Subcutaneous delivery of daratumumab in relapsed or refractory multiple myeloma

Abstract

Daratumumab, a human monoclonal antibody targeting CD38, is approved as monotherapy and in combination regimens for patients with multiple myeloma (MM). Currently, daratumumab is administered IV. The phase 1b PAVO (MMY1004) study evaluated subcutaneously administered daratumumab in combination with the recombinant human hyaluronidase PH20 enzyme (rHuPH20) in patients with relapsed or refractory MM. Part 1 of the study, reported here, evaluated a mix-and-deliver (MD) formulation of daratumumab and rHuPH20 (DARA-MD) administered by subcutaneous infusion. Patients received subcutaneous daratumumab according to the approved IV monotherapy dosing schedule at 1200 mg (n = 8) or 1800 mg (n = 45). Primary end points were safety and pharmacokinetic (PK) variables. The most common treatment-emergent adverse events with DARA-MD 1200 mg were thrombocytopenia, upper respiratory tract infection, insomnia, and decreased appetite (37.5% each). Anemia (33.3%), upper respiratory tract infection, pyrexia, and diarrhea (26.7% each) were the most common treatment-emergent adverse events with DARA-MD 1800 mg. One patient in the 1200-mg dose group (12.5%) and 11 patients in the 1800-mg dose group (24.4%) experienced infusion-related reactions, which were generally grade 1/2 and typically occurred at the first infusion. The 1800 mg dose achieved similar or greater serum concentrations compared with the 16 mg/kg IV dose. Overall response rates of 25.0% and 42.2% were achieved with 1200-mg and 1800-mg DARA-MD, respectively. Subcutaneous administration of DARA-MD was well tolerated in patients with relapsed or refractory MM, with the 1800-mg dose exhibiting PK concentrations and responses consistent with IV daratumumab in a similar patient population. This study was registered at www.clinicaltrials.gov as #NCT02519452.

Conflict of interest statement

Conflict-of-interest disclosure: S.Z.U. consulted for AbbVie, GlaxoSmithKline, Celgene, Amgen/Onyx, Takeda/Millennium, Sanofi, Seattle Genetics, Skyline, Merck, and Janssen; received research funding from Celgene, Amgen/Onyx, Takeda/Millennium, Sanofi, Seattle Genetics, Skyline, Merck, Janssen, Array BioPharma, and Pharmacyclics; served on speakers bureaus for Celgene, Amgen, Janssen, Sanofi, and Takeda; and received travel expenses from Janssen, Celgene, Amgen, and Takeda. M.-V.M. received honoraria from and consulted for Celgene, Janssen, Takeda, and Amgen. N.W.C.J.v.d.D. received research support from Janssen Pharmaceuticals, Amgen, Celgene, Novartis, and Bristol-Myers Squibb; and served on advisory boards for Janssen Pharmaceuticals, Amgen, Celgene, Bristol-Myers Squibb, Novartis, Bayer, Takeda, and Servier. A.C. consulted for Amgen, Array BioPharma, Celgene, Janssen, Millennium, Takeda, and Novartis; and received research funding from Amgen, Array BioPharma, Celgene, Janssen, Millennium, Takeda, Novartis, and Pharmacyclics. J.L.K. consulted for AbbVie, Roche, Takeda, Janssen, and Pharmacyclics; and received research funding from Amgen and Novartis. P.M. consulted for and received honoraria from Celgene, Takeda, and Janssen. A.O. consulted for and received honoraria from Amgen, Takeda, and Janssen; and served on speakers bureaus for Amgen and Janssen. T.P. received research support from Janssen Pharmaceuticals; and served on advisory boards for Janssen Pharmaceuticals, Celgene, Takeda, and Behring. L.B. consulted for and received honoraria from Takeda, Celgene, Janssen, and Amgen; and received travel expenses from Janssen, Celgene, and Amgen. P.H., T.M., P.L.C., M.L., and K.L. are employees of Janssen. P.H., T.M., P.L.C., and M.L. hold stock in Johnson & Johnson. J.S.-M. consulted for Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck Sharp & Dohme, Novartis, Takeda, Sanofi, and Roche. H.N. declares no competing financial interests.

© 2019 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Daratumumab serum concentration-time profiles. Mean daratumumab serum concentration over time profiles after the first (A) and eighth (B) weekly doses of DARA-MD. The eighth weekly dose was the last weekly dose, which was administered on cycle 2 day 22; this profile ends with the predose concentration on cycle 3 day 1. Error bars represent ±1 standard deviation. *From study GEN501 part 2. †Cycle 2 day 22. ‡Predose on cycle 3 day 1. §From study GEN501 part 1.

Figure 2.

Daratumumab serum concentration at Ctrough on cycle 3 day 1 after DARA-MD or IV administration. Daratumumab Ctrough was determined at the end of weekly dosing as the predose concentration on cycle 3 day 1. *From studies GEN501 and SIRIUS.

Figure 3.

Responses in the DARA-MD 1800 mg group. Summary of responses (A) and swim lane plot of responders in the DARA-MD 1800 mg group (B). Responses were evaluated in the overall study population.