SNPMiner Trials by Shray Alag

L858R (332) T790M (322) V600E (266) T315I (107) L861Q (92) M184V (68) V617F (58) K65R (53) G20210A (53) V600K (52) C282Y (50) V66M (49) G551D (42) P13K (39) C677T (35) A118G (29) I84V (27) V158M (26) H63D (25) V32I (24) S768I (24) I50V (23) I47V (21) K103N (21) K27M (20) Y181C (20) L33F (19) T380A (18) L76V (18) G12C (18) D842V (18) R117H (17) D816V (17) S1251N (17) S1255P (17) G178R (17) G1244E (17) S549R (17) G1349D (17) V82A (16) M41L (16) S549N (16) C3435T (16) G551S (16) Q151M (16) Q12H (15) K219Q (15) I54L (15) K70E (14) C797S (14) G719A (13) L90M (13) L74V (13) E138A (13) D67N (13) K70R (13) L89V (13) L210W (13) Y188L (13) G11778A (12) P4503A (12) L265P (12) M46I (12) I54M (12) G12D (12) E255K (12) V11I (12) R132H (12) G48V (11) V299L (11) D961H (11) T74P (11) R192G (11) T25W (10) K101E (10) G2677T (9) V106A (9) G12V (9) M184I (9) H221Y (9) V30M (9) Y253H (9) V600D (9) G1691A (8) F317L (8) F227C (8) T215Y (8) I50L (8) A1298C (8) L100I (8) I148M (7) N155H (7) F359C (7) S298P (7) G190A (7) M230I (7) C1236T (7) V600R (7) Y188C (7) G2019S (7) Q12W (6) P225H (6) Y93H (6) V108I (6) A3243G (6) G93A (6) G73S (6) P12A (6) Y115F (6) E545K (6) Q148H (6) Y537S (6) E542K (6) I10A (6) M230L (6) H1047R (6) N40D (6) D299G (6) N236T (6) D30N (6) M235T (6) T315A (6) D538G (6) T87Q (5) I47A (5) L74I (5) E92Q (5) N680S (5) A455E (5) M204V (5) D1152H (5) L755S (5) G13D (5) G190S (5) N363S (5) A181V (5) V179L (5) L24I (5) N88S (5) A2143G (5) T399I (5) M36I (5) F53L (5) R263K (5) R132C (5) V777L (5) T1405N (4) D579G (4) G719C (4) N370S (4) R117C (4) Q16W (4) L98H (4) A98G (4) K20M (4) E138G (4) E138K (4) L31M (4) E157Q (4) L10F (4) Q80K (4) C31G (4) G1202R (4) Q252H (4) L206W (4) P140K (4) C19P (4) I54V (4) K76T (4) Y537C (4) I1314L (4) S945L (4) Y402H (4) P1446A (4) V179D (4) N88D (4) A6986G (4) A1166C (4) G970R (4) Y181I (4) R352Q (4) G2385R (4) S310F (4) P67L (4) R1070W (4) G140A (4) E23K (4) S463P (4) T14484C (3) G719S (3) R206H (3) S1400A (3) S1400I (3) A71V (3) C134W (3) R24W (3) C481S (3) T24H (3) V122I (3) T47D (3) A636P (3) S977F (3) G118R (3) G3460A (3) N312S (3) D988Y (3) L444P (3) V659E (3) V769L (3) A147T (3) E10A (3) Q24W (3) L861R (3) R678Q (3) Q27E (3) E17K (3) Q148R (3) A1555G (3) S49G (3) Y537N (3) R16G (3) I10E (3) V158F (3) G21210A (3) K55R (3) V205C (3) Y181V (3) A2142G (3) R506Q (3) E298D (3) L211A (3) R172K (3) V843I (3) Y143R (3) R572Y (3) G143E (3) G1321A (3) V842I (3) H295R (3) G140S (3) T60A (3) P23H (3) F11N (2) S1009A (2) H275Y (2) T733I (2) F1074L (2) I1307K (2) Q36W (2) G250E (2) S77Y (2) E28A (2) E28C (2) E28D (2) T66A (2) S1400C (2) S1400E (2) S1400D (2) L833F (2) D1790G (2) S1400G (2) S1400F (2) R334W (2) L8585R (2) I105V (2) N375S (2) V560G (2) A194T (2) T20S (2) T69D (2) T69S (2) Y93C (2) E138R (2) E138Q (2) F359V (2) R776H (2) Q422H (2) D110H (2) D110E (2) R753Q (2) R404C (2) C283Y (2) L31F (2) S252W (2) L460D (2) L33I (2) R140W (2) R140L (2) R140Q (2) V106I (2) V106M (2) E709K (2) V697L (2) P50I (2) P535H (2) P51S (2) G1314A (2) S492R (2) G308A (2) V191T (2) G71R (2) T215F (2) E56K (2) A2063G (2) D769H (2) L248V (2) E280A (2) Q21D (2) E504K (2) Q141K (2) R496H (2) S100P (2) T128N (2) L536R (2) L536Q (2) L536P (2) A143T (2) T97A (2) G3556C (2) K751Q (2) T4396G (2) V151L (2) G170R (2) A581G (2) L536H (2) G12R (2) L180M (2) W153Q (2) G193E (2) V173L (2) F876L (2) R479H (2) L82M (2) Q28D (2) G190E (2) R347H (2) K601E (2) G16R (2) R831C (2) G5271C (2) V75I (2) G681A (2) A270S (2) L63P (2) L869R (2) P236L (2) R831H (2) T13D (2) H1047L (2) C3670T (2) V34L (2) E255V (2) G469A (2) V57I (2) L144F (2) M233I (2) C825T (2) C8092A (2) G776C (2) G776V (2) F121Y (2) R172S (2) R172W (2) R172M (2) Q192R (2) R172G (2) E380Q (2) F166L (2) A200V (2) Y121F (2) G145R (2) K101P (2) R61C (2) V600M (2) F31I (2) K540E (2) K103H (2) R132V (2) D1270N (2) R1628P (2) R132S (2) V534E (2) R132G (2) R132L (2) V207I (2) K238N (2) G4655A (2) S112A (2) I169T (2) I84A (2) Y129S (1) G1388A (1) S77F (1) R20A (1) V140A (1) C686A (1) I1768V (1) E25K (1) K652E (1) C420R (1) S9304A (1) R337H (1) C421A (1) V189I (1) K304E (1) A7445G (1) D19H (1) L304P (1) Y454S (1) A133S (1) M9T (1) P596L (1) E318D (1) C1156Y (1) N171K (1) A7445C (1) V82F (1) G47A (1) R447H (1) G47E (1) V82L (1) R776C (1) A92T (1) E27Q (1) F1052V (1) P27A (1) A289T (1) L523S (1) H54Y (1) T1095C (1) S428F (1) R400C (1) D313Y (1) Q12M (1) R139C (1) A393T (1) W719R (1) T862I (1) T66K (1) T66I (1) G49A (1) R48G (1) H58C (1) D203E (1) I104F (1) K656E (1) T40S (1) D312N (1) L747P (1) G276T (1) L747S (1) R200W (1) I1171N (1) Q14D (1) S1400K (1) R115G (1) F17L (1) A71T (1) S339F (1) A71L (1) I431V (1) F317V (1) F317S (1) G20201A (1) F317C (1) G2545R (1) C377T (1) P243R (1) S9346A (1) R25L (1) L528M (1) Q222R (1) I22M (1) I107M (1) C1858T (1) L859R (1) G2032R (1) A859S (1) G389D (1) V148I (1) K65E (1) V148G (1) C242T (1) G389R (1) H369P (1) A98S (1) G2500A (1) I349V (1) I107V (1) V561D (1) C481R (1) L833V (1) P200T (1) G1051A (1) Y93F (1) Y414C (1) Y1248H (1) K65N (1) L74M (1) P4502C (1) Y1248C (1) Y1248D (1) F227R (1) V89L (1) T164I (1) H1124D (1) C94A (1) G1628A (1) A2215D (1) E200K (1) F227L (1) I305F (1) N682S (1) T1010I (1) I655V (1) R885H (1) G7444A (1) R776G (1) E354Q (1) A21443C (1) M351T (1) R620W (1) A54T (1) D594G (1) F311L (1) T49A (1) F116Y (1) H870R (1) G205S (1) E355G (1) R535H (1) I767M (1) L55M (1) E571K (1) L55R (1) M2540A (1) E92K (1) G238A (1) L838P (1) E6V (1) L814P (1) K509I (1) V21I (1) G699A (1) V167F (1) D949V (1) L33P (1) M66V (1) D61804R (1) R849W (1) V762A (1) D816H (1) V108M (1) V326L (1) V411L (1) L10D (1) L58H (1) E158K (1) N334K (1) A1067T (1) S1800A (1) G894T (1) G202A (1) C282T (1) I191V (1) G435A (1) K1060T (1) A10H (1) R272G (1) V654A (1) V106T (1) C1091T (1) I638F (1) P317R (1) V433M (1) S230R (1) N550H (1) R4E (1) P1058A (1) M244V (1) N550K (1) E709Q (1) G304A (1) T124A (1) S253N (1) M680I (1) G1316A (1) M552V (1) M552I (1) R182H (1) D835V (1) A871E (1) D835Y (1) A677G (1) C1950G (1) H1505R (1) A893S (1) L597Q (1) S2808A (1) N55H (1) K28M (1) D89E (1) A38G (1) L485W (1) M9346A (1) L159F (1) A437G (1) R92Q (1) V29C (1) L38V (1) G135C (1) A677V (1) C34T (1) G93R (1) R270H (1) V321A (1) C10D (1) G308V (1) R122W (1) D614G (1) H2507Q (1) D20W (1) G309A (1) G721A (1) G309E (1) I90P (1) C59R (1) C416R (1) G71A (1) Q61R (1) Q61L (1) H835L (1) R498L (1) V941L (1) Q62E (1) R389G (1) D769N (1) G156A (1) E1784K (1) G98T (1) Q65E (1) T92A (1) S239D (1) C656G (1) R451C (1) G73C (1) G5665T (1) R72P (1) F64L (1) L248R (1) M204I (1) R149S (1) A105G (1) M28L (1) D769Y (1) V769M (1) R75T (1) E193K (1) T890M (1) P250R (1) P58A (1) L532S (1) S147G (1) S1235R (1) K660E (1) T454A (1) R76K (1) L1213V (1) V742I (1) V1238I (1) R74W (1) T102C (1) K3048A (1) T93M (1) D961S (1) G1269A (1) R277W (1) P187S (1) Q20W (1) A561P (1) V740A (1) T783I (1) T674I (1) T783A (1) S8814A (1) V90I (1) C325G (1) Q188R (1) R30H (1) C785T (1) S100A (1) R496L (1) G174S (1) L798F (1) V765A (1) P11A (1) C18S (1) L798H (1) G1049R (1) V765M (1) S366T (1) R230C (1) G1376T (1) H396R (1) H396P (1) S65D (1) T1191I (1) A277G (1) L755A (1) H131R (1) T878A (1) T854A (1) P253R (1) C1494T (1) L755P (1) P120H (1) E525K (1) C102T (1) Y1253D (1) G196A (1) A145T (1) K70N (1) L861G (1) H43R (1) I76V (1) C344T (1) F1174V (1) R677W (1) S9313A (1) I112T (1) G10V (1) R10C (1) F1174L (1) R10A (1) K860I (1) R34P (1) F1174C (1) R108K (1) I112M (1) V151I (1) I332E (1) S1369A (1) R32Q (1) N409S (1) C563T (1) Q24H (1) I113T (1) D761Y (1) N291S (1) Y114C (1) V151A (1) G34A (1) G1069R (1) R896C (1) S567L (1) A827G (1) G12S (1) I54T (1) D565H (1) Y113H (1) P367L (1) R102G (1) R368H (1) M3002A (1) P125A (1) V282M (1) M1040E (1) E545G (1) E545A (1) G398A (1) E545D (1) G12A (1) L409P (1) S1787N (1) S784P (1) L841V (1) R14C (1) V943A (1) S9333A (1) Q148K (1) Q148E (1) M1043I (1) Y220C (1) T416P (1) A3669G (1) R38H (1) T961C (1) V1110L (1) T961G (1) L84F (1) S108N (1) C365Y (1) A719G (1) D237E (1) G37R (1) D104N (1) S653C (1) S786I (1) V834I (1) Y376C (1) G3514C (1) G594A (1) G1947A (1) G190C (1) V834L (1) Q546R (1) F522C (1) Q546L (1) Q546K (1) P699S (1) F2004L (1) D101H (1) T393C (1) A1330T (1) R988C (1) H48Q (1) T174M (1) A62V (1) G595R (1) A62T (1) L84V (1) M165I (1) V222A (1) P479L (1) G908R (1) Y318F (1) V75M (1) D101Y (1) I10F (1) D90V (1) H1112L (1) G269S (1) R3500Q (1) V30A (1) S282R (1) D919G (1) I665V (1) H1112Y (1) D90A (1) C385A (1) M95L (1) G1170S (1) V244M (1) G17T (1) S26E (1) N251K (1) W574C (1) G464V (1) C807T (1) V77I (1) Y449D (1) C168H (1) D4064A (1) M50I (1) Q215S (1) F106C (1) K56M (1) G465R (1) G598V (1) S769N (1) E586K (1) T1482I (1) L1196M (1) E148Q (1) T12W (1) S720P (1) Y641S (1) S768R (1) F129L (1) Y641N (1) C938A (1) C165V (1) R19C (1) C383R (1) Y641H (1) C805S (1) Y641F (1) W64R (1) Y641C (1) H1047Y (1) M1268T (1) A736V (1) C61G (1) P1009S (1) V481F (1) S1612C (1) Q546E (1) L718P (1) V179F (1) G106R (1) M1002A (1) P300D (1) S131F (1) N63L (1) W21C (1) L144S (1) M1149T (1) H558R (1) S373C (1) A69S (1) V1180L (1) V774A (1) T377M (1) V689M (1) V774M (1) D164V (1) L387M (1) R199W (1) N86S (1) M694V (1) N86Y (1) G11053T (1) R175H (1) T17M (1) Y86N (1) A2144G (1) A2059G (1) N345K (1) D50W (1) I180V (1) A864V (1) L24E (1) V118I (1) G212S (1) I843S (1) N1303K (1) R1623Q (1) A1033V (1) L1198F (1) N1325S (1) Q812R (1) V773M (1) G212A (1) A997T (1) S241T (1) E167K (1) G1764A (1) G80A (1) E62D (1) E274Q (1) M34T (1) G401S (1) A2142C (1) G1631D (1) G211A (1) D76Y (1) D76N (1) E384G (1) V249I (1) M1106C (1) L234I (1) L101I (1) A2143C (1) K806E (1) A687V (1) A119S (1) P1028S (1) A313G (1) D824V (1) S9C (1) C182A (1) S9G (1) S153F (1) S1900E (1) S1900D (1) S1900C (1) R1644H (1) S1900A (1) R702W (1) T1456G (1) T1565C (1) E1021K (1) K15210D (1) G779C (1) G82S (1) G779F (1) G840A (1) V18M (1) A27L (1) L28M (1) T351I (1) K121Q (1) L28P (1) H180Q (1) G779S (1) M11T (1) M11Q (1) P549S (1) N215S (1) G60D (1) R352W (1) G623R (1) G84E (1) E161K (1) G951A (1) C23S (1) E184K (1) V1206L (1) Y842C (1) V736A (1) L432V (1) E89Q (1) R135W (1) Y253F (1) G843D (1) D820Y (1) F77L (1) S311C (1) D10W (1) Y143H (1) G86R (1) Y143C (1) R112H (1) Y143A (1) A227G (1) K101Q (1) R463C (1) G85E (1) L236P (1) A310V (1) T798M (1) S310Y (1) R222C (1) A4917G (1) T798I (1) E44D (1) L302P (1) Q30R (1) L786V (1) R287Q (1) P286R (1) D36Y (1) R263Q (1) T599I (1) K103M (1) S680N (1) K1270A (1) R88Q (1) T224M (1) P46L (1) N700D (1) A5147S (1) E21G (1) Y822D (1) Q260A (1) Y188H (1) R131H (1) R1070Q (1) C316N (1) T81C (1) T1304M (1) I167V (1) I82A (1) D13H (1) Q54H (1) Q30H (1) L239R (1) Y823D (1) T117S (1) I84T (1) A222V (1) L106V (1) K432Q (1) G163S (1) I1370K (1) G163E (1) K650E (1) E757A (1) R399Q (1) G41S (1) C1895T (1) P392L (1) T334G (1) H274Y (1) R399G (1)

SNPMiner SNPMiner Trials (Home Page)


Report for Mutation Q252H

Developed by Shray Alag, 2020-2021.
SNP Clinical Trial Gene

There are 4 clinical trials

Clinical Trials


1 Evaluating Efficacy and Safety of Flumatinib Versus Nilotinib for Chronic Phase Chronic Myeloid Leukemia(CML-CP) With Defined BCR-ABL1 Kinase Mutations in Imatinib or Dasatinib: A Prospective, Multicenter, Pragmatic Clinical Trial(FINESTdm)

Imatinib has revolutionized the treatment of chronic myeloid leukemia (CML) and is the current standard of care in the treatment of patients with newly diagnosed CML. However, about 30% of patients still show drug resistance or disease progression. Currently, the most widely studied mechanism of TKI resistance in CML patients is mutations in the ABL kinase region. So far, more than 100 kinase domain mutations have been found in disease progression and imatinib resistance. It is estimated that more than 25% of CML patients will change TKI at least once in their lifetime due to drug resistance or intolerance. The 2020 edition of the "Guidelines for the Diagnosis and Treatment of Chronic Myelogenous Leukemia in China" proposes that patients with F317L/V/I/C, V299L and T315A mutations are more likely to obtain clinical efficacy by switching to the second-generation TKI nilotinib; patients with Y253H, E255K/V and F359C/V/I mutations are more likely to obtain clinical efficacy by switching to the second-generation TKI dasatinib; patients with T315I mutations are resistant to both nilotinib and dasatinib. Flumatinib has been shown to be a more potent inhibitor of BCR-ABL1 tyrosine kinase than imatinib. In vitro studies, it has shown that flumatinib inhibits wild-type and common BCR-ABL mutations(Q252H, V299L, F317L/I, M351T, H396P, etc.) more potently, and the anti-mutation spectrum of flumatinib is similar to nilotinib. Therefore, this study is designed to provide clearer guidance for patients with specific BCR-ABL kinase point mutations during CML treatment.

NCT04681820
Conditions
  1. CML-CP; Mutation;TKI
Interventions
  1. Drug: Flumatinib
  2. Drug: Nilotinib
MeSH:Leukemia, Myelogenous, Chronic, BCR-ABL Positive Leukemia, Myelo Leukemia, Myeloid, Chronic-Phase
HPO:Chronic myelogenous leukemia

In vitro studies, it has shown that flumatinib inhibits wild-type and common BCR-ABL mutations(Q252H, V299L, F317L/I, M351T, H396P, etc.) more potently, and the anti-mutation spectrum of flumatinib is similar to nilotinib. --- Q252H ---

Inclusion Criteria: 1. Male or female patients ≥18 years of age; 2. CML-CP patients when enrolled Definition of diagnosis: Bone marrow cytogenetic confirmation of Philadelphia chromosome of t (9;22) translocations and/or the presence of P210 BCR-ABL1 transcripts via molecular assessment; Documented chronic phase CML will meet all the criteria defined as: < 15% blasts in peripheral blood and bone marrow < 30% blasts plus promyelocytes in peripheral blood and bone marrow < 20% basophils in the peripheral blood ≥ 100 x 109/L (≥ 100,000/mm3) platelets No evidence of extramedullary leukemic involvement, with the exception of hepatosplenomegaly 3. Specific BCR-ABL1 kinase mutations sensitive to flumatinib (including F317L/I, M351T, Q252H, M244V, V299L, F311L, H396R, E355G, L387M) were found in patients with poor response to imatinib or dasatinib treatment, treatment failure, disease progression, MMR but not DMR or unstable DMR. 4. Female patients of childbearing potential must have a negative serum pregnancy test; 5. Ability to provide written informed consent prior to any study related screening procedures being performed. --- F317L --- --- M351T --- --- Q252H ---

Primary Outcomes

Description: Major molecular response is defined as ≤ 0.1% BCR-ABL/ABL% by international scale

Measure: Major molecular response rate at 12 months

Time: 12 months

2 Dynamics of ABL Mutations in Imatinib Failed Ph Positive or Bcr-Abl Positive CML CP or AP Patients Who Treated With Nilotinib as Second-line TKI Therapy (AMICAN-Prospective)in Asia

The purposes of this study are to investigate expression and frequency of ABL point mutations, a major cause of resistance in imatinib failed CML Asian patients and to find causes of Asian-specific resistance to cancer-targeting therapies through a prospective investigation of dynamics of point mutations and expression of new point mutations during nilotinib treatment.

NCT01562847
Conditions
  1. Chronic Myeloid Leukemia
Interventions
  1. Drug: Nilotinib
MeSH:Leukemia, Myelogenous, Chronic, BCR-ABL Positive
HPO:Chronic myelogenous leukemia

With regard to peculiar point mutations, V299L, F317L, and E25K/V show relative resistance to dasatinib, and p-loop mutations including G250E, Q252H, Y253F/H and E255K/V and F359C/V show relative resistance to nilotinib. --- V299L --- --- F317L --- --- E25K --- --- G250E --- --- Q252H ---

Primary Outcomes

Measure: To confirm the patterns of resistance including point mutations which are newly expressed during the nilotinib treatment

Time: 5 years

Secondary Outcomes

Measure: To analyze and evaluate the overall survival and disease free survival in the nilotinib treatment according to progression of the disease and types of point mutations

Time: 5 years

3 A Randomized Multi-Center Open Label Study of BMS-354825 vs Imatinib Mesylate (Gleevec®) 800 mg/d in Subjects With Chronic Phase Philadelphia Chromosome-Positive Chronic Myeloid Leukemia Who Have Disease That is Resistant to Iamtinib at a Dose of 400-600 mg/d

RATIONALE: BMS-354825 and imatinib mesylate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. PURPOSE: This randomized phase II trial is studying BMS-354825 to see how well it works compared to imatinib mesylate in treating patients with chronic phase chronic myelogenous leukemia that did not respond to previous imatinib mesylate.

NCT00112775
Conditions
  1. Leukemia
Interventions
  1. Drug: dasatinib
  2. Drug: imatinib mesylate
MeSH:Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Leukemia, Myeloid, Chronic-Phase
HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia

DISEASE CHARACTERISTICS: - Diagnosis of chronic phase chronic myelogenous leukemia (CML), meeting all of the following criteria: - Less than 15% blasts in peripheral blood and bone marrow - Less than 20% basophils in peripheral blood - Less than 30% blasts and promyelocytes in peripheral blood and bone marrow - Platelet count ≥ 100,000/mm^3 (unless thrombocytopenia is due to recent therapy) - No extramedullary involvement (other than liver or spleen) - Philadelphia chromosome (Ph)-positive disease by cytogenetic analysis - Must have developed resistant disease during prior treatment with imatinib mesylate* at a dose of 400-600 mg/day**, as defined by 1 of the following: - Loss of major cytogenetic response (MCyR) - Achieved a confirmed MCyR and subsequently no longer meets the MCyR criteria - Documented increase in Ph-positive metaphases by 30% on 2 cytogenetic analyses performed ≥ 4 weeks apart during treatment with imatinib mesylate - Loss of complete hematologic response (CHR) - Achieved a confirmed CHR and subsequently no longer meets the CHR criteria on all asessments over a consecutive 2-week period during treatment with imatinib mesylate - Continuously increasing WBC count on ≥ 2 consecutive evaluations ≥ 2 weeks apart with the final assessment showing a doubling of WBC from the nadir to ≥ 20,000/mm^3 OR an absolute increase in WBC by > 50,000/mm^3 above the lowest count after starting imatinib mesylate - No CHR after 3 months of treatment with imatinib mesylate at a dose of 400-600 mg/day - No cytogenetic response after 6 months of treatment with imatinib mesylate at a dose of 400-600 mg/day - No MCyR after 12 months of treatment with imatinib mesylate at a dose of 400-600 mg/day NOTE: *Imatinib mesylate does not need to be the most recent treatment for CML NOTE: **Imatinib mesylate dose ≤ 600 mg/day - Able to tolerate chronic administration of imatinib mesylate at the highest dose received during prior treatment - No imatinib mesylate-related non-hematologic toxicity ≥ grade 3 - No grade 4 imatinib mesylate-related hematologic toxicity lasting more than 7 days - No imatinib mesylate-related toxicity that led to discontinuation or disruption of dosing for > 4 weeks - No previously identified BCR-ABL mutation of 1 of the following types: - L248V - G250E - Q252H/R - Y253H/F - E255K/V - T315I/D - F317L - H369P/R - No prior diagnosis of accelerated phase or blast crisis CML - Patients who previously met the criteria for accelerated phase or blast crisis CML who achieved CHR during treatment with imatinib mesylate and then subsequently progressed to chronic phase CML are not eligible - Ineligible for or unwilling to undergo hematopoietic stem cell transplantation PATIENT CHARACTERISTICS: Age - 18 and over Performance status - ECOG 0-1 Life expectancy - At least 3 months Hematopoietic - See Disease Characteristics - No history of a significant bleeding disorder unrelated to CML, including any of the following: - Congenital bleeding disorder (e.g., von Willebrand's disease) - Acquired bleeding disorder diagnosed within the past year (e.g. --- L248V --- --- G250E --- --- Q252H ---

acquired anti-factor VIII antibodies) Hepatic - Bilirubin ≤ 2.0 times upper limit of normal (ULN) - ALT and AST ≤ 2.5 times ULN Renal - Creatinine ≤ 1.5 times ULN - Total serum or ionized calcium normal (supplementation allowed) Cardiovascular - Heart rate ≥ 50 beats/minute by EKG - No myocardial infarction within the past 6 months - No uncontrolled angina within the past 3 months - No congestive heart failure within the past 3 months - No diagnosed or suspected congenital long QT syndrome - No history of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, or torsades de Pointes) - No prolonged QTc interval (i.e., > 450 msec) by EKG using Bazett's correction - High Bazett's correction (i.e., > 450 msec) allowed provided Fridericia correction is ≤ 450 msec - No history of second or third degree heart block - Pacemaker allowed - No uncontrolled hypertension - No other uncontrolled or significant cardiovascular disease Other - Not pregnant - No nursing during and for ≥ 3 months after study participation - Negative pregnancy test - Fertile patients must use effective contraception for ≥ 1 month before, during, and for ≥ 3 months after study participation - Magnesium and potassium normal (supplementation allowed) - No serious uncontrolled medical disorder or active infection that would preclude study participation - No dementia or altered mental status that would preclude giving informed consent - No significant bleeding from the gastrointestinal tract within the past 6 months - No evidence of organ dysfunction or any clinically significant deviation from normal on physical examination, vital signs, EKG, or clinical laboratory determinations unrelated to CML that would preclude study participation - No prisoners or patients who are involuntarily incarcerated for treatment of either a psychiatric or physical (e.g., infectious disease) illness PRIOR CONCURRENT THERAPY: Biologic therapy - More than 14 days since prior interferon Chemotherapy - More than 14 days since prior cytarabine - Prior or concurrent hydroxyurea for elevated WBC (i.e., WBC > 50,000/mm^3) allowed Endocrine therapy - Not specified Radiotherapy - Not specified Surgery - Not specified Other - More than 7 days since prior imatinib mesylate - At least 7 days since prior and no concurrent low-dose aspirin (≤ 325 mg/day) - At least 14 days since prior and no concurrent high-dose aspirin (> 325 mg/day) - More than 14 days since prior targeted small molecule anticancer agents - More than 28 days since prior investigational or antineoplastic agents except hydroxyurea or anagrelide - At least 5 days or 5 half-lives (whichever is greater) since prior and no concurrent drugs that carry a risk of causing torsades de Pointes, including any of the following: - Quinidine - Procainamide - Disopyramide - Amiodarone - Sotalol - Ibutilide - Dofetilide - Erythromycin - Clarithromycin - Chlorpromazine - Haloperidol - Mesoridazine - Thioridazine - Pimozide - Ziprasidone - Cisapride - Bepridil - Droperidol - Methadone - Arsenic trioxide - Chloroquine - Domperidone - Halofantrine - Levomethadyl - Pentamidine - Sparfloxacin - Lidoflazine - At least 5 days or 5 half-lives (whichever is greater) since prior and no concurrent medication that directly inhibits platelet function (except anagrelide for thrombocytosis due to CML), including any of the following: - Dipyridamole - Epoprostenol - Epitifibatide - Clopidogrel - Cilostazol - Abciximab - Ticlopidine - At least 5 days or 5 half-lives (whichever is greater) since prior and no concurrent anticoagulants (e.g., warfarin, heparin, or low molecular weight heparin [e.g., danaparoid, dalteparin, tinzaparin, or enoxaparin]) - Concurrent prophylactic low-dose warfarin for prevention of catheter thrombosis and heparin-flush for IV lines allowed - No prior BMS-354825 - No concurrent CYP3A4 inhibitors or inducers, including any of the following: - Ketoconazole - Ritonavir - Rifampin - Efavirenz - No other concurrent therapy for CML DISEASE CHARACTERISTICS: - Diagnosis of chronic phase chronic myelogenous leukemia (CML), meeting all of the following criteria: - Less than 15% blasts in peripheral blood and bone marrow - Less than 20% basophils in peripheral blood - Less than 30% blasts and promyelocytes in peripheral blood and bone marrow - Platelet count ≥ 100,000/mm^3 (unless thrombocytopenia is due to recent therapy) - No extramedullary involvement (other than liver or spleen) - Philadelphia chromosome (Ph)-positive disease by cytogenetic analysis - Must have developed resistant disease during prior treatment with imatinib mesylate* at a dose of 400-600 mg/day**, as defined by 1 of the following: - Loss of major cytogenetic response (MCyR) - Achieved a confirmed MCyR and subsequently no longer meets the MCyR criteria - Documented increase in Ph-positive metaphases by 30% on 2 cytogenetic analyses performed ≥ 4 weeks apart during treatment with imatinib mesylate - Loss of complete hematologic response (CHR) - Achieved a confirmed CHR and subsequently no longer meets the CHR criteria on all asessments over a consecutive 2-week period during treatment with imatinib mesylate - Continuously increasing WBC count on ≥ 2 consecutive evaluations ≥ 2 weeks apart with the final assessment showing a doubling of WBC from the nadir to ≥ 20,000/mm^3 OR an absolute increase in WBC by > 50,000/mm^3 above the lowest count after starting imatinib mesylate - No CHR after 3 months of treatment with imatinib mesylate at a dose of 400-600 mg/day - No cytogenetic response after 6 months of treatment with imatinib mesylate at a dose of 400-600 mg/day - No MCyR after 12 months of treatment with imatinib mesylate at a dose of 400-600 mg/day NOTE: *Imatinib mesylate does not need to be the most recent treatment for CML NOTE: **Imatinib mesylate dose ≤ 600 mg/day - Able to tolerate chronic administration of imatinib mesylate at the highest dose received during prior treatment - No imatinib mesylate-related non-hematologic toxicity ≥ grade 3 - No grade 4 imatinib mesylate-related hematologic toxicity lasting more than 7 days - No imatinib mesylate-related toxicity that led to discontinuation or disruption of dosing for > 4 weeks - No previously identified BCR-ABL mutation of 1 of the following types: - L248V - G250E - Q252H/R - Y253H/F - E255K/V - T315I/D - F317L - H369P/R - No prior diagnosis of accelerated phase or blast crisis CML - Patients who previously met the criteria for accelerated phase or blast crisis CML who achieved CHR during treatment with imatinib mesylate and then subsequently progressed to chronic phase CML are not eligible - Ineligible for or unwilling to undergo hematopoietic stem cell transplantation PATIENT CHARACTERISTICS: Age - 18 and over Performance status - ECOG 0-1 Life expectancy - At least 3 months Hematopoietic - See Disease Characteristics - No history of a significant bleeding disorder unrelated to CML, including any of the following: - Congenital bleeding disorder (e.g., von Willebrand's disease) - Acquired bleeding disorder diagnosed within the past year (e.g. --- L248V --- --- G250E --- --- Q252H ---

Primary Outcomes

Measure: Major cytogenic response (MCyR) rate at 12 weeks

Secondary Outcomes

Measure: MCyR at any time

Measure: Duration of MCyR

Measure: Time to MCyR

Measure: Complete hematologic response rate

4 Phase I Trial Adding Ruxolitinib to a Combination of Dasatinib Plus Dexamethasone in Remission Induction Therapy in Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Patients Aged 40 Years or Older.

The purpose of this study is to test the safety of a new combination of three oral drugs in Ph+ ALL. These drugs are dexamethasone, dasatinib, and ruxolitinib. All three drugs have been studied before in humans. This is a phase I study in which ruxolitinib dose will start low for the first patient together with dexamethasone plus dasatinib. If this dose does not cause a bad side effect, the ruxolitinib dose will slowly be made higher as new patients take part in the study. This will help the investigators find the right dose of ruxolitinib to give together with dexamethasone and dasatinib that will be used in future studies

NCT02494882
Conditions
  1. Acute Lymphoblastic Leukemia
Interventions
  1. Drug: Ruxolitinib
  2. Drug: Dasatinib
  3. Drug: Dexamethasone
MeSH:Leukemia Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Lymphoid Philadelphia Chromosome
HPO:Leukemia Lymphoid leukemia

L248R, L248V, Q252H, E255K, V299L, T315A, T315I, F317C, F317L, F317S, F317V) - Relapsed or refractory Ph-like ALL without prior exposure to dasatibin and with mutations or rearrangements of genes conferring sensitivity to dasatibin (ABL, CSF1R, PDGFRB) or ruxolitinib (CRLF2, JAK3, EPOR, TSLP) - Newly diagnosed or relapsed CML in lymphoid blast crisis - Confirmation of Philadelphia chromosome positivity by cytogenetics (karyotype/FISH) and/or molecular tests (BCR-ABL1 transcripts) - Acceptable end-organ function, except for documented exclusions for organ function compromise due to ALL itself - ECOG performance status ≤ 2 - Men and women of childbearing potential must be willing to practice an effective method of birth control during treatment and for at least 4 months following treatment on study Exclusion Criteria: - Ph-negative ALL - Patients with dominant leukemic clone bearing documented bcr-abl mutations enabling bcr-abl TKI resistance at diagnosis - Mature B-cell (Burkitt's) ALL - Serum creatinine > 1.5x ULN and calculated creatinine clearance, based on a 24-hour urine collection, < 30 mL/min--unless related to ALL/tumor lysis syndrome and able to be corrected - Direct Bilirubin > 2x ULN; AST/ALT > 10x ULN, unless related to ALL liver infiltration. --- L248R --- --- L248V --- --- Q252H ---

Primary Outcomes

Description: is to be evaluated by using a combination of criteria. Molecular remissions will be defined by standard criteria for BCR-ABL1 and IGH qRT-PCR. Flow cytometric assessment of MRD will be defined by standard flow cytometry criteria

Measure: Clinical response

Time: 2 years

Secondary Outcomes

Description: Molecular remission status will be defined by undetectable BCR-ABL1 transcripts and/or IGH clonal gene rearrangement in bone marrow aspirate (BMA) examination as determined by qRT-PCR in CLIA laboratory.

Measure: Complete Molecular Remission (CMR) rate

Time: 2 years


HPO Nodes