Contributions
Abstract: EP1030
Type: E-Poster Presentation
Session title: Myeloma and other monoclonal gammopathies - Clinical
Background
Bisthianostat is a novel Histone deacetylase inhibitor (HDACi), derived by systematic optimizations on the basis of the thiazole-thiazoline core structure in natural HDACi Largazole (Nan et al., ACS Med Chem Lett. 2014). It displayed potent anti-MM activity as single agents and good synergistic effect with bortezomib both in vitro and in vivo. Herein, we presented our updated in-patient findings from CH-020PI study, an ongoing dose-escalating phase 1a study of bisthianostat in patients(pts) with RRMM(NCT03618602).
Aims
To investigate the safety, tolerability, pharmacokinetics, and efficacy of single-agent bisthianostat in pts with RRMM.
Methods
Adult pts with RRMM who had received ≥2 prior regimens were enrolled. Bisthianostat was administered orally on a twice-weekly schedule, in 4-week cycles, until progressive disease or unacceptable toxicities. The criteria of dose escalation were based on a modified Fibonacci method with dose increased by 100mg, 200mg, 400mg, and 600mg, respectively.
Results
As of Dec 29, 2020, 15 pts were enrolled at 4 dose levels from 100 to 600mg. The median age at enrollment was 60 years (range, 49-70 years). The median number of previous lines of therapy was 3 (range, 2-9) and included treatment with bortezomib (100%), ixazomib (13.3%), immunomodulatory drugs (lenalidomide/thalidomide, 93.3%).
Among all treated pts (N=15), 93.3% of pts had treatment-emergent adverse events (TEAEs), which were mostly grade 1-2 (66.7%). Most common TEAEs (any grade, ≥20%) were: neutropenia (66.7%), urinary tract infection (33.3%), fever (20%), ECG QTc interval prolonged (20%) and diarrhea (20%). Grade 3/4 TEAEs were neutropenia (20%), anemia (6.7%) and pneumonitis (6.7%). Only one TEAE led to permanent treatment discontinuation in patient 009 (400mg cohort), who experienced QTc prolongation and was assessed as dose-limiting toxicity (DLT) per protocol. Later investigation indicated that this patient had QTc prolongation within 6 months prior enrollment. No further case of DLT or MTD was observed in cohort of 400mg and 600mg.
In the pharmacokinetic evaluation, for all of the 15 pts tested at day 1, the peak concentration of bisthianostat was reached within 0.5-2.25 h; half life time were 4.28-9.48 h; the mean Cmax was 0.599, 1.11, 1.16, and 0.996 mg/mL at dose levels of 100, 200, 400 and 600 mg, respectively, and the mean AUC0-∞ was 2.07, 3.76, 5.53, and 4.68 h·mg /mL, respectively. The AUC0-∞ and Cmax exhibited dose proportionality over the range of 100-200 mg, but they increased lower than dose-proportional manner from 200 to 400 mg. The exposure of bisthianostat at 600 mg was comparable to that at 400 mg. Similar results were found following multiple doses administration. Bisthianostat was not accumulated following a twice-weekly treatment.
The single-agent efficacy was modest. Of the 14 efficacy evaluable pts, seven pts (50%) experienced stable disease as their best response. One patient (004, 200mg cohort) remained stable for up to 6.5 months.
Conclusion
Bisthianostat proved to be well absorbed and tolerated. It exhibited modest anti-tumor efficacy in our cohort of RRMM pts. According to pharmacokinetic evaluation data, dose escalation will not proceed and a triple-weekly oral administration schedule is currently ongoing, Future trials in the combination with established MM therapy will be investigated in phase 1b study to enhance its efficacy via synergistic effect.
Keyword(s): Histone deacetylase inhibitor, Multiple myeloma, Pharmacokinetic, Safety
Abstract: EP1030
Type: E-Poster Presentation
Session title: Myeloma and other monoclonal gammopathies - Clinical
Background
Bisthianostat is a novel Histone deacetylase inhibitor (HDACi), derived by systematic optimizations on the basis of the thiazole-thiazoline core structure in natural HDACi Largazole (Nan et al., ACS Med Chem Lett. 2014). It displayed potent anti-MM activity as single agents and good synergistic effect with bortezomib both in vitro and in vivo. Herein, we presented our updated in-patient findings from CH-020PI study, an ongoing dose-escalating phase 1a study of bisthianostat in patients(pts) with RRMM(NCT03618602).
Aims
To investigate the safety, tolerability, pharmacokinetics, and efficacy of single-agent bisthianostat in pts with RRMM.
Methods
Adult pts with RRMM who had received ≥2 prior regimens were enrolled. Bisthianostat was administered orally on a twice-weekly schedule, in 4-week cycles, until progressive disease or unacceptable toxicities. The criteria of dose escalation were based on a modified Fibonacci method with dose increased by 100mg, 200mg, 400mg, and 600mg, respectively.
Results
As of Dec 29, 2020, 15 pts were enrolled at 4 dose levels from 100 to 600mg. The median age at enrollment was 60 years (range, 49-70 years). The median number of previous lines of therapy was 3 (range, 2-9) and included treatment with bortezomib (100%), ixazomib (13.3%), immunomodulatory drugs (lenalidomide/thalidomide, 93.3%).
Among all treated pts (N=15), 93.3% of pts had treatment-emergent adverse events (TEAEs), which were mostly grade 1-2 (66.7%). Most common TEAEs (any grade, ≥20%) were: neutropenia (66.7%), urinary tract infection (33.3%), fever (20%), ECG QTc interval prolonged (20%) and diarrhea (20%). Grade 3/4 TEAEs were neutropenia (20%), anemia (6.7%) and pneumonitis (6.7%). Only one TEAE led to permanent treatment discontinuation in patient 009 (400mg cohort), who experienced QTc prolongation and was assessed as dose-limiting toxicity (DLT) per protocol. Later investigation indicated that this patient had QTc prolongation within 6 months prior enrollment. No further case of DLT or MTD was observed in cohort of 400mg and 600mg.
In the pharmacokinetic evaluation, for all of the 15 pts tested at day 1, the peak concentration of bisthianostat was reached within 0.5-2.25 h; half life time were 4.28-9.48 h; the mean Cmax was 0.599, 1.11, 1.16, and 0.996 mg/mL at dose levels of 100, 200, 400 and 600 mg, respectively, and the mean AUC0-∞ was 2.07, 3.76, 5.53, and 4.68 h·mg /mL, respectively. The AUC0-∞ and Cmax exhibited dose proportionality over the range of 100-200 mg, but they increased lower than dose-proportional manner from 200 to 400 mg. The exposure of bisthianostat at 600 mg was comparable to that at 400 mg. Similar results were found following multiple doses administration. Bisthianostat was not accumulated following a twice-weekly treatment.
The single-agent efficacy was modest. Of the 14 efficacy evaluable pts, seven pts (50%) experienced stable disease as their best response. One patient (004, 200mg cohort) remained stable for up to 6.5 months.
Conclusion
Bisthianostat proved to be well absorbed and tolerated. It exhibited modest anti-tumor efficacy in our cohort of RRMM pts. According to pharmacokinetic evaluation data, dose escalation will not proceed and a triple-weekly oral administration schedule is currently ongoing, Future trials in the combination with established MM therapy will be investigated in phase 1b study to enhance its efficacy via synergistic effect.
Keyword(s): Histone deacetylase inhibitor, Multiple myeloma, Pharmacokinetic, Safety