title: 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.
authors.affiliation: Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Suite 110, 250 25th Avenue North, Nashville, TN, 37203, USA, jbendell@tnonc.com.
authors.forename: Johanna C
authors.initials: JC
authors.lastname: Bendell
authors.forename: Heinz-Josef
authors.initials: HJ
authors.lastname: Lenz
authors.forename: Theresa
authors.initials: T
authors.lastname: Ryan
authors.forename: Bassel F
authors.initials: BF
authors.lastname: El-Rayes
authors.forename: John L
authors.initials: JL
authors.lastname: Marshall
authors.forename: Manuel R
authors.initials: MR
authors.lastname: Modiano
authors.forename: Lowell L
authors.initials: LL
authors.lastname: Hart
authors.forename: Clint D
authors.initials: CD
authors.lastname: Kingsley
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: George
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nakashima
authors.forename: Jordan D
authors.initials: JD
authors.lastname: Berlin
mesh_terms: D000293:Adolescent; D000328:Adult; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use; D002166:Camptothecin / Q000031:analogs & derivatives / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008297:Male; D020714:Maximum Tolerated Dose; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D008875:Middle Aged; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000972:Antineoplastic Agents, Phytogenic; C104258:GPA33 protein, human; D008562:Membrane Glycoproteins; D000077146:Irinotecan; C581257:KRN-330; D002166:Camptothecin