Abstract 358TiP
Background
Sacituzumab Govitecan (SG) is a novel antibody-drug conjugate in which SN-38 (active metabolite of irinotecan), a topoisomerase I (TOP1) inhibitor, is coupled via a cleavable linker to the humanized monoclonal antibody targeting anti-trophoblast cell surface antigen 2 (Trop-2), an epithelial antigen overexpressed in many epithelial cancers including metastatic Triple Negative Breast Cancer (mTNBC). In a phase I/II clinical trial, single-agent SG demonstrated significant clinical activity in heavily pretreated patients with mTNBC leading to accelerated approval by the FDA in April 2020. As a TOP1 inhibitor, SN-38 will produce single-stranded DNA breaks (SSB) in tumor cells, which if left unrepaired, progress into double-stranded DNA breaks and cell death. In addition, PARP is required for clearance of stabilized TOP1 cleavage complexes TOP1CC, which require PARylation of both TOP1 itself and TDP1, a phosphodiesterase that hydrolyzes TOP1/DNA crosslinks. Consequently, PARP inhibitors (PARPi), such as talazoparib, constitute an ideal therapeutic partner with SG.
Trial design
Phase Ib/II, open-label study of SG in combination with talazoparib to patients with mTNBC. The study has a dose-escalation phase Ib followed by dose-expansion phase II. Treatment cycles continue until unacceptable toxicity or disease progression. The primary objective of the phase Ib is to assess the Dose-Limiting Toxicity (DLT) rate and Maximum Tolerated Dose (MTD) of SG in combination with talazoparib and to select the recommended phase II dose (RP2D) of this combination, in patients with mTNBC. The primary objective of phase II is to assess the confirmed objective response rate (ORR) and progression-free survival (PFS) of SG in combination with talazoparib at the RP2D. Statistical methods: The standard 3+3 design will be used in this study. Once the MTD/RP2D is determined in the phase Ib portion of the trial, there will be a dose-expansion cohort to confirm the safety profile and further assess the preliminary anti-tumor activity of SG in combination with talazoparib at the RP2D. The clinical trial, activated in September 2019, is currently open to enrolment.
Clinical trial identification
NCT04039230.
Editorial acknowledgement
Legal entity responsible for the study
L.W. Ellisen.
Funding
Pfizer (and Immunomedics for drug supply).
Disclosure
A. Bardia: Honoraria (self): Novartis, Pfizer, Daiichi/AstraZeneca, PUMA, Sanofi, Genentech/Roche, Radius Health, Merck, Immunomedics, Eli Lilly, Phillips, Foundation Medicine; Advisory/Consultancy: ovartis, Pfizer, Daiichi/AstraZeneca, PUMA, Sanofi, Genentech/Roche, Radius Health, Merck, Immunomedics, Eli Lilly, Phillips, Foundation Medicine; Research grant/Funding (institution): Novartis, Pfizer, Daiichi/AstraZeneca, Sanofi, Genentech/Roche, Radius Health, Merck, Immunomedics; Travel/Accommodation/Expenses: Novartis, Pfizer, Daiichi/AstraZeneca, PUMA, Sanofi, Genentech/Roche, Radius Health, Merck, Immunomedics, Eli Lilly, Phillips, Foundation Medicine. L.M. Spring: Travel/Accommodation/Expenses: Merck, Tesaro; Advisory/Consultancy: Novartis, Puma, Lumicell; Research grant/Funding (institution): Merck, Tesaro. D. Juric: Honoraria (self), Advisory/Consultancy: Novartis, Genentech, Eisai, EMD Serono, Ipsen, Syros, Relay Therapeutics, MapKure, Vibliome, and Petra Pharma; Research grant/Funding (institution): Novartis, Genetech, Eisai, EMD Serono, Takeda, Amgen, Celgene, Placon Therapeutics, Syros, Petra Pharma, InventisBio, and Infinity Pharmaceuticals. A. Partridge: Travel/Accommodation/Expenses: Novartis. J. Peppercorn: Advisory/Consultancy: Athenex; Research grant/Funding (institution): Pfizer. S.M. Tolaney: Advisory/Consultancy: Genentech, Eli Lilly, Novartis, Pfizer, Celldex, Paxman, Seattle Genetics, Nektar, Immunomedics, Nanostring, Daiichi Sankyo, Bristol-Meyers Squibb, Sanofi, AbbVie, Athenex, Oncopep, Kyowa Kirin, AstraZeneca, Eisai, Puma, and Merck; Research grant/Funding (institution): Merck, Bristol-Myers Squibb, Exelixis, Eli Lilly, Pfizer, Novartis, AstraZeneca, Eisai, Nektar, Odenate, Sanofi, Immunomedics, Cyclacel, and Genentech. All other authors have declared no conflicts of interest.