Phase I Study of DMOT4039A, an Antibody–Drug Conjugate Targeting Mesothelin, in Patients with Unresectable Pancreatic or Platinum-Resistant Ovarian Cancer

Abstract

DMOT4039A, a humanized anti-mesothelin mAb conjugated to the antimitotic agent monomethyl auristatin E (MMAE), was given to patients with pancreatic and ovarian cancer every 3 weeks (0.2-2.8 mg/kg; q3w) or weekly (0.8-1.2 mg/kg). A 3þ3 design was used for dose escalation followed by expansion at the recommended phase II dose (RP2D) to evaluate safety and pharmacokinetics. Antitumor response was evaluated per RECIST 1.1 and serum CA19-9 or CA125 declines. Tumor mesothelin expression was determined by IHC. Seventy-one patients (40 pancreatic cancer; 31 ovarian cancer) were treated with DMOT4039A. For the q3w schedule (n ¼ 54), the MTD and RP2D was 2.4 mg/kg, with dose-limiting toxicities of grade 3 hyperglycemia and grade 3 hypophosphatemia at 2.8 mg/kg. For the weekly schedule (n ¼ 17), the maximum assessed dose was 1.2 mg/kg, with further dose escalations deferred because of toxicities limiting scheduled retreatment in later cycles, and therefore the RP2D level for the weekly regimen was determined to be 1 mg/kg. Across both schedules, the most common toxicities were gastrointestinal and constitutional. Treatment-related serious adverse events occurred in 6 patients; 4 patients continued treatment following dose reductions. Drug exposure as measured by antibody-conjugated MMAE and total antibody was generally dose proportional over all dose levels on both schedules. A total of 6 patients had confirmed partial responses (4 ovarian; 2 pancreatic) with DMOT4039A at 2.4 to 2.8 mg/kg i.v. q3w. DMOT4039A administered at doses up to 2.4 mg/kg q3w and 1.0 mg/kg weekly has a tolerable safety profile and antitumor activity in both pancreatic and ovarian cancer.

Antibody Drug Conjugates for Cancer Therapy

“…An ADC targeting MSLN and armed with VC-MMAE was evaluated in a Phase I clinical trial for the treatment of pancreatic cancer (Weekes et al, 2014). Some grade 3/4 toxicities, including neutropenia, AST/ALT elevation, and fatigue were reported but were not consistent with disruption of mesothelial linings.…”

ImmunoPET with Anti-Mesothelin Antibody in Patients with Pancreatic and Ovarian Cancer before Anti-Mesothelin Antibody–Drug Conjugate Treatment

“…CT scans were evaluated centrally at UMCG for measurable lesions according to RECIST 1.1 (35). After the last PET scan (either on the same day or within a week thereafter), patients continued in the phase I study and received treatment with DMOT4039A (36). Archival tumor tissue (both primary and metastatic tissue, if available) was tested for MSLN expression with an immunohistochemical assay using 19C3 mouse anti-human antibody (37).…”

Aptamer-Drug Conjugates of Active Metabolites of Nucleoside Analogs and Cytotoxic Agents Inhibit Pancreatic Tumor Cell Growth

“…Up to now, there are few published studies regarding the use of MMAE with ADCs in pancreatic cancer. In a phase 1 study of patients with platinum-resistant ovarian cancer or unresectable PDAC, MMAE conjugated with a monoclonal antibody against mesothelin had antitumor activity in both types of cancer, with acceptable dose-limiting toxicity 28 . In another phase 1 study of patients with gastric or pancreatic cancer, MMAE targeting SLC44A4 was generally well tolerated but had limited antitumor activity 29 .…”