Mr. James Parsons reports
TRILLIUM THERAPEUTICS PROVIDES UPDATE ON ITS TTI-621 AND TTI-622 CD47 PROGRAMS
Trillium Therapeutics Inc. has provided an update on its TTI-621 and TTI-622 clinical programs.
"We have now completed the initial dose finding and signal seeking parts of our phase 1 study of intravenous TTI-621 at doses up to 0.5 milligram per kilogram," said Dr. Jan Skvarka, president and chief executive officer of Trillium. "The program continues to demonstrate clear single agent activity across a range of hematologic malignancies, as well as a strong tolerability profile. We believe that TTI-621, even at these low initial doses, is the only anti-CD47 agent that has shown meaningful single agent activity, including complete responses. Our immediate priority is to complete the ongoing monotherapy dose escalation under revised DLT criteria for thrombocytopenia. We are currently dosing at one mg per kg, or five times the dose level at which we observed initial single agent activity. Once we have defined the maximum tolerated dose (MTD), we intend to move TTI-621 into combinations with other agents in larger indications with high unmet need, namely acute myeloid leukemia (AML)/myelodysplastic syndromes (MDS), peripheral T-cell lymphoma (PTCL) and other oncology indications. We currently expect that we will identify the MTD and initiate one or more combination studies later this year."
"We are equally excited about the dose escalation progress with our IgG4-based agent, TTI-622," said Dr. Yaping Shou, Trillium's chief medical officer. "We believe that the clean binding profile on red blood cells provides TTI-622 with the opportunity to potentially achieve best-in-class status among IgG4-based anti-CD47 molecules."
An updated corporate presentation has been posted on Trillium's website. The presentation provides additional detail on the clinical data reported here in context with the corporate strategy.
TTI-621 program update
A phase 1, multicentre, open-label study in which patients with advanced relapsed or refractory hematologic malignancies receive intravenous TTI-621 is currently in progress (NCT02663518). The study consists of four parts: (a) parts 1 to 3 in hematologic malignancies, with dosing up to 0.5 mg/kg, conducted under initial DLT criteria, now completed; and (b) part 4 in cutaneous T-cell lymphoma (CTCL), utilizing revised DLT criteria for thrombocytopenia (as detailed herein) and an amended protocol to allow for dosing above 0.5 mg/kg, now continuing.
Over 200 patients received doses ranging from 0.05 to 0.5 mg/kg, with the majority enrolled at 0.2 to 0.5 mg/kg dose levels. Updated safety data demonstrate that TTI-621 is generally well tolerated. The most frequent drug-related adverse events were low-grade infusion reactions and transient thrombocytopenia that was not associated with bleeding.
TTI-621 activity has been observed in patients across a range of hematologic malignancies. Notably, most patients were at an advanced stage of their disease and heavily pretreated, with median number of prior systemic treatments between three and four (range from one to 26). Highlights of the updated, now complete, data set for parts 1 to 3 are shown in the included table.
HIGHLIGHTS OF TTI-621 PARTS 1-3 DATA (AT INITIAL DOSES UP TO 0.5 MG/KG)
CTCL PTCL DLBCL*
Therapy 621 mono 621 mono 621 mono 621+Rtx*
N (response evaluable) 42 22 7 25
% patients with equal stage III disease at diagnosis 57% 73% 86% 80%
# prior systemic treatments, median (min. to max.) 4 (1-26) 3 (1-6) 3 (2-8) 4 (2-10)
Objective response rate (n, %) 8 (19%) 4 (18%) 2 (29%) 6 (24%)
Complete responses (n, %) 1 (2%) 2 (9%) 1 (14%) 1 (4%)
*DLBCL -- diffuse large B-cell lymphoma; Rtx -- rituximab
Note: Objective response rate (ORR) includes partial response and complete response rates.
Part 4 of the study is now continuing under an amended protocol. Given the transient nature of thrombocytopenia observed in parts 1 to 3 of the study, the DLT definition for thrombocytopenia was revised, from grade 4 of any duration in parts 1 to 3, to grade 4 lasting 72-plus hours or a platelet count less than 10,000 per microlitre at any time in part 4. As previously reported, 0.5 and 0.7 mg/kg dose levels have not shown any DLTs; furthermore, no grade 4 thrombocytopenia of any duration has been observed. The study is now dosing at the one mg/kg level, or five-fold the 0.2 mg/kg dose level where monotherapy effect was initially observed. The protocol stipulates 1.4 mg/kg as the next potential dosing level and allows for higher dosing if appropriate.
While the dose escalation is conducted with TTI-621 monotherapy, further clinical development strategy will pursue primarily combinations with other agents.
The company plans to provide a study update by mid-2020.
TTI-622 program update
A two-part, multicentre, open-label, phase 1a/1b study of TTI-622 in patients with advanced relapsed or refractory lymphoma or multiple myeloma is currently in progress (NCT03530683). In the phase 1a dose-escalation part, patients are being enrolled in sequential dose cohorts to receive TTI-622 once weekly to characterize safety, tolerability, pharmacokinetics and to determine the maximum tolerated dose. In the phase 1b part, patients with hematologic malignancies will be treated with TTI-622 in combination with other agents.
The company is reporting that it has completed dosing in the fourth dose escalation cohort, where patients received a top dose of two mg/kg. No DLTs or drug-related serious adverse events have been observed, and enrollment is now open in the fifth cohort, with a top dose of four mg/kg. Although TTI-622 is being developed primarily as a combination therapy, a partial response has been observed in a DLBCL patient receiving 0.8 mg/kg TTI-622 monotherapy.
The company plans to provide a study update by mid-2020.
About TTI-621 and TTI-622 programs
TTI-621 (SIRPa-IgG1 Fc) is a decoy receptor that blocks CD47 and delivers an activating signal to effector cells such as macrophages through its IgG1 Fc region.
TTI-622 (SIRPa-IgG4 Fc) consists of the same CD47-binding domain of human SIRPa as TTI-621, however, it is linked to an IgG4 Fc region.
About Trillium Therapeutics Inc.
Trillium is an immuno-oncology company developing innovative therapies for the treatment of cancer. The company's two clinical programs, TTI-621 and TTI-622, target CD47, a "do not eat" signal that cancer cells frequently use to evade the immune system.
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