Phase 1 Study of TAK-659, an Investigational Reversible Dual SYK/FLT-3 Inhibitor, in Patients (Pts) with Lymphoma: Updated Results from Dose-Escalation and Expansion Cohorts

Background Spleen tyrosine kinase (SYK) is a nonreceptor kinase with a key role in B-cell receptor signaling-driven tumorigenesis and a key regulator of FMS-like tyrosine kinase 3 (FLT-3). TAK-659 is an investigational, oral, reversible, and potent dual inhibitor of SYK and FLT-3 that has demonstrated inhibition of cell proliferation in vitro and dose-dependent tumor growth inhibition in lymphoma xenograft models. This first-in-human, phase 1, dose-escalation and expansion study was conducted to determine the safety, tolerability, and potential efficacy of TAK-659 in pts with solid tumors and lymphomas. The MTD/RP2D of TAK-659 was determined as 100 mg QD (Petrich et al. Blood 2015; 126, 2693). Here we report updated data for the lymphoma pts from the dose-escalation and expansion phases. Methods Adult pts with relapsed and/or refractory lymphoma received oral TAK-659 60-120 mg (dose escalation) or 100 mg (expansion) QD in 28-d cycles. Adverse events (AEs) were assessed using NCI-CTCAE v4.03. Plasma and urine pharmacokinetic (PK) assessments occurred during cycle 1 (C1) in the dose-escalation phase. Response was assessed using IWG modified criteria (lymphoma) or IWCLL criteria (CLL) between d22 and d29 (pre-dose) of C2 (both phases), then during C4, C6, and every 3 cycles (dose escalation), or every even numbered cycle until C12, then every 4 cycles (expansion). Cell-of-origin (COO) classification data were assessed locally. Ibrutinib resistance mutations were identified by high-sensitivity Sanger sequencing of DNA isolated from bone marrow or whole blood. Results At data cut-off (2 June 2017), 92 pts with lymphoma (DLBCL 69; iNHL 13; CLL 5; MCL 4; PTLD 1) received TAK-659 60-120 mg QD (84 pts at 100 mg). Median age was 65 yrs (range 23-85), 60 pts (65%) were male. Drug-related Gr ≥3 AEs occurred in 66 (72%) pts, including elevated amylase (24%), hypophosphatemia (20%), elevated blood creatine phosphokinase (14%), elevated lipase (14%), and neutropenia (14%). 26 (28%) pts had drug-related serious AEs (all grades included), most commonly pyrexia (8%), pneumonia (7%), and pneumonitis (3%). Laboratory grade changes over 3 cycles are shown in Figure 1. Changes in amylase, lipase, and LDH were not associated with symptoms; nearly all pts experienced a rise in serum LDH approximately 1 week into therapy. Of 31 lymphoma pts who died on study, 3 deaths were considered drug-related (respiratory failure, multiorgan failure, and disseminated varicella). Response and target lesion change among 65 response-evaluable pts are shown in Figure 2. Median treatment duration for DLBCL responders (27% of evaluable patients) was 327 days (range 53-1018) or 10.9 mos and median duration of response (DOR) was 277 days (range 1-905) or 9.2 mos. In DLBCL pts, responses were seen in both de novo (germinal center B-cell [GCB] n=3, non-GCB n=2) and transformed (GCB n=4, non-GCB n=1) disease and appeared to be independent of COO classification. COO classification was not available for 3 additional de novo DLBCL responders. In DLBCL pts, median PFS in responding (not reached) and non-responding pts (47 days [95% CI 31, 50]) is shown in Figure 3. Of the 5 CLL pts enrolled, none had BTK mutations. One of 2 CLL responders with prior ibrutinib and idelalisib exposure had PLC-gamma-2 mutations. Responses were also observed in 7 of 10 evaluable iNHL and 1 of 2 MCL pts. TAK-659 PK profile in the dose-escalation phase was approximately dose-proportional over 60-100 mg. TAK-659 was absorbed quickly (median T max ≈ 2 h) with moderate variability (50% CV) in dose-normalized steady-state AUC. The overall mean accumulation was 2.1-fold in lymphoma pts after repeated QD dosing; geometric mean terminal half-life was ~34 h. Overall the mean proportion of TAK-659 excreted unmodified in the urine was 34%. Conclusions Our data suggest that TAK-659 is generally well tolerated in lymphoma pts, with evidence of single-agent activity across various lymphoma subtypes. Antitumor activity in DLBCL pts appeared durable (median DOR of >9 mos) and independent of COO subtype or disease history ( de novo vs transformed). Antitumor activity was also observed in CLL, iNHL, and MCL pts. CLL pts who have failed prior ibrutinib and/or prior idelalisib therapy may remain responsive to TAK-659. The TAK-659 PK profile supports continuous oral QD dosing. Enrollment of pts with DLBCL, iNHL, CLL, MCL, and PTLD is ongoing, with planned accrual of ~152 pts in the expansion phase. Disclosures Kaplan: Millennium: Research Funding; Takeda: Research Funding; Seattle Genetics: Research Funding; Janssen: Research Funding. Gordon: Janssen: Other: Data Monitoring Committee. Rambaldi: Novartis, Amgen, Celgene, Sanofi: Other: Travel, Accomodations, Expenses; Novartis, Roche/Genentech, Amgen, Italfarmaco: Consultancy. Popat: Amgen: Honoraria; Celgene: Honoraria, Other: Travel support for meetings; Takeda: Honoraria, Other: Travel support for meetings; Janssen: Honoraria, Other: Travel support for meetings. Patel: BMS: Speakers Bureau; Medivation: Speakers Bureau; Gilead: Speakers Bureau; Genentech: Speakers Bureau; Exelixis: Speakers Bureau. Madan: Amgen: Other: Advisory board; Takeda: Other: Advisory board; Takeda: Speakers Bureau; Janssen: Speakers Bureau; Celgene: Speakers Bureau; Amgen: Speakers Bureau. Chau: Novartis: Research Funding; Taiho: Honoraria; Merck-Serono: Research Funding; Sanofi Oncology: Research Funding; Janssen-Cilag: Research Funding; Five Prime Therapeutics: Other: Advisory board; Roche: Other: Advisory board; Bayer: Other: Advisory board; MSD: Other: Advisory board; Bristol Meyers Squibb: Other: Advisory board; Eli-Lilly: Other; Sanofi Oncology: Other: Advisory board; Pfizer: Honoraria; Amgen: Research Funding; Eli-Lilly: Research Funding; Gilead Science: Research Funding. Radford: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Speakers Bureau; GSK: Equity Ownership; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Consultancy; AstraZeneca: Equity Ownership; Novartis: Speakers Bureau; Seattle Genetics: Speakers Bureau; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Research Funding. Iyer: Takeda: Research Funding; Genentech: Research Funding. Perez De Oteyza: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Research Funding. Zinzani: Celgene: Other: Advisory board; Roche: Other: Advisory board; Karyopharma: Other: Advisory board; Gilead: Other: Advisory board; Janssen: Other: Advisory board; Takeda: Other: Advisory Board; Pfizer: Other: Advisory board; Sandoz: Other: Advisory board. Wang: Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Sheldon-Waniga: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Stumpo: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Shou: Takeda Pharmaceuticals: Employment, Equity Ownership. Bosch: Roche, Janssen, Abbvie: Membership on an entity9s Board of Directors or advisory committees; Roche, Novartis, Janssen, Abbvie, Gilead, Mundipharma: Speakers Bureau; Roche, Novartis, Janssen, Abbvie, Gilead, Mundipharma: Honoraria; Roche, Celgene, Karyospharm, Takeda: Research Funding; Roche, Novartis, Janssen, Abbvie, Gilead, Mundipharma: Consultancy; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Research Funding.