SNPMiner Trials by Shray Alag


SNPMiner Trials: Clinical Trial Report


Report for Clinical Trial NCT03106779

Developed by Shray Alag, 2019.
SNP Clinical Trial Gene

A Phase 3, Multi-center, Open-label, Randomized Study of Oral ABL001 Versus Bosutinib in Patients With Chronic Myelogenous Leukemia in Chronic Phase (CML-CP), Previously Treated With 2 or More Tyrosine Kinase Inhibitors

The purpose of this pivotal study is to compare the efficacy of ABL001 with that of bosutinib in the treatment of patients with CML-CP having previously been treated with a minimum of two prior ATP-binding site TKIs. Patients intolerant to the most recent TKI therapy must have BCR-ABL1 ratio > 0.1% IS at screening and patients failing their most recent TKI therapy must meet the definition of treatment failure as per the 2013 ELN guidelines. Patients with documented treatment failure while on bosutinib treatment will have the option to switch to asciminib treatment within 96 weeks after the last patient has been randomized on study.

NCT03106779 Chronic Myelogenous Leukemia
MeSH: Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive
HPO: Chronic myelogenous leukemia Leukemia Myeloid leukemia

2 Interventions

Name: ABL001

Description: 40 mg tablets will be taken orally twice a day (BID)

Type: Drug

ABL001

Name: Bosutinib

Description: 500 mg tablets will be taken orally once daily (QD)

Type: Drug

Bosutinib


Primary Outcomes

Description: To compare the MMR rate of ABL001 versus bosutinib

Measure: Major Molecular Response (MMR) rate

Time: at 24 weeks

Secondary Outcomes

Description: To compare additional parameters of the efficacy of ABL001 versus bosutinib

Measure: Major Molecular Response (MMR) rate

Time: 96 weeks after the last patient received the first study dose

Description: To compare additional parameters of the efficacy of ABL001 versus bosutinib. Cytogenic response will include Complete, Partial, Major, Minor, Minimal and no response.

Measure: Complete Cytogenetic response rate

Time: 96 weeks after the last patient received the first study dose

Description: To compare additional parameters of the efficacy of ABL001 versus bosutinib

Measure: Time to MMR

Time: 96 weeks after the last patient received the first study dose

Description: To compare additional parameters of the efficacy of ABL001 versus bosutinib

Measure: Duration of MMR

Time: 96 weeks after the last patient received the first study dose

Description: To compare additional parameters of the efficacy of ABL001 versus bosutinib

Measure: Time to CCyR

Time: 96 weeks after the last patient received the first study dose

Description: To compare additional parameters of the efficacy of ABL001 versus bosutinib

Measure: Duration of CCyR

Time: 96 weeks after the last patient received the first study dose

Description: To compare additional parameters of the efficacy of ABL001 versus bosutinib

Measure: Time to treatment failure

Time: 96 weeks after the last patient received the first study dose

Description: To compare additional parameters of the efficacy of ABL001 versus bosutinib

Measure: Progression free survival

Time: 96 weeks after the last patient received the first study dose

Description: To compare additional parameters of the efficacy of ABL001 versus bosutinib

Measure: Overall survival

Time: 96 weeks after the last patient received the first study dose

Description: To characterize the PK of ABL001 in the CML-CP population

Measure: Trough plasma concentrations

Time: 96 weeks after the last patient received the first study dose

Description: To characterize the PK of ABL001 in the CML-CP population

Measure: PK parameter: Cmax,

Time: 96 weeks after the last patient received the first study dose

Description: To characterize the PK of ABL001 in the CML-CP population

Measure: PK parameter: Tmax

Time: 96 weeks after the last patient received the first study dose

Description: To characterize the PK of ABL001 in the CML-CP population

Measure: PK parameter: AUC0-12h

Time: 96 weeks after the last patient received the first study dose

Description: To characterize the PK of ABL001 in the CML-CP population

Measure: PK parameter: CL/F

Time: 96 weeks after the last patient received the first study dose

Purpose: Treatment

Allocation: Randomized

Parallel Assignment


There are 2 SNPs

SNPs


1 T315I

- Three months after the initiation of therapy: No CHR or > 95% Ph+ metaphases - Six months after the initiation of therapy: BCR-ABL1 ratio > 10% IS and/or > 65% Ph+ metaphases - Twelve months after initiation of therapy: BCR-ABL1 ratio > 10% IS and/or > 35% Ph+ metaphases - At any time after the initiation of therapy, loss of CHR, CCyR or PCyR - At any time after the initiation of therapy, the development of new BCR-ABL1 mutations which potentially cause resistance to study treatment - At any time after the initiation of therapy, confirmed loss of MMR in 2 consecutive tests, of which one must have a BCR-ABL1 ratio ≥ 1% IS - At any time after the initiation of therapy, new clonal chromosome abnormalities in Ph+ cells: CCA/Ph+ - Intolerance is defined as: - Non-hematologic intolerance: Patients with grade 3 or 4 toxicity while on therapy, or with persistent grade 2 toxicity, unresponsive to optimal management, including dose adjustments (unless dose reduction is not considered in the best interest of the patient if response is already suboptimal) - Hematologic intolerance: Patients with grade 3 or 4 toxicity (absolute neutrophil count [ANC] or platelets) while on therapy that is recurrent after dose reduction to the lowest doses recommended by manufacturer Exclusion Criteria: Known presence of the T315I or V299L mutation at any time prior to study entry Known second chronic phase of CML after previous progression to AP/BC Previous treatment with a hematopoietic stem-cell transplantation Patient planning to undergo allogeneic hematopoietic stem cell transplantation Cardiac or cardiac repolarization abnormality, including any of the following: - History within 6 months prior to starting study treatment of myocardial infarction (MI), angina pectoris, coronary artery bypass graft (CABG) - Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II and third degree AV block) - QTcF at screening ≥450 msec (male patients), ≥460 msec (female patients) - Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome, or any of the following: - Risk factors for Torsades de Pointes (TdP) including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia - Concomitant medication(s) with a known risk of Torsades de Pointes per www.crediblemeds.org that cannot be discontinued or replaced 7 days prior to starting study drug by safe alternative medication. --- T315I ---


2 V299L

- Three months after the initiation of therapy: No CHR or > 95% Ph+ metaphases - Six months after the initiation of therapy: BCR-ABL1 ratio > 10% IS and/or > 65% Ph+ metaphases - Twelve months after initiation of therapy: BCR-ABL1 ratio > 10% IS and/or > 35% Ph+ metaphases - At any time after the initiation of therapy, loss of CHR, CCyR or PCyR - At any time after the initiation of therapy, the development of new BCR-ABL1 mutations which potentially cause resistance to study treatment - At any time after the initiation of therapy, confirmed loss of MMR in 2 consecutive tests, of which one must have a BCR-ABL1 ratio ≥ 1% IS - At any time after the initiation of therapy, new clonal chromosome abnormalities in Ph+ cells: CCA/Ph+ - Intolerance is defined as: - Non-hematologic intolerance: Patients with grade 3 or 4 toxicity while on therapy, or with persistent grade 2 toxicity, unresponsive to optimal management, including dose adjustments (unless dose reduction is not considered in the best interest of the patient if response is already suboptimal) - Hematologic intolerance: Patients with grade 3 or 4 toxicity (absolute neutrophil count [ANC] or platelets) while on therapy that is recurrent after dose reduction to the lowest doses recommended by manufacturer Exclusion Criteria: Known presence of the T315I or V299L mutation at any time prior to study entry Known second chronic phase of CML after previous progression to AP/BC Previous treatment with a hematopoietic stem-cell transplantation Patient planning to undergo allogeneic hematopoietic stem cell transplantation Cardiac or cardiac repolarization abnormality, including any of the following: - History within 6 months prior to starting study treatment of myocardial infarction (MI), angina pectoris, coronary artery bypass graft (CABG) - Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II and third degree AV block) - QTcF at screening ≥450 msec (male patients), ≥460 msec (female patients) - Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome, or any of the following: - Risk factors for Torsades de Pointes (TdP) including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia - Concomitant medication(s) with a known risk of Torsades de Pointes per www.crediblemeds.org that cannot be discontinued or replaced 7 days prior to starting study drug by safe alternative medication. --- T315I --- --- V299L ---



HPO Nodes


HPO:
Chronic myelogenous leukemia
Genes 5
MPL BCR JAK2 KIT THPO
Leukemia
Genes 125
MPL RNASEH2B KRAS NPM1 TET2 MYD88 TSR2 RPL26 RPL27 TREX1 EFL1 PIGL SCN11A FLT3 PMS2 RPL35A EVC2 ABL1 CEBPA RARA NRAS WAS WIPF1 ATRX SH2B3 PDGFRA RB1 RNASEH2A PDGFRB CALR ARHGAP26 SH3GL1 RPS7 RPS10 NUMA1 GATA1 GATA2 RPS15A APC NSD1 ETV6 TCIRG1 DNAJC21 EVC SRP54 RPS17 NBN RPS19 SAMHD1 MSH2 RPS24 NUP214 RPS26 RPS27 RPS28 RPS29 MLLT10 RUNX1 XRCC4 CBFB CBL BCR ADAR TRIP13 ADA2 NSUN2 CREBBP PICALM GFI1 F13A1 F13B FANCA FANCC BLM FANCD2 FANCE NUTM1 JAK2 IFIH1 TYROBP MSH6 FANCG LIG4 PTPN11 SAMD9L THPO NF1 STS PIGA BRCA2 DYNC2LI1 PIK3CA SBDS GLI1 PIK3R1 BRD4 SETBP1 RNASEH2C LPP BUB1 BUB1B SCN9A SCN10A TREM2 MLF1 MLH1 ELANE DKC1 ATM HAX1 RPL35 GNB1 BUB3 CEP57 TAL1 KIT TAL2 RPL5 EP300 TP53 RPL11 KIF11 RPL15 DNMT3A RPL18
Myeloid leukemia
Genes 12
GATA2 F13A1 CBL ARHGAP26 F13B KRAS PTPN11 SAMD9L KIT SETBP1 NF1 NRAS