BT062, an Antibody-Drug Conjugate Directed Against CD138, Given Weekly for 3 Weeks in Each 4 Week Cycle: Safety and Further Evidence of Clinical Activity

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. Data from the first in human study (969) of BT062 demonstrated an acceptable toxicity profile and evidence of clinical activity in heavily pretreated relapsed and/or refractory MM patients(1). Based on these data, a Phase I/IIa study in MM (975) was initiated to further evaluate the safety and efficacy of BT062 when given more frequently.

To determine the maximum tolerated dose (MTD), the dose-limiting toxicities (DLTs), pharmacokinetics (PK), and anti-MM activity of increasing doses of BT062, when administered on a repeated, multiple dose schedule (Days 1, 8, and 15, every 4 weeks) in patients with relapsed and/or refractory MM.

This is a prospective, open label, dose-escalation, multicenter Phase I/IIa study. The Phase I part includes dose escalation, and the Phase IIa the expansion of the MTD or Recommended Phase II Dose (RPTD) cohort. Patients aged ≥18 years with relapsed or relapsed/refractory MM who have failed previous treatment, 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 at least 3 at each dose level; DLT in the first cycle triggered cohort expansion. Toxicities were assessed by CTCAE v4 and clinical response was assessed according to the international myeloma working group criteria.

A total of 29 patients have been treated with BT062, receiving 1 of the first 8 dose levels ranging from 40 mg/m² to 160 mg/m². One out of 6 patients treated at 140 mg/m² experienced a palmar-plantar erythrodysesthesia syndrome that was assessed as DLT (SAE, CTC grade 3). Dose was escalated to 160 mg/m², and 1 of the 2 patients treated experienced an elevation of liver enzymes that was reported as DLT (non-serious, CTC grade 3). Maximum administered dose has not been reached and recruitment into the 160 mg/m² cohort is ongoing. About 90% of the reported Adverse Events (AE) are grades 1–2. The most frequently reported AEs are anemia, diarrhea, and fatigue. Among the 23 patients evaluable for efficacy, 1 patient achieved a partial response (PR) and has been on study treatment for more than 1 year. Stable disease (SD) for at least 3 months was noted in an additional 11 patients, with median progression free survival of 112 (90–245) days. Thus disease control (PR + SD) was noted in more than 50% (12/23) of patients. The most common reason for discontinuation was disease progression. Preliminary pharmacokinetic results indicate rapid early clearance of BT062 from plasma consistent with rapid delivery and binding of BT062 to the MM cells. No significant accumulation of BT062 was noted, even after the end of the 2^nd and 3^rd infusions within a cycle.

Preliminary data from this ongoing study indicate that BT062 is well tolerated even in this multiple dose schedule and provide further evidence of its clinical activity. Dose escalation is ongoing (now at 160 mg/m²) to define the MTD/RPTD, with cohort expansion then planned to further evaluate the safety and efficacy of BT062 at this dose. Based on the favorable safety profile, a Phase I/IIa study (983) has been initiated to evaluate the safety and efficacy of BT062 in combination with lenalidomide and dexamethasone.

Heffner:Millennium: Research Funding. Jagannath:Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: 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: Honoraria, Membership on an entity's Board of Directors or advisory committees. Zimmerman:Novartis: Consultancy; Millennium: Honoraria; Celgene: Honoraria. Lonial:Onyx: Consultancy; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Millennium: Consultancy; Merck and Co: Consultancy. Lutz:ImmunoGen, Inc.: Employment. Czeloth:Biotest AG: Employment. Osterroth:Biotest AG: Employment. Ruehle:Biotest AG: Employment. Beelitz:Biotest Pharmaceuticals Corporation: Employment. Wartenberg-Demand:Biotest AG: Employment. Haeder:Biotest AG: Employment. Anderson:Celgene: Consultancy; Onyx: Consultancy; Merck: Consultancy; Bristol-Myers Squibb: Consultancy; Acetylon: Membership on an entity's Board of Directors or advisory committees; Oncopep: Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals: Consultancy. Munshi:Oncopep: Patents & Royalties; Merck: Consultancy; Onyx: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.