CD47-Directed TTI-622 Elicits Early Efficacy Signals in Relapsed/Refractory Lymphoma

TTI-622, an investigational CD47 inhibitor, showed preliminary signs of clinical activity with a manageable safety profile among patients with relapsed/refractory lymphoma, according to findings from a phase 1a clinical trial (NCT03530683), which were presented during the 2020 ASH Annual Meeting & Exposition.

TTI-622 was explored in the study to address CD47 overexpression, which contributes to poor prognoses in patients with hematologic malignancies. The agent binds signal regulatory protein alpha (SIRPα) and links to the Fc region of IgG4 to enhance phagocytosis and antitumor activity. Importantly, unlike other anti-CD47 antibodies, TTI-662 binds minimally to human red blood cells.

A total of 31 patients were treated across 7 dose cohorts. Following a 3 + 3 design, dose-escalation cohorts 1 to 7 received 0.1 mg/kg of TTI-622, 0.3 mg/kg, 0.8 mg/kg, 2.0 mg/kg, 4.0 mg/kg, 8.0 mg/kg, or 12.0 mg/kg, respectively. Sixteen patients in the study had diffuse large B-cell lymphoma (DLBCL), 5 had Hodgkin lymphoma (HL), 3 had follicular lymphoma, 3 had peripheral T-cell lymphoma (PTCL), 3 had cutaneous T-cell lymphoma (CTCL) with large-cell transformation, and 1 patient had mantle cell lymphoma (MCL). The median age for the patient population was 66 years (range, 24-86) and patients were predominantly female (58%).

All of the patients enrolled had an ECOG performance status of 0 or 1, as was required per the inclusion criteria of the study. Most patients had advanced-stage disease, which was stage IV for 65% of patients, III for 26%, and I/II for 6%. Disease stage was not specified for 3% of patients.

Patients included in the study had a median of 3 prior lines of systemic therapy (range, 1-9). Additionally, 26% of patients underwent prior hematopoietic stem cell transplant and 19% had prior chimeric antigen receptor T-cell therapy.

Investigators first completed a dose-escalation analysis to determine the maximum tolerated dose and investigated adverse events (AEs) to characterize the safety of TTI-622 in patients with relapsed/refractory lymphoma, the primary end point of the study. The study also assessed the pharmacokinetics and pharmacodynamics of the agent as well as preliminary antitumor activity.

Dose-limiting toxicity (DLT) was evaluated for a period of 3 weeks. During weeks 1 and 2 of the 3-week period, cohorts 1 to 5 were given a lower ‘run in’ dose followed by the higher planned dose in the third week. Cohorts 6 and beyond received a flat dose. Another 2 patients with relapsed/refractory lymphoma were enrolled in an eighth cohort and were treated at 18.0 mg/kg; enrollment in cohort 8 is ongoing.

Thus far in the study, 5 patients continue to receive treatment in cohorts 3, 6, and 7. One DLT of grade 4 thrombocytopenia occurred in a patient from cohort 6. The event was resolved quickly with the protocol strategy of giving prophylactic platelet transfusion. No DLTs were observed in cohort 8 thus far.

In terms of AEs, the majority were grade 1 or 2 in severity. The most frequently observed AEs were thrombocytopenia (16%), neutropenia (13%), as well as nausea, anemia, and fatigue, which occurred in 10% of patients each. Grade 3 or higher AEs included neutropenia (13%), and thrombocytopenia and anemia in 3% of patients each. Two patients required treatment interruptions for 1 to 2 weeks due to neutropenia and 1 patient required a treatment interruption due to thrombocytopenia.

Notable platelet count decreases occurred in patients on dosing days, but patients recovered in the first week or during subsequent weeks.

The efficacy analysis showed an objective response rate (ORR) of 27% in the 22 response-evaluable patients. Responses included 1 complete response in a patient with DLBCL, and 5 partial responses in 2 patients with CTCL, 2 patients with DLBCL, and 1 patient with PTCL. Notably, the lowest dose level at which an objective response was observed was 0.8 mg/kg. The median time to response in these patients was 49 days (45-51) after a 113-day median duration of treatment (range, 92-534). One patient in the study had an ongoing complete response of 289 days at the time of data cutoff.

Pharmacokinetic properties associated with TTI-622 were demonstrated through mean concentration profiles following intravenous infusion. There was a dose-dependent increase in TTI-622 serum trough levels following single and repeat infusions. Up to 12.0 mg/kg, no plateau has been reached, which supported dose escalation beyond 12 mg/kg. The profiles showed that steady-state TTI-622 serum exposures would likely not be reached until week 5 or beyond.

In translation assessments, receptor occupancy (RO) and T-cell receptor (TCR) Vβ sequencing were evaluated. Investigators found dose-dependent increases in peak RO as well as RO durability. One patient who achieved a CR on treatment with TTI-622 had an increase in peripheral T-cell clonality and the patient’s T cell clones expanded. The TCR Vβ sequencing assessment showed an increased frequency of 5 pre-existing T-cell clones at every time point between the first week and week 32. Clones were still expanded at week 40 and new clones also demonstrated expansion.

The phase 1a study is ongoing with further dose escalation continuing at the dose level of 18 mg/kg.

Reference

1. Patel K, Ramchandren R, Maris M, et al. Investigational 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. Presented at: 2020 ASH Annual Meeting; December 5-8, 2020; Virtual. Abstract 1191.