Clinical Trials /

Ruxolitinib Phosphate or Dasatinib With Chemotherapy in Treating Patients With Relapsed or Refractory Philadelphia Chromosome-Like Acute Lymphoblastic Leukemia

NCT02420717

Description:

This phase II trial studies the side effects and best dose of ruxolitinib phosphate and how well it works compared to dasatinib when given with chemotherapy in treating patients with Philadelphia chromosome-like acute lymphoblastic leukemia that has come back (relapsed) or has not responded to treatment (refractory). Ruxolitinib phosphate and dasatinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether giving ruxolitinib phosphate or dasatinib with chemotherapy works better in treating patients with previously treated acute lymphoblastic leukemia.

Related Conditions:
  • B-Cell Acute Lymphoblastic Leukemia
Recruiting Status:

Completed

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Ruxolitinib Phosphate or Dasatinib With Chemotherapy in Treating Patients With Relapsed or Refractory Philadelphia Chromosome-Like Acute Lymphoblastic Leukemia
  • Official Title: A Phase I-II Study of the Combination of Ruxolitinib or Dasatinib With Chemotherapy in Patients With Philadelphia Chromosome (Ph)-Like Acute Lymphoblastic Leukemia (ALL)

Clinical Trial IDs

  • ORG STUDY ID: 2014-0521
  • SECONDARY ID: NCI-2015-00779
  • SECONDARY ID: 2014-0521
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT02420717

Conditions

  • Recurrent B Acute Lymphoblastic Leukemia
  • Recurrent Ph-Like Acute Lymphoblastic Leukemia
  • Refractory B Acute Lymphoblastic Leukemia
  • Refractory Ph-Like Acute Lymphoblastic Leukemia

Interventions

DrugSynonymsArms
Cyclophosphamide(-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamide Monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719Cohort A (ruxolitinib phosphate)
Cytarabine.beta.-Cytosine arabinoside, 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-.beta.-D-Arabinofuranosylcytosine, 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-Beta-D-arabinofuranosylcytosine, 1.beta.-D-Arabinofuranosylcytosine, 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-, 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-, Alexan, Ara-C, ARA-cell, Arabine, Arabinofuranosylcytosine, Arabinosylcytosine, Aracytidine, Aracytin, Aracytine, Beta-Cytosine Arabinoside, CHX-3311, Cytarabinum, Cytarbel, Cytosar, Cytosine Arabinoside, Cytosine-.beta.-arabinoside, Cytosine-beta-arabinoside, Erpalfa, Starasid, Tarabine PFS, U 19920, U-19920, Udicil, WR-28453Cohort A (ruxolitinib phosphate)
DasatinibBMS-354825, Dasatinib Hydrate, Dasatinib Monohydrate, SprycelCohort B (dasatinib)
DexamethasoneAacidexam, Adexone, Aknichthol Dexa, Alba-Dex, Alin, Alin Depot, Alin Oftalmico, Amplidermis, Anemul mono, Auricularum, Auxiloson, Baycadron, Baycuten, Baycuten N, Cortidexason, Cortisumman, Decacort, Decadrol, Decadron, Decadron DP, Decalix, Decameth, Decasone R.p., Dectancyl, Dekacort, Deltafluorene, Deronil, Desamethasone, Desameton, Dexa-Mamallet, Dexa-Rhinosan, Dexa-Scheroson, Dexa-sine, Dexacortal, Dexacortin, Dexafarma, Dexafluorene, Dexalocal, Dexamecortin, Dexameth, Dexamethasone Intensol, Dexamethasonum, Dexamonozon, Dexapos, Dexinoral, Dexone, Dinormon, Fluorodelta, Fortecortin, Gammacorten, Hexadecadrol, Hexadrol, Lokalison-F, Loverine, Methylfluorprednisolone, Millicorten, Mymethasone, Orgadrone, Spersadex, TaperDex, Visumetazone, ZoDexCohort A (ruxolitinib phosphate)
DoxorubicinAdriablastin, Hydroxydaunomycin, Hydroxyl Daunorubicin, HydroxyldaunorubicinCohort A (ruxolitinib phosphate)
LeucovorinFolinic acidCohort A (ruxolitinib phosphate)
Mercaptopurine3H-Purine-6-thiol, 6 MP, 6 Thiohypoxanthine, 6 Thiopurine, 6-Mercaptopurine, 6-Mercaptopurine Monohydrate, 6-MP, 6-Purinethiol, 6-Thiopurine, 6-Thioxopurine, 6H-Purine-6-thione, 1,7-dihydro- (9CI), 7-Mercapto-1,3,4,6-tetrazaindene, Alti-Mercaptopurine, Azathiopurine, Bw 57-323H, Flocofil, Ismipur, Leukerin, Leupurin, Mercaleukim, Mercaleukin, Mercaptina, Mercaptopurinum, Mercapurin, Mern, NCI-C04886, Puri-Nethol, Purimethol, Purine, 6-mercapto-, Purine-6-thiol (8CI), Purine-6-thiol, monohydrate, Purinethiol, Purinethol, U-4748, WR-2785Cohort A (ruxolitinib phosphate)
MethotrexateAbitrexate, Alpha-Methopterin, Amethopterin, Brimexate, CL 14377, CL-14377, Emtexate, Emthexat, Emthexate, Farmitrexat, Fauldexato, Folex, Folex PFS, Lantarel, Ledertrexate, Lumexon, Maxtrex, Medsatrexate, Metex, Methoblastin, Methotrexate LPF, Methotrexate Methylaminopterin, Methotrexatum, Metotrexato, Metrotex, Mexate, Mexate-AQ, MTX, Novatrex, Rheumatrex, Texate, Tremetex, Trexeron, Trixilem, WR-19039Cohort A (ruxolitinib phosphate)
Prednisone.delta.1-Cortisone, 1, 2-Dehydrocortisone, Adasone, Cortancyl, Dacortin, DeCortin, Decortisyl, Decorton, Delta 1-Cortisone, Delta-Dome, Deltacortene, Deltacortisone, Deltadehydrocortisone, Deltasone, Deltison, Deltra, Econosone, Lisacort, Meprosona-F, Metacortandracin, Meticorten, Ofisolona, Orasone, Panafcort, Panasol-S, Paracort, Perrigo Prednisone, PRED, Predicor, Predicorten, Prednicen-M, Prednicort, Prednidib, Prednilonga, Predniment, Prednisone Intensol, Prednisonum, Prednitone, Promifen, Rayos, Servisone, SK-PrednisoneCohort A (ruxolitinib phosphate)
RituximabABP 798, BI 695500, C2B8 Monoclonal Antibody, Chimeric Anti-CD20 Antibody, CT-P10, IDEC-102, IDEC-C2B8, IDEC-C2B8 Monoclonal Antibody, MabThera, Monoclonal Antibody IDEC-C2B8, PF-05280586, Rituxan, Rituximab ABBS, Rituximab Biosimilar ABP 798, Rituximab Biosimilar BI 695500, Rituximab Biosimilar CT-P10, Rituximab Biosimilar GB241, Rituximab Biosimilar IBI301, Rituximab Biosimilar JHL1101, Rituximab Biosimilar PF-05280586, Rituximab Biosimilar RTXM83, Rituximab Biosimilar SAIT101, rituximab biosimilar TQB2303, rituximab-abbs, RTXM83, TruximaCohort A (ruxolitinib phosphate)
Ruxolitinib PhosphateINCB-18424 Phosphate, JakafiCohort A (ruxolitinib phosphate)
VincristineLeurocristine, VCR, VincrystineCohort A (ruxolitinib phosphate)

Purpose

This phase II trial studies the side effects and best dose of ruxolitinib phosphate and how well it works compared to dasatinib when given with chemotherapy in treating patients with Philadelphia chromosome-like acute lymphoblastic leukemia that has come back (relapsed) or has not responded to treatment (refractory). Ruxolitinib phosphate and dasatinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether giving ruxolitinib phosphate or dasatinib with chemotherapy works better in treating patients with previously treated acute lymphoblastic leukemia.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the safety and maximal tolerated dose (MTD) of ruxolitinib phosphate
      (ruxolitinib) in combination with chemotherapy in patients with Philadelphia chromosome
      (Ph)-like acute lymphoblastic leukemia (ALL). (Phase I, ruxolitinib cohort only) II. To
      determine the response rate (complete response [CR]/CR with incomplete marrow recovery [CRi])
      of ruxolitinib or dasatinib in combination with chemotherapy in patients with Ph-like ALL.
      (Phase II)

      SECONDARY OBJECTIVES:

      I. To determine the response rate (CR/CRi) of ruxolitinib in combination with chemotherapy in
      patients with Ph-like ALL. (Phase I, ruxolitinib cohort only) II. To determine the duration
      of response, disease-free survival and overall survival of ruxolitinib in combination with
      chemotherapy in patients with Ph-like ALL. (Phase I, ruxolitinib cohort only) III. To
      determine the safety and toxicity profile of ruxolitinib or dasatinib in combination with
      chemotherapy in patients with Ph-like ALL. (Phase II) IV. To determine the duration of
      response, disease-free survival and overall survival of ruxolitinib or dasatinib in
      combination with chemotherapy in patients with Ph-like ALL. (Phase II)

      OUTLINE: This is a phase I, dose escalation study of ruxolitinib followed by a phase II
      study. Patients are assigned to 1 of 2 cohorts.

      COHORT A: Patients receive ruxolitinib phosphate orally (PO) twice daily (BID). Cycles repeat
      every 21 days in the absence of disease progression or unacceptable toxicity.

      COHORT B: Patients receive dasatinib PO once daily (QD). Cycles repeat every 21 days in the
      absence of disease progression or unacceptable toxicity.

      INTENSIVE CHEMOTHERAPY: After cycle 1, patients not achieving a response also receive
      cyclophosphamide intravenously (IV) over 3 hours BID on days 1-3, doxorubicin IV over 24-48
      hours on day 4, vincristine IV over 30 minutes on days 4 and 11, and dexamethasone PO QD or
      IV over 30 minutes on days 1-4 and 11-14 of cycles 1, 3, 5, and 7. Patients receive
      methotrexate IV over 24 hours on day 1, leucovorin IV over 1 hour or PO every 6 hours on days
      2-5, cytarabine IV over 2 hours BID on days on days 2 and 3 of cycles 2, 4, 6, and 8. At the
      discretion of the treating physician, patients may also receive rituximab IV over several
      hours on days 1 and 11 of cycles 1 and 3 and on days 1 and 8 of cycles 2 and 4 only.
      Treatment repeats every 21 days for up to 8 cycles in the absence of disease progression or
      unacceptable toxicity.

      MAINTENANCE THERAPY: Patients receive mercaptopurine PO thrice daily (TID), methotrexate PO
      once a week, vincristine IV over 30 minutes on day 1, and prednisone PO on days 1-5. Cycles
      repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable
      toxicity.

      After completion of study treatment, patients are followed up at 30 days.
    

Trial Arms

NameTypeDescriptionInterventions
Cohort A (ruxolitinib phosphate)ExperimentalPatients receive ruxolitinib phosphate PO BID. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  • Cyclophosphamide
  • Cytarabine
  • Dexamethasone
  • Doxorubicin
  • Leucovorin
  • Mercaptopurine
  • Methotrexate
  • Prednisone
  • Rituximab
  • Ruxolitinib Phosphate
  • Vincristine
Cohort B (dasatinib)ExperimentalPatients receive dasatinib PO QD. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  • Cyclophosphamide
  • Cytarabine
  • Dasatinib
  • Dexamethasone
  • Doxorubicin
  • Leucovorin
  • Mercaptopurine
  • Methotrexate
  • Prednisone
  • Rituximab
  • Vincristine

Eligibility Criteria

        Inclusion Criteria:

          -  Patients with previously treated B-cell ALL (relapsed and/or refractory after prior
             therapy)

          -  Bone marrow involvement with >= 5% lymphoblasts

          -  Documented genetic lesion(s) known to confer susceptibility to inhibition by either
             ruxolitinib or dasatinib or cytokine receptor-like factor 2 (CRLF2) positivity by flow
             cytometry (for the ruxolitinib cohort)

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2

          -  Total bilirubin < 2.0 mg/dL

          -  Serum glutamate pyruvate transaminase (SGPT) or serum glutamic oxaloacetic
             transaminase (SGOT) < 3 x upper limit of normal (ULN)

          -  Creatinine < 2 mg/dL

          -  Females of childbearing potential must have a negative serum or urine beta human
             chorionic gonadotropin (beta-hCG) pregnancy test result within 14 days prior to the
             first dose of study drugs and must agree to use an effective contraception method
             during the study and for 30 days following the last dose of study drug; females of
             non-childbearing potential are those who are postmenopausal greater than 1 year or who
             have had a bilateral tubal ligation or hysterectomy; appropriate methods of birth
             control include the following: any 2 of the following methods used together: birth
             control implants, injections, or pills (except for progesterone only pills),
             intrauterine device (IUD), vasectomy, tubal ligation, barrier method (female or male
             condom with spermicide, cervical cap with spermicide, diaphragm with spermicide); male
             condom with spermicide and diaphragm; male condom with spermicide and cervical cap;
             unacceptable methods of birth control include using no birth control, withdrawal,
             rhythm method, vaginal sponge, any barrier method that does not use spermicide,
             progesterone only pills, and using male and female condoms at the same time

          -  Males who have partners of childbearing potential must agree to use an effective
             contraceptive method during the study and for 30 days following the last dose of study
             drug

          -  Patients or their legally authorized representative must provide written informed
             consent

        Exclusion Criteria:

          -  Burkitt's leukemia or lymphoma, T-cell ALL or lymphoblastic lymphoma

          -  Patients having undergone prior allogeneic stem cell transplant within 3 months or
             having active graft versus host disease

          -  Patient is pregnant or breastfeeding

          -  Patients with uncontrolled active infections (fever >= 38 degrees Celsius [C], septic
             shock)

          -  Isolated extramedullary relapse (i.e. testicular, central nervous system)

          -  Current or chronic hepatitis B or C infection, or known seropositivity for human
             immunodeficiency virus (HIV)

          -  Concurrent chemotherapy (except intrathecal chemotherapy)

          -  Major surgery within 4 weeks prior to first study dose

          -  Systemic chemotherapy/radiotherapy/investigational therapy within 14 days (with the
             exception of hydroxyurea and steroids) prior to starting therapy; for patients
             receiving ALL maintenance with 6-mercaptopurine, methotrexate, vincristine, and
             steroids - these agents should be discontinued at least 48 hours prior to start of
             study drugs; for patients on oral targeted therapies (such as imatinib, dasatinib,
             ponatinib), - these agents should be discontinued at least 48 hours prior to start of
             study drugs

          -  Patients must have recovered from acute non hematologic toxicity (to =< grade 1) of
             all previous therapy prior to enrollment

          -  Known active central nervous system (CNS) leukemia, as defined by unequivocal
             morphologic evidence of lymphoblasts in the cerebrospinal fluid (CSF), use of
             CNS-directed local treatment for active disease within the prior 28 days, symptomatic
             CNS leukemia (i.e., cranial nerve palsies or other significant neurologic dysfunction)
             within 28 days; patients may have history of CNS leukemic involvement if definitively
             treated with prior therapy and no evidence of active disease (defined as >= 2
             consecutive spinal fluid assessments with no evidence of disease) at the time of
             registration; prophylactic intrathecal chemotherapy is not a criterion for exclusion

          -  Patients with active heart disease (New York Heart Association [NYHA] class 3-4 as
             assessed by history and physical examination, unstable angina/stroke/myocardial
             infarction within the last 6 months)

          -  Patients with a cardiac ejection fraction (as measured by either multi-gated
             acquisition [MUGA] scan or echocardiogram) < 40%; (Note: patients who have had prior
             anthracycline exposure of > 250 mg/m^2 may be eligible after discussion with the
             principal investigator [PI])

          -  Second malignancy other than basal cell or squamous cell carcinoma of the skin or in
             situ carcinoma of the cervix or the breast, unless they are successfully treated with
             curative intent for more than 2 years before entering the study

          -  Malabsorption syndrome or other conditions that preclude enteral route of
             administration

          -  Patients requiring strong cytochrome P450, family 3, subfamily A, polypeptide 4
             (CYP3A4) inhibitors

          -  Other severe acute or chronic medical or psychiatric condition or laboratory
             abnormality that in the opinion of the investigator may increase the risk associated
             with study participation or investigational product administration or may interfere
             with the interpretation of study results and/or would make the patient inappropriate
             for enrollment into this study
      
Maximum Eligible Age:N/A
Minimum Eligible Age:10 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximal tolerated dose (MTD) of ruxolitinib in combination with chemotherapy defined as the highest dose level at which no more than 1 out of 6 patients experience a dose limiting toxicity (Phase I)
Time Frame:42 days
Safety Issue:
Description:The method of Thall, Simon and Estey will be used for toxicity monitoring for this study. The severity of the toxicities will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 whenever possible. Safety data will be summarized by category, severity and frequency.

Secondary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Up to 30 days after completion of study treatment
Safety Issue:
Description:The method of Thall, Simon and Estey will be used for toxicity monitoring for this study. The severity of the toxicities will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 whenever possible. Safety data will be summarized by category, severity and frequency.
Measure:Duration of response
Time Frame:Up to 30 days after completion of study treatment
Safety Issue:
Description:Duration of response will be estimated using the Kaplan-Meier method. The association of the time to event outcomes with patient characteristics will be evaluated using the log rank test and Cox proportional hazards regression analysis.
Measure:Progression-free survival
Time Frame:Up to 30 days after completion of study treatment
Safety Issue:
Description:Progression-free survival will be estimated using the Kaplan-Meier method. The association of the time to event outcomes with patient characteristics will be evaluated using the log rank test and Cox proportional hazards regression analysis.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Completed
Lead Sponsor:M.D. Anderson Cancer Center

Last Updated

January 26, 2021