Clinical Trials /

Combination Chemotherapy and Ponatinib Hydrochloride in Treating Patients With Acute Lymphoblastic Leukemia

NCT01424982

Description:

This phase II trial studies the side effects and how well combination chemotherapy and ponatinib hydrochloride work in treating patients with acute lymphoblastic leukemia. Drugs used in chemotherapy, such as cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, and dexamethasone, 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. Ponatinib hydrochloride may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving combination chemotherapy and ponatinib hydrochloride may be an effective treatment for acute lymphoblastic leukemia.

Related Conditions:
  • Acute Lymphoblastic Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Combination Chemotherapy and Ponatinib Hydrochloride in Treating Patients With Acute Lymphoblastic Leukemia
  • Official Title: Phase II Study of Combination of Hyper-CVAD and Ponatinib in Patients With Philadelphia (PH) Chromosome Positive and/or BCR-ABL Positive Acute Lymphoblastic Leukemia (ALL)

Clinical Trial IDs

  • ORG STUDY ID: 2011-0030
  • SECONDARY ID: NCI-2011-02941
  • SECONDARY ID: 2011-0030
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT01424982

Conditions

  • Accelerated Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive
  • Acute Lymphoblastic Leukemia
  • Adult Acute Lymphoblastic Leukemia in Complete Remission
  • B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1
  • Blast Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive
  • Philadelphia Chromosome Positive
  • Untreated Adult 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, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719Treatment (combination chemotherapy, ponatinib hydrochloride)
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-28453Treatment (combination chemotherapy, ponatinib hydrochloride)
DexamethasoneAacidexam, Adexone, Aknichthol Dexa, Alba-Dex, Alin, Alin Depot, Alin Oftalmico, Amplidermis, Anemul mono, Auricularum, Auxiloson, Baycuten, Baycuten N, Cortidexason, Cortisumman, Decacort, Decadrol, Decadron, 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, Dexamethasonum, Dexamonozon, Dexapos, Dexinoral, Dexone, Dinormon, Fluorodelta, Fortecortin, Gammacorten, Hexadecadrol, Hexadrol, Lokalison-F, Loverine, Methylfluorprednisolone, Millicorten, Mymethasone, Orgadrone, Spersadex, VisumetazoneTreatment (combination chemotherapy, ponatinib hydrochloride)
DoxorubicinAdriablastin, Hydroxyl Daunorubicin, HydroxyldaunorubicinTreatment (combination chemotherapy, ponatinib hydrochloride)
Doxorubicin Hydrochloride5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI), ADM, Adriacin, Adriamycin, Adriamycin Hydrochloride, Adriamycin PFS, Adriamycin RDF, ADRIAMYCIN, HYDROCHLORIDE, Adriamycine, Adriblastina, Adriblastine, Adrimedac, Chloridrato de Doxorrubicina, DOX, DOXO-CELL, Doxolem, Doxorubicin.HCl, Doxorubin, Farmiblastina, FI 106, FI-106, hydroxydaunorubicin, RubexTreatment (combination chemotherapy, ponatinib hydrochloride)
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-19039Treatment (combination chemotherapy, ponatinib hydrochloride)
PonatinibAP-24534, AP24534Treatment (combination chemotherapy, ponatinib hydrochloride)
Ponatinib HydrochlorideAP24534 HCl, IclusigTreatment (combination chemotherapy, ponatinib hydrochloride)
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, PRED, Predicor, Predicorten, Prednicen-M, Prednicort, Prednidib, Prednilonga, Predniment, Prednisonum, Prednitone, Promifen, Servisone, SK-PrednisoneTreatment (combination chemotherapy, ponatinib hydrochloride)
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 Biosimilar ABP 798, Rituximab Biosimilar BI 695500, Rituximab Biosimilar CT-P10, Rituximab Biosimilar GB241, Rituximab Biosimilar IBI301, Rituximab Biosimilar PF-05280586, Rituximab Biosimilar RTXM83, Rituximab Biosimilar SAIT101, RTXM83Treatment (combination chemotherapy, ponatinib hydrochloride)
VincristineLEUROCRISTINE, VCR, VincrystineTreatment (combination chemotherapy, ponatinib hydrochloride)
Vincristine SulfateKyocristine, Leurocristine sulfate, Leurocristine, sulfate, Oncovin, Vincasar, Vincosid, Vincrex, Vincristine, sulfateTreatment (combination chemotherapy, ponatinib hydrochloride)

Purpose

This phase II trial studies the side effects and how well combination chemotherapy and ponatinib hydrochloride work in treating patients with acute lymphoblastic leukemia. Drugs used in chemotherapy, such as cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, and dexamethasone, 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. Ponatinib hydrochloride may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving combination chemotherapy and ponatinib hydrochloride may be an effective treatment for acute lymphoblastic leukemia.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To evaluate the clinical efficacy (event-free survival) of an intensive short-term
      chemotherapy regimen (hyperfractionated cyclophosphamide-vincristine sulfate-Adriamycin
      [doxorubicin hydrochloride]-dexamethasone [hyper-CVAD] program) given in combination with the
      tyrosine kinase inhibitor ponatinib hydrochloride (ponatinib) for Philadelphia (Ph)-positive
      and/or BCR-ABL-positive acute lymphoblastic leukemia (ALL).

      II. To evaluate other clinical efficacy endpoints (overall response rate and survival) and
      safety of the regimen.

      OUTLINE:

      ODD CYCLES (1, 3, 5, and 7): Patients receive cyclophosphamide intravenously (IV) over 3
      hours every 12 hours on days 1-3, doxorubicin hydrochloride IV continuously over 24 hours on
      day 4, vincristine sulfate IV over 30 minutes on days 1 and 11, dexamethasone IV over 30
      minutes or orally (PO) once daily (QD) on days 1-4 and 11-14, and ponatinib hydrochloride PO
      QD on days 1-14 of cycle 1 and continuously in cycles 3, 5, and 7. Patients with CD20
      expression may also receive rituximab IV on days 1 and 11 of cycle 1 and 3. Treatment repeats
      every 3-4 weeks for up to 8 cycle in the absence of disease progression or unacceptable
      toxicity.

      EVEN CYCLES (2, 4, 6, and 8): Patients receive methotrexate IV over 24 hours on day 1,
      ponatinib hydrochloride PO QD continuously, and cytarabine IV over 3 hours every 12 hours on
      days 2 and 3. Patients with CD20 expression may also receive rituximab IV on days 1 and 8 of
      cycle 2 and 4. Treatment repeats every 3-4 weeks for up to 8 cycle in the absence of disease
      progression or unacceptable toxicity.

      MAINTENANCE THERAPY: Patients receive vincristine sulfate IV on day 1, prednisone PO daily on
      days 1-5, and ponatinib hydrochloride PO QD on days 1-28. Cycle repeat every 28 days for 24
      months in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 30 days and then every 6
      months for up to 24 months.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (combination chemotherapy, ponatinib hydrochloride)ExperimentalSee Detailed Description.
  • Cyclophosphamide
  • Cytarabine
  • Dexamethasone
  • Doxorubicin
  • Doxorubicin Hydrochloride
  • Methotrexate
  • Ponatinib
  • Ponatinib Hydrochloride
  • Prednisone
  • Rituximab
  • Vincristine
  • Vincristine Sulfate

Eligibility Criteria

        Inclusion Criteria:

          -  Diagnosis of one of the following:

               -  Previously untreated Ph-positive ALL (either t[9;22] and/or bcr-abl positive)
                  (includes patients initiated on first course of hyper-CVAD before cytogenetics
                  known) or with lymphoid accelerated or blast phase chronic myelogenous leukemia
                  (CML)

               -  Previously treated Ph-positive ALL or CML (in accelerated phase or blast phase),
                  after 1-2 courses of chemotherapy with or without other tyrosine kinase
                  inhibitors (TKIs)

                    -  If they achieved complete response (CR), they are assessable only for
                       event-free and overall survival, or

                    -  If they failed to achieve CR, they are assessable for CR, event-free, and
                       overall survival

          -  Performance status =< 2 (Eastern Cooperative Oncology Group [ECOG] scale)

          -  Total serum bilirubin =< 1.5 x upper limit of normal (ULN), unless due to Gilbert's
             syndrome

          -  Alanine aminotransferase (ALT) =< 2 x ULN

          -  Aspartate aminotransferase (AST) =< 2.5 x ULN

          -  Serum lipase and amylase =< 1.5 x ULN

          -  For females of childbearing potential, a negative pregnancy test must be documented
             prior to randomization

          -  Female and male patients who are fertile must agree to use an effective form of
             contraception with their sexual partners from randomization through 4 months after the
             end of treatment

          -  Adequate cardiac function as assessed clinically by history and physical examination

          -  Signed informed consent

        Exclusion Criteria:

          -  Active serious infection not controlled by oral or intravenous antibiotics

          -  Known active hepatitis B; patients with chronic hepatitis B who are on appropriate
             viral suppressive therapy may be allowed after discussion with the principal
             investigator (PI)

          -  History of acute pancreatitis within 1 year of study or history of chronic
             pancreatitis

          -  History of alcohol abuse

          -  Uncontrolled hypertriglyceridemia (triglycerides > 450 mg/dL)

          -  Active secondary malignancy other than skin cancer (e.g., basal cell carcinoma or
             squamous cell carcinoma) that in the investigator's opinion will shorten survival to
             less than 1 year

          -  Active grade III-V cardiac failure as defined by the New York Heart Association
             criteria

          -  Clinically significant, uncontrolled, or active cardiovascular disease, specifically
             including, but not restricted to:

               -  Any history of myocardial infarction (MI), stroke, or revascularization

               -  Unstable angina or transient ischemic attack prior to enrollment

               -  Congestive heart failure prior to enrollment, or left ventricular ejection
                  fraction (LVEF) less than lower limit of normal per local institutional standards
                  prior to enrollment

               -  Diagnosed or suspected congenital long QT syndrome

               -  Any history of clinically significant atrial or ventricular arrhythmias (such as
                  atrial fibrillation, ventricular tachycardia, ventricular fibrillation, or
                  torsades de pointes) as determined by the treating physician

               -  Prolonged corrected QT (QTc) interval on pre-entry electrocardiogram (> 470 msec)
                  unless corrected after electrolyte replacement

               -  Any history of venous thromboembolism including deep venous thrombosis or
                  pulmonary embolism

               -  Uncontrolled hypertension (diastolic blood pressure > 90 mmHg; systolic > 140
                  mmHg); patients with hypertension should be under treatment on study entry to
                  effect blood pressure control

          -  Patients currently taking drugs that are generally accepted to have a risk of causing
             torsades de pointes (unless these can be changed to acceptable alternatives)

          -  Taking any medications or herbal supplements that are known to be strong inhibitors of
             cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) within at least 14 days
             before the first dose of ponatinib

          -  Prior history of treatment with ponatinibfor > 1 month; patient who has been treated
             with ponatinib for 1 month prior starting the treatment is eligible

          -  Treatment with any investigational antileukemic agents or chemotherapy agents in the
             last 7 days before study entry, unless full recovery from side effects has occurred or
             patient has rapidly progressive disease judged to be life-threatening by the
             investigator; patient who has been treated with ponatinib for 1 month prior starting
             the treatment is eligible

          -  Pregnant and lactating women will not be eligible; women of childbearing potential
             should have a negative pregnancy test prior to entering on the study and be willing to
             practice methods of contraception; women do not have childbearing potential if they
             have had a hysterectomy or are postmenopausal without menses for 12 months; in
             addition, men enrolled on this study should understand the risks to any sexual partner
             of childbearing potential and should practice an effective method of birth control

          -  History of significant bleeding disorder unrelated to cancer, including:

               -  Diagnosed congenital bleeding disorders (e.g., von Willebrand's disease)

               -  Diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor
                  VIII antibodies)

          -  Patients with documented significant pleural or pericardial effusions unless they are
             thought to be secondary to their leukemia
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Event-free survival
Time Frame:The time from the start of the treatment until any failure (resistant disease, relapse, or death), assessed up to 24 months
Safety Issue:
Description:Kaplan-Meier survival curves will be constructed.

Secondary Outcome Measures

Measure:Complete response rate
Time Frame:Up to 24 months after completion of study treatment
Safety Issue:
Description:Complete response is defined as achieving bone marrow blasts =< 5% AND platelets >= 100 AND absolute neutrophil count >= 1000 within 3 courses of treatment. The method of Thall, Simon, and Estey will be employed to perform short-term interim efficacy. Response rate and its corresponding 95% confidence interval will be provided at the end of the study.
Measure:Incidence of grade 3-4 toxicity according to the M.D. Anderson Leukemia-specific Adverse Event Recording and Reporting Guidelines
Time Frame:Up to 24 months
Safety Issue:
Description:The method of Thall, Simon, and Estey will be employed to perform short-term interim safety monitoring. Will be summarized in frequency tables or in the form of mean, standard deviation, and range where appropriate. Toxicity rate and its corresponding 95% confidence interval will be provided at the end of the study.
Measure:Overall survival
Time Frame:Up to 24 months after completion of study treatment
Safety Issue:
Description:Kaplan-Meier survival curves will be constructed. Survival rates at specific time points will be estimated along with corresponding 95% confidence intervals.
Measure:Disease-specific survival
Time Frame:Up to 24 months after completion of study treatment
Safety Issue:
Description:Kaplan-Meier survival curves will be constructed. Survival rates at specific time points will be estimated along with corresponding 95% confidence intervals.

Details

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

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