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J. San-Miguel et al.
city, antibody-dependent cell-mediated cytotoxicity, anti- body-dependent cellular phagocytosis, and apoptosis.1-4 The immunomodulatory actions of daratumumab lead to modulation of the tumor microenvironment, including the depletion of CD38+ immunosuppressive cells, which may explain the clonal expansion of cytotoxic T cells, increase in helper T cells, and increase in granzyme B+ CD8+ T cells observed following exposure to this drug.5-7
Intravenous (IV) daratumumab 16 mg/kg is approved as a monotherapy and in combination with bortezomib/dex- amethasone, lenalidomide/dexamethasone, or pomalido- mide/dexamethasone (in the USA) in patients with relapsed or refractory (RR) multiple myeloma (MM).8,9 Daratumumab 16 mg/kg IV is also approved in combina- tion with bortezomib/melphalan/prednisone or lenalido- mide/dexamethasone (in the USA) for the treatment of patients with newly diagnosed MM who are ineligible for autologous stem cell transplantation, and in combination with bortezomib/thalidomide/dexamethasone (in the USA) for patients with newly diagnosed MM who are eli- gible for autologous stem cell transplantation.8,9 In clinical studies of daratumumab, the median durations of the first, second, and subsequent daratumumab IV infusions were 7.0, 4.3, and 3.4 hours (h), respectively.8 For the conven- ience of patients and healthcare providers, the first daratu- mumab 16 mg/kg IV dose may be split over 2 days (8 mg/kg administered on days 1 and 2 of cycle 1), which is associated with a shorter median infusion duration of 4.2h on day 1 of cycle 1.8,10,11 In addition to split-dose administration of daratumumab, alternative approaches to reducing the duration of the first daratumumab infusion include administering a low priming dose on day 1 of cycle 1 and the remainder of the 16 mg/kg IV dose on day2, or giving an 8 mg/kg IV dose on day 1 of cycle1 before proceeding with the 16 mg/kg IV dose from day 8 of cycle 1 onwards.12 Furthermore, a shorter, 90-minute (min) infusion for subsequent (day 15 of cycle 1 and beyond) 16mg/kg IV administrations of daratumumab was shown to be well tolerated.13 Infusion-related reac- tions (IRR) occur in approximately 50% of patients treated with IV daratumumab; these reactions are manageable and occur primarily during the first infusion.8
Given the infusion time required for IV administration and the incidence of IRR associated with daratumumab, a subcutaneous (SC) delivery method is in development, with the goal of shortening the duration of infusion with- out compromising the safety or efficacy of the drug. SC administration of daratumumab may be associated with a lower risk of IRR, improved tolerability due to a more gradual systemic absorption of the drug, and greater con- venience for both patients and healthcare providers by reducing infusion times.
Recombinant human hyaluronidase PH20 (rHuPH20; ENHANZE® drug delivery technology, Halozyme, Inc., San Diego, CA, USA) depolymerizes hyaluronan in the SC space, allowing rapid administration of large volumes of injected drugs, thus facilitating SC delivery.14 A mix-and- deliver formulation of daratumumab (20 mg/mL) and rHuPH20 (DARA-MD), given SC by means of a syringe pump at two dose levels (DARA-MD 1,200 mg and DARA-MD 1,800 mg) over 20 to 30 min, was evaluated in part 1 of PAVO, a phase Ib study in patients with RRMM.15 Results from part 1 showed that SC administration of daratumumab is feasible in patients with MM. DARA- MD was well tolerated, with low rates of IRR (23%). The
serum concentrations achieved with the 1,800 mg dose of DARA-MD were consistent with those observed for dara- tumumab 16 mg/kg IV in patients with RRMM. Moreover, the efficacy of the 1,800 mg dose of DARA- MD was comparable to that of daratumumab 16 mg/kg IV in a similar population of patients.16 At the 1,800 mg dose level of DARA-MD, the overall response rate (ORR) was 42%, and responses were deep and durable, with four (9%) patients achieving a stringent complete response.15
Based on the results from part 1 of the PAVO study, a concentrated, pre-mixed co-formulation of daratumumab 1,800 mg (120 mg/mL) and rHuPH20 (DARA SC) with a smaller injection volume (15 mL for DARA SC vs. 60 mL for DARA-MD 1,200 mg and 90 mL for DARA-MD 1,800mg) and shorter injection time was developed, enabling manual SC injection into the abdomen.17 This report describes part 2 of PAVO, which investigated the safety, pharmacokinetics (PK), and efficacy of DARA SC in patients with RRMM.
Methods
Study design and patients
PAVO (MMY1004) is a phase Ib, open-label, multicenter, dose- finding, proof-of-concept study. Detailed eligibility criteria have already been published.15 Briefly, patients were ≥18 years of age, had RRMM and had received two or more prior lines of treatment, including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD), and were naïve to anti-CD38 therapy. In part 1, DARA-MD was administered by SC infusion over 20 to 30 min through a syringe pump to determine the recommended dose for part 2. In part 2, a concentrated co-formulation of the selected daratumumab dose (1,800 mg) and rHuPH20 concentration (30,000 U; in 15 mL) in a single, pre-mixed vial was administered over 3 to 5 min by manual SC injection (DARA SC) at alternating locations in the periumbilical area of the abdominal wall. Treatment was given in 28-day cycles: once weekly during cycles 1 and 2, every 2 weeks during cycles 3 through 6, and every 4 weeks thereafter until disease progression or unacceptable toxi- city. All patients remained in the hospital for observation for at least 24 h after the end of the SC injection on day 1 of cycle 1. Inpatient observation after subsequent doses was implemented if deemed necessary based on safety observations.
Endpoints and assessments
The primary endpoints were daratumumab trough concentra- tion (Ctrough) at the end of weekly dosing (just prior to administra- tion of the day 1 dose of cycle 3) and safety. Secondary endpoints included ORR and complete response rate.
Blood samples for PK analysis were collected on days 1, 2, 3, 4, 8,15,and22ofcycle1;days1,8,15,22,23,and25ofcycle2; day 1 of cycles 3, 4, 6, and 8; and 4 and 8 weeks after the final dose of study medication. Blood samples collected prior to dosing on days1and15ofcycle1,day22ofcycle2,andday1ofcycle4as well as 4 and 8 weeks after the end of treatment were assessed for anti-daratumumab antibodies and anti-rHuPH20 antibodies.
Safety assessments included adverse-event monitoring, physical examinations, electrocardiograms, injection-site evaluations, clini- cal laboratory parameters, vital sign measurements, and Eastern Cooperative Oncology Group Performance Status. Adverse events were assessed using National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03.18
Responses were assessed according to International Myeloma Working Group consensus recommendations19,20 at the beginning
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haematologica | 2021; 106(6)