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Report for Clinical Trial NCT01784068

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

A Single-arm, Multicenter, Nilotinib Treatment-free Remission Study in Patients With BCR-ABL1 Positive Chronic Myelogenous Leukemia in Chronic Phase Who Have Achieved Durable Minimal Residual Disease (MRD) Status on First Line Nilotinib Treatment.

The main purpose of the study is to investigate whether nilotinib treatment can be safely suspended with no recurrence of CML in selected patients who responded optimally on this treatment

NCT01784068 Chronic Myelogenous Leukemia
MeSH: Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive
HPO: Chronic myelogenous leukemia Leukemia Myeloid leukemia

1 Interventions

Name: Nilotinib followed by treatment-free

Description: Nilotinib will be used as commercial available capsules (except in Japan where clinical supplies is used) of 150 mg and 200 mg strength. treatment occurs during consolidation, continuation, prolonged continuation, re-initiation and re-initiation-2 phases of the study.

Type: Drug

Nilotinib followed by treatment-free


Primary Outcomes

Description: Primary endpoint is the proportion of patients who are in MMR at 48 weeks after starting the TFR phase and is calculated by dividing the number of patients with MMR at 48 weeks after starting the TFR phase with no loss of MMR and no re-initiation of nilotinib therapy in the first 48 weeks after starting the TFR phase by the number of patients entered the TFR phase. Patients who required re-initiation of treatment will be considered as non-responders

Measure: Percentage of patients who are in MMR (major molecular response) at 48 weeks after starting the treatment-free remission (TFR) phase

Time: 48 weeks

Secondary Outcomes

Description: Proportion of patients who are in MR4.5 at 48 weeks after starting the TFR phase is calculated by dividing the number of patients with MR4.5 at 48 weeks after starting the TFR phase with no loss of MR4.5 and no re-initiation of nilotinib therapy in the first 48 weeks after starting the TFR phase by the number of patients who entered the TFR phase. Patients who required re-initiation of treatment will be considered as non-responders. MR4.5 = log reductions of the BCR-ABR transcript load in blood as a measurement of deep molecular response of the CML clone to treatment.

Measure: Percentage of patients who are in MR4.5 (BCR-ABL ≤ 0.0032% IS) at 48 weeks after starting the TFR phase

Time: 48 weeks

Description: Proportion of patients who are in MMR at 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase is calculated by dividing the number of patients with MMR at 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase with no loss of MMR and no re-initiation of nilotinib therapy in the first 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase by the number of patients who entered the TFR phase. Patients who required re-initiation of treatment will be considered as non-responders

Measure: Percentage of patients who are in MMR at 96, 144,192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase

Time: 96, 144, 192, 264 weeks, end of 6, 7, 8, 9 and 10 years

Description: Proportion of patients who are in MR4.5 at 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 yearsafter starting the TFR phase is calculated by dividing the number of patients with MR4.5 at 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase with no loss of MR4.5 and no re-initiation of nilotinib therapy in the first 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase by the number of patients who entered the TFR phase. Patients who required re-initiation of treatment will be considered as non-responders

Measure: Percentage of patients who are in MR4.5 at 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 yearsafter starting the TFR phase

Time: 96, 144, 192, 264 weeks, end of 6, 7, 8, 9 and 10 years

Description: Proportion of patients who are in MMR at 48, 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase is calculated by dividing the number of patients with MMR at 48, 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase by the number of patients who entered the TFR phase. Patients who are re-initiated with nilotinib but have less than 12 weeks of re-initiation of treatment will be excluded from the analysis

Measure: Percentage of patients in MMR at 48, 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase of nilotinib

Time: 48, 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years

Description: Proportion of patients who are in MR4.5 at 48, 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase is calculated by dividing the number of patients with MR4.5 at 48, 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase by the number of patients who entered the TFR phase. Patients who are re-initiated with nilotinib but have less than 12 weeks of re-initiation of treatment will be excluded from the analysis

Measure: Percentage of patients in MR4.5 at 48, 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase of nilotinib

Time: 48, 96, 144, 192, 264 weeks, end of 6, 7, 8, 9 and 10 years

Description: Proportion of patients who achieve MMR within 12 weeks of re-initiation of nilotinib is calculated by dividing the number of patients who are in MMR at least at one assessment within 12 weeks after re-start of nilotinib treatment by the number of patients who are re-initiated for at least 12 weeks

Measure: Percentage of patients who achieve MMR within 12 weeks of re-treatment with nilotinib

Time: 12 weeks

Description: Descriptive statistics of BCR-ABL levels (IS) over time after re-start of nilotinib therapy up to 528 weks after the last patient has entered TFR

Measure: Kinetics of BCR-ABL transcript after re-start of nilotinib therapy

Time: Every 4 weeks up to week 24 and every 12 weeks thereafter up to 528 after last patient has entered the TFR

Description: Defined as time from date of start of re-initiation of treatment after loss of MMR to the date of first achievement of MMR. Patients who do not regain MMR after re-initiation of treatment on or before the cut-off date, duration will be censored at the date of last PCR assessment

Measure: Duration of re-initiated treatment required to regain MMR after loss of MMR

Time: Every 4 weeks up to week 24 and every 12 weeks therefater up to 528 weks after the last patient has entered TFR

Description: Defined as the time from start of re-initiation of treatment after loss of MMR to the first achievement of MR4.5. Patients who do not regain MR4.5 after re-initiation of treatment on or before the cut-off date, duration will be censored at the date of last PCR assessment

Measure: Duration of re-initiated treatment required to regain MR4.5 after loss of MMR

Time: Every 4 weeks up to week 24 and every 12 weeks thereafter up to 528 weks after the last patient has entered TFR

Description: TFS is defined as the time from the start of the TFR phase to the earliest occurrence of loss of MMR, re-initiation of treatment due to any cause, progression of AP/BC or death due to any cause. For patients without any event on or before the cut-off date, survival time will be censored at the date of their last assessment (PCR, cytogenetic, hematologic or extramedullary). A TFS sensitivity analysis will be conducted to consider discontinuation from TFR phase due to any reason as a TFS event, in addition to the TFS events as defined above.

Measure: Treatment-free survival (TFS) after the start of the TFR phase

Time: Every 4 weeks in the first period of 48 weeks of the TFR, every 6 weeks in the second period of 48 weeks in TFR and every 12 weeks in the last period of 432 weeks of the TFR

Description: PFS is defined as the time from the start of the TFR phase to the earliest occurrence of progression to AP/BC or death due to any cause. For patients without any event on or before the cut-off date, survival time will be censored at the date of their last assessment (cytogenetic, hematologic or extramedullary) for patients who are still on study and at the date of last contact for patients who are in follow-up

Measure: Progression-free survival (PFS) after the start of the TFR phase

Time: Every 4 weeks in the first period of 48 weeks of the TFR, every 6 weeks in the second period of 48 weeks of TFR and every 12 weeks in the last period of 432 weeks of the TFR

Description: OS is defined as the time from start of the TFR phase to death due to any cause. For patients without any event on or before the cut-off date, survival time will be censored at the date of their last assessment for patients who are still on study and at the date of last contact for patients who are in follow-up

Measure: Overall survival (OS) after the start of the TFR phase

Time: Every 4 weeks in the first period of 48 weeks of the TFR, every 6 weeks in the second period of 48 weeks of TFR and every 12 weeks in the last period of 432 weeks of the TFR

Description: Safety profile includes type, frequency and severity of adverse events, laboratory abnormalities and clinically notable ECG and other safety parameters during the nilotinib treatment consolidation phase, during the TFR phase and during re-initiation of treatment with nilotinib

Measure: Safety profile during the nilotinib treatment consolidation phase, during the TFR phase and during re-initiation treatment with nilotinib

Time: Every 4 weeks in the treatment consolidation and during the first 24 weeks of the re-initaion phase, every 12 weeks thereafter. Every 4, 6 and 12 weeks respectively in the first and second period of 48 weeks and in the last period of 432 weeks of the TFR

Description: Proportion will be calculated by dividing the number of patients who developT315I, E255K/V, Y253H, F359V/C/I mutations after nilotinib suspension by the number of patients who lost MMR

Measure: Proportion of patients who develop T3151, E255K/V, Y253H, F359V/C/I mutations on study or any other BCR-ABL mutations in patients who lost MMR after nilotinib suspension

Time: Every 3 months in patients who lost MMR until the result is negative or up to 528 weeks after the last patient entered TFR. On average 3 analyses (every 3 months or up to 264 weeks after the last patient has entered TFR.)

Description: Proportion of patients who are in stable MMR/MR4.5 after achievement of that response in the nilotinib re-initiation phase for 48, 96, 144, 192, 240, 288, 336, 384 and 432 weeks, based on availability of appropriate data, is calculated by dividing the number of patients achieving MMR/MR4.5 any time during the nilotinib re-initiation phase and having the same response 48, 96, 144, 192, 240, 288, 336, 384 and 432 weeks after the first achievement of MMR/MR4.5, irrespective of whether there is loss of MMR in between, by the number of patients who achieved MMR/MR4.5 at any time during the nilotinib re-initiation phase

Measure: Percentage of patients who are in stable response (MMR and MR4.5) after achievement of that response in nilotinib re-initiation phase for 48, 96, 144, 192, 240, 288, 336, 384 and 432 weeks, based on availability of appropriate data

Time: 48, 96, 144, 192, 240, 288, 336, 384 and 432 weeks

Purpose: Other

Single Group Assignment


There are 3 SNPs

SNPs


1 E255K

Proportion of patients who develop T3151, E255K/V, Y253H, F359V/C/I mutations on study or any other BCR-ABL mutations in patients who lost MMR after nilotinib suspension. --- E255K ---

Proportion will be calculated by dividing the number of patients who developT315I, E255K/V, Y253H, F359V/C/I mutations after nilotinib suspension by the number of patients who lost MMR. --- E255K ---


2 F359V

Proportion of patients who develop T3151, E255K/V, Y253H, F359V/C/I mutations on study or any other BCR-ABL mutations in patients who lost MMR after nilotinib suspension. --- E255K --- --- Y253H --- --- F359V ---

Proportion will be calculated by dividing the number of patients who developT315I, E255K/V, Y253H, F359V/C/I mutations after nilotinib suspension by the number of patients who lost MMR. --- E255K --- --- Y253H --- --- F359V ---


3 Y253H

Proportion of patients who develop T3151, E255K/V, Y253H, F359V/C/I mutations on study or any other BCR-ABL mutations in patients who lost MMR after nilotinib suspension. --- E255K --- --- Y253H ---

Proportion will be calculated by dividing the number of patients who developT315I, E255K/V, Y253H, F359V/C/I mutations after nilotinib suspension by the number of patients who lost MMR. --- E255K --- --- Y253H ---



HPO Nodes


HPO:
Chronic myelogenous leukemia
Genes 9
KIT MPL ASXL1 TET2 ABL1 JAK2 THPO BCR SRSF2
Leukemia
Genes 190
ATM KRAS KIT RPS15A NF1 MPL RPL35A RPL11 RPL18 DDX41 SBDS LPP ETV6 BUB1B F13A1 DNMT3A JAK2 NUP214 FANCD2 MSH6 FANCA PIGL NRAS TCIRG1 BUB1 TET2 FLT3 TAL1 ATRX TREX1 PDGFRA SRP54 RPS29 PTPN11 CALR FANCE WIPF1 SF3B1 GATA2 GLI1 STS SH3GL1 XRCC4 MPL SH2B3 EFL1 PIGA TREM2 CBL MPL RUNX1 MPL PIGL THPO FANCG NSD1 BRD4 NSUN2 SH2B3 RARA GATA2 NPM1 CBL CHIC2 ERBB3 GFI1 TERT KIT BCR ARHGAP26 DYNC2LI1 EVC SCN10A GATA1 ELANE RNASEH2B RPS14 SH2B3 JAK2 RPL15 SBDS NRAS RPL26 RPL27 ADA2 RPS7 TYROBP F13B MSH2 BCR WAS TERC TP53 TRIP13 MYD88 NUTM1 RPS24 GNB1 TP53 DNMT3A TERT NUMA1 NUP214 RPL5 SAMD9L TET2 CFTR POT1 FANCC RPS10 EP300 EVC2 BUB1B CEBPA BRCA2 DNAJC21 CALR SCN9A LIG4 ADAR BLM TET2 JAK2 SMPD1 RNASEH2C SCN11A GATA2 BUB3 PRSS1 KIF11 BCR RPL35 TAL2 SRP54 IFIH1 ABL1 PDGFRB KRAS RNASEH2A TET2 MLLT10 SRP54 DNAJC21 DKC1 RUNX1 APC LIG4 CBFB BLM THPO CALR NBN JAK2 MLH1 RPS19 ELANE SAMD9L RPL31 PMS2 ASXL1 TSR2 MLF1 PIK3CA DNAJC21 RUNX1 GFI1 SRSF2 SETBP1 HAX1 RPS26 RPS17 FLT3 RPS27 PIK3R1 KRAS CEP57 PICALM CREBBP GATA2 CTRC MYD88 TET2 RPS28 ABL1 RB1 SPINK1 GATA1 NBN JAK2 SAMHD1
Myeloid leukemia
Genes 20
KIT SETBP1 NF1 ARHGAP26 CBL TET2 KRAS PTPN11 F13A1 SAMD9L SAMD9L GATA2 CBL ASXL1 DNMT3A F13B NRAS SRSF2 TERC TERT