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

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

ACTIVE_NOT_RECRUITING

Clinical Phase

PHASE2

Total Enrollment

88 participants

Study Classification

INTERVENTIONAL

Study Start Date

2011-10-05

Study Completion Date

2027-10-31

Brief Summary

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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.

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Detailed Description

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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.

Conditions

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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

Study Design

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Allocation Method

NA

Intervention Model

SINGLE_GROUP

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Treatment (combination chemotherapy, ponatinib hydrochloride)

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Group Type EXPERIMENTAL

Cyclophosphamide

Intervention Type DRUG

Given IV

Cytarabine

Intervention Type DRUG

Given IV

Dexamethasone

Intervention Type DRUG

Given IV or PO

Doxorubicin

Intervention Type DRUG

Given IV

Doxorubicin Hydrochloride

Intervention Type DRUG

Given IV

Laboratory Biomarker Analysis

Intervention Type OTHER

Correlative studies

Methotrexate

Intervention Type DRUG

Given IV

Ponatinib

Intervention Type DRUG

Given PO

Ponatinib Hydrochloride

Intervention Type DRUG

Given PO

Prednisone

Intervention Type DRUG

Given PO

Rituximab

Intervention Type BIOLOGICAL

Given IV

Vincristine

Intervention Type DRUG

Given IV

Vincristine Sulfate

Intervention Type DRUG

Given IV

Interventions

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Cyclophosphamide

Given IV

Intervention Type DRUG

Cytarabine

Given IV

Intervention Type DRUG

Dexamethasone

Given IV or PO

Intervention Type DRUG

Doxorubicin

Given IV

Intervention Type DRUG

Doxorubicin Hydrochloride

Given IV

Intervention Type DRUG

Laboratory Biomarker Analysis

Correlative studies

Intervention Type OTHER

Methotrexate

Given IV

Intervention Type DRUG

Ponatinib

Given PO

Intervention Type DRUG

Ponatinib Hydrochloride

Given PO

Intervention Type DRUG

Prednisone

Given PO

Intervention Type DRUG

Rituximab

Given IV

Intervention Type BIOLOGICAL

Vincristine

Given IV

Intervention Type DRUG

Vincristine Sulfate

Given IV

Intervention Type DRUG

Other Intervention Names

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(-)-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- 138719 .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-28453 Aacidexam 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 Visumetazone Adriablastin Hydroxyl Daunorubicin Hydroxyldaunorubicin 5,12-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 Rubex Abitrexate 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-19039 AP-24534 AP24534 AP24534 HCl Iclusig .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-Prednisone ABP 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 RTXM83 LEUROCRISTINE VCR Vincrystine Kyocristine Leurocristine sulfate Leurocristine, sulfate Oncovin Vincasar Vincosid Vincrex Vincristine, sulfate

Eligibility Criteria

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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, Appendix E)
* Adequate liver function as defined by the following criteria:
* 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
* Adequate pancreatic function as defined by the following criteria:
* 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
* 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

Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No