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A Phase I Study of HCD122 (formerly CHIR-12.12), a Monoclonal Antibody to CD40, in Relapsed/Refractory Myeloma
By William Bensinger, MD
12.18.06





An interim report on the safety and efficacy of a new monoclonal antibody. Patients have been treated at two of three planned dose levels. There have been responses, although maximum tolerated dose (MTD) has not been reached, and the antibody appears to be safe and well tolerated. Enrollment is ongoing.

ABSTRACT:

A Phase 1 Dose Escalation Study of a Fully Human, Antagonist Anti-CD40 Antibody, HCD122 (Formerly CHIR-12.12) in Patients with Relapsed and Refractory Multiple Myeloma. Session Type: Poster Session, Board #804-III

William Bensinger, Sundar Jagannath, Pamela S. Becker, Kenneth C. Anderson, Edward A. Stadtmauer, Lea Aukerman, Judith Fox, Sandhya Girish, Sanela Bilic, Serge Guzy, Alan Solinger, Sherri Dort, Yongyu Wang, Deborah Hurst Fred Hutchinson Cancer Research Center, Seattle, WA, USA; St. Vincents Comprehensive Cancer Center, New York, NY, USA; Dana-Farber Cancer Institute, Boston, MA, USA; University of Pennsylvania, Philadelphia, PA, USA; Novartis Oncology, Florham Park, NJ, USA; XOMA Ltd, Berkeley, CA, USA

HCD122 is a novel, fully human, IgG1 antagonistic monoclonal antibody targeting the CD40 receptor. This antibody blocks CD40-mediated signaling and is a potent mediator of antibody-dependent cellular cytotoxicity (ADCC). Previous preclinical investigation confirmed expression of CD40 on myeloma cells in the majority of patients and reported antitumor activity of HCD122 against multiple myeloma cells ex vivo (Tai, Y et al. Cancer Res 2005; 65(13): 5898-5906). This ongoing phase 1 study will determine the maximum tolerated dose of CHIR-12.12 in multiple myeloma patients (pts) who are relapsed or refractory after at least one prior therapy. Planned dose levels are 1, 3 and 10 mg/kg administered IV once weekly for 4 weeks. Each dose group will enroll 3-6 pts to evaluate safety, pharmacokinetics (PK) and clinical response. To date, 9 pts have been treated at 2 dose levels: 3 pts at 1 mg/kg and 6 pts at 3 mg/kg. Median patient age is 65 yrs (46-81 yrs); median number of prior therapies is 3 (2-12). No dose limiting toxicity (DLT) occurred at the 1mg/kg dose level. At 3 mg/kg, 1 DLT of grade 4 thrombocytopenia occurred in 1 pt. No other grade 3 and 4 lab abnormalities and adverse events have been reported. In 7 pts with available data, infusions were well tolerated, with easily managed grade 1-2 toxicities, primarily chills (5 pts), nausea (3 pts), pyrexia (2 pts), and arthralgia (2 pts) mainly reported during the first infusion. Preliminary PK analysis showed more than dose proportional - increase in Cmax and AUC at the 3 mg/kg dose level compared to the 1 mg/kg dose level. At the 3 mg/kg dose, antibody accumulation occurred week-to-week; the mean Cmax after the fourth infusion on Day 22 was 126.1 mg/mL(range 52 - 195 ug/mL) and HCD122 levels were measurable up to Day 57 and in one patient up to Day 99. One week after the last 3 mg/kg dose, trough levels ranged from 28 to 109 mg/mL. Of the 3 pts at 1 mg/kg, one showed stable disease (SD) for >23 weeks and two had progressive disease (PD) by week 5. Of the 6 pts at 3 mg/kg, one had partial response (PR) at week 9 and was confirmed at week 15, one had SD for > 5 weeks, and 4 had PD at week 5. One pt with PD terminated the study before final safety evaluation, and must be replaced before assessment of the 3mg/kg dose level is complete. Thus, in preliminary studies, HCD122 appears to be safe and well tolerated to date at doses of 1 mg/kg and 3 mg/kg weekly for 4 doses and shows promising anti-myeloma activity. Enrollment is continuing to determine MTD.
Abstract #3575 appears in Blood, Volume 108, issue 11, November 16, 2006


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