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 - Funding Information:
Medical writing assistance provided by Peter Todd of Tajut Ltd. (Kaiapoi, New Zealand) was supported financially by Kyowa Kirin Pharmaceutical Development, Inc. during the preparation of this manuscript. This work was supported and funded by Kyowa Kirin Pharmaceutical Development, Inc.
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
VL - 11
SP - 807
EP - 814
JO - Targeted Oncology
JF - Targeted Oncology
SN - 1776-2596
IS - 6
ER -