A phase II study of IMGN242 (huC242-DM4) in patients with CanAg-positive gastric or gastroesophageal (GE) junction cancer

Abstract

e15625 Background: IMGN242 is a conjugate of the cytotoxic maytansinoid DM4 and the monoclonal antibody huC242, which binds to CanAg. In a Phase I study, the maximum tolerated dose for IMGN242 was determined to be 168 mg/m2, with ocular changes the primary dose-limiting toxicity. This Phase II study was initiated to assess IMGN242 for the treatment of gastric cancer. Methods: In this open-label, multi-center study, IMGN242 is given as a single IV infusion every three weeks to patients with CanAg-expressing metastatic or locally-advanced gastric or GE junction cancer. Patients must have been treated with at least one prior therapy to qualify for enrollment. The study has a 2-step design: If ≥1 objective response is achieved among the first 23 patients (Step 1), a total of 39 response-evaluable patients will be enrolled (Step 2). Results: Overall, 9 patients have received IMGN242. The first 6 were treated with 168 mg/m2, and 1 of these patients showed a marked biologic response by the FDG-PET scan in Cycle 1 followed by an unconfirmed partial response based on CT scan in Cycle 2. However, 3 of these 6 patients developed ocular toxicities assessed to be study drug related. Only patients with low plasma CanAg levels (<1000 U/ml) developed ocular toxicities, and clinical pharmacokinetic and pharmacodynamic (PK/PD) analyses revealed that plasma CanAg affects study drug exposures. The study was amended to differentiate the IMGN242 doses (126 mg/m2 or 168 mg/m2) administered based on the patient's plasma CanAg levels (< or >1000 U/mL). To date, 3 patients have received IMGN242 with this dosing strategy and no ocular toxicities have been reported. Conclusions: IMGN242 showed preliminary evidence of activity in this patient population. A novel Phase II dosing strategy is being used that should enhance tolerability. Patient enrollment is ongoing and updated results will be reported. [Table: see text]

Antibody–Drug Conjugates for Cancer Therapy

“…Dose limiting ocular toxicities have been described for ADCs conjugated with MMAF [ 75 , 76 ]. Similarly, reversible ocular toxicity in the cornea has been reported for DM4-conjugated antibodies [ 77 , 78 , 79 ]. This appears independent of the target antigen, which does not have significant expression in the eye.…”

Antibody-Drug Conjugates Targeting Tumor-Specific Mucin Glycoepitopes

“…With that in mind, careful measurement of the target glycoepitope entering the circulation during the clinical trials to assess potential of shedding to undermine efficacy could prove to be an important further criterion and evaluating potential of these types of targets in evaluating the potential of these types of targets. This approach was used in the IMGN242 trial to adjust dosing in patients with low CanAg circulating in plasma to mitigate off-target toxicity [99]. Another consideration should be the tumor specificity of the glycoepitope.…”

“…In a Phase II trial (NCT00620607) [120], in 6 patients with CanAgpositive gastric or gastroesophageal junction cancer, a partial response was observed in 1 patient. Unfortunately, 3 out of 6 patients developed ocular toxicities that were assessed to be study drug related [99] and the huC242-DM4 program was later discontinued [118].…”

Potential of Anti-MUC1 Antibodies as a Targeted Therapy for Gastrointestinal Cancers

“…The phase II trial was started in CanAg-expressing gastric cancer patients at a dose of 168 mg/m 2 . The data has been amended to differentiate the administered dose of IMGN242 based on the patient’s plasma CanAg levels [ 88 ].…”