J F Liu1, K N Moore2, M J Birrer3, S Berlin4,5, U A Matulonis4, J R Infante6, B Wolpin4, K A Poon7, R Firestein7, J Xu7, R Kahn7, Y Wang7, K Wood7, W C Darbonne7, M R Lackner7, S K Kelley7, X Lu7, Y J Choi7, D Maslyar7, E W Humke7, H A Burris6. 1. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston joyce_liu@dfci.harvard.edu. 2. Division of Gynecologic Oncology, Stephenson Oklahoma Cancer Center at the University of Oklahoma Health Sciences Center, Oklahoma City. 3. Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston. 4. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston. 5. Department of Oncology, New England Cancer Care Specialists, Kennebunk. 6. Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville. 7. Early Development, Genentech, South San Francisco, USA.
Abstract
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.
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.
Authors: Matts Kågedal; Leonid Gibiansky; Jian Xu; Xin Wang; Divya Samineni; Shang-Chiung Chen; Dan Lu; Priya Agarwal; Bei Wang; Ola Saad; Neelima Koppada; Bernard M Fine; Jin Y Jin; Sandhya Girish; Chunze Li Journal: J Pharmacokinet Pharmacodyn Date: 2017-09-16 Impact factor: 2.745
Authors: Madeline T Olson; Nicholas E Wojtynek; Geoffrey A Talmon; Thomas C Caffrey; Prakash Radhakrishnan; Quan P Ly; Michael A Hollingsworth; Aaron M Mohs Journal: Mol Cancer Ther Date: 2020-05-13 Impact factor: 6.261
Authors: Daniel C Danila; Russell Z Szmulewitz; Ulka Vaishampayan; Celestia S Higano; Ari D Baron; Houston N Gilbert; Flavia Brunstein; Marija Milojic-Blair; Bei Wang; Omar Kabbarah; Michael Mamounas; Bernard M Fine; Daniel J Maslyar; Alexander Ungewickell; Howard I Scher Journal: J Clin Oncol Date: 2019-11-05 Impact factor: 44.544
Authors: Chi Lin; Vivek Verma; Audrey Lazenby; Quan P Ly; Lyudmyla D Berim; James K Schwarz; Madi Madiyalakan; Christopher F Nicodemus; Michael A Hollingsworth; Jane L Meza; Chandrakanth Are; James Padussis; Jean L Grem Journal: Am J Clin Oncol Date: 2019-10 Impact factor: 2.339
Authors: Jose F Ponte; Leanne Lanieri; Eshita Khera; Rassol Laleau; Olga Ab; Christopher Espelin; Neeraj Kohli; Bahar Matin; Yulius Setiady; Michael L Miller; Thomas A Keating; Ravi Chari; Jan Pinkas; Richard Gregory; Greg M Thurber Journal: Mol Cancer Ther Date: 2020-11-11 Impact factor: 6.009