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Phase I Study of the CD47 Blocker TTI-621 in Patients with Relapsed or Refractory Hematologic Malignancies
Stephen M Ansell1, Michael B Maris2, Alexander M Lesokhin3
1Division of Hematology, Mayo Clinic, Rochester, Minnesota. ansell.stephen@mayo.edu.
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.
Insights
TTI-621, a novel checkpoint inhibitor, showed good tolerability and antitumor activity in patients with relapsed/refractory hematologic malignancies. This therapy blocks the CD47 "don't eat me" signal, activating the immune system against cancer cells.
Area of Science:
- Oncology
- Immunotherapy
- Clinical Trials
Background:
- TTI-621 is a novel SIRPα-IgG1 Fc fusion protein designed as a checkpoint inhibitor.
- It functions by blocking the CD47 "don't eat me" signal, thereby activating anti-tumor immune responses.
- This mechanism is particularly relevant for overcoming immune evasion in hematologic malignancies.
Purpose of the Study:
- To evaluate the safety and activity of TTI-621 in a first-in-human Phase I clinical trial.
- To determine the maximum tolerated dose (MTD) of TTI-621 in patients with relapsed/refractory (R/R) hematologic malignancies.
- To assess the overall response rate (ORR) as a secondary endpoint.
Main Methods:
- A Phase I, first-in-human study (NCT02663518) involving patients with R/R lymphoma.
- Escalating weekly intravenous doses of TTI-621 were administered to determine the MTD.
- Expansion cohorts included single-agent TTI-621 or combinations with rituximab (for B-cell NHL) or nivolumab (for Hodgkin lymphoma).
Main Results:
- The MTD was established at 0.2 mg/kg based on transient grade 4 thrombocytopenia; 0.1 mg/kg was used in combination cohorts.
- Adverse events included infusion reactions, thrombocytopenia, chills, and fatigue. Grade ≥3 thrombocytopenia occurred in 20% of patients but was reversible and not associated with bleeding.
- The overall response rate (ORR) across all patients was 13%, with notable responses in diffuse large B-cell lymphoma (DLBCL) and T-cell NHL (T-NHL) monotherapy arms.
Conclusions:
- TTI-621 was well-tolerated in patients with R/R hematologic malignancies.
- The agent demonstrated clinical activity as monotherapy in B-cell NHL and T-NHL.
- TTI-621 also showed activity when combined with rituximab in R/R B-NHL.
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