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

• ClinicalTrials.gov Identifier: NCT01985126
• Recruitment Status: Completed
• First Posted: November 15, 2013
• Results First Posted: February 2, 2017
• Last Update Posted: June 25, 2018
• Sponsor: Janssen Research & Development, LLC
• Information provided by (Responsible Party): Janssen Research & Development, LLC

Tracking Information

• First Submitted Date: July 22, 2013
• First Posted Date: November 15, 2013
• Results First Submitted Date: September 30, 2016
• Results First Posted Date: February 2, 2017
• Last Update Posted Date: June 25, 2018
• Actual Study Start Date: September 27, 2013
• Actual Primary Completion Date: January 9, 2015 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 17, 2018)

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.

• Original Primary Outcome Measures (submitted: November 7, 2013): Overall response rate following treatment with daratumumab [ Time Frame: Up to 6 months after the last participant is enrolled in the study ]

Current Secondary Outcome Measures (submitted: May 17, 2018)

• 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.

Original Secondary Outcome Measures (submitted: November 7, 2013)

• Number of participants affected by adverse events by MedDRA system organ class (SOC) and Preferred term (PT) [ Time Frame: Up to 30 days after the last dose of study medication ]
• Duration of and time to response to daratumumab [ Time Frame: Up to 18 months after last participant receives first dose of study drug ]
• Clinical benefit rate following treatment with daratumumab [ Time Frame: Up to 8 weeks after the last dose of daratumumab administered ]
• Overall survival following treatment with daratumumab [ Time Frame: Up to 18 months after last participant receives first dose of study drug ]
• Progression-free survival following treatment with daratumumab [ Time Frame: Up to 18 months after last participant receives first dose of study drug ]
• Time to disease progression following treatment with daratumumab [ Time Frame: Up to 18 months after last participant receives first dose of study drug ]
• Total systemic clearance of daratumumab [ Time Frame: Up to post-treatment visit Week 8 ]
• Maximum observed concentration of daratumumab [ Time Frame: Up to post-treatment visit Week 8 ]
• Minimum observed concentration of daratumumab [ Time Frame: Up to post-treatment visit Week 8 ]
• Volume of distribution of daratumumab [ Time Frame: Up to post-treatment visit Week 8 ]
• Number of participants with generation of antibodies to daratumumab [ Time Frame: Up to post-treatment visit Week 8 ]
• Number of participants with soluble CD38 levels [ Time Frame: Up to post-treatment visit Week 8 ]
• Number of participants with complement inhibitory protein expression [ Time Frame: Up to post-treatment visit Week 8 ]
• Number of participants with antibody-dependent cell-mediated cytotoxicity expression [ Time Frame: Up to post-treatment visit Week 8 ]
• Number of participants with complement-dependent cytotoxicity expression [ Time Frame: Up to post-treatment visit Week 8 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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
• 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.
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Multiple Myeloma

Intervention

• 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.
• 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.

Study Arms

• 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.
  Interventions:

  • Drug: Daratumumab 16 mg/kg (Part 1)
  • Drug: Daratumumab 8 mg/kg (Part 1)
  • Drug: Methylprednisolone
  • Drug: Acetaminophen
  • Drug: Diphenhydramine
• 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.
  Interventions:

  • Drug: Methylprednisolone
  • Drug: Acetaminophen
  • Drug: Diphenhydramine
  • Drug: Daratumumab (Part 2)

Publications *

• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 4, 2015): 124
• Original Estimated Enrollment (submitted: November 7, 2013): 110
• Actual Study Completion Date: May 30, 2017
• Actual Primary Completion Date: January 9, 2015 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, Spain, United States
• Removed Location Countries: Belgium

Administrative Information

• NCT Number: NCT01985126
• Other Study ID Numbers: CR102651; 54767414MMY2002 ( Other Identifier: Janssen Research & Development, LLC ); 2013-000752-18 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

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

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Janssen Research & Development, LLC
• Original Responsible Party: Same as current
• Current Study Sponsor: Janssen Research & Development, LLC
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

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

• PRS Account: Janssen Research & Development, LLC
• Verification Date: June 2018