Abstract
Introduction: CMC-544 is an antibody-targeted chemotherapy agent composed of a humanized antibody that specifically targets the CD22 antigen, conjugated to calicheamicin, a potent cytotoxic antitumor agent. Malignant cells of mature B-lymphocyte lineage express CD22, suggesting that CMC-544 may be useful for treating lymphomas of B-cell origin. A phase 1 dose-escalation trial of CMC-544 was performed at 14 European and US sites with 36 patients in the dose escalation portion and 48 in the expanded MTD portion. The MTD dose was 1.8 mg/m2 every 4 weeks. In the dose escalation phase the main toxicities observed were thrombocytopenia, asthenia, nausea, neutropenia, elevated liver function tests (LFTs) and anorexia. Grade 3–4 levels were only seen for thrombocytopenia, asthenia, neutropenia and LFTs (incidence of 40%, 13%, 9% and 9% respectively). Responses were seen in 8/22 (36%) patients (
Patients and Methods: Relapsed/refractory lymphoma patients were treated at the 1.8 mg/m2 dose level every 4 weeks. In addition to safety data, preliminary efficacy data (assessed using the International Workshop to Standardize Response Criteria for NHL) were collected.
Results: As of July 2006, 48 patients were treated: median age 57 years (range 26–75); 51% females; 61% with ≥ 4 prior lines of therapy; 22 (46%) follicular lymphomas (FL) and 26 (54%) diffuse large B-cell lymphomas (DLBCL). Data were available on 48 patients evaluable for safety and 34 patients (19 FL and 15 DLBCL) evaluable for response. The overall safety profile was manageable; the most common drug-related adverse events (all grades) included thrombocytopenia (90%; the only bleeding noted was grade 1–2 epistaxis [12%]), asthenia (57%), nausea (39%), neutropenia (37%) and elevated levels of AST/SGOT (41%), ALT/SGPT (18%), alkaline phosphatase (27%) and bilirubin (18%). Grade 3–4 AEs that occurred with a frequency ≥ 10% included thrombocytopenia (57%) and neutropenia (29%). Responses in evaluable patients are shown in Table 1. The objective response rate was 69% and 33% for patients with FL and DLBCL, respectively.
Conclusions: CMC-544 exhibits effficacy against recurrent/refractory B-cell lymphomas, with the main toxicity being clinically manageable, self limited thrombocytopenia. These encouraging data support the continuing development of CMC-544.
Response . | Follicular Lymphoma (n=19) . | DLBCL (n=15) . |
---|---|---|
ORR = Overall Remission Rate, (CR/CRu+PR) | ||
CR/CRu | 6 (31.7) | 2 (13.3) |
PR | 7 (36.8) | 3 (20.0) |
ORR | 13 (68.5) | 5 (33.3) |
Response . | Follicular Lymphoma (n=19) . | DLBCL (n=15) . |
---|---|---|
ORR = Overall Remission Rate, (CR/CRu+PR) | ||
CR/CRu | 6 (31.7) | 2 (13.3) |
PR | 7 (36.8) | 3 (20.0) |
ORR | 13 (68.5) | 5 (33.3) |
Disclosures: H.Patel & M.Shapiro are employees of Wyeth Pharmaceuticals.; L. Fayad, M. Smith & J. Foran have been engaged as consultants for Wyeth Pharmaceuticals.; H.Patel & M.Shapiro hold stock options in Wyeth Pharmaceuticals.; L. Fayed, G. Verhoef, M. Czuczman, J. Foran, E. Gine, Rohatiner, M. Smith & A. Advani are investigators in clinical trials sponsored by Wyeth Pharmaceuticals.; L. Fayad, M. Smith & J. Foran have been paid honararia from Wyeth Pharmaceuticals for past consultancy work.
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