TY - JOUR
T1 - Phase 1 Study of CEP-37250/KHK2804, a Tumor-specific Anti-glycoconjugate Monoclonal Antibody, in Patients with Advanced Solid Tumors
AU - Mita, Monica M.
AU - Nemunaitis, John
AU - Grilley-Olson, Juneko
AU - El-Rayes, Bassil
AU - Bekaii-Saab, Tanios
AU - Harvey, R. Donald
AU - Marshall, John
AU - Zhang, Xiaoping
AU - Strout, Vincent
N1 - Publisher Copyright:
© 2016, Springer International Publishing Switzerland.
PY - 2016/12/1
Y1 - 2016/12/1
N2 - Background: CEP-37250/KHK2804 is a recombinant, humanized, non-fucosylated, monoclonal antibody directed to sialic acid-containing glycoconjugates frequently found on certain tumor cell types. Objective: The objective was to determine the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics, potential immunogenicity, and preliminary clinical efficacy of CEP-37250/KHK2804 monotherapy in patients with advanced cancer in a first-in-human, phase 1 study. Materials and Methods: In phase 1a, patients (n = 31) with solid tumors received increasing doses of CEP-37250/KHK2804 (0.03–1.0 mg/kg) intravenously once weekly using a standard 3 + 3 dose-escalation design. In phase 1b, two dose-expansion cohorts of patients with colorectal (n = 15) and pancreatic (n = 16) cancer, respectively, received the maximum tolerated dose (MTD). Results: The MTD of CEP-37250/KHK2804 was 0.3 mg/kg weekly. Dose-limiting toxicities were infusion-related reactions and increased serum transaminases. In the overall population (N = 62), the most frequent treatment-related adverse event (AE) was an infusion-related reaction (45.2 %). Positive post-baseline CEP-37250/KHK2804 neutralizing antibodies were reported in 14 patients (22.6 %), almost exclusively in patients who developed infusion-related reactions. The most frequent treatment-related AE grade ≥3 was increased AST or ALT in six patients (9.7 %). Three patients experienced treatment-related serious cardiac events (grade 4 ECG abnormality, grade 4 atrial fibrillation, and grade 3 acute myocardial infarction, respectively). Pharmacokinetic exposure to CEP-37250/KHK2804 increased proportionally to dose, with accumulation up to two fold with repeated administration. Mean elimination half-life was 34.1 to 70.3 hours over the dose range from 0.03 to 1.0 mg/kg. No patient had a complete or partial best response. Thirteen of 40 (32.5 %) evaluable patients had unconfirmed stable disease, four of which were confirmed (10.0 %). Conclusions: The study was stopped early due to the lack of efficacy. Additionally, safety concerns (i.e., cardiac issues, hepatic toxicity, and infusion-related reactions) made the benefit-risk assessment unfavorable for continued development of CEP-37250/KHK2804, which was halted indefinitely. [Study registered at ClinicalTrials.gov #NCT01447732]. [MediaObject not available: see fulltext.]
AB - Background: CEP-37250/KHK2804 is a recombinant, humanized, non-fucosylated, monoclonal antibody directed to sialic acid-containing glycoconjugates frequently found on certain tumor cell types. Objective: The objective was to determine the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics, potential immunogenicity, and preliminary clinical efficacy of CEP-37250/KHK2804 monotherapy in patients with advanced cancer in a first-in-human, phase 1 study. Materials and Methods: In phase 1a, patients (n = 31) with solid tumors received increasing doses of CEP-37250/KHK2804 (0.03–1.0 mg/kg) intravenously once weekly using a standard 3 + 3 dose-escalation design. In phase 1b, two dose-expansion cohorts of patients with colorectal (n = 15) and pancreatic (n = 16) cancer, respectively, received the maximum tolerated dose (MTD). Results: The MTD of CEP-37250/KHK2804 was 0.3 mg/kg weekly. Dose-limiting toxicities were infusion-related reactions and increased serum transaminases. In the overall population (N = 62), the most frequent treatment-related adverse event (AE) was an infusion-related reaction (45.2 %). Positive post-baseline CEP-37250/KHK2804 neutralizing antibodies were reported in 14 patients (22.6 %), almost exclusively in patients who developed infusion-related reactions. The most frequent treatment-related AE grade ≥3 was increased AST or ALT in six patients (9.7 %). Three patients experienced treatment-related serious cardiac events (grade 4 ECG abnormality, grade 4 atrial fibrillation, and grade 3 acute myocardial infarction, respectively). Pharmacokinetic exposure to CEP-37250/KHK2804 increased proportionally to dose, with accumulation up to two fold with repeated administration. Mean elimination half-life was 34.1 to 70.3 hours over the dose range from 0.03 to 1.0 mg/kg. No patient had a complete or partial best response. Thirteen of 40 (32.5 %) evaluable patients had unconfirmed stable disease, four of which were confirmed (10.0 %). Conclusions: The study was stopped early due to the lack of efficacy. Additionally, safety concerns (i.e., cardiac issues, hepatic toxicity, and infusion-related reactions) made the benefit-risk assessment unfavorable for continued development of CEP-37250/KHK2804, which was halted indefinitely. [Study registered at ClinicalTrials.gov #NCT01447732]. [MediaObject not available: see fulltext.]
UR - http://www.scopus.com/inward/record.url?scp=84979561747&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84979561747&partnerID=8YFLogxK
U2 - 10.1007/s11523-016-0449-2
DO - 10.1007/s11523-016-0449-2
M3 - Article
C2 - 27457707
AN - SCOPUS:84979561747
SN - 1776-2596
VL - 11
SP - 807
EP - 814
JO - Targeted Oncology
JF - Targeted Oncology
IS - 6
ER -