Clinical trial NCT00574288: Daratumumab (HuMax®-CD38) Safety Study in Multiple Myeloma
Official title: Daratumumab (HuMax®-CD38) Safety Study in Multiple Myeloma - Open Label, Dose-escalation Followed by Open Label, Single-arm Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Multiple Myeloma
Keywords: Multiple Myeloma
Daratumumab
Safety
HuMax-CD38
Dose-escalation
Lead sponsor: Janssen Research & Development, LLC
Sponsor class: INDUSTRY
First posted: 2007-12-17
Enrollment: 104
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Establishment of safety profile of HuMax-CD38 when given as monotherapy in participants with multiple myeloma relapsed from or refractory to at least 2 different cytoreductive therapies and without further established treatment options.

Detailed description: This study is conducted in two parts. In part I, participants are enrolled into cohorts at increasing dose levels. Participant safety and efficacy during part I will determine the doses used for Part II. In part II participants will be enrolled into one of two sequential treatment arms using two of the doses defined in part 1 of the study. Part II was 5 cohorts, 3 with 8 milligram per kilogram (mg/kg) and 2 with 16 mg/kg. Part I and all but the last cohort in Part II were dosed with Phase 1/ 2 drug product. The last cohort in Part II was dosed with Phase 3 drug product. Both Part I and Part II are open-label/unmasked.

Eligibility criteria: Inclusion criteria

* Diagnosis of multiple myeloma (MM) requiring systemic therapy
* Age greater than or equal to (\>=) 18 years
* Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
* Life expectancy greater than (\>) 3 months
* Relapsed from or refractory to two or more different prior therapies
* Signed Informed consent

Exclusion criteria

* Plasma cell leukemia defined as a plasma cell count \> 2000/millimeter\^3 (mm\^3)
* Known amyloidosis
* Participants who previously have received an allogeneic stem cell transplant
* Sensory or motor neuropathy of \>= grade 3
* Past or current malignancy
* Chronic or ongoing active infectious disease
* Clinically significant cardiac disease
* Significant concurrent, uncontrolled medical condition including, but not limited to, renal (except related to MM), hepatic, hematological except MM, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease
* A baseline QT interval as corrected by Fridericia's formula \> 470 millisecond (msec) for female participants or \> 450 msec for male participants or a complete left bundle branch block (defined as a QRS interval \>= 120 msec in left bundle branch block form)
* Hypokalemia
* Clinical signs of meningeal involvement of MM
* Known severe chronic obstructive pulmonary disease or asthma defined as forced expiratory volume in 1 second (FEV1) less than (\<) 60 percentage (%) of expected
* History of significant cerebrovascular disease
* Known Human Immunodeficiency Virus seropositivity
* Positive serology for hepatitis B
* Screening laboratory values
* Concomitant corticosteroid
* Other chemotherapy that is or may be active against myeloma within 3 weeks prior to Visit 2 (Part 1) or the first dose of daratumumab (Part 2). However, corticosteroid for myeloma (less than a 4-day course) could be administered within 1 week before Visit 2 (Part 1) or the first dose of daratumumab (Part 2)
* Known hypersensitivity to components of the investigational product or severe allergic or anaphylactic reactions to humanized products
* Participants who have received treatment with any nonmarket drug substance within 4 weeks before the first dose of daratumumab
* Current participation in any other interventional clinical trial
* Participants known or suspected of not being able to comply with a trial protocol (example, due to alcoholism, drug dependency, or psychological disorder)
* Breastfeeding women or women with a positive pregnancy test at Screening
* Women of childbearing potential not willing to use adequate contraception, defined as hormonal birth control or intrauterine device, during the trial and for 1 year after the last dose of daratumumab. For participants in the United States, the use of a double-barrier method is also considered adequate

Primary outcomes:
measure: Number of Participants With Adverse Events
timeFrame: Up to Week 28 (for Part 1) and up to approximately 2.5 years (for Part 2)
Secondary outcomes:
measure: Overall Response Rate
timeFrame: Up to Week 28 (for Part 1) and Week 27 (for Part 2)
measure: Part 1: Time to Response
timeFrame: Up to Week 28
measure: Part 2: Time to Progression (TTP)
timeFrame: Up to Week 27
measure: Part 2: Duration of Response as Assessed Using the Method of Kaplan-Meier
timeFrame: Up to Week 27
measure: Part 2: Progression-Free Survival
timeFrame: Up to Week 27
measure: Part 2: Time to Response
timeFrame: Up to Week 27
measure: Part 2: Overall Survival
timeFrame: Approximately 3 years
Other outcomes:
Locations:
city: Boston
country: United States
state: Massachusetts
city: Copenhagen Ø
country: Denmark
city: Vejle
country: Denmark
city: Amsterdam
country: Netherlands
city: Utrecht
country: Netherlands
city: Huddinge
country: Sweden
city: Lund
country: Sweden
Study officials:
affiliation: Janssen Research & Development, LLC
name: Janssen Research & Development, LLC Clinical Trial
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: Krejcik J, Frerichs KA, Nijhof IS, van Kessel B, van Velzen JF, Bloem AC, Broekmans MEC, Zweegman S, van Meerloo J, Musters RJP, Poddighe PJ, Groen RWJ, Chiu C, Plesner T, Lokhorst HM, Sasser AK, Mutis T, van de Donk NWCJ. Monocytes and Granulocytes Reduce CD38 Expression Levels on Myeloma Cells in Patients Treated with Daratumumab. Clin Cancer Res. 2017 Dec 15;23(24):7498-7511. doi: 10.1158/1078-0432.CCR-17-2027. Epub 2017 Oct 12.
citation: 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.
citation: Lokhorst HM, Plesner T, Laubach JP, Nahi H, Gimsing P, Hansson M, Minnema MC, Lassen U, Krejcik J, Palumbo A, van de Donk NW, Ahmadi T, Khan I, Uhlar CM, Wang J, Sasser AK, Losic N, Lisby S, Basse L, Brun N, Richardson PG. Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma. N Engl J Med. 2015 Sep 24;373(13):1207-19. doi: 10.1056/NEJMoa1506348. Epub 2015 Aug 26.