PMID- 30132271 OWN - NLM STAT- MEDLINE DCOM- 20200205 LR - 20200309 IS - 1573-0646 (Electronic) IS - 0167-6997 (Print) IS - 0167-6997 (Linking) VI - 37 IP - 2 DP - 2019 Apr TI - A phase 1 trial of SGN-CD70A in patients with CD70-positive diffuse large B cell lymphoma and mantle cell lymphoma. PG - 297-306 LID - 10.1007/s10637-018-0655-0 [doi] AB - Purpose This first-in-human study evaluated SGN-CD70A, an antibody-drug conjugate (ADC) directed against the integral plasma membrane protein CD70 and linked to a pyrrolobenzodiazepine (PBD) dimer, in patients with relapsed or refractory (R/R) CD70-positive non-Hodgkin lymphoma (NHL) including diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL), and Grade 3b follicular lymphoma (FL3b). Methods SGN-CD70A was administered intravenously on Day 1 of 3-week cycles beginning at 8 mcg/kg with planned dose escalation to 200 mcg/kg. Due to observations of prolonged thrombocytopenia, the study was amended to dose every 6 weeks (q6wk). Results Twenty patients were enrolled and treated with SGN-CD70A. The maximum tolerated dose of SGN-CD70A was 30 mcg/kg q6wk. The most common adverse events (AEs) reported were thrombocytopenia (75%), nausea (55%), anemia (50%), and fatigue (50%). The onset for treatment-related thrombocytopenia typically occurred during Cycle 1. Most of the treatment-related events of thrombocytopenia were >/= Grade 3. Antitumor activity in patients included 1 complete remission (CR) and 3 partial remissions (PRs), 2 of which were ongoing for at least 42.9 weeks. SGN-CD70A exposures were approximately dose proportional, with a mean terminal half-life of 3 to 5 days. Conclusions While modest single-agent activity was observed in heavily pretreated NHL patients, the applicability of SGN-CD70A is limited by the frequency and severity of thrombocytopenia, despite the long-term response with limited drug exposure. FAU - Phillips, Tycel AU - Phillips T AUID- ORCID: 0000-0003-2143-9672 AD - University of Michigan Comprehensive Cancer Center, 1500 E. Medical Center Dr. SPC 591, Ann Arbor, MI, 48109, USA. tycelp@med.umich.edu. FAU - Barr, Paul M AU - Barr PM AD - James P. Wilmot Cancer Center, University of Rochester Medical Center, 601 Elmwood Ave, Rochester, NY, 14642, USA. FAU - Park, Steven I AU - Park SI AD - Levine Cancer Institute and Carolinas Healthcare System, 100 Medical Park Dr Ste 110, Concord, NC, 28025, USA. FAU - Kolibaba, Kathryn AU - Kolibaba K AD - Northwest Cancer Specialists, P.C, 210 SE. 136th Ave, Vancouver, WA, 98684, USA. FAU - Caimi, Paolo F AU - Caimi PF AD - Case Western Reserve University, University Hospitals Cleveland Medical Center, 11100 Euclid Ave Ste 1, Cleveland, OH, 44106, USA. FAU - Chhabra, Saurabh AU - Chhabra S AD - Medical College of Wisconsin, 9200 West Wisconsin Avenue, Milwaukee, WI, 53226, USA. FAU - Kingsley, Edwin C AU - Kingsley EC AD - Comprehensive Cancer Centers of Nevada, 3730 S. Eastern Ave, Las Vegas, NV, 89169, USA. FAU - Boyd, Thomas AU - Boyd T AD - Yakima Valley Memorial Hospital, North Star Lodge, 808 N 39 Ave, Yakima, WA, 98902, USA. FAU - Chen, Robert AU - Chen R AD - City of Hope National Medical Center, 1500 East Duarte Rd, Duarte, CA, 91010, USA. FAU - Carret, Anne-Sophie AU - Carret AS AD - Seattle Genetics, Inc., 21823 20th Dr SE, Bothell, WA, 98021, USA. FAU - Gartner, Elaina M AU - Gartner EM AD - Seattle Genetics, Inc., 21823 20th Dr SE, Bothell, WA, 98021, USA. FAU - Li, Hong AU - Li H AD - Seattle Genetics, Inc., 21823 20th Dr SE, Bothell, WA, 98021, USA. FAU - Yu, Cindy AU - Yu C AD - Seattle Genetics, Inc., 21823 20th Dr SE, Bothell, WA, 98021, USA. FAU - Smith, David C AU - Smith DC AD - University of Michigan Comprehensive Cancer Center, 1500 E. Medical Center Dr. SPC 591, Ann Arbor, MI, 48109, USA. LA - eng PT - Clinical Trial, Phase I PT - Journal Article PT - Multicenter Study PT - Research Support, Non-U.S. Gov't DEP - 20180822 PL - United States TA - Invest New Drugs JT - Investigational new drugs JID - 8309330 RN - 0 (Antibodies, Monoclonal) RN - 0 (Biomarkers, Tumor) RN - 0 (CD27 Ligand) RN - 0 (CD70 protein, human) RN - 0 (Immunoconjugates) RN - 0 (Pyrroles) RN - 0 (pyrrolo(2,1-c)(1,4)benzodiazepine) RN - 12794-10-4 (Benzodiazepines) SB - IM MH - Adult MH - Aged MH - Aged, 80 and over MH - Antibodies, Monoclonal/pharmacokinetics/*therapeutic use MH - Benzodiazepines/chemistry MH - Biomarkers, Tumor/metabolism MH - CD27 Ligand/*antagonists & inhibitors/immunology/metabolism MH - Drug Resistance, Neoplasm/drug effects MH - Female MH - Follow-Up Studies MH - Gene Expression Regulation, Neoplastic/*drug effects MH - Humans MH - Immunoconjugates/pharmacokinetics/therapeutic use MH - Lymphoma, B-Cell/*drug therapy/immunology/metabolism/pathology MH - Lymphoma, Large B-Cell, Diffuse/drug therapy/immunology/metabolism/pathology MH - Lymphoma, Mantle-Cell/*drug therapy/immunology/metabolism/pathology MH - Male MH - Maximum Tolerated Dose MH - Middle Aged MH - Neoplasm Recurrence, Local/*drug therapy/immunology/metabolism/pathology MH - Prognosis MH - Pyrroles/chemistry MH - *Salvage Therapy MH - Tissue Distribution PMC - PMC6440937 OTO - NOTNLM OT - Antibody-drug conjugate OT - CD70 antigen OT - Diffuse, large B cell, lymphoma (DLBCL) OT - Grade 3 follicular lymphoma OT - Mantle-cell lymphoma OT - Pyrrolobenzodiazepine dimer (PBD) COIS- AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST: The institutions of SIP, KK, and DCS received research funding from Seattle Genetics, Inc. PMB has served as a consultant to Seattle Genetics, SIP has received honoraria from the Seattle Genetics Speakers' Bureau, and TP reports advisory board membership with Seattle Genetics. AC, EMG, HL, and CY are employees of and hold equity interest in Seattle Genetics. ETHICAL APPROVAL: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. INFORMED CONSENT: Informed consent was obtained from all individual participants included in the study. EDAT- 2018/08/23 06:00 MHDA- 2020/02/06 06:00 PMCR- 2018/08/22 CRDT- 2018/08/23 06:00 PHST- 2018/06/21 00:00 [received] PHST- 2018/08/10 00:00 [accepted] PHST- 2018/08/23 06:00 [pubmed] PHST- 2020/02/06 06:00 [medline] PHST- 2018/08/23 06:00 [entrez] PHST- 2018/08/22 00:00 [pmc-release] AID - 10.1007/s10637-018-0655-0 [pii] AID - 655 [pii] AID - 10.1007/s10637-018-0655-0 [doi] PST - ppublish SO - Invest New Drugs. 2019 Apr;37(2):297-306. doi: 10.1007/s10637-018-0655-0. Epub 2018 Aug 22.