Background

CD47 is an innate immune checkpoint that binds signal regulatory protein alpha (SIRPα) and delivers a "do not eat" signal to suppress macrophage phagocytosis. Overexpression of CD47 can allow tumor cells to escape immune surveillance. TTI-621 (SIRPαFc) is a fusion protein consisting of the CD47 binding domain of human SIRPα linked to the Fc region of human IgG1, designed to enhance phagocytosis and antitumor activity by blocking the CD47-SIRPα interaction between malignant cells and macrophages, and engaging Fcγ receptors. Here we report updates from the first-in-human study of TTI-621 (NCT02663518) in hematologic malignancies.

Methods

Study Part 1 tested increasing weekly intravenous doses of TTI-621 based on 3+3 escalation. The maximum tolerated dose was initially determined to be 0.2 mg/kg based on dose limiting toxicity (DLT) of thrombocytopenia [Grade (Gr) 4 of any duration]. Expanded testing followed in patients (pts) with hematologic malignancies, including leukemia, lymphoma, and multiple myeloma. In Part 2, most pts received 0.2 mg/kg. However, based on investigator discretion, a subset of pts received escalating doses up to 0.5 mg/kg. In Part 3, pts with T-cell lymphomas received stepwise dose escalations from 0.2 to 0.5 mg/kg over the first 5−8 weeks. In over 200 pts tested in Parts 1−3, thrombocytopenia did not increase with dose, typically recovered within 2−4 days, and was not associated with clinical sequelae.

Part 4 was then undertaken to optimize TTI-621 dosing and is currently escalating doses in a 3+3 manner through pre-planned dose levels (0.5, 0.7, 1, and 1.4 mg/kg) in pts with cutaneous T-cell lymphoma (CTCL). The DLT criteria was modified to require Gr 4 thrombocytopenia lasting >72 hours. Safety monitoring includes weekly clinical laboratories and assessments of adverse events (AEs) per CTCAE v 4.03. Blood samples are obtained for pharmacokinetics (PK) and for pharmacodynamic (PD) assessments of receptor occupancy (RO) on normal peripheral T cells. Disease assessments are performed per Olsen's criteria.

Results

In Parts 1−3 (n=214), the most common related AEs were infusion-related reaction (IRR, 43%; 3% Gr ≥3), thrombocytopenia (30%; 22% Gr ≥3), chills (21%; 0% Gr ≥3), and fatigue (15%; 1% Gr ≥3). Objective responses to single agent TTI-621 were achieved in 14/71 (20%) NHL pts including CTCL (n=42, 1 CR, 7 PRs), PTCL (n=22, 2 CRs, 2 PRs) and DLBCL (n=7, 1 CR, 1 PR).

In Part 4, as of July 10, 2020, 15 pts (9M/6F, median age 67 years) have enrolled into 4 dose cohorts (0.5−1.4 mg/kg). CTCL subtypes include mycosis fungoides (MF, n=10) and Sézary syndrome (n=5) with advanced (≥IIB) disease in 9 (60%) pts who received a median of 3 (range 1−12) prior systemic therapies. Related AEs have occurred in 11 (73%) pts including IRR (n=10) and thrombocytopenia (n=3); Gr ≥3 AEs have occurred in 4 (27%) pts including thrombocytopenia (n=3), IRRs (n=2), and exfoliative dermatitis (n=1). Thrombocytopenia generally occurred on dosing days, recovered in 2-4 days, and has not worsened with increasing doses. IRRs typically occurred during initial infusions. The Gr 3 IRR events occurred in 2 pts in the 1 and 1.4 mg/kg cohorts; low Gr IRRs have occurred across doses in 8 pts. IRRs typically resolved without recurrence and low Gr events often resolved allowing for completion of infusions. For initial infusions, the Gr 3 IRRs prompted increasing infusion times from 1 hour up to 4 hours and discretional use of steroid pre-medication. The exfoliative dermatitis occurred Day 80 and led to treatment discontinuation in 1 pt with MF whose underlying disease confounded the etiology. PK results reveal dose dependent increases in exposure; PD studies indicate ~60% RO at end of infusion up to 1 mg/kg. Antitumor activity to date includes 1 PR and 1 skin CR in 6 evaluable pts in the 1 mg/kg cohort; 2 responding pts bridged to allogeneic transplantation. The mean % change in mSWAT scores were -0.4%, -27%, and -37% for 0.5, 0.7 and 1 mg/kg cohorts, respectively. 1.4 mg/kg cohort results will be presented at the meeting.

Conclusions

In Parts 1−3, TTI-621 doses of 0.05 to 0.5 mg/kg were well-tolerated and demonstrated single agent activity in multiple hematologic malignancies. Preliminary data from Part 4 dose optimization indicate that weekly infusions of TTI-621 up to 1.4 mg/kg are well-tolerated without dose limiting or cumulative thrombocytopenia. Antitumor activity was seen at 1 mg/kg; dose escalation is continuing at 2 mg/kg.

Disclosures

Horwitz:Janssen: Consultancy; Verastem: Consultancy, Research Funding; Daiichi Sankyo: Research Funding; GlaxoSmithKline: Consultancy; ASTEX: Consultancy; Portola: Consultancy, Research Funding; C4 Therapeutics: Consultancy; Beigene: Consultancy; Myeloid Therapeutics: Consultancy; Vividion Therapeutics: Consultancy; Infinity/Verastem: Research Funding; Aileron: Consultancy, Research Funding; ADCT Therapeutics: Consultancy, Research Funding; Affirmed: Consultancy; Trillium: Consultancy, Research Funding; Corvus: Consultancy; Millenium/Takeda: Consultancy, Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; Innate Pharma: Consultancy; Forty Seven: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Kura Oncology: Consultancy; Miragen: Consultancy; Mundipharma: Consultancy. Foran:Agios: Honoraria, Research Funding; H3Biosciences: Research Funding; Xencor: Research Funding; Trillium: Research Funding; Takeda: Research Funding; Kura Oncology: Research Funding; Aptose: Research Funding; Aprea: Research Funding; Actinium: Research Funding; Boehringer Ingelheim: Research Funding; Abbvie: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Revolution Medicine: Consultancy. Sawas:Flatiron Health: Current Employment; Gilead: Speakers Bureau; Seattle Genetics: Speakers Bureau; Daiichi Sankyo: Speakers Bureau; Affimed: Research Funding; Roche: Current equity holder in publicly-traded company. Feldman:AstraZeneca: Consultancy; Viracta: Research Funding; Trillium: Research Funding; Pfizer: Research Funding; Janssen: Speakers Bureau; Bayer: Consultancy, Honoraria; Kyowa Kirin: Consultancy, Research Funding; Eisai: Research Funding; Cell Medica: Research Funding; Amgen: Research Funding; Pharmacyclics: Honoraria, Other, Speakers Bureau; Abbvie: Honoraria; Takeda: Honoraria, Other: Travel expenses; Celgene: Honoraria, Research Funding; Kite: Honoraria, Other: Travel expenses, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding; Corvus: Research Funding; Rhizen: Research Funding; Seattle Genetics, Inc.: Consultancy, Honoraria, Other: Travel expenses, Research Funding, Speakers Bureau; Portola: Research Funding. Sokol:EUSA Pharma: Consultancy, Honoraria, Speakers Bureau; Kyowa/Kirin Inc.: Membership on an entity's Board of Directors or advisory committees; Kymera Therapeutics: Membership on an entity's Board of Directors or advisory committees. Mei:Sanofi: Consultancy; Morphosys: Membership on an entity's Board of Directors or advisory committees. Flinn:Gilead Sciences: Consultancy, Research Funding; F. Hoffmann-La Roche: Research Funding; Roche: Consultancy, Research Funding; Vincera Pharma: Consultancy; Agios: Research Funding; Iksuda Therapeutics: Consultancy; Great Point Partners: Consultancy; Genentech, Inc.: Research Funding; Forty Seven: Research Funding; Forma Therapeutics: Research Funding; ArQule: Research Funding; Kite Pharma: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Trillium Therapeutics: Research Funding; Triphase Research & Development Corp.: Research Funding; Curio Science: Consultancy; Constellation Pharmaceuticals: Research Funding; MorphoSys: Consultancy, Research Funding; Curis: Research Funding; Nurix Therapeutics: Consultancy; Novartis: Research Funding; Pfizer: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Portola Pharmaceuticals: Research Funding; Seattle Genetics: Consultancy, Research Funding; Teva: Research Funding; Loxo: Research Funding; BeiGene: Consultancy, Research Funding; Calithera Biosciences: Research Funding; Johnson & Johnson: Other; Rhizen Pharmaceuticals: Research Funding; Yingli Pharmaceuticals ≠: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; Karyopharm Therapeutics: Research Funding; AstraZeneca: Consultancy, Research Funding; Incyte: Research Funding; Takeda: Consultancy, Research Funding; IGM Biosciences: Research Funding; Infinity Pharmaceuticals: Research Funding; Unum Therapeutics: Consultancy, Research Funding; Juno Therapeutics: Consultancy, Research Funding; Acerta Pharma: Research Funding; Celgene: Research Funding; Merck: Research Funding. Villa:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; AZ: Consultancy, Honoraria, Research Funding; Kite/Gilead: Consultancy, Honoraria; Nano String: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Sandoz Canada: Consultancy, Honoraria; Immunovaccine: Consultancy, Honoraria; Purdue Pharma: Consultancy, Honoraria. Percival:Pfizer: Research Funding; Trillium: Research Funding; Nohla Therapeutics: Research Funding; Biosight: Research Funding; Oscotec: Research Funding; Cardiff Oncology: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Glycomimetics: Research Funding. Jagadeesh:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron: Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Research Funding; Debiopharm Group: Research Funding. Savage:Merck, BMS, Seattle Genetics, Gilead, AstraZeneca, AbbVie, Servier: Consultancy; Roche (institutional): Research Funding; Merck, BMS, Seattle Genetics, Gilead, AstraZeneca, AbbVie: Honoraria; BeiGene: Other: Steering Committee. Akilov:Mallinckrodt: Consultancy; Medivir: Consultancy; Seattle Genetics, Inc.: Consultancy; Kyowa Hakko Kirin: Consultancy; Soligenix: Honoraria; Pfizer: Research Funding; Actelion: Consultancy, Research Funding; Trillium Therapeutics Inc.: Consultancy, Research Funding. Diefenbach:Trillium: Research Funding; Millenium/Takeda: Research Funding; Seattle Genetics: Consultancy, Research Funding; Merck: Consultancy, Research Funding; MEI: Research Funding; LAM Therapeutics: Research Funding; Incyte: Research Funding; Genentech, Inc.: Consultancy, Research Funding; Denovo: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Kim:Kyowa-Kirin Pharma: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Medivir: Membership on an entity's Board of Directors or advisory committees; Horizon Pharma: Consultancy, Research Funding; Merck: Research Funding; miRagen: Research Funding; Trillium: Research Funding; Galderma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Corvus: Research Funding; Elorac: Research Funding; Forty Seven Inc: Research Funding; Neumedicine: Consultancy, Research Funding; Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Solingenix: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Portola: Research Funding. Lin:Trillium Therapeutics Inc.: Current Employment. Catalano:Trillium Therapeutics Inc.: Current Employment. Petrova:Trillium Therapeutics Inc.: Current Employment. Uger:Trillium Therapeutics Inc.: Current Employment. Molloy:Trillium Therapeutics Inc.: Current Employment. Large:Trillium Therapeutics Inc.: Current Employment. Shou:Trillium Therapeutics Inc.: Current Employment. Ansell:Affimed: Research Funding; Bristol Myers Squibb: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; ADC Therapeutics: Research Funding; Seattle Genetics: Research Funding; Takeda: Research Funding; AI Therapeutics: Research Funding.

Author notes

*

Asterisk with author names denotes non-ASH members.

© 2020 by The American Society of Hematology
2020
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