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

Study Overview
=================
Brief Summary
-----------------
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.

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)

Conditions
-----------------
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, Accelerated Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Acute Lymphoblastic Leukemia, Adult Acute Lymphoblastic Leukemia in Complete Remission

Intervention / Treatment
-----------------
* Drug: Cyclophosphamide
* Drug: Cytarabine
* Drug: Dexamethasone
* Drug: Doxorubicin
* Drug: Doxorubicin Hydrochloride
* Other: Laboratory Biomarker Analysis
* Drug: Methotrexate
* Drug: Ponatinib
* Drug: Ponatinib Hydrochloride
* Drug: Prednisone
* Biological: Rituximab
* Drug: Vincristine
* Drug: Vincristine Sulfate


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (combination chemotherapy, ponatinib hydrochloride)<br>See Detailed Description. | Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Drug: Cytarabine<br>* Given IV<br>* Other names: WR-28453;Drug: Dexamethasone<br>* Given IV or PO<br>* Other names: Visumetazone;Drug: Doxorubicin<br>* Given IV<br>* Other names: Hydroxyldaunorubicin;Drug: Doxorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubex;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Methotrexate<br>* Given IV<br>* Other names: WR-19039;Drug: Ponatinib<br>* Given PO<br>* Other names: AP24534;Drug: Ponatinib Hydrochloride<br>* Given PO<br>* Other names: Iclusig;Drug: Prednisone<br>* Given PO<br>* Other names: SK-Prednisone;Biological: Rituximab<br>* Given IV<br>* Other names: RTXM83;Drug: Vincristine<br>* Given IV<br>* Other names: Vincrystine;Drug: Vincristine Sulfate<br>* Given IV<br>* Other names: Vincristine, sulfate;|

What is the study measuring?
-----------------
Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete response rate | 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. | Up to 24 months after completion of study treatment | 
| Incidence of grade 3-4 toxicity according to the M.D. Anderson Leukemia-specific Adverse Event Recording and Reporting Guidelines | 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. | Up to 24 months | 
| Overall survival | Kaplan-Meier survival curves will be constructed. Survival rates at specific time points will be estimated along with corresponding 95% confidence intervals. | Up to 24 months after completion of study treatment | 
| Disease-specific survival | Kaplan-Meier survival curves will be constructed. Survival rates at specific time points will be estimated along with corresponding 95% confidence intervals. | Up to 24 months after completion of study treatment |