A Study of Daratumumab With the Addition of Recombinant Human Hyaluronidase (rHuPH20) for the Treatment of Participants With Relapsed or Refractory Multiple Myeloma

NCT ID: NCT02519452

Last Updated: 2025-05-23

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 120 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-10-22
• Study Completion Date: 2023-04-03

Brief Summary

The purpose of the study is to evaluate the pharmacokinetics and safety from the mixture of daratumumab and rHuPH20 prepared immediately before administration via Subcutaneous (SC) delivery (Part 1) and CF (co-formulated daratumumab and rHuPH20 preparation) administration via SC delivery of daratumumab (Part 2) and to evaluate the safety of Dara-CF 1800 milligram (mg) SC delivery without pre-dose and post-dose corticosteroids (Part 3).

Detailed Description

This is an open-label (identity of assigned study drug will be known), multicenter, 3-part, Phase 1b dose escalation/expansion study to evaluate the safety, pharmacokinetics (study of what the body does to a drug), and antitumor activity of SC delivery of daratumumab to participant with relapsed or refractory multiple myeloma. Up to approximately 53 participants in part 1, 80 participants in part 2 and 15 participants per corticosteroid tapering cohort (up to approximately 30 participants total) in Part 3 will be enrolled. The purpose of Part 1 is to select an appropriate SC therapeutic dose for the mixture of daratumumab with rHuPH20 based on safety and pharmacokinetics. This dose, selected from part 1 will be the initial dose for the co-formulated daratumumab and rHuPH20 preparation to be evaluated in Part 2. The purpose of Part 2 is to evaluate the SC delivery of CF and confirm the dose level selected from Part 1 based on the pharmacokinetics, safety, and antitumor activity. The purpose of Part 3 is to evaluate the safety of Dara-CF 1800 mg SC delivery without pre-dose and post-dose corticosteroids. Participant's safety will be monitored throughout the study.

Conditions

Multiple Myeloma

Study Design

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

Study Groups

Part 1: Cohort 1

Participants will receive 1200 mg (daratumumab 1200 milligram (mg) with Recombinant Human Hyaluronidase \[rHuPH20\] 30,000 U) via mixing immediately before Subcutaneous (SC) infusion once weekly in Cycles 1 (each cycle is 28 days) and 2, every 2 weeks in Cycles 3-6, and then every 4 weeks in subsequent cycles until disease progression.

Group Type: EXPERIMENTAL

Daratumumab Subcutaneous (SC) Administration

Intervention Type: DRUG

Participants will receive Daratumumab mixed with rHuPH20 in part 1 and co-formulated with rHuPH20 in part 2 and part 3 administered via SC administration once weekly in Cycles 1 (each cycle is 28 days) and 2, every 2 weeks in Cycles 3-6, and every 4 weeks in subsequent cycles.

Recombinant Human Hyaluronidase [rHuPH20]) SC Administration

Intervention Type: DRUG

Participants will receive Recombinant Human Hyaluronidase \[rHuPH20\]) mixed with Daratumumab in part 1 and co-formulated with Daratumumab in part 2 and part 3 administered as SC administration once weekly in Cycles 1 (each cycle is 28 days) and 2, every 2 weeks in Cycles 3-6, and every 4 weeks in subsequent cycles.

Part 1: Cohort 2

Participants will receive 1800 mg (daratumumab 1800 milligram (mg) with Recombinant Human Hyaluronidase \[rHuPH20\] 45,000 U) via mixing immediately before SC infusion once weekly in Cycles 1 and 2, every 2 weeks in Cycles 3-6, and then every 4 weeks in subsequent cycles until disease progression.

Group Type: EXPERIMENTAL

Daratumumab Subcutaneous (SC) Administration

Intervention Type: DRUG

Participants will receive Daratumumab mixed with rHuPH20 in part 1 and co-formulated with rHuPH20 in part 2 and part 3 administered via SC administration once weekly in Cycles 1 (each cycle is 28 days) and 2, every 2 weeks in Cycles 3-6, and every 4 weeks in subsequent cycles.

Recombinant Human Hyaluronidase [rHuPH20]) SC Administration

Intervention Type: DRUG

Participants will receive Recombinant Human Hyaluronidase \[rHuPH20\]) mixed with Daratumumab in part 1 and co-formulated with Daratumumab in part 2 and part 3 administered as SC administration once weekly in Cycles 1 (each cycle is 28 days) and 2, every 2 weeks in Cycles 3-6, and every 4 weeks in subsequent cycles.

Part 1: Cohort 3

Participants will receive mixture of daratumumab and rHuPH20 prepared immediately before administration via Subcutaneous (SC) delivery at a dose which will be decided by Study Evaluation Team (SET) once weekly by SC infusion in Cycles 1 and 2, every 2 weeks in Cycles 3-6, and then every 4 weeks in subsequent cycles until disease progression. Also up to three additional optional cohorts (Cohorts 3b, 3c, and 3d) may be enrolled to repeat a dose level of daratumumab.

Group Type: EXPERIMENTAL

Daratumumab Subcutaneous (SC) Administration

Intervention Type: DRUG

Participants will receive Daratumumab mixed with rHuPH20 in part 1 and co-formulated with rHuPH20 in part 2 and part 3 administered via SC administration once weekly in Cycles 1 (each cycle is 28 days) and 2, every 2 weeks in Cycles 3-6, and every 4 weeks in subsequent cycles.

Recombinant Human Hyaluronidase [rHuPH20]) SC Administration

Intervention Type: DRUG

Participants will receive Recombinant Human Hyaluronidase \[rHuPH20\]) mixed with Daratumumab in part 1 and co-formulated with Daratumumab in part 2 and part 3 administered as SC administration once weekly in Cycles 1 (each cycle is 28 days) and 2, every 2 weeks in Cycles 3-6, and every 4 weeks in subsequent cycles.

Part 2: Cohort 4

Participants will receive 1800 mg co-formulated daratumumab and rHuPH20 preparation initially administered by SC injection once weekly in Cycles 1 and 2, every 2 weeks in Cycles 3-6, and then every 4 weeks in subsequent cycles. The dose level and schedule for any additional cohorts would be selected based on the daratumumab pharmacokinetic profile and safety profile (reviewed by the SET) that will be observed in Cohort 4.

Group Type: EXPERIMENTAL

Daratumumab Subcutaneous (SC) Administration

Intervention Type: DRUG

Participants will receive Daratumumab mixed with rHuPH20 in part 1 and co-formulated with rHuPH20 in part 2 and part 3 administered via SC administration once weekly in Cycles 1 (each cycle is 28 days) and 2, every 2 weeks in Cycles 3-6, and every 4 weeks in subsequent cycles.

Recombinant Human Hyaluronidase [rHuPH20]) SC Administration

Intervention Type: DRUG

Participants will receive Recombinant Human Hyaluronidase \[rHuPH20\]) mixed with Daratumumab in part 1 and co-formulated with Daratumumab in part 2 and part 3 administered as SC administration once weekly in Cycles 1 (each cycle is 28 days) and 2, every 2 weeks in Cycles 3-6, and every 4 weeks in subsequent cycles.

Part 3: Dara-CF 1800 mg

Participants will receive co-formulated daratumumab 1800 mg and rHuPH20 preparation (Dara-CF) initially administered by SC injection once weekly in Cycles 1 and 2, every 2 weeks in Cycles 3-6, and then every 4 weeks in subsequent cycles.

Group Type: EXPERIMENTAL

Daratumumab Subcutaneous (SC) Administration

Intervention Type: DRUG

Participants will receive Daratumumab mixed with rHuPH20 in part 1 and co-formulated with rHuPH20 in part 2 and part 3 administered via SC administration once weekly in Cycles 1 (each cycle is 28 days) and 2, every 2 weeks in Cycles 3-6, and every 4 weeks in subsequent cycles.

Recombinant Human Hyaluronidase [rHuPH20]) SC Administration

Intervention Type: DRUG

Participants will receive Recombinant Human Hyaluronidase \[rHuPH20\]) mixed with Daratumumab in part 1 and co-formulated with Daratumumab in part 2 and part 3 administered as SC administration once weekly in Cycles 1 (each cycle is 28 days) and 2, every 2 weeks in Cycles 3-6, and every 4 weeks in subsequent cycles.

Interventions

Daratumumab Subcutaneous (SC) Administration

Participants will receive Daratumumab mixed with rHuPH20 in part 1 and co-formulated with rHuPH20 in part 2 and part 3 administered via SC administration once weekly in Cycles 1 (each cycle is 28 days) and 2, every 2 weeks in Cycles 3-6, and every 4 weeks in subsequent cycles.

Intervention Type: DRUG

Recombinant Human Hyaluronidase [rHuPH20]) SC Administration

Participants will receive Recombinant Human Hyaluronidase \[rHuPH20\]) mixed with Daratumumab in part 1 and co-formulated with Daratumumab in part 2 and part 3 administered as SC administration once weekly in Cycles 1 (each cycle is 28 days) and 2, every 2 weeks in Cycles 3-6, and every 4 weeks in subsequent cycles.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Participants proven to have multiple myeloma (MM) diagnosis according to the International Myeloma Working Group (IMWG) diagnostic criteria
• Measurable disease as defined by any of the following: (a) immunoglobulin (Ig) G myeloma (serum monoclonal paraprotein [M-protein] level >=1.0 gram/deciliter [g/dL] or urine M-protein level greater than or equal to (>=) 200 milligram[mg]/24 hours[hrs]; or (b) IgA, IgD, or IgE multiple myeloma (serum M-protein level >= 0.5 g/dL or urine M-protein level >= 200 mg/24 hrs); or (c) light chain multiple myeloma (serum immunoglobulin free light chain >=10 mg/dL and abnormal serum immunoglobulin kappa lambda free light chain ratio)
• Participant must have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2
• Pretreatment clinical laboratory values must meet protocol-defined parameters during the Screening phase
• Man, who is sexually active with a woman of child-bearing potential and has not had a vasectomy, must agree to use a barrier method of birth control example (eg), either condom with spermicidal foam/gel/film/cream/suppository or partner with occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository, and all men must also not donate sperm during the study and for 3 months after receiving the final dose of study drug
• Relapsed or refractory disease. Relapse is defined as progression of disease after an initial response to previous treatment, more than 60 days after cessation of treatment. Refractory disease is defined as less than (<) 25 percent (%) reduction in M-protein or progression of disease during treatment or within 60 days after cessation of treatment
• Prior treatment with less than or equal to (>=) 2 treatment lines of anti-myeloma therapy. Prior lines of therapy must include a proteasome inhibitor (PI) (eg, bortezomib, carfilzomib) and an immunomodulatory drug (IMiD) (example, thalidomide, lenalidomide, pomalidomide) in any order during the course of treatment. Each prior line of therapy may consist of one or more agents and may include induction, hematopoietic stem cell transplantation, and/or maintenance therapy. Radiotherapy, bisphosphonates, or a single short course of steroids is not considered a prior line of therapy

Exclusion Criteria

• Participant has received daratumumab or other anti-cluster of differentiation 38 (anti-CD38) therapies previously
• Participant has received anti-myeloma treatment within 2 weeks before Cycle 1 Day 1
• Participant has previously received an allogenic stem cell transplant; or participant has received autologous stem cell transplantation (ASCT) within 12 weeks before Cycle 1 Day 1
• Participant has a history of malignancy (other than multiple myeloma) within 5 years before Cycle 1 Day 1 (exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or malignancy that in the opinion of the investigator, with concurrence with the sponsor's medical monitor, is considered cured with minimal risk of recurrence)
• Participant is exhibiting clinical signs of meningeal involvement of multiple myeloma

• 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

Atlanta, Georgia, United States

New York, New York, United States

Charlotte, North Carolina, United States

Philadelphia, Pennsylvania, United States

Vejle, , Denmark

Nantes, , France

Tours, , France

Amsterdam, , Netherlands

Badalona, , Spain

Pamplona, , Spain

Salamanca, , Spain

Stockholm, , Sweden

Countries

United States; Denmark; France; Netherlands; Spain; 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)

Nahi H, Usmani SZ, Mateos MV, van de Donk NWCJ, Oriol A, Plesner T, Bandyopadhyay N, Hellemans P, Tromp B, Nnane I, Zemlickis D, Chari A, Moreau P. Corticosteroid tapering is a safe approach in patients with relapsed or refractory multiple myeloma receiving subcutaneous daratumumab: part 3 of the open-label, multicenter, phase 1b PAVO study. Leuk Lymphoma. 2023 Feb;64(2):468-472. doi: 10.1080/10428194.2022.2148221. Epub 2023 Jan 2. No abstract available.

Reference Type: DERIVED

PMID: 36593729 (View on PubMed)

Usmani SZ, Nahi H, Mateos MV, van de Donk NWCJ, Chari A, Kaufman JL, Moreau P, Oriol A, Plesner T, Benboubker L, Hellemans P, Masterson T, Clemens PL, Luo M, Liu K, San-Miguel J. Subcutaneous delivery of daratumumab in relapsed or refractory multiple myeloma. Blood. 2019 Aug 22;134(8):668-677. doi: 10.1182/blood.2019000667. Epub 2019 Jul 3.

Reference Type: DERIVED

PMID: 31270103 (View on PubMed)

Other Identifiers

2015-001210-94

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

54767414MMY1004

Identifier Type: OTHER

Identifier Source: secondary_id

CR107838

Identifier Type: -

Identifier Source: org_study_id