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

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2014 by M.D. Anderson Cancer Center
Sponsor:
Collaborator:
Ariad Pharmaceuticals
Information provided by (Responsible Party):
M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier:
NCT01424982
First received: August 24, 2011
Last updated: September 3, 2014
Last verified: September 2014
  Purpose

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.


Condition Intervention 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

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: 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)

Resource links provided by NLM:


Further study details as provided by M.D. Anderson Cancer Center:

Primary Outcome Measures:
  • Participants' Median Event-Free Survival (EFS) [ Time Frame: Baseline to time to failure (disease progression or death) up to 2 years. ] [ Designated as safety issue: No ]
    Event-free survival interval is the time from the start of the treatment until any failure (resistant disease, relapse, or death), measured in months.


Estimated Enrollment: 60
Study Start Date: October 2011
Estimated Primary Completion Date: October 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
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 arterial 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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01424982

Contacts
Contact: Susan O'Brien, MD,BA 713-792-7543

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: Susan O'Brien, MD,BA M.D. Anderson Cancer Center
  More Information

Additional Information:
No publications provided

Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT01424982     History of Changes
Other Study ID Numbers: 2011-0030, NCI-2011-02941
Study First Received: August 24, 2011
Last Updated: September 3, 2014
Health Authority: United States: Food and Drug Administration

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
Leukemia, Lymphoid
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Mesna
Levoleucovorin
Methylprednisolone
Methylprednisolone Hemisuccinate
Cyclophosphamide
Cytarabine
Methotrexate
Rituximab
Liposomal doxorubicin
Ponatinib
Dexamethasone
Doxorubicin
Prednisolone
Prednisone
Vincristine
Lenograstim
Dexamethasone acetate
Methylprednisolone acetate
Prednisolone acetate
Dexamethasone 21-phosphate
Prednisolone hemisuccinate

ClinicalTrials.gov processed this record on September 14, 2014