A Phase I/II, Dose-Escalation Study of Daratumumab, A CD38 Mab in Patients with Multiple Myeloma – Preliminary Safety Data

Patients with multiple myeloma (MM) relapsed or refractory to current treatment options and ineligible for ASCT have a poor prognosis. Therefore new treatment options are highly needed for this patient population. Malignant MM cells exhibit very strong CD38 surface expression. Daratumumab is a human CD38 antibody with broad spectrum killing activity. Daratumumab mediates MM cell death via antibody dependent cellular cytotoxicity, complement dependent cytotoxicity and apoptosis. Daratumumab has been shown to inhibit growth of CD38-expression tumor cells in SCID mouse xenografts. We report the preliminary safety results from the ongoing first in man dose-escalation study (clin.trial.gov. NCT00574288).

Patients (age > 18 yrs) ineligible for ASCT and relapsed or refractory to at least two different prior therapies receive 7 full and 2 pre-dose infusions of daratumumab (1^st pre-dose day 1, 1^st full dose day 2, 2^nd pre-dose day 21, 2^nd full-dose day 22 and thereafter weekly full-dose daratumumab). The study design encompasses a classic 3 + 3 dose escalation with the possibility to limit exposure to 1 patient in the first 2 cohorts pending safety data. The dose range is from 0.005 mg/kg to 24 mg/kg. The primary objective is to establish the safety profile and secondary objectives are to establish MTD and evaluate the efficacy. An independent Data Monitoring Committee evaluates the safety data for each cohort before dose-escalation.

Until May 31^st, 2011 safety data for 20 patients, including dose range from 0.005 mg/kg up to 2 mg/kg cohort, were collected. Median age 62 yrs (42–76), F/M: 7/13, stage of MM (ISS): 1: 5 patients; 2: 9 patients; 3: 5 patients and 1 unknown. The most common AEs reported across all cohorts are pyrexia (35%), free hemoglobin (25%), anemia (25%), proteinuria (25%), cough (15%), dizziness (10%), flushing (10%), influenza-like-illness (10%), nausea (10%) hypo/hypertension (10%/10%), thrombocytopenia (10%), hemolysis (15%), lymphopenia (10%), arthralgia (10%), abdominal pain (10%) and chest pain (10%). Five SAE were assessed as related to daratumumab. One patient had anemia grade 3 and thrombocytopenia grade 4, one patient experienced cytokine release syndrome grade 2 and based on these DLT events 3 more patients were enrolled in the 0.1 mg/kg and 1.0mg/kg cohorts, one patient experienced a grade 3 bronchospasm 40 hours after end of trial drug infusion and one patient had AST elevation. All patients recovered after relevant treatment. Since implementation of relevant pre-medication and dilution of trial drug no severe infusion related AEs have been reported.

The MTD has not been reached at the cut-off time point for this evaluation.

Efficacy evaluation is ongoing and preliminary data will be presented at the meeting.

Daratumumab has a favorable safety profile as monotherapy in patients with multiple myeloma in doses up to and including 2 mg/kg. The dose-escalation is ongoing and updated safety data will be presented at the meeting. When the MTD is established, an extension study with daratumumab as monotherapy will be conducted.

Plesner:Genmab A/S: Consultancy. Lokhorst:Genmab: Consultancy. Valentin:Genmab A/S: Employment. Lisby:Genmab A/S: Employment. Richardson:Genmab: Consultancy.