title: First-in-Human Trial of a Novel Anti-Trop-2 Antibody-SN-38 Conjugate, Sacituzumab Govitecan, for the Treatment of Diverse Metastatic Solid Tumors.
abstract: OBJECTIVE
  Sacituzumab govitecan (IMMU-132) is an antibody-drug conjugate (ADC) targeting Trop-2, a surface glycoprotein expressed on many epithelial tumors, for delivery of SN-38, the active metabolite of irinotecan. This phase I trial evaluated this ADC as a potential therapeutic for pretreated patients with a variety of metastatic solid cancers.
  
  
  METHODS
  Sacituzumab govitecan was administered on days 1 and 8 of 21-day cycles, with cycles repeated until dose-limiting toxicity or progression. Dose escalation followed a standard 3 + 3 scheme with 4 planned dose levels and dose delay or reduction allowed.
  
  
  RESULTS
  Twenty-five patients (52-60 years old, 3 median prior chemotherapy regimens) were treated at dose levels of 8 (n = 7), 10 (n = 6), 12 (n = 9), and 18 (n = 3) mg/kg. Neutropenia was dose limiting, with 12 mg/kg the maximum tolerated dose for cycle 1, but too toxic with repeated cycles. Lower doses were acceptable for extended treatment with no treatment-related grade 4 toxicities and grade 3 toxicities limited to fatigue (n = 3), neutropenia (n = 2), diarrhea (n = 1), and leukopenia (n = 1). Using CT-based RECIST 1.1, two patients achieved partial responses (triple-negative breast cancer, colon cancer) and 16 others had stable disease as best response. Twelve patients maintained disease control with continued treatment for 16 to 36 weeks; 6 survived 15 to 20+ months. No preselection of patients based on tumor Trop-2 expression was done.
  
  
  CONCLUSIONS
  Sacituzumab govitecan had acceptable toxicity and encouraging therapeutic activity in patients with difficult-to-treat cancers. The 8 and 10 mg/kg doses were selected for phase II studies.
authors.affiliation: Indiana University Health Goshen Center for Cancer Care, Goshen, Indiana.
authors.forename: Alexander N
authors.initials: AN
authors.lastname: Starodub
authors.affiliation: NewYork Presbyterian Hospital/Weill Cornell Medical Center, New York, New York.
authors.forename: Allyson J
authors.initials: AJ
authors.lastname: Ocean
authors.affiliation: NewYork Presbyterian Hospital/Weill Cornell Medical Center, New York, New York.
authors.forename: Manish A
authors.initials: MA
authors.lastname: Shah
authors.affiliation: Christiana Care Health System Graham Cancer Center, Newark, Delaware.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Guarino
authors.affiliation: Virginia Mason Medical Center, Seattle, Washington.
authors.forename: Vincent J
authors.initials: VJ
authors.lastname: Picozzi
authors.affiliation: NewYork Presbyterian Hospital/Weill Cornell Medical Center, New York, New York.
authors.forename: Linda T
authors.initials: LT
authors.lastname: Vahdat
authors.affiliation: UF Health Cancer Center, Orlando, Florida.
authors.forename: Sajeve S
authors.initials: SS
authors.lastname: Thomas
authors.affiliation: Immunomedics, Inc., Morris Plains, New Jersey.
authors.forename: Serengulam V
authors.initials: SV
authors.lastname: Govindan
authors.affiliation: Immunomedics, Inc., Morris Plains, New Jersey.
authors.forename: Pius P
authors.initials: PP
authors.lastname: Maliakal
authors.affiliation: Immunomedics, Inc., Morris Plains, New Jersey.
authors.forename: William A
authors.initials: WA
authors.lastname: Wegener
authors.affiliation: Immunomedics, Inc., Morris Plains, New Jersey.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Hamburger
authors.affiliation: Immunomedics, Inc., Morris Plains, New Jersey.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Sharkey
authors.affiliation: Immunomedics, Inc., Morris Plains, New Jersey. dmg.gscancer@att.net.
authors.forename: David M
authors.initials: DM
authors.lastname: Goldenberg
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology / Q000627:therapeutic use*; D000951:Antigens, Neoplasm / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D015815:Cell Adhesion Molecules / Q000378:metabolism; D003131:Combined Modality Therapy; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000628:therapy; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D015815:Cell Adhesion Molecules; D018796:Immunoconjugates; C499380:TACSTD2 protein, human; C000608132:sacituzumab govitecan; D002166:Camptothecin