Ignite Creation Date:
2024-05-06 @ 4:52 PM
Last Modification Date:
2024-10-26 @ 2:17 PM
Study NCT ID:
NCT05115344
Status:
UNKNOWN
Last Update Posted:
2021-11-10
First Post:
2021-08-12
Brief Title:
Study of Flonoltinib Maleate Tablets in the Treatment of Proliferative Bone Marrow Tumors
Sponsor:
Chengdu Zenitar Biomedical Technology Co Ltd
Organization:
Guizhou Bailing Group Pharmaceutical Co Ltd
Study Overview
Official Title:
A Phase I Study Evaluating the Safety Tolerability and Pharmacokinetic and Pharmacodynamic Dose-escalation of Flonoltinib Maleate Tablets in Patients With Bone Marrow Proliferative Tumors
Status:
UNKNOWN
Status Verified Date:
2021-11
Last Known Status:
NOT_YET_RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Flonoltinib Maleate FM targets Janus kinase 2 JAK2 and FMS-like tyrosine kinase 3 FLT3 FM is a dual target inhibitor of JAK2FLT3FM has the activity of inhibiting JAK2 signaling pathway and pharmacodynamics evaluation also confirmed that FM has a good therapeutic effect on the primary splenomegaly model of mice induced by JAK2V617 mutationTherefore FM has the potential to treat bone marrow proliferative tumorsThe drug is intended to be used in patients with MPN mainly including medium-risk or high-risk myelofibrosis FM including primary myelofibrosis PMF post-polycythemia vera myelofibrosis PostPV-MF and post-primary thrombocythemia myelofibrosis postET-MF Polycythemia vera PV and essential thrombocythemia ET were the primary causes of thrombocythemia and thrombocythemia
FM has high inhibitory activity against JAK family and FLT3 kinase suggesting that FM may have a certain therapeutic effect on AML diseaseThe IC50 of JAK2 kinase inhibition by FM was as low as 08 nM while the IC50 of JAK1 JAK3 and Tyk2 kinase inhibition was 690 nM 557 nM and 65nM respectively The selectivity of JAK2 kinase inhibition by FM was 8625 6963 and 813 times respectively Therefore FM showed highly selective inhibition of JAK2 kinaseThe IC50 for FLT3 kinase was 15 nM FM has better inhibitory activity against JAK2 kinase than the listed Ruxolitinib and Fedratinib and has better selectivity against JAK familyIn order to determine whether FM has targets other than JAK2 and Flt3 kinases we tested FMs inhibitory activity against 100 human kinases that are highly associated with tumors including some common drug-resistant mutant kinasesThe results showed that except for CDK46 LCK and LN FM had no obvious inhibitory activity against the screened kinases at 01 μm and no other targets were found
In vitro experiments on the proliferation of JAK2-dependent and Flt3-related tumor cell lines with FM showed that the tumor cell lines had a significant inhibitory effect The IC50 of half of the tumor cell lines was less than 05 μm which was better than or equal to the similar drugs Ruxolitinib and Fedratinib
The effect of FM on tumor cells from MPN patients indicated that FM has the potential to treat MPN disease
In multiple animal models of bone marrow proliferative tumors with JAK2V617F mutations FM showed superior efficacy and low toxicity no obvious VISCAL toxicity than existing drugs on the market and the tumor inhibition effect of FM showed a good dose-dependent relationship
Objectives of Study
Main Purpose
1 Tolerance and safety of flonoltinib maleate Tablets tablets in patients with bone marrow proliferative tumors
2 To observe the possible dose-limiting toxicityDLT of flonoltinib maleate tablets in patients with bone marrow proliferative tumorsTo determine the maximum tolerated doseMTD of flonoltinib maleate tabletsTo provide the basis for the recommended dose and design scheme of the later clinical trial
Secondary Purpose
1 To evaluate the pharmacokinetic characteristics of single and repeated oral administration of flonoltinib maleate tablets in patients with bone marrow proliferative tumors
2 To evaluate the primary efficacy of single and multiple oral flonoltinib maleate tablets in patients with bone marrow proliferative tumors
FM has high inhibitory activity against JAK family and FLT3 kinase suggesting that FM may have a certain therapeutic effect on AML diseaseThe IC50 of JAK2 kinase inhibition by FM was as low as 08 nM while the IC50 of JAK1 JAK3 and Tyk2 kinase inhibition was 690 nM 557 nM and 65nM respectively The selectivity of JAK2 kinase inhibition by FM was 8625 6963 and 813 times respectively Therefore FM showed highly selective inhibition of JAK2 kinaseThe IC50 for FLT3 kinase was 15 nM FM has better inhibitory activity against JAK2 kinase than the listed Ruxolitinib and Fedratinib and has better selectivity against JAK familyIn order to determine whether FM has targets other than JAK2 and Flt3 kinases we tested FMs inhibitory activity against 100 human kinases that are highly associated with tumors including some common drug-resistant mutant kinasesThe results showed that except for CDK46 LCK and LN FM had no obvious inhibitory activity against the screened kinases at 01 μm and no other targets were found
In vitro experiments on the proliferation of JAK2-dependent and Flt3-related tumor cell lines with FM showed that the tumor cell lines had a significant inhibitory effect The IC50 of half of the tumor cell lines was less than 05 μm which was better than or equal to the similar drugs Ruxolitinib and Fedratinib
The effect of FM on tumor cells from MPN patients indicated that FM has the potential to treat MPN disease
In multiple animal models of bone marrow proliferative tumors with JAK2V617F mutations FM showed superior efficacy and low toxicity no obvious VISCAL toxicity than existing drugs on the market and the tumor inhibition effect of FM showed a good dose-dependent relationship
Objectives of Study
Main Purpose
1 Tolerance and safety of flonoltinib maleate Tablets tablets in patients with bone marrow proliferative tumors
2 To observe the possible dose-limiting toxicityDLT of flonoltinib maleate tablets in patients with bone marrow proliferative tumorsTo determine the maximum tolerated doseMTD of flonoltinib maleate tabletsTo provide the basis for the recommended dose and design scheme of the later clinical trial
Secondary Purpose
1 To evaluate the pharmacokinetic characteristics of single and repeated oral administration of flonoltinib maleate tablets in patients with bone marrow proliferative tumors
2 To evaluate the primary efficacy of single and multiple oral flonoltinib maleate tablets in patients with bone marrow proliferative tumors
Detailed Description:
None
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None