Phase 1/2 study of KRN330, a fully human anti-A33 monoclonal antibody, plus irinotecan as second-line treatment for patients with metastatic colorectal cancer

Abstract

KRN330 is a recombinant, fully-human monoclonal antibody directed against A33, a surface differentiation antigen that is uniformly expressed in 95 % of colorectal cancers. A previous Phase 1 study of single-agent KRN330 identified a maximum tolerated dose (MTD) of 3 mg/kg q2w and preliminary evidence of clinical activity among patients with advanced and metastatic colorectal cancer (mCRC). This Phase 1/2 trial sought to assess the safety and activity of second-line KRN330 plus irinotecan in patients with mCRC. Patients with mCRC who showed disease progression after FOLFOX/CapOx received intravenous doses of KRN330 (0.5 or 1.0 mg/kg qw or q2w) plus irinotecan (180 mg/m(2)) in a standard 3 + 3 dose escalation. The MTD of KRN330 with irinotecan in 19 patients was 0.5 mg/kg qw in the Phase 1 study with gastrointestinal effects and neutropenia being the predominant dose-limiting toxicities. In the Phase 2 study, the most frequent treatment-related Grade ≥3 toxicities in 44 patients were fatigue (15.9 %), neutropenia (13.6 %), leukopenia (6.8 %), diarrhea (4.5 %), and dehydration (4.5 %). Objective response rate (ORR) was 4.5 % and disease control rate was 45.5 % for the intent-to-treat population. Median progression-free survival was 87 days (95 % CI, 43-136 days). The prespecified ORR of KRN330 plus irinotecan was not met. Further investigation of KRN330 plus other agents may be warranted.

Selective Photokilling of Colorectal Tumors by Near-Infrared Photoimmunotherapy with a GPA33-Targeted Single-Chain Antibody Variable Fragment Conjugate

“…However, KRN330 combined with chemotherapy has not achieved the prespecified objective response rate in clinical phase I/II trials. 19,34 Thus, a more efficient therapeutic strategy that targets the CRC A33 antigen needs to be developed to improve therapeutic outcomes.…”

“…Notably, it is encouraging that the first in-human trial of an anti-A33 antibody (fully human monoclonal antibody, KRN330) showed the acceptable safety profile of KRN330 in patients with advanced CRC. However, KRN330 combined with chemotherapy has not achieved the prespecified objective response rate in clinical phase I/II trials. , Thus, a more efficient therapeutic strategy that targets the CRC A33 antigen needs to be developed to improve therapeutic outcomes.…”

Development of MGD007, a gpA33 x CD3-Bispecific DART Protein for T-Cell Immunotherapy of Metastatic Colorectal Cancer

“…More recently, clinical evaluation of KRN330, a fully-human anti-gpA33 mAb, revealed initial evidence of clinical activity among patients with advanced and metastatic colorectal cancer, with effective tumor targeting at doses that were well tolerated (24). Unfortunately, KRN330 in combination with irinotecan failed to achieve significant clinical outcome in a subsequent study (46), suggesting the need for alternative gpA33 targeting modalities to yield benefit.…”

New therapeutic agents for metastatic colorectal cancer: literature review

“…Иммуногистохимическое исследование на образцах биопсии показало, что KRN330 остается связанным с опухолью через 2 нед после введения. KRN330 безопасен и хорошо переносится при введении в максимально переносимой дозе 3 мг / кг 1 раз в неделю у пациентов с КРР поздней стадии [56,69,70].…”