Phase I Study of the CD47 Blocker TTI-621 in Patients with Relapsed or Refractory Hematologic Malignancies.

Autor:	Ansell SM; Division of Hematology, Mayo Clinic, Rochester, Minnesota. ansell.stephen@mayo.edu., Maris MB; Colorado Blood Cancer Institute and Sarah Cannon Research Institute, Denver, Colorado., Lesokhin AM; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York., Chen RW; Department of Hematology and Hematopoietic Transplantation, City of Hope Medical Center, Duarte, California., Flinn IW; Sarah Cannon Research Institute, Nashville, Tennessee.; Tennessee Oncology, Nashville, Tennessee., Sawas A; Center for Lymphoid Malignancies, Columbia University Medical Center, College of Physicians and Surgeons, New York, New York., Minden MD; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada., Villa D; Division of Medical Oncology and Centre for Lymphoid Cancer, BC Cancer, Vancouver, British Columbia, Canada., Percival MM; Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington.; Division of Hematology, University of Washington, Seattle, Washington., Advani AS; Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio., Foran JM; Division of Hematology and Medical Oncology, Mayo Clinic, Jacksonville, Florida., Horwitz SM; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York., Mei MG; Department of Hematology and Hematopoietic Transplantation, City of Hope Medical Center, Duarte, California., Zain J; Department of Hematology and Hematopoietic Transplantation, City of Hope Medical Center, Duarte, California., Savage KJ; Division of Medical Oncology and Centre for Lymphoid Cancer, BC Cancer, Vancouver, British Columbia, Canada., Querfeld C; Department of Hematology and Hematopoietic Transplantation, City of Hope Medical Center, Duarte, California., Akilov OE; Cutaneous Lymphoma Program, Department of Dermatology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania., Johnson LDS; Trillium Therapeutics Inc., Mississauga, Ontario, Canada., Catalano T; Trillium Therapeutics Inc., Mississauga, Ontario, Canada., Petrova PS; Trillium Therapeutics Inc., Mississauga, Ontario, Canada., Uger RA; Trillium Therapeutics Inc., Mississauga, Ontario, Canada., Sievers EL; Trillium Therapeutics Inc., Mississauga, Ontario, Canada., Milea A; Trillium Therapeutics Inc., Mississauga, Ontario, Canada., Roberge K; Trillium Therapeutics Inc., Mississauga, Ontario, Canada., Shou Y; Trillium Therapeutics Inc., Mississauga, Ontario, Canada., O'Connor OA; University of Virginia Cancer Center, Charlottesville, Virginia.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2021 Apr 15; Vol. 27 (8), pp. 2190-2199. Date of Electronic Publication: 2021 Jan 15.
DOI:	10.1158/1078-0432.CCR-20-3706
Abstrakt:	Purpose: TTI-621 (SIRPα-IgG1 Fc) is a novel checkpoint inhibitor that activates antitumor activity by blocking the CD47 "don't eat me" signal. This first-in-human phase I study (NCT02663518) evaluated the safety and activity of TTI-621 in relapsed/refractory (R/R) hematologic malignancies. Patients and Methods: Patients with R/R lymphoma received escalating weekly intravenous TTI-621 to determine the maximum tolerated dose (MTD). During expansion, patients with various malignancies received weekly single-agent TTI-621 at the MTD; TTI-621 was combined with rituximab in patients with B-cell non-Hodgkin lymphoma (B-NHL) or with nivolumab in patients with Hodgkin lymphoma. The primary endpoint was the incidence/severity of adverse events (AEs). Secondary endpoint included overall response rate (ORR). Results: Overall, 164 patients received TTI-621: 18 in escalation and 146 in expansion (rituximab combination, n = 35 and nivolumab combination, n = 4). On the basis of transient grade 4 thrombocytopenia, the MTD was determined as 0.2 mg/kg; 0.1 mg/kg was evaluated in combination cohorts. AEs included infusion-related reactions, thrombocytopenia, chills, and fatigue. Thrombocytopenia (20%, grade ≥3) was reversible between doses and not associated with bleeding. Transient thrombocytopenia that determined the initial MTD may not have been dose limiting. The ORR for all patients was 13%. The ORR was 29% (2/7) for diffuse large B-cell lymphoma (DLBCL) and 25% (8/32) for T-cell NHL (T-NHL) with TTI-621 monotherapy and was 21% (5/24) for DLBCL with TTI-621 plus rituximab. Further dose optimization is ongoing. Conclusions: TTI-621 was well-tolerated and demonstrated activity as monotherapy in patients with R/R B-NHL and T-NHL and combined with rituximab in patients with R/R B-NHL. (©2021 American Association for Cancer Research.)
Databáze:	MEDLINE
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