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

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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: Alexander N Starodub, Allyson J Ocean, Manish A Shah, Michael J Guarino, Vincent J Picozzi Jr, Linda T Vahdat, Sajeve S Thomas, Serengulam V Govindan, Pius P Maliakal, William A Wegener, Steven A Hamburger, Robert M Sharkey, David M Goldenberg
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 21 Issue 17 Pg. 3870-8 (Sep 01 2015) ISSN: 1557-3265 [Electronic] United States
• PMID: 25944802 (Publication Type: Clinical Trial, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Antibodies, Monoclonal, Humanized
• Antigens, Neoplasm
• Antineoplastic Agents
• Cell Adhesion Molecules
• Immunoconjugates
• TACSTD2 protein, human
• sacituzumab govitecan
• Camptothecin

Topics

• Adult
• Aged
• Aged, 80 and over
• Antibodies, Monoclonal, Humanized (pharmacology, therapeutic use)
• Antigens, Neoplasm (metabolism)
• Antineoplastic Agents (pharmacology, therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Camptothecin (analogs & derivatives, pharmacology, therapeutic use)
• Cell Adhesion Molecules (metabolism)
• Combined Modality Therapy
• Drug Monitoring
• Female
• Humans
• Immunoconjugates (pharmacology, therapeutic use)
• Male
• Middle Aged
• Neoplasm Metastasis
• Neoplasms (diagnosis, drug therapy, therapy)
• Tomography, X-Ray Computed
• Treatment Outcome