Subcutaneous daratumumab in patients with relapsed or refractory multiple myeloma: Part 2 of the open-label, multicenter, dose-escalation phase 1b study (PAVO)

Abstract

Intravenous daratumumab is approved for the treatment of multiple myeloma. In Part 1 of the PAVO study, a mix-and-deliver subcutaneous formulation of daratumumab with recombinant human hyaluronidase PH20 (rHuPH20) was well tolerated, with low rates of infusion-related reactions and similar efficacy to intravenous daratumumab. Part 2 of PAVO evaluated a concentrated, pre-mixed co-formulation of daratumumab and rHuPH20 (DARA SC). Patients with ≥2 prior lines of therapy, including a proteasome inhibitor and immunomodulatory drug, received daratumumab (1800 mg) and rHuPH20 (30,000 U) in 15 mL subcutaneously over 3-5 minutes per the approved intravenous monotherapy dosing schedule. Primary endpoints were daratumumab trough concentration at the end of weekly dosing (just prior to the Cycle 3 Day 1 dose) and safety. Twenty-five patients were enrolled in PAVO Part 2. DARA SC achieved daratumumab trough concentrations similar to or greater than intravenous daratumumab 16 mg/kg. The adverse event profile of DARA SC was consistent with intravenous daratumumab, with no new safety concerns and a lower infusion-related reaction rate. At a median follow-up of 14.2 months, the overall response rate was 52%, median duration of response was 15.7 months, and median progression-free survival was 12.0 months. DARA SC 1800 mg was well tolerated in relapsed/refractory multiple myeloma, with a low infusion-related reaction rate and reduced administration time. Daratumumab serum concentrations following DARA SC were consistent with intravenous dosing, and deep and durable responses were observed. Based on these results, ongoing studies are investigating DARA SC in multiple myeloma and other conditions. (ClinicalTrials.gov identifier: 02519452).

Figures

Figure 1.

Serum concentrations of daratumumab over time. The mean (± standard deviation) serum concentrations of daratumumab over time (A) after the first dose and (B) after the last weekly dose (eighth dose). DARA: daratumumab; Ctrough: trough concentration; C3D1: day 1 of cycle 3; IV: intravenous; SC: subcutaneous. aFrom the GEN501 study.

Figure 2.

Simulation of mean concentration-time profiles of daratumumab following subcutaneous and intravenous dosing.a,b QW: weekly; Q2W: every 2 weeks; Q4W: every 4 weeks; SC: subcutaneous; IV: intravenous; DARA: daratumumab. aThe dosing schedule is once weekly in cycles 1 and 2, every 2 weeks in cycles 3 through 6, and every 4 weeks thereafter. bSimulations were conducted based on a population pharmacokinetic (PK) model developed for daratumumab following SC and IV administration using scheduled dosing and estimated individual PK parameters. Serum concentration-time data (from the PAVO, GEN501, and SIRIUS studies) were used for the population PK model development using a nonlinear mixed-effects modeling (NONMEMR, version 7.2) approach with the first-order conditional estimation with interaction method. The daratumumab SC model was based on a previous population PK model for daratumumab IV except for the absorption, which was described by a first-order process and a relative bioavailability parameter.

Figure 3.

Responses to DARA SC 1,800 mg. (A) Summary of responses. Responses were evaluated in the all-treated population, which included all patients who received at least one dose of the study drug. (B) Swim lane plot of responders. White text indicates the first response and pink text indicates the best response. ‘X’ indicates disease progression. DARA: daratumumab; SC: subcutaneous; ORR: overall response rate; CR: complete response; VGPR: very good partial response; PR: partial response.