SNPMiner Trials by Shray Alag


SNPMiner Trials: Clinical Trial Report


Report for Clinical Trial NCT02311569

Developed by Shray Alag, 2019.
SNP Clinical Trial Gene

Effects of Sympathicomimetic Agonists on the Disease Course and Mutant Allele Burden in Patients With JAK2-mutated Myeloproliferative Neoplasms. A Multicenter Phase II Trial.

The aim of this phase II study is to test a novel concept in the treatment of patients with myeloproliferative neoplasms (MPN), a disease of the bone marrow. With no current cure available, MPN are a group of chronic leukemias (blood cancers) in which patients produce too many blood cells. These increased blood cell numbers cause problems to the patient such as bleedings or thrombosis and some patients may progress to acute leukemia, a life threatening condition. Most MPN patients have a gene mutation called JAK2-V617F. The disease is maintained by mutant MPN stem cells that reside in the bone marrow in specialized locations called "niches". These niches need connections to the nervous system. New findings show that these connections are destroyed by the presence of the mutated MPN stem cells. Research teams found that some drugs (beta3-sympathicomimetics) can restore these damaged niches and at the same time reduce the MPN disease manifestation in a mouse model of MPN. Such sympathicomimetic drugs are already being used to treat patients with asthma or hyperactive bladder. These drugs have shown to have only few side effects. The study tests the effects of the beta-3-sympathicomimetic drug Mirabegron (Betmiga®) on MPN disease in 39 patients that carry a JAK2-V617F mutation. The hypothesis is that Mirabegron will have a beneficial effect on bone marrow niche cells and will thereby improve the disease manifestation in MPN patients. This study should provide a rapid answer whether targeting the nervous system of the niche cells could be useful for patients with MPN and warrants to be tested in larger and more long-term studies.

NCT02311569 Myeloproliferative Neoplasm Primary Myelofibrosis Essential Thrombocythemia Polycythemia Vera
MeSH: Neoplasms Primary Myelofibrosis Polycythemia Myeloproliferative Disorders Polycythemia Vera Thrombocytosis Thrombocythemia, Essential
HPO: Myeloproliferative disorder Neoplasm Polycythemia Thrombocytosis

1 Interventions

Name: Mirabegron

Description: 25 mg daily during the first week followed by 50 mg Mirabegron daily during the remaining treatment period.

Type: Drug

Arm Mirabegron


Primary Outcomes

Description: Primary endpoint of the trial is reduction in the burden of mutated alleles of ≥50% at 24 weeks (Red-50@24). Patients are defined as success for this endpoint, if they show a reduction of the JAK2-V617F allelic burden of 50% or more 24 weeks ± 4 weeks after registration when compared to baseline, and if they did not start a new MPN treatment before. All other evaluable patients will be considered as failures for this endpoint.

Measure: Reduction in the burden of mutated alleles of ≥50% at 24 weeks.

Time: at 24 weeks

Secondary Outcomes

Description: Reduction in the burden of mutated alleles of ≥50% at 12 weeks (Red-50@12) defined in the same way as the primary endpoint, but evaluated at 12 weeks ± 4 weeks after registration.

Measure: Reduction in the burden of mutated alleles of ≥50%

Time: at 12 weeks

Description: Reduction in the burden of mutated alleles of ≥25% at 24 weeks (Red-25@24): Patients are defined as success for the Red-25@24 endpoint, if they show a reduction of the Jak2-V617F allelic burden of 25% or more 24 weeks ± 4 weeks after registration when compared to baseline, and if they did not start a new MPN treatment before. All other evaluable patients will be considered as failures for this endpoint.

Measure: Reduction in the burden of mutated alleles of ≥25%

Time: at 24 weeks

Description: Reduction in the burden of mutated alleles of ≥25% at 12 weeks (Red-25@12) defined in the same way as the Red-25@24 endpoint, but evaluated at 12 weeks ± 4 weeks after registration.

Measure: Reduction in the burden of mutated alleles of ≥25%

Time: at 12 weeks

Purpose: Treatment

Single Group Assignment


There is one SNP

SNPs


1 V617F

Most MPN patients have a gene mutation called JAK2-V617F. --- V617F ---

The study tests the effects of the beta-3-sympathicomimetic drug Mirabegron (Betmiga®) on MPN disease in 39 patients that carry a JAK2-V617F mutation. --- V617F ---

Patients are defined as success for this endpoint, if they show a reduction of the JAK2-V617F allelic burden of 50% or more 24 weeks ± 4 weeks after registration when compared to baseline, and if they did not start a new MPN treatment before. --- V617F ---

Reduction in the burden of mutated alleles of ≥25% at 24 weeks (Red-25@24): Patients are defined as success for the Red-25@24 endpoint, if they show a reduction of the Jak2-V617F allelic burden of 25% or more 24 weeks ± 4 weeks after registration when compared to baseline, and if they did not start a new MPN treatment before. --- V617F ---

Reduction in the burden of mutated alleles of ≥25% at 12 weeks (Red-25@12) defined in the same way as the Red-25@24 endpoint, but evaluated at 12 weeks ± 4 weeks after registration.. Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of JAK2-V617F positive ET, PV or PMF at primary diagnosis or pretreated - JAK2-V617F mutant allele burden > 20% in the peripheral blood at study entry - Patient must give written informed consent before registration - WHO performance status 0-2 - Age ≥ 18 years - Adequate hematological values: neutrophils ≥ 1.5 x 109/L, platelets ≥ 100 x 109/ L - Adequate hepatic function: bilirubin ≤ 1.5 x ULN, AST/ALT/AP ≤ 2.5 x ULN - Adequate renal function (calculated creatinine clearance > 50 mL/min, according to the formula of Cockcroft-Gault) - Women are not breastfeeding. --- V617F ---

Reduction in the burden of mutated alleles of ≥25% at 12 weeks (Red-25@12) defined in the same way as the Red-25@24 endpoint, but evaluated at 12 weeks ± 4 weeks after registration.. Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of JAK2-V617F positive ET, PV or PMF at primary diagnosis or pretreated - JAK2-V617F mutant allele burden > 20% in the peripheral blood at study entry - Patient must give written informed consent before registration - WHO performance status 0-2 - Age ≥ 18 years - Adequate hematological values: neutrophils ≥ 1.5 x 109/L, platelets ≥ 100 x 109/ L - Adequate hepatic function: bilirubin ≤ 1.5 x ULN, AST/ALT/AP ≤ 2.5 x ULN - Adequate renal function (calculated creatinine clearance > 50 mL/min, according to the formula of Cockcroft-Gault) - Women are not breastfeeding. --- V617F --- --- V617F ---

Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of JAK2-V617F positive ET, PV or PMF at primary diagnosis or pretreated - JAK2-V617F mutant allele burden > 20% in the peripheral blood at study entry - Patient must give written informed consent before registration - WHO performance status 0-2 - Age ≥ 18 years - Adequate hematological values: neutrophils ≥ 1.5 x 109/L, platelets ≥ 100 x 109/ L - Adequate hepatic function: bilirubin ≤ 1.5 x ULN, AST/ALT/AP ≤ 2.5 x ULN - Adequate renal function (calculated creatinine clearance > 50 mL/min, according to the formula of Cockcroft-Gault) - Women are not breastfeeding. --- V617F ---

Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of JAK2-V617F positive ET, PV or PMF at primary diagnosis or pretreated - JAK2-V617F mutant allele burden > 20% in the peripheral blood at study entry - Patient must give written informed consent before registration - WHO performance status 0-2 - Age ≥ 18 years - Adequate hematological values: neutrophils ≥ 1.5 x 109/L, platelets ≥ 100 x 109/ L - Adequate hepatic function: bilirubin ≤ 1.5 x ULN, AST/ALT/AP ≤ 2.5 x ULN - Adequate renal function (calculated creatinine clearance > 50 mL/min, according to the formula of Cockcroft-Gault) - Women are not breastfeeding. --- V617F --- --- V617F ---

Three genes are frequently mutated in MPN and are implicated to be the phenotypic driver mutations: more than 95% of PV patients carry a somatic JAK2-V617F mutation, while about half of the remaining PV patients (2-3%) display mutations in JAK2 exon 12. Thus, almost all patients with PV have somatic mutations in the JAK2 gene. --- V617F ---

The mutational profiles of ET and PMF are more diverse: JAK2-V617F is found in 50-60% of the patients, whereas the recently described mutations in calreticulin (CALR) occur in 20-25% of the patients. --- V617F ---

Ruxolitinib, recently approved for PMF with splenomegaly, is effective in reducing spleen size and improving quality of life, but has little effect on the JAK2-V617F mutant allele burden and has so far not been reported to induce remissions. --- V617F ---

Furthermore, in a mouse model of MPN expressing the human JAK2-V617F mutation, this effect was found to be caused by early glial and sympathetic nerve damage and apoptosis of nestin+ MSCs triggered by the mutant HSCs. --- V617F ---

Mice with JAK2-V617F driven MPN treated with a beta-3-sympathicomimetic agonist not only restored nestin+ MSCs numbers, but also showed correction of thrombocytosis, neutrophilia, and bone marrow fibrosis, and efficiently reduced mutant hematopoietic progenitor numbers in bone marrow and peripheral blood. --- V617F ---



HPO Nodes


HPO:
Myeloproliferative disorder
Genes 12
GATA2 MPL SH2B3 PDGFRA BCR JAK2 PDGFRB ABL1 THPO CALR RUNX1 GATA1
Neoplasm
Genes 762
CDKN1A CDKN1B CDKN1C CDKN2A HFE CDKN2B CDKN2C GDF5 TSR2 CDKN2D H19-ICR TMEM67 RPL26 RPL27 TREX1 ASXL1 ERBB2 SCN11A POU6F2 ERCC2 RPL35A ERCC3 BRIP1 ERCC4 ABL1 ERCC5 CEBPA ERCC6 PDE6D GCM2 CEL PDGFB PDGFRA PDGFRL MNX1 PDGFRB LEMD3 ENPP1 CTSC ESR1 HLA-DRB1 SLC26A4 MAX APC2 RPS7 TMC6 TMEM216 TRPS1 ACTB RPS10 MC1R MC2R BLNK RPS14 RPS15A ACTG2 ETV6 TCIRG1 DNAJC21 EVC HMBS L2HGDH RPS17 MCM4 RPS19 RPS20 TSC1 TSC2 EWSR1 EXT1 EXT2 RPS24 RPS26 RPS27 ACVR1 EYA1 RPS28 RPS29 MAGT1 ACVRL1 MDH2 MDM2 ADA HNF4A ADAR TRIP13 LYST PICALM ALX4 F13A1 TERF2IP PHF21A F13B RYR1 MAP3K1 AXIN1 TBC1D24 AXIN2 BAP1 CHRNG TWIST1 MEN1 TNFRSF4 FANCA FANCC FANCD2 FANCE TYR GFI1B FAH MET TYROBP FANCB FANCF FANCG SERPINA1 ARID1B SAMD9L AP2S1 MGAT2 DLC1 ICOS DMRT3 SFTPA2 PIGA MGMT MBTPS2 CLCNKB HOXD13 PIK3CA PIK3R1 ACAN FDPS HPGD JAG1 RNASEH2C RECQL4 SCN4A HACE1 RAD54B NR0B1 MITF AHCY GPC4 SCN9A SCN10A HRAS MLF1 MLH1 CTHRC1 TJP2 GTF2H5 FGF3 CC2D2A ANTXR1 LMOD1 PLAG1 FGF8 COL14A1 AKT1 NOP10 ASPSCR1 FGFR1 PLCB4 FGFR3 PLCD1 FGFR2 HAX1 MMP1 MAD2L2 UROD FH MN1 ALK HSPA9 SEC23B SEC23A CARD14 SDHA RAD54L SDHB SDHC SDHD FOXI1 COL1A1 FOXC2 COL2A1 FOXE1 MPL VEGFC ALX3 PMS1 FOXO1 VHL COL4A5 FLI1 MRE11 HSPG2 FLNA KLF11 COL7A1 PIGL SEMA3C BIN1 FLT3 PMS2 FLT4 COL11A2 CIB1 CCDC22 WAS COMP FN1 WIPF1 OFD1 KLF6 ADAMTS3 RNASEH2A LIN28B SFTPC CTC1 PUF60 WHCR NSD2 PPM1D NELFA MAP3K8 INPP5E POLD1 POLE WNT5A POLH GNPTAB SH3GL1 POT1 SH3KBP1 FERMT1 POLR1C WRN TUBB KCNAB2 WT1 APC IKBKG SHH PORCN SHOX BIRC3 POU2AF1 XIAP NLRP1 SAMHD1 XPA MSH2 CHD7 XPC MSH3 ZSWIM6 IDH1 MINPP1 IDH2 TMEM107 TXNRD2 XRCC2 XRCC4 SIX1 SIX3 FANCM SKI FAS FCN3 NHP2 FASLG CR2 CTSA TMEM127 CREB1 CREBBP AR ZAP70 ABCC6 CRKL ZIC2 FAN1 MSR1 MST1 PPP2R1B SETD2 C2CD3 MLH3 PIEZO2 IGF2 ARSA IGF2R MTAP MMEL1 STS GNA14 PMVK SLC12A3 COX1 COX2 UBE2T COX3 IGH SLC17A9 DYNC2LI1 PRCC ELMO2 ASCL1 PRF1 TP63 SLCO2A1 IGHM MTM1 ND1 SETBP1 ND4 ND5 ND6 SNAI2 PTCH2 RNR1 MPLKIP PRKAR1A SMARCB1 ABCB11 WNT10A FLCN SMARCD2 APPL1 PRKCD FOXP1 TRNF C11ORF95 CTBP1 SMO NR5A1 TRNH CTLA4 TRNK IGLL1 TRNL1 ATM RERE MAPK1 CTNNB1 TRNP TRNQ TRNS1 TRNS2 TRNW KDSR SUFU MAP2K1 MAP2K2 CEP57 FZD2 PRDM16 IL2RG G6PC SLC37A4 STAG3 PALLD TRIM37 SLX4 PRLR MUTYH H19 MVD IL7 MVK IL7R SOS1 MYC SOX2 GABRD CYLD MYCN TET2 SOX9 MYD88 IL12A IL12RB1 MYF6 TCTN3 ATP6V1B2 INTU MYH8 MYH11 SAMD9 ATP7A DIS3L2 ATP7B PSAP WWOX MYLK HDAC4 ATR SPIB ACD ATRX SPINK1 ING1 TNFSF12 RTEL1 INHBA PSENEN INS GJB4 CYP11B1 CYP11B2 GJB6 ARHGAP26 KIF1B MAFA RNF113A SRC GAS1 GATA1 CPLX1 GATA2 GATA4 PDX1 BARD1 GBA CDH23 SRP54 FGFRL1 IRF1 NBN SRP72 IRF5 DAXX SRY GCGR CCND1 BCL2 SMARCAD1 GCK NDP KEAP1 TNFRSF10B BCL6 RB1CC1 DCC GPR101 PTCH1 PTEN GDF2 SSX1 BCR SSX2 ADA2 NSUN2 NEK9 DDB2 GDNF DPM1 GINS1 RNF43 GFI1 PTH1R STAR BDNF NAGS STAT1 ITK STAT3 KIAA0753 NOD2 BLK BLM NUTM1 JAK2 STK4 IFIH1 GJA1 STK11 MALT1 NEK1 PTPN3 FAM20C BMPR1A BMPR1B GJB2 GJB3 CCM2 PTPN11 ARL6IP6 KARS NEUROD1 NF1 ANTXR2 DHH GPC3 BRCA1 BRAF BRCA2 NF2 TINF2 SDHAF2 WASHC5 KCNH1 CXCR4 SQSTM1 GLI1 GLI2 GLI3 ABCC8 NBEAL2 DHCR7 DHCR24 KCNJ10 NFKB1 BTK KCNJ11 NFKB2 BUB1 CYP26C1 BUB1B VAMP7 TMC8 MFN2 DKC1 KCNQ1 C1S GNA11 KDR TRPV3 BCL10 DLEC1 GNAI3 GNAQ CDC73 BMPER GNAS SEMA4A GNB1 NME1 TMEM231 FOXH1 PHOX2B CPLANE1 MAPRE2 NODAL TAL1 KIT TAL2 KCNQ1OT1 TNFSF15 DNASE1L3 NOTCH1 NOTCH3 KIF11 CDON DNM2 DNMT3A PNP RAD21 TBX2 RAD51 RAD51C RNASEH2B RAD51D KRAS NPM1 RAF1 KRT1 RAG1 RAG2 CACNA1S KRT5 TCF4 KRT6B EFL1 HNF1A FAT4 HNF1B KRT9 TCF3 CYSLTR2 KRT10 KRT14 EVC2 KCNE3 RARA RPGRIP1L KRT16 CARMIL2 NRAS SRD5A3 KRT17 SASH1 RASA1 RHBDF2 SH2B3 USB1 RB1 TCOF1 NRTN DOCK8 DYNC2H1 CALR GPR35 SLC26A2 NTHL1 NTRK1 MYO1H NUMA1 DVL1 ASCC1 DVL3 NSD1 LAMA3 AGGF1 GPR143 CASP8 B3GALT6 LAMB3 CASP10 GJC2 NR4A3 CASR LAMC2 FANCL RELA OCA2 TDGF1 NUP214 OCRL AIP REST RET MLLT10 RUNX1 WRAP53 CBFB ECE1 GPC6 DLL1 TEK CBL TERC ECM1 AAGAB TERT OGG1 TFAP2A DICER1 WDPCP PALB2 EDN1 LETM1 OPCML MSTO1 EDN3 EDNRB TFE3 ZFPM2 RFWD3 KRIT1 KIF7 SIX6 TG RAD50 ESCO2 VANGL2 RMRP TBX18 TGFBR2 POLR1D SLC22A18 TGIF1 MSH6 COL18A1 USP8 RASGRP1 LIG4 SEMA3D GTF2E2 KLLN RNASEL THPO SF3B1 HMGA2 ALX1 LMNA RNF6 CD19 MS4A1 MTMR14 EGFR LMO1 DCLRE1C ABCA5 LZTS1 LMX1B CD27 TRIM28 CD28 VANGL1 CCBE1 SBDS FANCI BRD4 SLC25A13 MRAP ARMC5 LPP SLC49A4 CHEK2 TREM2 TNFRSF13C FIBP LRRC8A ELANE TNFRSF13B LRP5 CD70 SPRED1 CD79A CD79B CD81 SLC45A2 PRKN PARN HABP2 TAF15 PAX3 EIF2AK4 PAX4 RPL35 PAX6 GREM1 PAX7 SPRTN TNFRSF1B BUB3 KAT6B HBB PDCD10 RNF139 SH2D1A ENG CDH1 EPCAM RSPO1 NNT RPL5 TNPO3 CD96 EP300 DISP1 TOP2A TP53 RPL10 RPL11 SMAD4 RPL15 CDK4 RPL18
Polycythemia
Genes 15
PKLR SH2B3 VHL JAK2 ENG EPO EPOR SLC30A10 EPAS1 EGLN1 BPGM ACVRL1 CYB5R3 FH GATA1
Thrombocytosis
Genes 25
MPL IFNGR1 CD55 JAK2 TET2 ELANE RPS19 RPSA HMGCL TMEM173 ABL1 THPO RUNX1 ZMPSTE24 LMNA SH2B3 HBB BCR ACAT1 ADA2 MTHFD1 CALR TTC37 TBC1D24 PMM2