Phase I study of safety and pharmacokinetics of the anti-MUC16 antibody–drug conjugate DMUC5754A in patients with platinum-resistant ovarian cancer or unresectable pancreatic cancer
| Autor: | Joyce F. Liu, S. K. Kelley, J. R. Infante, Daniel J. Maslyar, Katie Wood, Brian M. Wolpin, Ursula A. Matulonis, J. Xu, Michael J. Birrer, H. A. Burris, Kirsten Achilles Poon, Walter C. Darbonne, Kathleen N. Moore, YounJeong Choi, Suzanne Berlin, Yulei Wang, Robert Kahn, Mark R. Lackner, Xuyang Lu, Eric W. Humke, Ron Firestein |
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| Rok vydání: | 2016 |
| Předmět: |
Adult
0301 basic medicine medicine.medical_specialty Immunoconjugates Drug-Related Side Effects and Adverse Reactions Nausea MUC16 DMUC5754a pancreatic cancer Neutropenia Gastroenterology Drug Administration Schedule antibody-drug conjugate 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Pharmacokinetics Internal medicine Journal Article medicine Humans Adverse effect Aged Ovarian Neoplasms business.industry Membrane Proteins Hematology Middle Aged medicine.disease Antibodies Anti-Idiotypic Pancreatic Neoplasms ovarian cancer 030104 developmental biology Oncology Monomethyl auristatin E chemistry CA-125 Antigen 030220 oncology & carcinogenesis Pharmacodynamics Immunology Vomiting Female medicine.symptom Hyponatremia business |
| Zdroj: | Annals of Oncology, 27(11), 2124. Oxford University Press |
| ISSN: | 0923-7534 |
| DOI: | 10.1093/annonc/mdw401 |
| Popis: | Background MUC16 is a tumor-specific antigen overexpressed in ovarian (OC) and pancreatic (PC) cancers. The antibody–drug conjugate (ADC), DMUC5754A, contains the humanized anti-MUC16 monoclonal antibody conjugated to the microtubule-disrupting agent, monomethyl auristatin E (MMAE). Patients and methods This phase I study evaluated safety, pharmacokinetics (PK), and pharmacodynamics of DMUC5754A given every 3 weeks (Q3W, 0.3–3.2 mg/kg) or weekly (Q1W, 0.8–1.6 mg/kg) to patients with advanced recurrent platinum-resistant OC or unresectable PC. Biomarker studies were also undertaken. Results Patients (66 OC, 11 PC) were treated with DMUC5754A (54 Q3W, 23 Q1W). Common related adverse events (AEs) in >20% of patients (all grades) over all dose levels were fatigue, peripheral neuropathy, nausea, decreased appetite, vomiting, diarrhea, alopecia, and pyrexia in Q3W patents, and nausea, vomiting, anemia, fatigue, neutropenia, alopecia, decreased appetite, diarrhea, and hypomagnesemia in Q1W patients. Grade ≥3-related AE in ≥5% of patients included neutropenia (9%) and fatigue (7%) in Q3W patients, and neutropenia (17%), diarrhea (9%), and hyponatremia (9%) in Q1W patients. Plasma antibody-conjugated MMAE (acMMAE) and serum total antibody exhibited non-linear PK across tested doses. Minimal accumulation of acMMAE, total antibody, or unconjugated MMAE was observed. Confirmed responses (1 CR, 6 PRs) occurred in OC patients whose tumors were MUC16-positive by IHC (2+ or 3+). Two OC patients had unconfirmed PRs; six OC patients had stable disease lasting >6 months. For CA125, a cut-off of ≥70% reduction was more suitable for monitoring treatment response due to the binding and clearance of serum CA125 by MUC16 ADC. We identified circulating HE4 as a potential novel surrogate biomarker for monitoring treatment response of MUC16 ADC and other anti-MUC16 therapies in OC. Conclusions DMUC5754A has an acceptable safety profile and evidence of anti-tumor activity in patients with MUC16-expressing tumors. Objective responses were only observed in MUC16-high patients, although prospective validation is required. Clinical Trial Number NCT01335958. |
| Databáze: | OpenAIRE |
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