SYK Inhibitor TAK-659 Shows Promising Results in Lymphoid Malignancies

Adam M. Petrich, MD

TAK-659, an inhibitor of spleen tyrosine kinase (SYK), showed early signs of antitumor activity in patients with lymphoma, with two expansion arms planned for patients with diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL), according to findings reported at the 13th International Conference on Malignant Lymphoma, held in Lugano, Switzerland.

In patients with DLBCL who were ineligible or stopped responding to standard therapies (n = 6), the objective response rate (ORR) with TAK-659 was 33%, which consisted entirely of partial responses (PRs). In 3 patients with follicular lymphoma (FL), the ORR was 67%. In this arm, 1 patient experienced a complete remission. Additionally, no significant safety concerns were seen in the investigation, with a maximum tolerated dose not yet identified.

”SYK is a key mediator of signaling through immune receptors, including B-cell and Fc receptors, and proteins associated with Epstein-Barr virus (EBV) latency,” explained Adam M. Petrich MD, Northwestern University. “TAK-659 has demonstrated activity against SYK and FLT3 in vitro and has shown activity in multiple DLBCL xenograft tumor models.”

B-cell and myeloid tumor populations are enriched for activated SYK expression, as are EBV-associated hematologic malignancies and solid tumors that signal through latent membrane protein 2A. B-cell receptor-mediated SYK activation can be seen in many lymphoid malignancies, including DLBCL, FL, CLL, and mantle cell lymphoma (MCL).

In the phase I study, the safety and pharmacokinetics (PK) of TAK-659 at doses of 60 mg escalated to 120 mg was evaluated in 12 patients with solid tumors and in 9 with DLBCL or FL for whom no standard treatment options were available. The median age of the patients was 60 years (range, 43-80) and 76% were male. Eight (38%) patients had received 3 or fewer therapies and 13 patients (62%) had received 4 or more prior treatments. Patients received 2 cycles of TAK-659 (range, 1-10) and 5 patients (24%) remained on active treatment.

The preliminary plasma PK profile was evaluated in 21 patients across all doses. The PK of TAK-659 was characterized by rapid absorption (median Tmax 2 h), moderate variability in steady-state exposures (47% coefficient of variation for d15 AUCtau), mean peak-to-trough ratio of 3.9 (range, 1.3-11.5) at steady state, and mean accumulation of 2.7-fold after repeated daily dosing for 15 days. Steady state PK was achieved by day 8 and the TAK-659 half-life was just over 24 hours.

“Although the observed clearance in humans is lower than that predicted based on preclinical data, these findings, support daily dosing,” said Petrich.

Treatment related toxicities occurring in 2 or more patients were mostly grades 1/2 and included fatigue, anemia, diarrhea, elevated AST or ALT, hypophosphatemia, nausea, rash, and anorexia. One grade 3/ 4 case of elevated lipase was seen and grades 3/4 anemia and diarrhea were reported.

Two dose limiting toxicities (asymptomatic lipase elevation) were seen at the 120 mg dose. Three patients discontinued due to adverse events (one patients receiving 60 mg, and 2 at 120 mg). Four deaths determined as unrelated to TAK-659 occurred on study (3 patients at 60 mg, one patient at 120 mg).

“No significant safety concerns have been raised to date with TAK-659,” commented Petrich. “The hematological profile in particular suggests that this is a well-tolerated drug.”

In response to a question from co-chair of the Novel Agents session Giles Salles, MD, PhD, Hospices Civel de Lyon, France regarding whether any DLTs were observed after data cut-off, Petrich clarified that 2 DLTs occurred after the data cut-off of April 13, 2015.

In addition to the two expansion arms, a phase Ib/II trial exploring TAK-659 in patients with acute myeloid leukemia is ongoing. This analysis is based on dual SYK and FLT-3 activity seen with TAK-659. The primary endpoint in the phase II portion of the study is ORR. Additionally, outcomes will be independently assessed in patients with FLT-3-ITD mutations (NCT02323113).

Petrich AM, Gordon LI, Infante JR, et al. Ongoing, first-in-human, phase 1 dose-escalation study of investigational SYK inhibitor TAK-659 in patients with advanced solid tumours or lymphoma. Presented at: 13th International Conference on Malignant Lymphoma; June 16-20, 2015; Lugano, Switzerland. Abstract 039.

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