und Onkologie Koblenz	Koblenz
Germany	Universitaetsklinikum Koelnt	Koeln
Germany	Universitätsmedizin der Johannes gutenberg-Universität; III. Med. Klinik - Germany	Mainz
Germany	Onkologische Schwerpunkt Praxis	Saarbrucken
Germany	Klinikum der Eberhard-Karls-Universität/Abt. für innere Med. II/Hämatologie/Onkologie-Germany	Tubingen
Germany	Schwarzwald-Baar Klinikum	Villingen-Schwenningen
Germany	Universitätsklinikum Würzburg Med. Klinik U. Poliklinik Ii	Würzburg
Greece	University of Athens - Evaggelismos Hospital (Evangelismos Hospital)	Athens
Greece	Alexandra General Hospital of Athens	Athens Attica
Greece	University Hospital Of Larissa	Larisa
Greece	University General Hospital of Rio	Patra
Greece	Anticancer Hospital of Thessaloniki 'Theageneio'	Thessaloniki
Italy	Azienda Ospedaliera Papa Giovanni XXIII	Bergamo
Italy	Istituto di Ematologia Seràgnoli azienda ospedaliera univeristaria Policlinico S.Orsola-Malpighi	Bologna
Italy	Azienda Ospedaliera Universitaria Careggi	Firenze
Italy	IRCCS Azienda Ospedaliera San Martino - IST	Genova
Italy	San Martino Hospital	Genova
Italy	Asst Ovest Milanese - Ospedale Di Legnano	Legnano
Italy	Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori	Meldola
Italy	ASST Grande Ospedale Metropolitano Niguarda	Milano
Italy	Ospedale Maggiore della Carità	Novara
Italy	Casa di Cura La Maddalena	Palermo
Italy	Ospedale Villa Sofia-Cervello	Palermo
Italy	Fondazione IRCCS Policlinico San Matteo	Pavia
Italy	ASL ROMA	Roma
Italy	Fondazione Policlinico Universitario A. Gemelli IRCCS	Roma
Italy	Sapienza University of Rome	Roma
Italy	Universita Degli Studi di Roma 'Tor Vergata'	Roma
Italy	IRCCS Ospedale Casa Sollievo della Sofferenza	San Giovanni Rotondo
Italy	Azienda Ospedaliera Santa Maria	Terni
Netherlands	Albert Schweitzer ziekenhuis-lokatie Dordwijk	Dordrecht
Netherlands	Zuyderland Medical Center	Sittard
Poland	Szpital Uniwersytecki nr 2 im. Jana Biziela w Bydgoszczy	Bydgoszcz
Poland	Szpital Wojewodzki w Opolu	Opole
Poland	Szpital Magodent	Warszawa
Poland	Uniwersytecki Szpital Kliniczny im. Jana Mikulicza-Radeckiego we Wroclawiu	Wroclaw
Russian Federation	Emergency Hospital of Dzerzhinsk	Dzerzhinsk
Russian Federation	S.P. Botkin Moscow City Clinical Hospital	Moscow
Russian Federation	Nizhniy Novgorod Region Clinical Hospital	Nizhny Novgorod
Russian Federation	Ryazan Regional Clinical Hospital	Ryazan
Russian Federation	Oncological dispensary #2	Sochi
Russian Federation	Clinical Research Institute of Hematology and Transfusiology	St-Petersburg
Russian Federation	Oncology Dispensary of Komi Republic	Syktyvkar
Spain	Hosp. Clinic I Provincial de Barcelona	Barcelona
Spain	Inst. Cat. Doncologia-H Duran I Reynals	Barcelona
Spain	Hosp. de Jerez de La Frontera	Jerez de la Frontera
Spain	Hosp. de Leon	Leon
Spain	Hosp. Univ. 12 de Octubre	Madrid
Spain	Hosp. Univ. de La Paz	Madrid
Spain	Hosp. Univ. Ramon Y Cajal	Madrid
Spain	Hosp. Costa Del Sol	Malaga
Spain	Hosp. Univ. Son Espases	Palma
Spain	Clinica Univ. de Navarra	Pamplona
Spain	Hosp. Clinico Univ. de Salamanca	Salamanca
Spain	Hosp. Univ. de Canarias	San Cristóbal de La Laguna
Spain	Hosp. Virgen Del Rocio	Sevilla
Spain	Hosp. Gral. Univ. de Toledo	Toledo
United States	Cleveland Clinic Main Campus	Cleveland	Ohio
United States	Baylor Scott and White Health	Dallas	Texas
United States	Karmanos Cancer Institute - Wayne State University	Detroit	Michigan
United States	Fort Wayne Medical Oncology and Hematology, Inc.	Fort Wayne	Indiana
United States	Banner MD Anderson Cancer Center	Gilbert	Arizona
United States	Millennium Oncology	Houston	Texas
United States	Weill Medical College of Cornell University	New York	New York
United States	Mayo Clinic - Rochester	Rochester	Minnesota
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Oncology Institute of Hope and Innovation	Tucson	Arizona
United States	American Institute of Research (AIR)	Whittier	California

Sponsors (1)

Lead Sponsor	Collaborator
Janssen Research & Development, LLC

Countries where clinical trial is conducted

United States,  Belgium,  Brazil,  Canada,  Denmark,  France,  Germany,  Greece,  Italy,  Netherlands,  Poland,  Russian Federation,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants Achieving Very Good Partial Response (VGPR) or Better Response	Percentage of participants achieving VGPR or better response were reported. VGPR or better rate was defined as the percentage of participants achieving VGPR, complete response (CR), or stringent complete response (sCR) in accordance with the International Myeloma Working Group (IMWG) criteria, during or after the study treatment but before the start of subsequent anti-myeloma therapy. 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; for CR: Negative immunofixation on the serum and urine, and Disappearance of any soft tissue plasmacytomas (PCs), and <5% PCs in bone marrow; for sCR: CR plus normal free light chain (FLC) ratio, and Absence of clonal PCs by immunohistochemistry, immunofluorescence or 2- to 4- color flow cytometry.	Up to 3 years and 4 months
Secondary	Overall Response Rate (ORR)	ORR was defined as the percentage of participants who achieved partial response (PR) or better responses based on the computerized algorithm, in accordance with the IMWG criteria, during or after the study treatment but before the start of subsequent anti-myeloma therapy. IMWG criteria for PR: greater than or equal to (>=)50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by >=90% or less than (<)200 mg/24 hours; If the serum and urine M-protein were not measurable, a decrease of >=50% in the difference between involved and uninvolved free light chain (FLC) levels was required in place of the M-protein criteria; If serum and urine M-protein were not measurable, and serum free light assay is 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%; additionally, if present at baseline, >=50% reduction in the size of soft tissue PCs was also required.	Up to 3 years and 7 months
Secondary	Percentage of Participants Achieving Complete Response (CR) or Better	Percentage of participants achieving CR or better were reported. CR or better rate was defined as the percentage of participants achieving CR or sCR based on the computerized algorithm, according to IMWG response criteria. 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.	Up to 3 years and 7 months
Secondary	Progression Free Survival (PFS)	PFS was defined as the duration from the date of randomization to either progressive disease (PD) 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.	Up to 3 years and 7 months
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 and 7 months
Secondary	Percentage of Participants With Negative Minimal Residual Disease (MRD)	Percentage of participants with negative MRD were reported. MRD negativity rate, defined as the percentage of participants who had MRD negative status at 10^-5 by bone marrow aspirate after the date of randomization and prior to PD or subsequent anti-myeloma therapy.	Up to 3 years and 7 months
Secondary	Time to Next Treatment	Time to next treatment was defined as the time from randomization to the start of the next-line treatment.	Up to 3 years and 7 months
Secondary	Serum Concentrations of Daratumumab	Serum concentrations of daratumumab were assessed. This outcome measure was planned to be analyzed for specified arm only.	Day 1 of Cycles 1, 3, and 7 (each cycle of 28 days) and Follow Up (post treatment Week 8; up to 30.3 months)
Secondary	Number of Participants With Anti-recombinant Human Hyaluronidase (rHuPH20) Antibodies	The incidence of anti-rHuPH20 antibodies were summarized for all participants who received at least one dose of Dara-SC and had appropriate plasma samples for detection of antibodies to rHuPH20 (at least 1 sample after the start of the first dose of Dara-SC). This outcome measure was planned to be analyzed for specified arm only.	Up to end of study; up to 30.3 months
Secondary	Number of Participants With Anti-Daratumumab Antibodies	Number of participants who test positive for anti-daratumumab antibodies were reported. This outcome measure was planned to be analyzed for specified arm only.	Up to end of study; up to 30.3 months