PMID- 27091421 OWN - NLM STAT- MEDLINE DCOM- 20171101 LR - 20181113 IS - 1549-490X (Electronic) IS - 1083-7159 (Print) IS - 1083-7159 (Linking) VI - 21 IP - 5 DP - 2016 May TI - Phase I Study of the Prolactin Receptor Antagonist LFA102 in Metastatic Breast and Castration-Resistant Prostate Cancer. PG - 535-6 LID - 10.1634/theoncologist.2015-0502 [doi] AB - LESSONS LEARNED: Despite evidence for a role for prolactin signaling in breast and prostate tumorigenesis, a prolactin receptor-binding monoclonal antibody has not produced clinical efficacy.Increased serum prolactin levels may be a biomarker for prolactin receptor inhibition.Results from the pharmacokinetic and pharmacodynamics (PD) studies suggest that inappropriately long dosing intervals and insufficient exposure to LFA102 may have resulted in lack of antitumor efficacy.Based on preclinical data, combination therapy of LFA102 with those novel agents targeting hormonal pathways in metastatic castration-resistant prostate cancer and metastatic breast cancer is promising.Given the PD evidence of prolactin receptor blockade by LFA102, this drug has the potential to be used in conditions such as hyperprolactinemia that are associated with high prolactin levels. BACKGROUND: Prolactin receptor (PRLR) signaling is implicated in breast and prostate cancer. LFA102, a humanized monoclonal antibody (mAb) that binds to and inhibits the PRLR, has exhibited promising preclinical antitumor activity. METHODS: Patients with PRLR-positive metastatic breast cancer (MBC) or metastatic castration-resistant prostate cancer (mCRPC) received doses of LFA102 at 3-60 mg/kg intravenously once every 4 weeks. Objectives were to determine the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) to investigate the safety/tolerability of LFA102 and to assess pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity. RESULTS: A total of 73 patients were enrolled at 5 dose levels. The MTD was not reached because of lack of dose-limiting toxicities. The RDE was established at 60 mg/kg based on PK and PD analysis and safety data. The most common all-cause adverse events (AEs) were fatigue (44%) and nausea (33%) regardless of relationship. Grade 3/4 AEs reported to be related to LFA102 occurred in 4% of patients. LFA102 exposure increased approximately dose proportionally across the doses tested. Serum prolactin levels increased in response to LFA102 administration, suggesting its potential as a biomarker for PRLR inhibition. No antitumor activity was detected. CONCLUSION: Treatment with LFA102 was safe and well tolerated, but did not show antitumor activity as monotherapy at the doses tested. CI - (c)AlphaMed Press; the data published online to support this summary is the property of the authors. FAU - Agarwal, Neeraj AU - Agarwal N AD - Huntsman Cancer Institute, Division of Medical Oncology, Department of Medicine, University of Utah, Salt Lake City, Utah, USA neeraj.agarwal@hci.utah.edu. FAU - Machiels, Jean-Pascal AU - Machiels JP AD - Roi Albert II Institute, Medical Oncology Service, University Clinic Saint Luc and Institute of Experimental and Clinical Research (Pole Molecular Imaging, Radiotherapy & Oncology), Catholic University of Louvain, Brussels, Belgium. FAU - Suarez, Cristina AU - Suarez C AD - Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Barcelona, Spain. FAU - Lewis, Nancy AU - Lewis N AD - Thomas Jefferson University, Philadelphia, Pennsylvania, USA. FAU - Higgins, Michaela AU - Higgins M AD - Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts, USA. FAU - Wisinski, Kari AU - Wisinski K AD - University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA. FAU - Awada, Ahmad AU - Awada A AD - Jules Bordet Institute, Brussels, Belgium. FAU - Maur, Michela AU - Maur M AD - Oncology Unit, Department of Oncology, Hematology and Respiratory Disease, University Hospital Policlinico of Modena, Modena, Italy. FAU - Stein, Mark AU - Stein M AD - Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, USA. FAU - Hwang, Andy AU - Hwang A AD - Novartis Pharmaceutical Corporation, East Hanover, New Jersey, USA. FAU - Mosher, Rebecca AU - Mosher R FAU - Wasserman, Ernesto AU - Wasserman E AD - Novartis Pharmaceutical Corporation, East Hanover, New Jersey, USA. FAU - Wu, Gang AU - Wu G AD - Novartis Pharmaceutical Corporation, East Hanover, New Jersey, USA. FAU - Zhang, Hefei AU - Zhang H AD - Novartis Pharmaceutical Corporation, East Hanover, New Jersey, USA. FAU - Zieba, Renata AU - Zieba R AD - Novartis Pharmaceutical Corporation, East Hanover, New Jersey, USA. FAU - Elmeliegy, Mohamed AU - Elmeliegy M AD - Novartis Pharmaceutical Corporation, East Hanover, New Jersey, USA. LA - eng SI - ClinicalTrials.gov/NCT01338831 GR - P30 CA042014/CA/NCI NIH HHS/United States PT - Clinical Trial, Phase I PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20160418 PL - England TA - Oncologist JT - The oncologist JID - 9607837 RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (LFA102 monoclonal antibody) RN - 0 (Receptors, Prolactin) SB - IM CIN - Oncologist. 2016 May;21(5):523-6. PMID: 27107001 MH - Adult MH - Aged MH - Aged, 80 and over MH - Antibodies, Monoclonal, Humanized/adverse effects/*therapeutic use MH - Breast Neoplasms/*drug therapy/pathology MH - Female MH - Humans MH - Male MH - Maximum Tolerated Dose MH - Middle Aged MH - Neoplasm Metastasis MH - Prostatic Neoplasms, Castration-Resistant/*drug therapy/pathology MH - Receptors, Prolactin/*antagonists & inhibitors/physiology PMC - PMC4861370 EDAT- 2016/04/20 06:00 MHDA- 2017/11/02 06:00 PMCR- 2016/04/18 CRDT- 2016/04/20 06:00 PHST- 2015/12/09 00:00 [received] PHST- 2016/01/11 00:00 [accepted] PHST- 2016/04/20 06:00 [entrez] PHST- 2016/04/20 06:00 [pubmed] PHST- 2017/11/02 06:00 [medline] PHST- 2016/04/18 00:00 [pmc-release] AID - theoncologist.2015-0502 [pii] AID - T15502CTR [pii] AID - 10.1634/theoncologist.2015-0502 [doi] PST - ppublish SO - Oncologist. 2016 May;21(5):535-6. doi: 10.1634/theoncologist.2015-0502. Epub 2016 Apr 18.