Daratumumab, a CD38 Monoclonal Antibody in Patients with Multiple Myeloma - Data From a Dose-Escalation Phase I/II Study
Authors: Plesner Torben , Lokhorst Henk , Gimsing Peter , Nahi Hareth , Lisby Steen , Richardson Paul G. 
Published: October 2019

Abstract
Abstract 73

Background
Daratumumab (HuMax™-CD38) is a human CD38 monoclonal antibody with broad-spectrum killing activity and effectively mediates killing of CD38-expressing tumor cells via antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity and apoptosis. In this present ongoing first-in-human (FIH) dose-escalation study of daratumumab in pts with multiple myeloma (MM) (ClinicalTrials.gov CT00574288), the safety profile has been acceptable and preliminary efficacy data have already been published1,2. Here we present data from the dose escalation part of the study.

Objectives
The primary objective was to establish the safety profile. The secondary objectives were to establish the maximum tolerated dose (MTD), assessment of efficacy, pharmacokinetics (PK) and immunogenicity – Anti-Drug-Antibodies (ADA).

Methods
Pts ≥18 years and diagnosed with MM requiring systemic therapy and considered relapsed or refractory to at least two different prior lines of therapy and ineligible for ASCT were enrolled. The study was based on a 3+3 dose-escalation design. Daratumumab was administered over a 9-week period consisting of 2 pre- and 7 full doses. The doses ranged from 0.005 mg/kg to 24 mg/kg. Prednisolone/methylprednisolone was administered to prevent infusion related events (IREs) in a maximum dose equivalent to 27mg dexamethasone per week. Daratumumab plasma concentrations were measured by ELISA. Evaluation of efficacy data was according to IMGW guidelines3. A bridging ElectroChemiLuminesence (ELC) method on the MesoScale Discovery platform was used to detect ADA responses in pts to daratumumab.
The results presented are based on data analyzed before database lock.

Results
Data from 32 pts including 2 pts in the ongoing 24mg/kg cohort were collected until now. Median age was 61 years (42–76). The median number of prior treatment lines was: 6.3 (2–12).
PK analysis showed plasma peak levels as expected, but relatively rapid clearance at low dose levels. The clearance rate decreased with increasing dose suggesting an effect of target binding on the PK. At doses ≥ 4 mg/kg, daratumumab trough levels were consistent ≥ 10 μg/ml and observed PK values approximately estimated PK values (Figure 1).
Preliminary efficacy evaluation in this abstract was based on best response to paraprotein as reflected by change in serum or urine M-component or free light chains (FLC) according to IMGW guidelines3. For groups ≤ 2 mg/kg, 4/20 pts achieved a reduction in paraprotein (12%, 14%, 19%, 55%); in the 4 mg/kg group, 3/3 pts had a reduction in paraprotein of 49%, 100%, and 64%, respectively. In the 8 mg/kg group, 2/3 pts had a reduction in paraprotein of 39%, and 100%, respectively whereas in the 16mg/kg cohort, 2/3 pts had a reduction in paraprotein of 50%, and 33%, respectively. A reduction of 80%-100% in the bone marrow plasma cells was seen in the 4 mg/kg group and onwards. No detectable ADA responses were found in the pts.
No DLTs were reported in the 2, 4, 8 and 16mg/kg cohorts. The most common adverse events reported were infusion related events. The observed IREs occurred predominantly during the initial infusions, 10% of pts reported IREs during the pre-dose, 30% during the first full infusion with a gradual decrease in frequency after the 2nd full infusion. No dose relationship was observed. Most IREs had onset within 3–4 hours of infusion, two of the IREs were grade 3 and the remaining grade 1–2. Four IREs were SAEs; however, since implementation of steroids before all infusions and dilution of trial drug, no serious IREs were reported in the 4, 8 and 16mg/kg cohorts.

Conclusion
In pts with relapsed or refractory MM treated with daratumumab, a marked reduction in paraprotein and bone marrow plasma cells was observed in the higher dose cohorts. This has not previously been demonstrated with a single-agent monoclonal antibody in MM. No unexpected buildup of daratumumab was seen and in pts treated with 4mg/kg and upwards the observed plasma concentrations were close to those predicted. No ADA responses were detected. The MTD was not yet established and the toxicity was manageable. All data available from part 1 will be presented at the meeting.

Disclosures:
Plesner: Genmab: Consultancy; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees. Lokhorst:Genmab: Consultancy. Lisby:Genmab: Employment. Richardson:Millenium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees.