Phase I Study of BT062 Given as Repeated Single Dose Once Every 3 Weeks in Patients with Relapsed or Relapsed/Refractory Multiple Myeloma.

Biotest AG (Dreieich, Germany) is developing the immunoconjugate BT062, which comprises the anti-CD138 chimerized MAb (nBT062) and the cytotoxic agent maytansinoid (DM4). Once bound to CD138 on a target cell, the conjugate is internalized and releases DM4. At present, CD138 represents one of the most reliable target antigens for identification of multiple myeloma (MM) cells and has been reported to be a highly sensitive and specific diagnostic marker of MM. Preclinical investigations demonstrated significant in vitro and in vivo anti-MM activity of BT062, providing the rationale for the conduct of clinical trials (Ikeda et al., 2009).

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 relapsed or relapsed/refractory MM. Clinical response was assessed as per the international working group criteria (Durie et al., 2006).

This is a prospective, open label, dose-escalation multicenter study. Patients aged ≥ 18 years with relapsed or relapsed/refractory MM who have failed previous treatments including an immunomodulating 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 are enrolled in cohorts of 3 at each dose level, with DLT in the first cycle triggering cohort expansion.

To date 20 patients have been treated with BT062 at 7 dose levels ranging from 10 mg/m² to 200 mg/m². Maximum administered dose has not been defined to date with continued enrollment at 200 mg/m² dose. None of the patients treated experienced serious hypersensitivity reactions or humoral responses (HAHA) against BT062. The most frequently reported adverse events to date cover primarily events expected for the underlying disease. Nevertheless, a few adverse events have also been observed involving skin and mucosa (tissues of epithelial origin with CD138 expressing cells). No grade 4 toxicity has been reported. Preliminary PK results indicate an unusual rapid clearance from plasma in the early elimination phase, followed by a generally normal terminal elimination phase at dose levels up to 120 mg/m², whereas a more typical clearance profile was observed for all 3 patients at the 160 mg/m² dose. Interestingly, even in phase I study decreased urine M-Protein or serum FLC levels have been observed in 2 patients. One of these patients showed a decrease in urine M-Protein by more than 50% after administration of 8 repeated low doses. At a high dose level another patient without detectable M-Protein levels, showed a decrease of serum FLC by more than 50% after having received the second dose of BT062. Furthermore, evidence of clinical benefit has been observed in at least 6 patients with early stabilization of M-protein levels (and light-chain burden) in serum and /or urine.

Development of a monoclonal antibody in MM remains an important therapeutic option and BT062 is an exciting possibility. Preliminary data from this phase I study, demonstrate an acceptable toxicity profile of BT062 in the clinics. Even in phase I study, evidence of clinical activity is observed. These encouraging results and the unique PK observed support investigation of a more frequent dosing regimen for optimizing anti-MM responses. Updated data on safety, PK and efficacy of BT062 from this clinical trial will be presented at the meeting.

Jagannath:Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Avigan:Genzyme: Consultancy, Research Funding; Celgene: Research Funding. Lutz:Immunogen, Inc.: Employment. Haeder:Biotest AG: Employment. Ruehle:Biotest AG: Employment. Uherek:Biotest AG: Employment. Wartenberg-Demand:Biotest AG: Employment. Munshi:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Anderson:Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Biotest AG: Consultancy, Research Funding.