Use of KRN330, A Fully Human Antibody Against A33, in Combination with Irinotecan for Patients with Metastatic Colorectal Cancer (mCRC) J.C. Bendell, 1 J.L. Marshall, 2 J. Berlin, 3 H.S. Hochster, 4 1 Sarah Cannon Research Institute, Nashville, TN; 2 Georgetown University Hospital, Washington DC; 3 Vanderbilt University Medical Center, Nashville, TN ; 4 New York University Cancer Institute, New York, NY Abstract ID #534 Introduction Patient Demographics TreatmentDoseTotal (N=19) Q2W KRN330, N 0.5 mg/kg8 1.0 mg/kg4 QW KRN330, N0.5 mg/kg7 All patients received Q2W treatment with irinotecan (180 mg/m 2 ) Design: ●A standard dose-escalation design. ●Patients (N=19) received weekly (QW) or biweekly (Q2W) intravenous doses of KRN330 at 0.5 to 1 mg/kg with irinotecan at 180 mg/m 2 Q2W for 6 weeks, with a 3-week follow-up period. ●Extended treatment, at the assigned dose and schedule, was permitted in patients with no safety concerns and no radiographic evidence of progressive disease (PD). A33 is a surface differentiation antigen on normal colonic and small bowel epithelium that is uniformly expressed in 95% of all colorectal cancers (CRCs). A33-bound monoclonal antibodies (MAbs) stay bound for long periods on colorectal tumors whereas they are more rapidly cleared from the normal intestinal epithelial cells. A33 is not secreted or shed into the blood. Humanized mAbs directed against A33 have shown promise in CRC clinical trials but immunogenicity has been a primary concern. KRN330, the fully human mAb against A33, was developed to preserve activity and reduce immunogenicity. A Phase I study of KRN330 monotherapy showed over 1 year of stable disease in 2 patients with refractory metastatic CRC (mCRC). Common drug-related side effects were nausea, diarrhea, and vomiting; 3.0 mg/kg of KRN330 was the recommended Phase II dose. We report results of the Phase I portion of a Phase I/II trial of KRN330 in combination with irinotecan in patients with mCRC. Results Key Eligibility Criteria: ●Diagnosis of mCRC with measurable disease. ●Recurrence or PD despite prior treatment with 1FOLFOX/CapOx ± bevacizumab regimen but not more than 3 prior chemotherapy or biologic regimens for mCRC, not a candidate for a surgical cure. ●Adequate: bone marrow, hematologic, renal, and hepatic function. ●3 patients who received 1.0 mg/kg of KRN330 Q2W and irinotecan treatment developed dose limiting toxicities (DLTs), which included Grade 4 febrile neutropenia and Grade 3 colitis, prolonged Grade 3 diarrhea, and, Grade 4 neutropenia with prolonged Grade 3 diarrhea. ●KRN330 was de-escalated to 0.5 mg/kg Q2W and 0.5 mg/kg QW. In the Q2W cohort, 1 pt had a DLT of Grade 3 colitis. None of the patients in the QW cohort experienced DLT. ●The most common Grade 3/4 toxicities included diarrhea (26%), abdominal pain (16%), leukopenia (16%), and febrile neutropenia (16%). ●No deaths were reported during the study or within 30 days after the last dose of study drug. ●There is currently no evidence of HAHA. Adverse Events (≥ 5 Patients) Preferred Term Frequency (%) Total (N=19) 0.5 mg/kg (N=15) 1.0 mg/kg (N=4) Diarrhea15 (79)12 (80)3 (75) Nausea15 (79)12 (80)3 (75) Vomiting11 (58)10 (67)1 (25) Fatigue9 (47)7 (47)2 (50) Abdominal pain7 (37)6 (40)1 (25) Alopecia7 (37)7 (47)0 Anorexia5 (26)5 (33)0 Cough5 (26)5 (33)0 ●QW and Q2W intravenous doses of KRN330 at 0.5 mg/kg KRN330 with irinotecan were tolerable and anti-tumor effects were suggested in patients who had received previous irinotecan-containing regimens. ●The PK of KRN330 was linear over the dose range studied, and did not change after repeated administration. ●The lack of immunogenicity and prolonged SD warrants further investigation. ●The Phase II portion of this study of KRN330 in combination with irinotecan in patients with second-line mCRC is ongoing (NCT ). Conclusions 1.Ishida I, et al. Production of human monoclonal and polyclonal antibodies in TransChromo animals. Cloning Stem Cells. 2002;4(1): References Activity Profile of KRN330: Toxicity Profile of KRN330: ●2 patients on 0.5 mg/kg QW had SD for 22 and 42 weeks. ●1 patient on 0.5 mg/kg QW who had 4 prior chemo/biologic regimens had SD for 25 weeks. This patient had previously received an irinotecan-containing regimen with a best overall response of CR. ●A recombinant fully human IgG1 anti-A33 mAb was designed to reduce immunogenicity. ●Created using KM mouse TM technology. 1 ●Exhibits antibody-dependent cellular cytotoxicity (ADCC) activity against colon tumor cell lines expressing A33. ●Exhibits complement-dependent cytotoxicity (CDC) activity. ●No significant direct tumor killing effect. KRN330 Study Objectives & Methods Primary Objectives: ●Assess the safety of KRN330 in combination with irinotecan. Secondary Objectives: ●Assess the anti-tumor activity of KRN330 in combination with irinotecan. ●Pharmacokinetics (PK). ●Degree of immunogenicity, human anti-human antibody (HAHA). ●KRN330 exhibits little or no accumulation with QW or Q2W dosing at 0.5 mg/kg (Accumulation ratios average about 1-1.1). ●Average terminal half-life (t 1/2 ) across all treatments and dose groups is between hours.* ●KRN330 exhibits linear PK behavior between single and multiple doses. ●KRN330 exhibits dose- and time-independent clearance. Pharmacokinetics of KRN330: Patient Demographics (continued) Total (N=19) Age (years), Mean/Median (Range) 59.6/61.0 ( ) Gender, N (%) Male9 (47) Female10 (53) Ethnic Origin, N (%) Black or African American2 (11) Hispanic1 (5) White16 (84) Figure 4. QW Dosing 0.5 mg/kg Figure 1. Treatment Schema (Phase I Portion) Pharmacokinetic Parameters, Mean (CV,%) Treatment Dose WeekN t max (hr) C max (ug/mL) AUC 0-t (ug.hr/mL) AUC * (ug.hr/mL) t 1/2 (hr)RaRa Degree of Non-linearity Q2W 0.5 mg/kg Week (27) 10.1 (18) 619 (22) 682 (22) 83.9 (27) Q2W 0.5 mg/kg Week (16) 9.52 (20) 634 (27) 604 (28) 116 (31) (17) (18) Q2W 1 mg/kg Week (17) 21.4 (26) 930 (24) 1084 (21) 60.8 (51) QW 0.5 mg/kg Week (27) 11.1 (13) 552 (20) 634 (20) 59.0 (16) QW 0.5 mg/kg Week (31) 11.9 (18) 726 (20) 606 (19) 115 (33) 1.11 (8) (7) * AUC 0-∞ for Week 1 and AUC 0-  for Week 5 * Only 1 patient’s data was available for 1.0 mg/kg Q2W after 3 doses; t 1/2 in this patient was about 38 hours. Figure 3. Q2W Dosing 1.0 mg/kg Figure 2. Q2W Dosing 0.5 mg/kg ●14 patients received the planned doses in the initial treatment period and best overall response was evaluated by RECIST criteria: 1 (7%) had partial response (PR), 7 (50%) had stable disease (SD), and 6 (43%) had PD. ●1 patient on 0.5 mg/kg Q2W had SD for 48 weeks with a best overall response of PR. This patient had previously received an irinotecan-containing regimen with a best overall response of SD. This study was sponsored by Kyowa Hakko Kirin Pharma, Inc. and this poster was presented at the Gastrointestinal Cancer Symposium, held January 20-22, 2011 in San Francisco, CA, USA.