Background: CD138 (Syndecan-1) is highly overexpressed in various solid tumors and hematological malignancies and represents one of the most specific target antigens for identification of multiple myeloma (MM) cells. BT062 (Biotest AG Dreieich, Germany) is an antibody-drug conjugate, comprised of the anti-CD138 chimerized MAb (nBT062) and the cytotoxic agent DM4. Once bound to CD138 on a target cell, the conjugate is internalized and releases DM4, leading to target cell death. We performed the first in man study (969) to investigate safety and efficacy of BT062 in MM.
Objectives: To determine the maximum tolerated dose (MTD), the dose-limiting toxicities (DLTs), pharmacokinetics (PK) and anti-MM activity of increasing doses of BT062 on a repeated single dose schedule once every three weeks in patients with relapsed and/or refractory MM.
Methods: This is a prospective, open label, dose-escalation, multicenter phase I study. Patients aged ≥18 years with relapsed or relapsed/refractory MM who have failed previous treatments including an immunomodulatory agent and a proteasome inhibitor were eligible to participate. Patients with clinical response (or no evidence of progressive disease) and without unacceptable toxicities were eligible for further treatment cycles. Patients were enrolled in cohorts of 3 at each dose level, with DLT in the first cycle triggering cohort expansion. Toxicities were assessed by CTCAE v3 and clinical response was assessed according to the international myeloma working group criteria. Results: A total of 32 patients have been treated with BT062, receiving one of 7 dose levels ranging from 10 mg/m² to 200 mg/m². Maximum administered dose has been defined at 200 mg/m², with mucositis as the dose limiting toxicity (CTC grade III in 2 of the 3 patients in this cohort). Thirteen of 32 patients have been treated in an expanded MTD-cohort at 160 mg/m². The most frequently reported adverse events to date are mild to moderate and cover primarily events expected for the underlying disease and patient group. A few adverse events have also been observed involving skin and/or mucosa (tissues of epithelial origin with CD138 expressing cells), as well as the eye. CTC grade II/III toxicity involving skin and/or mucosa (e.g. mucositis, stomatitis, hand/foot syndrome) has been observed mainly at the dose levels 160 mg/m² or higher. Adverse events involving the eye (e.g. blurred vision, dry eye) have also been reported mainly in patients at the dose levels 160 mg/m² or higher, all restricted to CTC grade I/II. Among the 27 evaluable patients, 3 patients responded including 1 partial response and 2 minor responses, with one patient (minor response) remaining on treatment for more than a year. Stabilization of disease was noted in an additional 11 patients, receiving a median of 5 cycles of therapy (range of 4-10). Thus stable disease or better was noted in 52% of patients. Most patients came off study due to disease progression.
Conclusion:Preliminary data from this study demonstrate an acceptable toxicity profile of BT062. Even in this phase I patient population, evidence of clinical activity was observed. Based on the favourable safety profile, the pharmacokinetic data and early signs of clinical activity, a Phase I/IIa study in MM (975) is initiated to further evaluate the safety and anti-MM efficacy of BT062 in a more frequent dosing regimen. To date 13 patients have been treated with BT062 on the intensified multi-dose regimen, receiving one of the first four dose levels. Updated results on safety, PK and anti-MM efficacy of BT062 will be presented.