SNPMiner Trials by Shray Alag


SNPMiner Trials: Clinical Trial Report


Report for Clinical Trial NCT01914484

Developed by Shray Alag, 2019.
SNP Clinical Trial Gene

A PHASE I/II, MULTI-CENTRE, TRIAL OF RUXOLITINIB THERAPY IN COMBINATION WITH NILOTINIB IN PATIENTS WITH PHILADELPHIA POSITIVE CHRONIC MYELOID LEUKEMIA OR ACUTE LYMPHOBLASTIC LEUKEMIA WHO HAVE FAILED TYROSINE KINASE INHIBITOR THERAPY

This is the study to test combination regimen of Nilotinib and Ruxolitinib therapy for the treatment of patients with Philadelphia positive chronic myeloid leukemia (CML) or acute lymphoblastic leukemia (ALL) who is resistant to multiple tyrosine kinase inhibitor therapies with BCR-ABL kinase inhibition activity. Ruxolitinib is a tyrosine kinase inhibitor blocking alternative pathway independent of BCR-ABL mediated pathway, thus having a potential to overcome tyrosine kinase inhibitor resistance in Philadelphia positive CML or ALL patients. Phase I study will be conducted to define a recommended phase II dose (RPTD) and phase II study will examine the hypothesis that combinational approach will increase response rate of resistant CML/ALL patients, thus evaluating efficacy of the combination regimen.

NCT01914484 Chronic Phase Chronic Myeloid Leukemia Accelerated Phase Chronic Myeloid Leukemia Blastic Phase Chronic Myeloid Leukemia Philadelphia Positive Acute Lymphoblastic Leukemia Resistant to Tyrosine Kinase Inhibitor Therapy
MeSH: Leukemia Leukemia, Myeloid Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Lymphoid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Blast Crisis Leukemia, Myeloid, Chronic-Phase Leukemia, Myeloid, Accelerated Phase
HPO: Chronic myelogenous leukemia Leukemia Lymphoid leukemia Myeloid leukemia

2 Interventions

Name: Nilotinib

Description: Nilotinib dose will remain fixed at 400mg bid throughout the cycles. BCR-ABL kinase inhibitor

Type: Drug

Nilotinib with Ruxolitinib

Name: Ruxolitinib

Description: In the phase I part of the study, dose escalation will follow a 3+3 study design at either of 3 fixed dose levels (10 mg bid, 15 mg bid or 20 mg bid). No intra-patient dose-escalation will occur. JAK inhibitor

Type: Drug

Nilotinib with Ruxolitinib


Primary Outcomes

Description: Maximum Tolerated Dose (MTD) of Ruxolitinib with fixed dose of Nilotinib. Dose escalation will follow a 3+3 study design. The CTCAE v4.03 criteria will be used. Grade 4 toxicity will be accounted as dose limiting toxicity (DLT).

Measure: Phase I: Maximum Tolerated Dose (MTD)

Time: Average of 6 months

Description: Major cytogenetic response defined by 35% or less of Philadelphia chromosomes by metaphase cytogenetics in marrow from CML and ALL patients

Measure: Phase II: Major cytogenetic response

Time: Average of 6 months

Secondary Outcomes

Description: Complete hematologic response defined by CBC differential without any evidence of leukemia. It will be evaluated in CML patients in AP or BP, and patients with Ph+ ALL.

Measure: Phase I: complete hematologic response

Time: Average of 3 months

Description: Major cytogenetic response defined by 35% or less of Philadelphia chromosomes by metaphase cytogenetics in marrow taken at 6 months.

Measure: Phase I: major cytogenetic response

Time: Average of 6 months

Description: It will be defined by NCI Common Terminology Criteria for Adverse Events (CTCAE)version 4.03 for adverse event reporting.

Measure: Phase I: Safety and tolerability

Time: Average of 6 months

Description: Complete hematologic response defined by CBC differential without any evidence of leukemia. It will be evaluated in the CML patients in AP or BP and in patients with Ph+ ALL.

Measure: Phase II: complete hematologic response

Time: Average of 3 months

Other Outcomes

Description: Cmax will be measured for the maximum plasma concentration of nilotinib after oral administration.

Measure: Phase II (exploratory): pharmacokinetic profile of combination of Nilotinib with Ruxolitinib

Time: During first 24 hours of first dose

Purpose: Treatment

Single Group Assignment


There are 5 SNPs

SNPs


1 E255K

Developed the T315I, T315A Y253H, E255K/V or F359C/V mutation after any TKI therapy. --- T315I --- --- T315A --- --- Y253H --- --- E255K ---


2 F359C

Developed the T315I, T315A Y253H, E255K/V or F359C/V mutation after any TKI therapy. --- T315I --- --- T315A --- --- Y253H --- --- E255K --- --- F359C ---


3 T315A

Developed the T315I, T315A Y253H, E255K/V or F359C/V mutation after any TKI therapy. --- T315I --- --- T315A ---


4 T315I

Developed the T315I, T315A Y253H, E255K/V or F359C/V mutation after any TKI therapy. --- T315I ---


5 Y253H

Developed the T315I, T315A Y253H, E255K/V or F359C/V mutation after any TKI therapy. --- T315I --- --- T315A --- --- Y253H ---



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
Lymphoid leukemia
Myeloid leukemia
Genes 12
GATA2 F13A1 CBL ARHGAP26 F13B KRAS PTPN11 SAMD9L KIT SETBP1 NF1 NRAS