Novel Dosing Strategy for IMGN242 in Gastric Cancer Based on Circulating-Antigen Plasma Levels: Presented at EORTC-NCI-AACR

GENEVA--October 29, 2008 -- IMGN242, a conjugate of the cytotoxic maytansinoid DM4 and the monoclonal antibody huC242 that binds to circulating cancer antigen (CanAg), demonstrates initial evidence of activity in patients with metastatic and locally advanced gastric or gastro-oesophageal junction cancer. .

“Researchers presented results of phase 1 and 2 studies of the investigational drug at the 20th International Symposium of the European Organisation for Research and Treatment of Cancer (EORTC), the National Cancer Institute (NCI), and the American Association for Cancer Research (AACR).”

A high incidence of ocular toxicities was observed, however, with the predefined maximum tolerated dose of IMGN242. Indeed, early data indicated an association among IMGN242 exposure, plasma CanAg levels, and ocular toxicities that led to protocol amendments to differentiate IMGN242 dosing based on patient plasma CanAg levels, noted lead investigator Anthony W. Tolcher, MD, South Texas Accelerated Research Therapeutics, San Antonio, Texas, speaking here on October 24.

Subjects for these trials all had histologically documented metastatic or locally advanced gastric or gastro-oesophageal junction cancer, with 1 prior chemotherapy regimen and documented disease progression. The Eastern Cooperative Oncology Group performance status (ECOG-PS) was set for 0 to 1, with measurable disease.

The laboratory criteria specified for inclusion were as follows: absolute neutrophils >=1.5x 109/L; haemoglobin >=9 g/dL; platelets >=100x 109/L; creatinine <=1.5x upper limit of normal (ULN); aspartate aminotransferase and alanine aminotransferase <=2.5x ULN; and bilirubin <=1.5x ULN.

Following determination of the maximum tolerated dose for IMGN242 at 168 mg/m2 in the phase 1 stage, the primary objective of the phase 2 trial was response rate to the treatment when administered as a single intravenous infusion once every 3 weeks.

Secondary objectives included response duration, progression-free survival, safety and tolerability, and pharmacokinetics.

During early recruitment in the phase 2 trial, 1 patient had a marked biological response with an unconfirmed partial response according to the Response Evaluation Criteria in Solid Tumours (RECIST) classification. The high incidence of ocular toxicities, however, prompted an analysis of the combined phase 1 and 2 data for IMGN242 dosing, CanAg levels, and ocular toxicities.

These analyses, Dr. Tolcher stressed, demonstrated that all of the patients with ocular toxicities had low plasma CanAg levels, with relatively high area under the curve values and slow clearance. Conversely, no correlation was seen between incidence of ocular toxicity and low levels of free maytansinoid in plasma.

Therefore, across both studies, in patients with low levels of plasma CanAg, maximum tolerated dose levels of 168 mg/m2 or greater were associated with occurrence of ocular toxicities related to IMGN242.

Based on safety and thorough pharmacokinetic/pharmacodynamic analyses, to avoid these ocular toxicities, the novel dosing strategy for the phase 2 study was for patients with low plasma CanAg levels to receive IMGN242 126 mg/m2, while patients with high plasma CanAg levels remained on the prespecified maximum tolerated dose of 168 mg/m2.

Subjects with specified known hypersensitivity to previous monoclonal antibody therapy or maytansinoids, peripheral neuropathy grade >=2, and need for contact lens use were excluded from these trials.

Funding for this study was provided by ImmunoGen Inc.

[Presentation title: A Novel Dosing Strategy Based on Plasma Levels of CanAg in a Phase 2 Study of IMGN242 (huC242-DM4) in Gastric Cancer. Abstract 514]