mivavotinib (CB-659)

The combination of paclitaxel and TAK-659 showed preliminary activity possibly overcoming resistance to taxane-based therapy as well as a tolerable safety profile in patients with advanced solid tumors.

We searched and reviewed clinical trial reports on the monotherapy of 13 FLT3 inhibitors, including sorafenib, lestaurtinib, midostaurin, gilteritinib, quizartinib, sunitinib, crenolanib, tandutinib, cabozantinib, pexidartinib, pacritinib, famitinib, and TAK-659 in patients with hematological and solid malignancies before May 31, 2023...The ORRs of FLT3 inhibitors in hematologic malignancies and solid tumors were 40.8% and 18.8%, respectively, indicating FLT3 inhibitors were more effective for hematologic malignancies than for solid tumors. In addition, time to maximum plasma concentration (Tmax) in these FLT3 inhibitors ranged from 0.7-12.0 hours, but the elimination half-life (T1/2) range was highly variable, from 6.8 to 151.8 h. FLT3 inhibitors monotherapy has shown significant anti-tumor effect in clinic, and the effectiveness may be further improved through combination medication.

Low response rates highlight the challenges of treating unresponsive tumor types, such as TNBC, with this combination and immunotherapies in general. TRIAL REGISTRATION ID: NCT02834247.

TAK-659 exhibited low to moderate single-agent in vivo activity against pediatric ALL PDXs representative of diverse subtypes.

No abstract available

A TAK-659 dose of 60 mg was well tolerated, did not require dose modifications, and maintained a similar AUC to the MTD. The combination of R-CHOP and TAK-659 in patients with newly diagnosed high-risk DLBCL produces promising CR rates.

These findings support SYK as a potential therapeutic target for the treatment of patients with B-cell lymphomas, including DLBCL. Trial registration: ClinicalTrials.gov number: NCT02000934.

In this study, we evaluated the in vitro antileukemic effects of five SYK inhibitors, fostamatinib, entospletinib, cerdulatinib, TAK-659, and RO9021, in a consecutive AML patient cohort. Finally, most of the SYK inhibitors caused a significant decrease in the release of cytokines and chemokines from primary AML cells, indicating a potent inhibitory effect on the release of these leukemic signaling molecules. We concluded that the SYK inhibitors had antileukemic effects in AML, although larger studies are strongly needed to identify which patient subsets will benefit most from such a treatment.

Following standard first-line R-CHOP (or equivalent), patients must have received 2nd-line salvage therapy with or without autologous stem cell transplant (ASCT), and/or CAR-T therapy, unless ineligible for 2nd-line salvage, ASCT, or CAR-T. Exploratory endpoints include pharmacokinetic, biomarker assessments, and investigator-assessed ORR, DoR, PFS, and CR rate. Result s of this study will help to define the optimal dose and provide confirmatory efficacy and safety data of mivavotinib in patients with non-GCB DLBCL, including MYD88/CD79b-mutated DLBCL to guide further expansion in these biomarker-defined cohorts.

Expanding eligibility by enrolling patients with moderate renal impairment in phase 1 increased the diversity of patients in early trials and allowed the model to inform dose adjustment in patients with moderate renal impairment in future trials. In addition, simulations showed median steady-state trough concentration of mivavotinib following 70 mg twice daily and 160 mg daily dosing to be commensurate with 100 ng/mL, the level leading to >90% FLT3 inhibition per ex-vivo plasma immune assays and considered a potential exposure threshold required for FLT3-driven efficacy.

Overall, these findings indicate that the activity of mivavotinib in R/R AML is modest. Furthermore, any future clinical investigation of this agent should be undertaken with caution, particularly in thrombocytopenic patients, due to the potential bleeding risk of SYK inhibition.

Patients must have had ≥2 but no more than 5 prior lines of systemic anticancer therapy; following standard first-line R-CHOP (or equivalent), patients must have received 2nd line salvage therapy with or without autologous stem cell transplant (ASCT), and/or CAR-T therapy, unless ineligible for 2nd line salvage, ASCT, or CAR-T. Exploratory endpoints include pharmacokinetic, biomarker assessments, and investigator-assessed ORR, DoR, PFS, and CR rate. Results of this study will inform the optimal dose and provide confirmatory efficacy and safety data of mivavotinib in patients with non-GCB DLBCL, including MYD88/CD79bmutated DLBCL to guide further expansion in these biomarker-defined cohorts.

P1/2; Trial completion date: Oct 2023 --> Feb 2022 | Active, not recruiting --> Terminated | Trial primary completion date: Oct 2022 --> Sep 2021; Funder requested termination due to halting internal development of TAK-659

P1, N=81, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting

Aside from dose modifications of vincristine for peripheral neuropathy, no additional dose modifications for R-CHOP were needed. TAK-659, a novel SYK inhibitor combined with R-CHOP in pts with newly diagnosed high-risk DLBCL including DLBCL transformed from follicular lymphoma and DEL produces high CR rates; survival at 12 months appears promising. A dose of 60 mg was well tolerated, did not require dose modifications and maintained a similar AUC to the MTD of 100 mg with ongoing treatment. Opportunistic infections were noted with this treatment combination suggesting that patients should receive aggressive anti-microbial prophylaxis with future evaluation of this combination.

P1/2, N=8, Active, not recruiting, H Scott Boswell | Recruiting --> Active, not recruiting | N=54 --> 8

P1, N=12, Active, not recruiting, Northwestern University | Recruiting --> Active, not recruiting | N=18 --> 12

TAK-659 exhibited low to moderate single-agent in vivo activity against pediatric B-ALL PDXs representative of diverse disease subtypes.

Overall, these findings provide initial evidence of the role of TAK 659 in potentiating the anti-tumoral immune response during treatment of DLBCL. Therefore, we believe that treatment with TAK659 can help to reinstall immune surveillance by exerting direct immunomodulatory effects which provides rationale for combination therapy not only in B-cell derived malignancies but also in solid tumors.

TAK-659 has single-agent activity in patients with B-cell lymphoma. Further studies of the drug in combination, including an evaluation of the biologically optimal and safest long-term dose and schedule, are warranted.

P2, N=49, Terminated, Millennium Pharmaceuticals, Inc. | N=122 --> 49 | Trial completion date: Jul 2020 --> Dec 2019 | Active, not recruiting --> Terminated | Trial primary completion date: Jul 2020 --> Dec 2019; Lack of efficacy of the drug; no safety concern