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

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.

Confirmation of Biosimilarity in a Pharmacokinetic/Pharmacodynamic Study in Healthy Volunteers for an Analytically Highly Similar Pegfilgrastim.

A phase 1 pharmacokinetic (PK) and pharmacodynamic (PD) study was conducted to demonstrate similarity of a proposed pegfilgrastim biosimilar to its reference product. In a single-dose, randomized, assessor-blinded, 2-way crossover, active-controlled PK/PD study, 66 healthy adults received the proposed pegfilgrastim biosimilar and US-licensed pegfilgrastim reference product. Primary end points were pegfilgrastim AUCt and Cmax (PK), and absolute neutrophil count AUECt and Emax (PD). Safety and immunogenicity were also measured. Fifty-six subjects completed both arms of the study. Mean pegfilgrastim concentration-time profile for both products was similar, with the 90% confidence intervals (CI) of the relative mean ratio for the primary end points falling within the predefined acceptance criteria of 80%-125% (91.7%-116.1% and 86.7%-110.2% for AUCt and Cmax , respectively). PD similarity was also demonstrated by the 95%CI of the relative mean ratio of the primary end point parameters within the predefined acceptance margins of 80%-125% (96.0%-101.6% and 92.6%-100.1% for AUECt and Emax , respectively). No statistically meaningful PK/PD differences were observed. No clinically meaningful safety or immunological differences were observed with the proposed pegfilgrastim biosimilar that were not previously identified with the reference product. The proposed pegfilgrastim biosimilar product is highly similar to the reference product with regard to PK/PD.