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

NCT ID: NCT01985126

Last Updated: 2018-06-25

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 124 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-09-27
• Study Completion Date: 2017-05-30

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.

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.

Conditions

Multiple Myeloma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Daratumumab 16 mg/kg (Part 1)

Intervention Type: DRUG

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

Daratumumab 8 mg/kg (Part 1)

Intervention Type: DRUG

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

Methylprednisolone

Intervention Type: DRUG

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

Acetaminophen

Intervention Type: DRUG

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

Diphenhydramine

Intervention Type: DRUG

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

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.

Group Type: EXPERIMENTAL

Methylprednisolone

Intervention Type: DRUG

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

Acetaminophen

Intervention Type: DRUG

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

Diphenhydramine

Intervention Type: DRUG

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

Daratumumab (Part 2)

Intervention Type: DRUG

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.

Interventions

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

Intervention Type: DRUG

Daratumumab 8 mg/kg (Part 1)

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

Intervention Type: 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

Intervention Type: DRUG

Acetaminophen

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

Intervention Type: 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.

Intervention Type: 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.

Intervention Type: DRUG

Eligibility 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Janssen Research & Development, LLC

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Janssen Research & Development, LLC Clinical Trial

Role: STUDY_DIRECTOR

Janssen Research & Development, LLC

Locations

Duarte, California, United States

Los Angeles, California, United States

Atlanta, Georgia, United States

Chicago, Illinois, United States

Louisville, Kentucky, United States

Detroit, Michigan, United States

New Brunswick, New Jersey, United States

New York, New York, United States

Chapel Hill, North Carolina, United States

Charlotte, North Carolina, United States

Portland, Oregon, United States

Philadelphia, Pennsylvania, United States

Nashville, Tennessee, United States

Houston, Texas, United States

Madison, Wisconsin, United States

Calgary, Alberta, Canada

Edmonton, Alberta, Canada

Vancouver, British Columbia, Canada

Halifax, Nova Scotia, Canada

Montreal, Quebec, Canada

Barcelona, , Spain

Salamanca, , Spain

Valencia, , Spain

Countries

United States; Canada; Spain

References

Li X, Dosne AG, Perez Ruixo C, Perez Ruixo JJ. Pharmacodynamic-Mediated Drug Disposition (PDMDD) Model of Daratumumab Monotherapy in Patients with Multiple Myeloma. Clin Pharmacokinet. 2023 May;62(5):761-777. doi: 10.1007/s40262-023-01232-8. Epub 2023 Apr 6.

Reference Type: DERIVED

PMID: 37022569 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 32470437 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 30536810 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 29445583 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 27307294 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 26778538 (View on PubMed)

Other Identifiers

54767414MMY2002

Identifier Type: OTHER

Identifier Source: secondary_id

2013-000752-18

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

CR102651

Identifier Type: -

Identifier Source: org_study_id