An Efficacy and Safety Study of Daratumumab in Patients With Multiple Myeloma Who Have Received at Least 3 Prior Lines of Therapy (Including a Proteasome Inhibitor [PI] and Immunomodulatory Drug [IMiD]) or Are Double Refractory to a PI and an IMiD

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ClinicalTrials.gov Identifier: NCT01985126

Recruitment Status : Completed

First Posted : November 15, 2013

Results First Posted : February 2, 2017

Last Update Posted : June 25, 2018

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Sponsor:

Information provided by (Responsible Party):

Janssen Research & Development, LLC

Study Description

Brief Summary:

The purpose of this study is to evaluate the efficacy and safety of 2 daratumumab treatment regimens in participants with multiple myeloma who have received at least 3 prior lines of therapy (including a proteasome inhibitor [PI] and immunomodulatory drug [IMiD]) or are double refractory to a PI and an IMiD.

Condition or disease	Intervention/treatment	Phase
Multiple Myeloma	Drug: Daratumumab 16 mg/kg (Part 1) Drug: Daratumumab 8 mg/kg (Part 1) Drug: Methylprednisolone Drug: Acetaminophen Drug: Diphenhydramine Drug: Daratumumab (Part 2)	Phase 2

Detailed Description:

This is an open-label (identity of assigned study drug will be known) study of daratumumab for the treatment of participants with multiple myeloma who have received at least 3 prior lines of therapy including a PI and an IMiD or whose disease is double refractory to both a PI and an IMiD. Up to approximately 150 participants are to be enrolled. The study includes screening, treatment, and follow-up phases. Participants will receive daratumumab by intravenous infusion (28-day cycles) until disease progression, unacceptable toxicity, or other protocol-defined reasons. For all study drug administrations, participants will receive pre- and post-infusion medications for the prevention of infusion related reactions. Follow-up will continue until death, loss to follow up, consent withdrawal for study participation, or study end, whichever occurs first. The study will consist of 2 sequential parts (Part 1 and Part 2). The purpose of Part 1 is to select a dose and schedule for Part 2 of the study. Assessment of tumor response and disease progression will be conducted according to IMWG response criteria. Serial pharmacokinetic blood samples and a pharmacogenomic blood sample will be collected. Safety will be monitored throughout the study. At the end of the study, participants who are benefiting from treatment with daratumumab will have the option to continue treatment.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	124 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	An Open-label, Multicenter, Phase 2 Trial Investigating the Efficacy and Safety of Daratumumab in Subjects With Multiple Myeloma Who Have Received at Least 3 Prior Lines of Therapy (Including a Proteasome Inhibitor and IMiD) or Are Double Refractory to a Proteasome Inhibitor and an IMiD
Actual Study Start Date :	September 27, 2013
Actual Primary Completion Date :	January 9, 2015
Actual Study Completion Date :	May 30, 2017

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Multiple myeloma

MedlinePlus related topics: Multiple Myeloma

Drug Information available for: Daratumumab

Genetic and Rare Diseases Information Center resources: Multiple Myeloma

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
Experimental: Part 1 During Stage 1 of Part 1, participants will be randomized to receive daratumumab treatment regimens in Group A and Group B. If in Stage 1, 1 or both of the treatment groups is considered to be ineffective and/or not well tolerated, then that treatment group will be terminated. Participants in Group B will be given the option to cross over to Group A if the investigator deems it in the best interest of the participants.	Drug: Daratumumab 16 mg/kg (Part 1) Daratumumab 16 mg/kg administered at weekly intervals (QW) for 8 weeks, then every 2 weeks (Q2W) for an additional 16 weeks, then every 4 weeks (Q4W) thereafter by intravenous infusion Drug: Daratumumab 8 mg/kg (Part 1) Daratumumab 8 mg/kg every 4 weeks (Q4W) continuously by intravenous infusion Drug: Methylprednisolone Administered in prophylactic doses intravenously (or equivalent in accordance with local standards) prior to and after study drug administration. Intravenous administration is preferred, but oral steroids may be substituted Drug: Acetaminophen 650 to 1000 mg administered in prophylactic doses by mouth prior to study drug administration. Drug: Diphenhydramine 25 to 50 mg administered in prophylactic doses by mouth (or equivalent in accordance with local standards) prior to and after study drug administration.
Experimental: Part 2 Based on the Part 1 response rate, Group A or B daratumumab treatment will be selected as the treatment regimen for participants enrolled in Part 2.	Drug: Methylprednisolone Administered in prophylactic doses intravenously (or equivalent in accordance with local standards) prior to and after study drug administration. Intravenous administration is preferred, but oral steroids may be substituted Drug: Acetaminophen 650 to 1000 mg administered in prophylactic doses by mouth prior to study drug administration. Drug: Diphenhydramine 25 to 50 mg administered in prophylactic doses by mouth (or equivalent in accordance with local standards) prior to and after study drug administration. Drug: Daratumumab (Part 2) Based on the Part 1 response rate, Group A or B treatment will be selected as the treatment regimen for participants enrolled in Part 2.

Arm

Intervention/treatment

Experimental: Part 1

During Stage 1 of Part 1, participants will be randomized to receive daratumumab treatment regimens in Group A and Group B. If in Stage 1, 1 or both of the treatment groups is considered to be ineffective and/or not well tolerated, then that treatment group will be terminated. Participants in Group B will be given the option to cross over to Group A if the investigator deems it in the best interest of the participants.

Drug: Daratumumab 16 mg/kg (Part 1)

Daratumumab 16 mg/kg administered at weekly intervals (QW) for 8 weeks, then every 2 weeks (Q2W) for an additional 16 weeks, then every 4 weeks (Q4W) thereafter by intravenous infusion

Drug: Daratumumab 8 mg/kg (Part 1)

Daratumumab 8 mg/kg every 4 weeks (Q4W) continuously by intravenous infusion

Drug: Methylprednisolone

Administered in prophylactic doses intravenously (or equivalent in accordance with local standards) prior to and after study drug administration. Intravenous administration is preferred, but oral steroids may be substituted

Drug: Acetaminophen

650 to 1000 mg administered in prophylactic doses by mouth prior to study drug administration.

Drug: Diphenhydramine

25 to 50 mg administered in prophylactic doses by mouth (or equivalent in accordance with local standards) prior to and after study drug administration.

Experimental: Part 2

Based on the Part 1 response rate, Group A or B daratumumab treatment will be selected as the treatment regimen for participants enrolled in Part 2.

Drug: Methylprednisolone

Drug: Acetaminophen

650 to 1000 mg administered in prophylactic doses by mouth prior to study drug administration.

Drug: Diphenhydramine

25 to 50 mg administered in prophylactic doses by mouth (or equivalent in accordance with local standards) prior to and after study drug administration.

Drug: Daratumumab (Part 2)

Based on the Part 1 response rate, Group A or B treatment will be selected as the treatment regimen for participants enrolled in Part 2.

Outcome Measures

Primary Outcome Measures :

Percentage of Participants With Overall Response [ Time Frame: Up to 14.4 Months ]
Overall response defined as percentage of participants who achieved stringent complete response (sCR), complete response (CR), very good partial response (VGPR) or partial response (PR). Per IMWG criteria, sCR: is defined as normal free light chain (FLC) ratio, and absence of clonal plasma cells (PCs) by immunohistochemistry, immunofluorescence or 2- to 4-color flow cytometry; CR: Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and < 5 % plasma cells in bone marrow; VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or >= 90% reduction in serum M-protein plus urine M-protein level < 100mg/24 hours; 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.

Secondary Outcome Measures :

Duration of Response [ Time Frame: Up to 14.4 Months ]
Duration of response was calculated from the date of initial documentation of a response (PR or better) to the date of first documented evidence of progressive disease, as defined in IMWG criteria. Disease progression (IMWG criteria): increase of 25 percent (%) from lowest response level in Serum M-component (the absolute increase must be >=0.5 g/dL) and/or; urine M-component (the absolute increase must be >=200 mg/24 hours) and/or; only in participants without measurable serum and urine M-protein levels: the difference between involved and uninvolved free light chain levels (absolute increase must be >10 milligram per deciliter (mg/dL); Development of hypercalcemia (corrected serum calcium >11.5 mg/dL or 2.65 millimole per liter [mmol/L]) that can be attributed solely to the plasma cell proliferative disorder.
Overall Survival [ Time Frame: Approximately up to 3 years ]
Overall Survival (OS) was defined as the number of days from administration of the first infusion (Day 1) to date of death. Median Overall Survival was estimated by using the Kaplan-Meier method.
Percentage of Participants With Clinical Benefit [ Time Frame: Up to 14.4 Months ]
Clinical benefit rate defined as percentage of participants who achieved minimal response (MR) or better. MR: >=25% but <= 49% reduction of serum M-protein and reduction in urine M-protein by 50%-89%. If present at baseline 25% to 49% reduction in size of soft tissue plasmacytomas.
Time to Response [ Time Frame: Up to 14.4 Months ]
Time to response was defined as the time from the date of first dose of daratumumab to the date of initial documentation of a response (PR or better).
Progression Free Survival [ Time Frame: Up to 14.4 Months ]
Progression free survival (PFS) was defined as the time between the date of first dose of daratumumab and either disease progression or death, whichever occurs first.
Time to Disease Progression [ Time Frame: Up to 14.4 Months ]
Time to progression was defined as the number of days from the date of first dose of daratumumab to the date of first record of disease progression.

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Documented multiple myeloma according to protocol-defined criteria
Evidence of disease progression on the most recent prior treatment regimen based on International Myeloma Working Group criteria
Eastern Cooperative Oncology Group performance status score of 0, 1, or 2
Laboratory values and electrocardiogram within protocol-defined parameters at screening

Exclusion Criteria:

Received daratumumab or other anti-CD38 therapies previously
Nonsecretory multiple myeloma
Previously received an allogenic stem cell transplant or has received an autologous stem cell transplantation within 12 weeks
Exhibiting clinical signs of meningeal involvement of multiple myeloma
Known chronic obstructive pulmonary disease, persistent asthma, or a history of asthma within 5 years
Seropositive for human immunodeficiency virus, hepatitis B or antibodies to hepatitis B surface and core antigens, or hepatitis C
Has plasma cell leukemia, Waldenstrom's macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes), or amyloidosis

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01985126

Locations

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United States, California

Duarte, California, United States

Los Angeles, California, United States
United States, Georgia

Atlanta, Georgia, United States
United States, Illinois

Chicago, Illinois, United States
United States, Kentucky

Louisville, Kentucky, United States
United States, Michigan

Detroit, Michigan, United States
United States, New Jersey

New Brunswick, New Jersey, United States
United States, New York

New York, New York, United States
United States, North Carolina

Chapel Hill, North Carolina, United States

Charlotte, North Carolina, United States
United States, Oregon

Portland, Oregon, United States
United States, Pennsylvania

Philadelphia, Pennsylvania, United States
United States, Tennessee

Nashville, Tennessee, United States
United States, Texas

Houston, Texas, United States
United States, Wisconsin

Madison, Wisconsin, United States
Canada, Alberta

Calgary, Alberta, Canada

Edmonton, Alberta, Canada
Canada, British Columbia

Vancouver, British Columbia, Canada
Canada, Nova Scotia

Halifax, Nova Scotia, Canada
Canada, Quebec

Montreal, Quebec, Canada
Spain

Barcelona, Spain

Salamanca N/A, Spain

Valencia, Spain

Sponsors and Collaborators

Janssen Research & Development, LLC

Investigators

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

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Usmani SZ, Nahi H, Plesner T, Weiss BM, Bahlis NJ, Belch A, Voorhees PM, Laubach JP, van de Donk NWCJ, Ahmadi T, Uhlar CM, Wang J, Feng H, Qi M, Richardson PG, Lonial S. Daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma: final results from the phase 2 GEN501 and SIRIUS trials. Lancet Haematol. 2020 Jun;7(6):e447-e455. doi: 10.1016/S2352-3026(20)30081-8.

Adams HC 3rd, Stevenaert F, Krejcik J, Van der Borght K, Smets T, Bald J, Abraham Y, Ceulemans H, Chiu C, Vanhoof G, Usmani SZ, Plesner T, Lonial S, Nijhof I, Lokhorst HM, Mutis T, van de Donk NWCJ, Sasser AK, Casneuf T. High-Parameter Mass Cytometry Evaluation of Relapsed/Refractory Multiple Myeloma Patients Treated with Daratumumab Demonstrates Immune Modulation as a Novel Mechanism of Action. Cytometry A. 2019 Mar;95(3):279-289. doi: 10.1002/cyto.a.23693. Epub 2018 Dec 11.

Usmani SZ, Khan I, Chiu C, Foureau D, Druhan LJ, Rigby K, Casneuf T, Sasser AK. Deep sustained response to daratumumab monotherapy associated with T-cell expansion in triple refractory myeloma. Exp Hematol Oncol. 2018 Feb 7;7:3. doi: 10.1186/s40164-018-0096-7. eCollection 2018.

Nijhof IS, Casneuf T, van Velzen J, van Kessel B, Axel AE, Syed K, Groen RW, van Duin M, Sonneveld P, Minnema MC, Zweegman S, Chiu C, Bloem AC, Mutis T, Lokhorst HM, Sasser AK, van de Donk NW. CD38 expression and complement inhibitors affect response and resistance to daratumumab therapy in myeloma. Blood. 2016 Aug 18;128(7):959-70. doi: 10.1182/blood-2016-03-703439. Epub 2016 Jun 15.

Lonial S, Weiss BM, Usmani SZ, Singhal S, Chari A, Bahlis NJ, Belch A, Krishnan A, Vescio RA, Mateos MV, Mazumder A, Orlowski RZ, Sutherland HJ, Blade J, Scott EC, Oriol A, Berdeja J, Gharibo M, Stevens DA, LeBlanc R, Sebag M, Callander N, Jakubowiak A, White D, de la Rubia J, Richardson PG, Lisby S, Feng H, Uhlar CM, Khan I, Ahmadi T, Voorhees PM. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. Lancet. 2016 Apr 9;387(10027):1551-1560. doi: 10.1016/S0140-6736(15)01120-4. Epub 2016 Jan 7.

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Responsible Party:	Janssen Research & Development, LLC
ClinicalTrials.gov Identifier:	NCT01985126
Other Study ID Numbers:	CR102651 54767414MMY2002 ( Other Identifier: Janssen Research & Development, LLC ) 2013-000752-18 ( EudraCT Number )
First Posted:	November 15, 2013 Key Record Dates
Results First Posted:	February 2, 2017
Last Update Posted:	June 25, 2018
Last Verified:	June 2018

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Studies a U.S. FDA-regulated Device Product:	No

Keywords provided by Janssen Research & Development, LLC:


Multiple myeloma Daratumumab Proteasome inhibitor Immunomodulatory drug IMiD

Additional relevant MeSH terms:

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Multiple Myeloma Neoplasms, Plasma Cell Neoplasms by Histologic Type Neoplasms Hemostatic Disorders Vascular Diseases Cardiovascular Diseases Paraproteinemias Blood Protein Disorders Hematologic Diseases Hemorrhagic Disorders Lymphoproliferative Disorders Immunoproliferative Disorders Immune System Diseases Acetaminophen	Diphenhydramine Promethazine Methylprednisolone Daratumumab Antibodies, Monoclonal Analgesics, Non-Narcotic Analgesics Sensory System Agents Peripheral Nervous System Agents Physiological Effects of Drugs Antipyretics Anti-Inflammatory Agents Antiemetics Autonomic Agents Gastrointestinal Agents

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