Hyper-CVAD and Ponatinib in Ph-Positive and/or BCR-ABL Positive Acute Lymphoblastic Leukemia (ALL)

Study Description

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Brief Summary:

The goal of this clinical research study is to learn if intensive chemotherapy combined with ponatinib, followed by maintenance therapy, can help to control ALL with the Ph chromosome and/or BCR-ABL. The safety of this treatment will also be studied.

Ponatinib may cause a blood clot to form in an artery or in a vein. Depending on the location of the clot, this could cause a heart attack, a stroke, severe damage to other tissue, or death. A blood clot may occur within 2 weeks after you start taking the drug. About 25% (1 in 4) of patients taking the drug form an abnormal clot. Blood clots can occur in patients that do not have other known risk factors for forming clots. If you develop a blood clot, you will need to stop taking ponatinib. In some cases, emergency surgery could be needed to remove the clot and restore blood flow.

This is an investigational study. Ponatinib is FDA approved to treat patients with certain types of leukemia. Its use in this study is investigational.

All other drugs used in this study are FDA approved and commercially available. Their use together in this study is investigational.

Up to 100 patients will take part in this study. All will be enrolled at MD Anderson.

Condition or disease	Intervention/treatment	Phase
Leukemia	Drug: Cyclophosphamide; Drug: Mesna; Drug: Doxorubicin; Drug: Vincristine; Drug: Dexamethasone; Drug: Ponatinib; Drug: G-CSF (Filgrastim); Drug: Rituximab; Drug: Methotrexate; Drug: Cytarabine; Drug: Solu-medrol ( Methyl Prednisolone); Drug: Citrovorum (Leucovorin); Drug: Prednisone; Drug: Pegfilgrastim (Neulasta)	Phase 2

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Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	100 participants
Allocation:	Non-Randomized
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
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)
Actual Study Start Date :	October 2011
Estimated Primary Completion Date :	October 2020
Estimated Study Completion Date :	October 2021

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Hyper-CVAD + Ponatinib; Hyper-CVAD Odd courses 1, 3, 5, 7. Cyclophosphamide 300 mg/m^2 by vein (IV) every 12 hours for 6 doses Days 1-3; Vincristine 2 mg IV Day 1 and Day 11; Doxorubicin (Adriamycin) 50 mg/m^2 continuous IV Day 4; Dexamethasone 40 mg IV/orally/day Days 1-4 and days 11-14; Methotrexate 12 mg intrathecally (6mg via Ommaya reservoir) on Day 2; Cytarabine 100 mg intrathecally Day 7; and Ponatinib 45 mg orally daily days 1-14 for Course 1 then 30 mg daily other odd courses. Pegfilgrastim (Neulasta) may replace G-CSF at 6 mg subcutaneously on Day 4.	Drug: Cyclophosphamide; 300 mg/m^2 by vein over 3 hours every 12 hrs for 6 doses days 1,2,3 (total dose 1800mg/m2) for Odd Courses 1,3,5,7.; Other Names: Cytoxan; Neosar Drug: Mesna; 600 mg/m^2 by vein continuous infusion daily for 24 hours for Odd Courses 1,3,5,7.; Other Name: Mesnex Drug: Doxorubicin; 50 mg/m2 by vein over 24 hrs via central venous catheter on Day 4 of Odd Courses 1,3,5,7.; Other Names: Doxorubicin Hydrochloride; Adriamycin PFS; Adriamycin RDF; Rubex Drug: Vincristine; 2 mg by vein on day 1 and day 11 of Odd Courses 1,3,5,7. Maintenance Therapy Starting Dose: 2 mg by vein on day 1 approximately every 28 days for 24 months. Drug: Dexamethasone; 40 mg by vein or by mouth daily on days 1-4 and days 11-14 of Odd Courses 1,3,5,7.; Other Name: Decadron Drug: Ponatinib; Odd Courses 1,3,5,7: 45 mg by mouth daily days 1-14 for Course 1. For subsequent courses 3, 5, and 7, 30 mg by mouth daily. Even Courses 2,4,6,8: 30 mg by mouth daily. Maintenance Therapy Starting Dose: 30 mg by mouth daily and 15 mg by mouth daily in patients who have achieved complete molecular response. Drug: G-CSF (Filgrastim); Even and Odd Courses: 10 mcg/kg subcutaneously daily (or 5mcg/kg twice daily) until post-nadir granulocytes >1.0 x 109/L.; Other Names: Filgrastim; NeupogenTM Drug: Rituximab; Odd Courses: 375 mg/m2 by vein on days 1 and 11 of Cycles 1 and 3 for patients with CD20 expression (>20% by flow cytometry). Even Courses: 375 mg/m2 by vein on days 1 and 8 of cycles 2 and 4 for patients with CD20 expression (>20% by flow cytometry).; Other Name: Rituxan Drug: Methotrexate; 12 mg intrathecally (6mg via Ommaya reservoir) on day 2 for Odd Courses. 200 mg/m2 by vein over 2 hours (+ 1 hr) followed by 800 mg/m2 over 22 hours on day 1 for Even Courses. Drug: Cytarabine; CNS prophylaxis: 100 mg intrathecally day 7 for Even and Odd Courses. Even Course 2,4,6,8: 3g/m2 by vein over 3 hours every 12 hours for 4 doses on days 2, 3.; Other Names: Ara-C; Cytosar; DepoCyt; Cytosine Arabinosine Hydrochloride Drug: Pegfilgrastim (Neulasta); Even Courses: Neulasta may replace G-CSF at a dose of 6 mg subcutaneously on Day 5. Odd Courses: Neulasta may replace G-CSF at 6 mg subcutaneously on Day 4.; Other Names: NeulastaTM; PEG-G-CSF
Experimental: Methotrexate + Cytarabine + Ponatinib; Even courses 2,4, 6, and 8. Methotrexate 12 mg intrathecally (6 mg via Ommaya reservoir); Cytarabine 3 g/m^2 IV every 12 hours for 4 doses Days 2 + 3; Ponatinib 30 mg orally/day; Citrovorum (Leucovorin) rescue 50 mg by vein or by mouth followed by 15 mg by vein or by mouth every 6 hours for 8 doses beginning 12 hours post Methotrexate completion. Pegfilgrastim (Neulasta) may replace G-CSF at a dose of 6 mg subcutaneously on Day 5.	Drug: Ponatinib; Odd Courses 1,3,5,7: 45 mg by mouth daily days 1-14 for Course 1. For subsequent courses 3, 5, and 7, 30 mg by mouth daily. Even Courses 2,4,6,8: 30 mg by mouth daily. Maintenance Therapy Starting Dose: 30 mg by mouth daily and 15 mg by mouth daily in patients who have achieved complete molecular response. Drug: G-CSF (Filgrastim); Even and Odd Courses: 10 mcg/kg subcutaneously daily (or 5mcg/kg twice daily) until post-nadir granulocytes >1.0 x 109/L.; Other Names: Filgrastim; NeupogenTM Drug: Rituximab; Odd Courses: 375 mg/m2 by vein on days 1 and 11 of Cycles 1 and 3 for patients with CD20 expression (>20% by flow cytometry). Even Courses: 375 mg/m2 by vein on days 1 and 8 of cycles 2 and 4 for patients with CD20 expression (>20% by flow cytometry).; Other Name: Rituxan Drug: Methotrexate; 12 mg intrathecally (6mg via Ommaya reservoir) on day 2 for Odd Courses. 200 mg/m2 by vein over 2 hours (+ 1 hr) followed by 800 mg/m2 over 22 hours on day 1 for Even Courses. Drug: Cytarabine; CNS prophylaxis: 100 mg intrathecally day 7 for Even and Odd Courses. Even Course 2,4,6,8: 3g/m2 by vein over 3 hours every 12 hours for 4 doses on days 2, 3.; Other Names: Ara-C; Cytosar; DepoCyt; Cytosine Arabinosine Hydrochloride Drug: Solu-medrol ( Methyl Prednisolone); 50 mg by vein every 12 hours for 6 doses days 1-3 of Even Course 2,4,6,8.; Other Names: Depo-Medrol; Medrol; Methyl Prednisolone Drug: Citrovorum (Leucovorin); Even Courses 2,4,6,8 on Days 2 - 5: Rescue 50 mg by vein or mouth followed by 15 mg by vein or by mouth every 6 hours for 8 doses beginning 12 hours post Methotrexate completion, i.e. approximately 36 hours from start of Methotrexate.; Other Names: Leucovorin; Wellcovorin Drug: Pegfilgrastim (Neulasta); Even Courses: Neulasta may replace G-CSF at a dose of 6 mg subcutaneously on Day 5. Odd Courses: Neulasta may replace G-CSF at 6 mg subcutaneously on Day 4.; Other Names: NeulastaTM; PEG-G-CSF
Experimental: Maintenance Therapy; Maintenance chemotherapy with vincristine, and prednisone for approximately 24 months. Vincristine 2 mg by vein on day 1 approximately every 28 days for 24 months. Ponatinib 30 mg by mouth daily as tolerated and 15 mg by mouth daily in patients who have achieved complete molecular response. Prednisone 200 mg by mouth daily days 1-5 approximately every 28 days with vincristine for 24 months.	Drug: Vincristine; 2 mg by vein on day 1 and day 11 of Odd Courses 1,3,5,7. Maintenance Therapy Starting Dose: 2 mg by vein on day 1 approximately every 28 days for 24 months. Drug: Ponatinib; Odd Courses 1,3,5,7: 45 mg by mouth daily days 1-14 for Course 1. For subsequent courses 3, 5, and 7, 30 mg by mouth daily. Even Courses 2,4,6,8: 30 mg by mouth daily. Maintenance Therapy Starting Dose: 30 mg by mouth daily and 15 mg by mouth daily in patients who have achieved complete molecular response. Drug: Prednisone; Maintenance Therapy Starting Dose: 200 mg by mouth daily days 1-5 approximately every 28 days with vincristine for 24 months.

Outcome Measures

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Primary Outcome Measures :

1. Participants' Median Event-Free Survival (EFS) [ Time Frame: Baseline to time to failure (disease progression or death) up to 2 years. ]
   Event-free survival interval is the time from the start of the treatment until any failure (resistant disease, relapse, or death), measured in months.

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

1. Diagnosis of one of the following: a) 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); b) Previously treated Ph-positive ALL, after 1-2 courses of chemotherapy with or without other TKIs 1) If they achieved CR, they are assessable only for event-free and overall survival, or 2) If they failed to achieve CR, they are assessable for CR, event-free, and overall survival.
2. Age >/= 18 years
3. Performance status </= 2 (ECOG Scale, Appendix E)
4. Adequate liver function as defined by the following criteria: a) Total serum bilirubin </= 1.5 x upper limit of normal (ULN), unless due to Gilbert's syndrome, b) Alanine aminotransferase (ALT) </= 2 x ULN, c) Aspartate aminotransferase (AST) </= 2.5 x ULN)
5. Adequate pancreatic function as defined by the following criteria: a) Serum lipase and amylase </= 1.5 x ULN),
6. For females of childbearing potential, a negative pregnancy test must be documented prior to randomization
7. 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
8. Adequate cardiac function as assessed clinically by history and physical examination.
9. Signed informed consent

Exclusion Criteria:

1. Active serious infection not controlled by oral or intravenous antibiotics
2. History of acute pancreatitis within 1 year of study or history of chronic pancreatitis
3. History of alcohol abuse
4. Uncontrolled hypertriglyceridemia (triglycerides > 450mg/dL)
5. 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
6. Active Grade III-V cardiac failure as defined by the New York Heart Association Criteria
7. 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 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;
8. Continued from #7: Uncontrolled hypertension (diastolic blood pressure >90mmHg; systolic >140mmHg). Patients with hypertension should be under treatment on study entry to effect blood pressure control.
9. 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)
10. Taking any medications or herbal supplements that are known to be strong inhibitors of CYP3A4 within at least 14 days before the first dose of ponatinib
11. Prior history of treatment with ponatinib
12. 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
13. 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
14. History of significant bleeding disorder unrelated to cancer, including: a) Diagnosed congenital bleeding disorders (e.g., von Willebrand's disease), b) Diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor VIII antibodies)
15. Patients with documented significant pleural or pericardial effusions unless they are thought to be secondary to their leukemia

Contacts and Locations

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Contacts

Contact: Elias Jabbour, MD	713-792-7026

Locations

United States, Texas
University of Texas MD Anderson Cancer Center	Recruiting
Houston, Texas, United States, 77030

Sponsors and Collaborators

M.D. Anderson Cancer Center

Ariad Pharmaceuticals

Investigators

Principal Investigator:	Elias Jabbour, MD	M.D. Anderson Cancer Center

More Information

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Additional Information:

University of Texas MD Anderson Cancer Center Website 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Jabbour E, Kantarjian H, Ravandi F, Thomas D, Huang X, Faderl S, Pemmaraju N, Daver N, Garcia-Manero G, Sasaki K, Cortes J, Garris R, Yin CC, Khoury JD, Jorgensen J, Estrov Z, Bohannan Z, Konopleva M, Kadia T, Jain N, DiNardo C, Wierda W, Jeanis V, O'Brien S. Combination of hyper-CVAD with ponatinib as first-line therapy for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia: a single-centre, phase 2 study. Lancet Oncol. 2015 Nov;16(15):1547-1555. doi: 10.1016/S1470-2045(15)00207-7. Epub 2015 Sep 30.

Responsible Party:	M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier:	NCT01424982 History of Changes
Other Study ID Numbers:	2011-0030; NCI-2011-02941 ( Registry Identifier: NCI CTRP )
First Posted:	August 29, 2011
Last Update Posted:	April 20, 2018
Last Verified:	April 2018

Studies a U.S. FDA-regulated Drug Product:		Yes
Studies a U.S. FDA-regulated Device Product:		No

Keywords provided by M.D. Anderson Cancer Center:

Leukemia; Ph-positive acute lymphoblastic leukemia; ALL; Philadelphia (Ph) chromosome; BCR-ABL; Depo-Medrol; Medrol; Solu-Medrol; Methylprednisolone; Vincristine; Dexamethasone; Decadron; Ponatinib; G-CSF; Filgrastim	NeupogenTM; Cyclophosphamide; Cytoxan; Neosar; Doxorubicin; Doxorubicin Hydrochloride; Adriamycin PFS; Adriamycin RDF; Adriamycin; Rubex; Rituximab; Rituxan; Mesna; Mesnex; Cytarabine

Additional relevant MeSH terms:

Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Dexamethasone acetate; Prednisolone acetate; Methylprednisolone acetate; Dexamethasone; Prednisone; Prednisolone	Methylprednisolone; Methylprednisolone Hemisuccinate; Prednisolone hemisuccinate; Prednisolone phosphate; Liposomal doxorubicin; Ponatinib; Cyclophosphamide; Rituximab; Doxorubicin; Methotrexate; Cytarabine; Vincristine; BB 1101; Lenograstim; Mesna