CD47-Blocker TTI-622 Shows Single-Agent Activity in Patients with Advanced Relapsed or Refractory Lymphoma: Update from the Ongoing First-in-Human Dose Escalation Study
Authors: Patel Krish , Zonder Jeffrey A. , Sano Dahlia , Maris Michael , Lesokhin Alexander , von Keudell Gottfried , Lai Catherine , Ramchandren Rod , Catalano Tina , Lin Gloria H. Y. , Uger Bob , Petrova Penka S. , Molloy Naomi , Bruns Ingmar , Iyer Swaminathan P 
Published: November 2021

Abstract
Background
CD47 is an innate immune checkpoint that binds signal regulatory protein alpha (SIRPα) and delivers a "don't eat me" signal to suppress macrophage phagocytosis. Overexpression of CD47 serves as a mechanism of immune surveillance evasion, and is associated with poor prognosis in both hematologic and solid malignancies. TTI-622 is a fusion protein consisting of the CD47-binding domain of human SIRPα linked to the Fc region of human IgG4. It is designed to enhance phagocytosis and antitumor activity by preventing CD47 from delivering its inhibitory signal as well as generating a moderate pro-phagocytic signal via IgG4 Fc. Importantly, unlike many CD47-blocking agents, TTI-622 does not bind to human red blood cells.
Methods
This is an ongoing multicenter, Phase 1a/1b dose-escalation and expansion trial of TTI-622 (NCT03530683). Based on a modified 3+3 scheme, dose escalation proceeded through 8 dose levels ranging from 0.05 to 18 mg/kg weekly dosing in patients with refractory or relapsed (r/r) lymphomas. Testing of every two and three week schedules of single agent TTI-622 at doses up to 24 mg/kg is ongoing. Safety monitoring includes clinical laboratories and assessments of adverse events (AEs) based on CTCAE v 4.03.
Results
As of April 12, 2021, 42 patients (18M/24F) with a median age of 67 years (range 24-86) have received dose levels of 0.05−18 mg/kg weekly TTI-622. Lymphoma histologies enrolled include diffuse large B-cell lymphoma (DLBCL; n=19), cutaneous T-cell lymphoma - mycosis fungoides (CTCL-MF; n=6), peripheral T-cell lymphoma (PTCL; n=6), Hodgkin lymphoma (HL; n=5), and follicular lymphoma (FL; n=4). Additional histologies with single patients only accounted for the remaining 2 patients. Disease stages at entry have been III or IV in 38 patients and median prior systemic therapies of 3 (range 1-9) have been received, including CAR-T and HSCT in 9 and 10 patients, respectively. One additional patient with Erdheim-Chester disease initially diagnosed as lymphoma is included in the safety analysis only. Treatment-related AEs have occurred in 20 (47%) patients; most AEs have been Grade 1 or 2 and reversible. The most frequent treatment-related AEs include thrombocytopenia (n=9, 21%), neutropenia (n=5, 12%), and anemia and fatigue (n=4 each, 9%). Related adverse events of Grade ≥ 3 intensity include thrombocytopenia (n=2, 5%; 1 each Grade 3 & 4), neutropenia (n=4, 9%; all Grade 3), and anemia (n=1, 2%; Grade 3). These Grade 3 and 4 hematologic events occurred in dose levels ranging from 0.8 to 18 mg/kg without apparent dose relationship. Mild to moderate platelet decreases seen in the majority of patients generally occurred on dosing days and recovered quickly to baseline levels. Preliminary PK results suggest dose-dependent increases in exposure following both single and repeated TTI-622 infusions. A total of 27 patients were response-evaluable at dose levels ≥0.8 mg/kg at the time of the data-cut. Objective responses have been achieved in 9 patients, including 2 complete responses (CR) - 1 in DLBCL (0.8 mg/kg) and 1 in CTCL (18 mg/kg) - and 7 partial responses (PR) - 2 in CTCL (both 8 mg/kg), 2 in PTCL (2 and 12 mg/kg), 2 in DLBCL (4 and 18 mg/kg), and 1 in FL (8 mg/kg). Initial responses were achieved at the first disease assessment (week 8) in all 9 responders. In the dose range of 0.8-18 mg/kg, objective responses occurred in 33% (9/27) of response-evaluable patients. At the time of the data cut-off 4 responders were active on treatment; both patients with CR, ongoing 22+ months (0.8 mg/kg) and 12 weeks on an every three week dosing schedule (18 mg/kg). Two patients with PR were ongoing 18 weeks (12 mg/kg) and 11 weeks (18 mg/kg).
Conclusions
Results to date in patients with r/r lymphomas indicate that weekly doses of single agent TTI-622 up to 18 mg/kg are well tolerated. TTI-622 has shown activity in r/r lymphoma with objective responses across a broad dose range (0.8-18 mg/kg), in highly pre-treated patients, across multiple histologies, and with onset of action consistently observed at the first response assessment at Week 8. The study is ongoing evaluating single agent TTI-622 in every two and three week schedules. Updated data including additional patients will be presented at the conference. Based on these results demonstrating promising single-agent activity as well as good tolerability, TTI-622 is currently being investigated in combination regimens in a range of hematologic malignancies.

Disclosures
Patel: Xencor: Research Funding; Velos Bio: Research Funding; Trillium Therapeutics: Research Funding; TG Therapeutics: Consultancy, Speakers Bureau; Sunesis Pharmaceuticals: Research Funding; Pharmacyclics/Janssen: Consultancy, Research Funding, Speakers Bureau; Morphosys: Consultancy; Millenium/Takeda: Research Funding; MEI Pharma: Consultancy, Research Funding; Kite: Consultancy, Research Funding, Speakers Bureau; Juno Pharmaceuticals: Consultancy; Genentech/Roche: Consultancy, Research Funding, Speakers Bureau; Fate Therapeutics: Research Funding; Curis, Inc: Research Funding; Celgene: Consultancy, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Research Funding, Speakers Bureau; BeiGene: Consultancy; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Aptevo Therapeutics: Research Funding; Abbvie: Consultancy. Zonder: Amgen: Consultancy; BMS: Consultancy, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Caelum Biosciences: Consultancy; Intellia: Consultancy; Regeneron: Consultancy; Alnylam: Consultancy. Lesokhin: pfizer: Consultancy, Research Funding; Genetech: Research Funding; Janssen: Honoraria, Research Funding; Iteos: Consultancy; bristol myers squibb: Research Funding; Serametrix, Inc: Patents & Royalties; Trillium Therapeutics: Consultancy; Behringer Ingelheim: Honoraria. von Keudell: Merck: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Merck: Research Funding; Incyte: Consultancy, Honoraria; AbbVie: Research Funding; BMS: Research Funding; Janssen: Research Funding. Lai: Macrogenics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Speakers Bureau; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Speakers Bureau; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees. Ramchandren: curis: Research Funding; seattle genetics: Consultancy, Research Funding; MERCK: Consultancy, Research Funding; pharmacyclics: Consultancy, Research Funding; BMS: Consultancy; Trillium: Research Funding. Catalano: Trillium Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Lin: Trillium Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Uger: Trillium Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Petrova: Trillium Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Molloy: Trillium Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Bruns: Trillium Therapeutics: Current Employment, Current holder of stock options in a privately-held company.