Preliminary Report of a Phase 1 Study of CMC-544, an Antibody-Targeted Chemotherapy Agent, in Patients with B-Cell Non-Hodgkin’s Lymphoma (NHL).

Introduction: CMC-544 is an antibody-targeted chemotherapy agent composed of a monoclonal antibody, which specifically targets the CD22 antigen, conjugated to calicheamicin, a potent cytotoxic antitumor antibiotic. Malignant cells of mature B-lymphocyte lineage express CD22 and thus, CMC-544 may be useful for treating lymphomas of B-cell origin.

Methods: A phase 1, dose escalation trial of CMC-544 is ongoing in patients (pts) with relapsed or refractory B-cell NHL across 13 European and US sites. CMC-544 was administered intravenously every 3–4 weeks at doses of 0.4, 0.8, 1.34, 1.8, and 2.4 mg/m². Standard safety and pharmacokinetic data and preliminary efficacy data (assessed using the International Workshop to Standardize Response Criteria for NHL) are being collected. Enrollment of pts with any type of B-cell NHL, except for Burkitt’s and lymphoblastic lymphomas, was allowed in the dose escalation phase (1–6 pts per cohort). After the maximum tolerated dose (MTD) was identified, 15 pts with follicular lymphoma and 15 pts with diffuse large B-cell lymphoma will be enrolled in an expanded MTD cohort.

Results: As of June 2005, 34 pts (8 women, median 71 yrs; 26 men, median 62 yrs; number of previous treatments, median 4, range 2–11) were enrolled. Dose escalation was based on 1^st cycle safety evaluations of pt cohorts. Dose-limiting toxicities (DLTs) were reported for dose levels of 1.34 mg/m² (grade 4 thrombocytopenia, 2/11 pts), 1.8 mg/m² (bleeding requiring platelet transfusion, 1/6), and 2.4 mg/m² (grade 4 thrombocytopenia, 1/6; grade 4 neutropenia for 7 days, 1/6). Thus, the MTD, the dose level prior to the one where ≥ 33% DLTs occurred, was 1.8 mg/m². The most common drug-related adverse events (AEs, all grades) were: thrombocytopenia (65%), asthenia (47%), nausea (41%), neutropenia (29%), elevated liver function tests (27%), anorexia (14%), and epistaxis (12%). Grade 3–4 AEs that occurred with a frequency ≥ 10% included: thrombocytopenia (38%), asthenia (12%), and neutropenia (12%). The nadir of the thrombocytopenia was 9±2 days and platelet counts recovered spontaneously. No major bleeding episodes were reported. At the 1.8 and 2.4 mg/m² dose levels, data suggested a dose-dependent component of platelet recovery to baseline levels and dose delays were required between successive doses. CMC-544 and total calicheamicin exposures in serum increased with dose. Clearance after 2^nd or 3^rd doses decreased approximately 8–14-fold compared with 1^st dose, and half-life increased from approximately 1 day to 4 days. Available data suggested an association of peak CMC-544 exposures and/or total calicheamicin levels with decreases in platelet counts. Accordingly, pts in the expanded MTD cohort receive 1.8 mg/m² CMC-544 every 4 weeks. Preliminary antitumor activity was observed in most cohorts. Complete and/or partial responses were observed in the 0.8 mg/m² (1/3 pts), 1.34 mg/m² (3/9), 1.8 mg/m² (2/5), and 2.4 mg/m² (2/5) cohorts, and in the 1^st 6 pts in the expanded MTD cohort (4/6).

Conclusion: CMC-544 shows promising preliminary efficacy in pts with B-cell NHL, with an associated thrombocytopenia that is clinically manageable. The expanded MTD cohort (1.8 mg/m² every 4 weeks) continues to be enrolled.