Daratumumab (HuMax®-CD38) Safety Study in Multiple Myeloma

NCT ID: NCT00574288

Last Updated: 2018-04-27

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 104 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-03-26
• Study Completion Date: 2017-04-03

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.

Conditions

Multiple Myeloma

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Dose Escalation: Daratumumab

Group Type: EXPERIMENTAL

Part 1: Daratumumab

Intervention Type: DRUG

First participant will receive intravenous (injection of a substance into a vein) 0.005 milligram per kilogram (mg/kg) (planned dose) infusion of daratumumab and other participants will receive different doses. The participants will receive 7 full infusions of daratumumab and 2 predose infusions every 2 weeks. The dose of daratumumab will be escalated sequentially and considering the safety and efficacy of dose in Part 1, dose for Part 2 of the study will be decided. A predose infusion of 10% of the full dose of daratumumab will be administered a day before the first 2 full infusions.

Methylprednisolone

Intervention Type: OTHER

Pre-dose: Participants (part 1) will receive methylprednisolone 80 mg intravenous (IV) injection 30 minutes to 2 hours before treatment. Participants (part 2) will receive 100 mg methylprednisolone IV 60 minutes to 2 hours before treatment; if a patient experiences no significant infusion-related reactions, the dose of methylprednisolone may be decreased to 50 mg after Visit 4.

Post-dose: All participants (part 1) will receive 40 mg methylprednisolone orally on the first and the second day after all full infusions. During Part 2, all participants will receive 20-25 mg methylprednisolone orally or equivalent on the first and second days after all full-dose infusions.

Dose Expansion: Daratumumab

Group Type: EXPERIMENTAL

Part 2: Daratumumab

Intervention Type: DRUG

In Part 2, the participants will receive dose of daratumumab as determined in part 1 (16 mg/kg) of the study. Participants will receive 8 full infusions at weekly intervals followed by biweekly (every 2 weeks) infusions for 16 additional weeks and monthly infusions until disease progression or unmanageable toxicity, whichever comes first. Predose was dropped at some point in Part 2. A predose infusion of 10 mg daratumumab will be administered on the day before the first full infusion in select cohorts.

Methylprednisolone

Intervention Type: OTHER

Pre-dose: Participants (part 1) will receive methylprednisolone 80 mg intravenous (IV) injection 30 minutes to 2 hours before treatment. Participants (part 2) will receive 100 mg methylprednisolone IV 60 minutes to 2 hours before treatment; if a patient experiences no significant infusion-related reactions, the dose of methylprednisolone may be decreased to 50 mg after Visit 4.

Post-dose: All participants (part 1) will receive 40 mg methylprednisolone orally on the first and the second day after all full infusions. During Part 2, all participants will receive 20-25 mg methylprednisolone orally or equivalent on the first and second days after all full-dose infusions.

Dexamethasone

Intervention Type: OTHER

Participants (Part 2) will receive 20 mg dexamethasone intravenous (IV) injection pre-dose, on the first and second days after every full-dose infusions.

Interventions

Part 1: Daratumumab

First participant will receive intravenous (injection of a substance into a vein) 0.005 milligram per kilogram (mg/kg) (planned dose) infusion of daratumumab and other participants will receive different doses. The participants will receive 7 full infusions of daratumumab and 2 predose infusions every 2 weeks. The dose of daratumumab will be escalated sequentially and considering the safety and efficacy of dose in Part 1, dose for Part 2 of the study will be decided. A predose infusion of 10% of the full dose of daratumumab will be administered a day before the first 2 full infusions.

Intervention Type: DRUG

Part 2: Daratumumab

In Part 2, the participants will receive dose of daratumumab as determined in part 1 (16 mg/kg) of the study. Participants will receive 8 full infusions at weekly intervals followed by biweekly (every 2 weeks) infusions for 16 additional weeks and monthly infusions until disease progression or unmanageable toxicity, whichever comes first. Predose was dropped at some point in Part 2. A predose infusion of 10 mg daratumumab will be administered on the day before the first full infusion in select cohorts.

Intervention Type: DRUG

Methylprednisolone

Pre-dose: Participants (part 1) will receive methylprednisolone 80 mg intravenous (IV) injection 30 minutes to 2 hours before treatment. Participants (part 2) will receive 100 mg methylprednisolone IV 60 minutes to 2 hours before treatment; if a patient experiences no significant infusion-related reactions, the dose of methylprednisolone may be decreased to 50 mg after Visit 4.

Post-dose: All participants (part 1) will receive 40 mg methylprednisolone orally on the first and the second day after all full infusions. During Part 2, all participants will receive 20-25 mg methylprednisolone orally or equivalent on the first and second days after all full-dose infusions.

Intervention Type: OTHER

Dexamethasone

Participants (Part 2) will receive 20 mg dexamethasone intravenous (IV) injection pre-dose, on the first and second days after every full-dose infusions.

Intervention Type: OTHER

Other Intervention Names

HuMax-CD38; HuMax-CD38

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

• 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

Boston, Massachusetts, United States

Copenhagen Ø, , Denmark

Vejle, , Denmark

Amsterdam, , Netherlands

Utrecht, , Netherlands

Huddinge, , Sweden

Lund, , Sweden

Countries

United States; Denmark; Netherlands; Sweden

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)

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.

Reference Type: DERIVED

PMID: 29025767 (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)

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.

Reference Type: DERIVED

PMID: 26308596 (View on PubMed)

Related Links

http://www.nejm.org/doi/full/10.1056/NEJMoa1506348

Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma

Other Identifiers

GEN501

Identifier Type: OTHER

Identifier Source: secondary_id

DARA-GEN501

Identifier Type: OTHER

Identifier Source: secondary_id

2007-003783-22

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

CR101876

Identifier Type: -

Identifier Source: org_study_id