Hyper-CVAD With Liposomal Vincristine in Acute Lymphoblastic Leukemia

Overview[ - collapse ][ - ]

Purpose The goal of this clinical research study is to learn if intensive chemotherapy (hyper-CVAD therapy) given in combination with liposomal vincristine (Marqibo), in addition to rituximab for patients who are CD20 positive and/or imatinib or dasatinib for patients with the Philadelphia (Ph) chromosome, can help to control ALL or lymphoblastic lymphoma. The safety of this treatment will also be studied. CD20 is a protein "marker" that is found in leukemia or lymphoma cells.
ConditionLeukemia
InterventionDrug: Rituximab
Drug: Imatinib
Drug: Cyclophosphamide
Drug: Doxorubicin
Drug: Mesna
Drug: VSLI
Drug: Solu-Medrol
Drug: Methotrexate
Drug: Ara-C
Drug: G-CSF
Drug: Pegfilgrastim
Drug: Dexamethasone
PhasePhase 2
SponsorM.D. Anderson Cancer Center
Responsible PartyM.D. Anderson Cancer Center
ClinicalTrials.gov IdentifierNCT01319981
First ReceivedMarch 18, 2011
Last UpdatedDecember 9, 2013
Last verifiedDecember 2013

Tracking Information[ + expand ][ + ]

First Received DateMarch 18, 2011
Last Updated DateDecember 9, 2013
Start DateMarch 2013
Estimated Primary Completion DateNot Provided
Current Primary Outcome MeasuresNumber of Patients With Complete Remission at One Year [Time Frame: 1 year] [Designated as safety issue: Yes]
Current Secondary Outcome MeasuresNot Provided

Descriptive Information[ + expand ][ + ]

Brief TitleHyper-CVAD With Liposomal Vincristine in Acute Lymphoblastic Leukemia
Official TitleHyper-CVAD With Liposomal Vincristine (Hyper-CMAD) in Acute Lymphoblastic Leukemia
Brief Summary
The goal of this clinical research study is to learn if intensive chemotherapy (hyper-CVAD
therapy) given in combination with liposomal vincristine (Marqibo), in addition to rituximab
for patients who are CD20 positive and/or imatinib or dasatinib for patients with the
Philadelphia (Ph) chromosome, can help to control ALL or lymphoblastic lymphoma. The safety
of this treatment will also be studied. CD20 is a protein "marker" that is found in
leukemia or lymphoma cells.
Detailed Description
The Study Drugs:

Adriamycin (doxorubicin) is designed to stop the growth of cancer cells, which may cause the
cells to die.

Cyclophosphamide is designed to disrupt with the multiplication of cancer cells, which may
slow or stop their growth and spread throughout the body. This may cause the cancer cells
to die.

Cytarabine (Ara-C) is designed to insert itself into DNA (the genetic material of cells) of
cancer cells and stop the DNA from repairing itself.

Dexamethasone is a corticosteroid that is similar to a natural hormone made by your body.

Methotrexate is designed to disrupt cells from making and repairing DNA and "copying"
themselves.

Vincristine is designed to disrupt the multiplication of cancer cells, which may slow or
stop their growth and spread throughout the body. This may cause the cancer cells to die.

Liposomal Vincristine (Marqibo) is designed to help vincristine stay in the bloodstream for
a longer time, more specifically target tumor tissue, and deliver more of the drug to a
tumor site over a longer period of time. This may increase how effective the drug is and
lower the risk of possible side effects in healthy, non-tumor tissue.

Rituximab is a monoclonal antibody that is designed to attach to leukemia cells and activate
a series of events that may cause the cancer cells to die.

Tyrosine Kinase Inhibitors (TKI--Imatinib or Dasatinib) Imatinib is a drug designed to block
cancer cells from growing and dividing. Dasatinib is designed to block a protein that cancer
may need to grow, survive, or spread.

Study Groups:

If you are found to be eligible to take part in this study, you will be assigned to 1 of 2
groups, based on your already performed diagnostic test for a certain protein, called CD20.

- If you test positive for CD20, you will receive hyper-CVAD therapy plus rituximab.

- If you test negative for CD20, you will receive hyper-CVAD therapy only.

In addition, patients with the Philadelphia chromosome (considered Philadelphia-positive or
Ph+) will receive imatinib or dasatinib in either group. The study doctor will decide which
drug these participants will receive.

Study Drug Administration:

Hyper-CVAD therapy is a combination of 7 chemotherapy drugs: the combination of adriamycin
(doxorubicin), cyclophosphamide, and liposomal vincristine, alternating with the combination
of cytarabine (Ara-C), dexamethasone, methotrexate, and liposomal vincristine. You will
receive the 2 different study drug combinations over 21-28 day "courses." You will begin
with Course A treatment and alternate with the Course B treatment every other course. You
will stay overnight in the hospital for the first 4-5 days of each course.

For Course A of treatment, you will receive cyclophosphamide, liposomal vincristine,
doxorubicin, and dexamethasone.

For Course B of treatment, you will receive methotrexate, cytarabine, and liposomal
vincristine.

Courses of treatment on this study will continue to alternate or switch between the Course A
study drug combination for all odd number courses (3, 5, and 7) and the Course B study drug
combination for all even number courses (4, 6, and 8) for a total of up to 8 courses.

While you are on study, all doses of study drug combinations will be given through a central
venous catheter (CVC). A CVC is a sterile flexible tube that will be placed into a large
vein while you are under local anesthesia. Your doctor will explain this procedure to you
in more detail, and you will be required to sign a separate consent form for this procedure.

Course 1:

On Days 1, 2, and 3 you will receive cyclophosphamide by vein over 2-3 hours, mesna by vein
continuously over 24 hours, and liposomal vincristine by vein over 1 hour +/- 30 minutes
(Day 1 only). Mesna is given to help prevent blood in the urine, which is sometimes caused
by cyclophosphamide.

On Days 2 and 7, methotrexate then cytarabine will be given by intrathecal (IT) infusion
directly into your spinal fluid to lower the risk of the disease spreading to the brain.

On Day 4, you will receive doxorubicin by vein over 24 hours.

On Day 5 or 6, G-CSF will be injected under the skin to help with the recovery of bone
marrow cells recovery 24 hours after the dose of study drugs.

On Day 8, you will receive liposomal vincristine by vein over 1 hour +/- 30 minutes.

On Days 1-4 and Days 11-14, dexamethasone will be given by mouth with a glass of water or by
vein as a short infusion.

CD20 positive patients only will also receive rituximab by vein over 6 hours, on Days 1 and
8, in addition to receiving all study drugs, as described above. If you are CD20 negative,
you will not receive rituximab.

Ph+ participants will receive imatinib by mouth with breakfast and a large glass of water
(about 8 ounces) or dasatinib by mouth on Days 1-14 during Course 1.

Course 2:

On Day 1, you will receive methotrexate by vein over 24 hours and liposomal vincristine by
vein over 1 hour +/- 30 minutes.

On Days 2 and 3, you will receive cytarabine by vein over 2 hours every 12 hours for a total
of 4 doses. You will also be given citrovorum factor (leucovorin) by vein or by mouth to
help prevent the possible side effects of methotrexate.

On Day 5 or 6, G-CSF will be injected under the skin to help with bone marrow recovery 24
hours after the dose of study drugs.

On Days 2 and 7, methotrexate then cytarabine will be given by IT infusion to lower the risk
of the disease spreading to the brain.

CD20 positive patients only will also receive rituximab by vein over 4 hours, on Days 1 and
8, in addition to receiving all study drugs, as described above. If you are CD20 negative,
you will not receive rituximab.

Ph+ participants will receive imatinib by mouth with breakfast and a large glass of water
(about 8 ounces) every day during Courses 2-8. Dasatinib will be given by mouth every day
during Courses 2-8.

Course 1 Study Visits:

- Blood (about 5 teaspoons each time) will be drawn weekly for routine tests.

- During Week 2 and 3 or 4, a bone marrow aspirate will be performed to check the status
of the disease.

- At the end of Course 1, if the study doctor thinks it is needed, a chest X-ray or CT
scan will be performed to check the status of the disease.

If the study doctor thinks it is needed, any of these tests may be repeated at any time
while you are receiving the study drug combination.

Radiation Treatment:

If you have lymphoblastic lymphoma and you have enlarged lymph glands in the chest, you may
receive radiation treatment to the chest after completing 8 courses of therapy and before
you begin maintenance therapy. If you are to receive radiation therapy to the chest, the
study doctor will discuss this procedure and its known risks with you in more detail, and
you will be given a separate consent form to sign.

Maintenance Therapy -- Non-Ph+ Participants:

After completing 8 courses of the study drug combinations, you will begin maintenance
therapy for a total of 30 months, and will be interrupted by 2 periods of intensive
chemotherapy consolidation courses.

Every month during maintenance therapy:

- You will take 6-mercaptopurine every day by mouth.

- You will receive methotrexate by vein or mouth 1 time every week.

- You will receive liposomal vincristine by vein over 1 hour +/- 30 minutes on Day 1.

- You will take dexamethasone by mouth on Days 1-5 each month.

First intensive chemotherapy consolidation courses:

- Six (6) months after you begin maintenance therapy, you will receive two months of
intensive chemotherapy courses.

- First, you will receive cyclophosphamide, liposomal vincristine, doxorubicin, and
dexamethasone (similar to Course 1) for Month 6 of therapy.

- About one (1) month later, you will receive methotrexate by vein (at a lower dose than
given during Course 2) on Day 1 and L-asparaginase by vein on Day 2. You will be given
each drug 1 time each week for a total of 4 weeks for Month 7 of therapy.

About eighteen (18) months after you begin maintenance therapy, you will repeat the
intensive chemotherapy courses just described.

Maintenance Therapy -- Ph+ Participants:

After completing 8 courses of the study drug combinations, you will begin maintenance
chemotherapy plus imatinib or dasatinib. Maintenance chemotherapy will be given for a total
of 24 months, and will be interrupted by 2 periods of intensive chemotherapy courses and
imatinib or dasatinib at 6 and 13 months from the start of maintenance. You will continue
receiving imatinib or dasatinib every day from that point on, unless intolerable side
effects occur.

Every month during maintenance therapy:

- You will take imatinib or dasatinib every day by mouth.

- You will receive liposomal vincristine by vein over 1 hour +/- 30 minutes on Day 1.

- You will take dexamethasone by mouth on Days 1-5 each month.

Intensive chemotherapy consolidation courses:

-At six (6) and thirteen (13) months after you begin maintenance therapy, you will receive
two months of intensive chemotherapy courses. You will receive cyclophosphamide, liposomal
vincristine, doxorubicin, and dexamethasone with imatinib or dasatinib (similar to Course
1).

Blood Tests:

During maintenance therapy and the intensive consolidation therapy, you will have blood
(about 5 teaspoons) drawn every 4 weeks +/- 4 weeks for routine tests.

After intensive chemotherapy consolidation, for as long as you continue to receive
maintenance therapy, blood (about 5 teaspoons) will be drawn every 4 weeks +/- 4 weeks,
until maintenance therapy is completed:

Additional Tests while on Study:

Every 3-6 months:

- You will have a bone marrow biopsy performed to check the status of the disease.

- If you have mediastinal disease, you will have a chest x-ray or CT scan.

Length of Study:

You will receive up to 8 courses of therapy. If you are not Ph+, you will continue to
receive maintenance therapy for up to 30 months. If you are Ph+, you will continue to
receive maintenance therapy for up to 24 months, followed by imatinib or dasatinib alone
indefinitely. You will be taken off the study if disease gets worse, you experience
intolerable side effects, or the study doctor thinks it is in your best interest.

Additional Information:

If you are 60 years or older, you will receive Course 1 chemotherapy in a protective
isolation room to decrease the risk of any infection(s) that you may be exposed to while
receiving the Course 1 treatment.

This is an investigational study. Liposomal vincristine is FDA approved for the treatment
of patients with CLL who have relapsed at least 2 times. All of the other study drugs used
in this study are FDA approved and commercially available. The combination of liposomal
vincristine with the other study drugs is also being used in research only.

Up to 65 patients will take part in this study. All will be enrolled at MD Anderson.
Study TypeInterventional
Study PhasePhase 2
Study DesignAllocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
ConditionLeukemia
InterventionDrug: Rituximab
In CD20-positive patients, 375 mg/m2 by vein on day 1 and 8 for Courses 1 and 3; and day 1 and 8 of Courses 2 and 4.
Other Names:
RituxanDrug: Imatinib
600 mg by mouth daily days 1-14 for course 1 and continuously on all other courses for patients who are Philadelphia chromosome positive (Ph+).
Other Names:
  • Imatinib Mesylate
  • Gleevec
  • ST1571
  • NSC-716051
Drug: Cyclophosphamide
300 mg/m2 by vein over 3 hours every 12 hours x 6 doses days 1, 2, 3 (total dose 1800 mg/m2) for courses 1, 3, 5, 7
Other Names:
  • Cytoxan
  • Neosar
Drug: Doxorubicin
50 mg/m2 by vein over 24 hours on day 4 after last dose of Cyclophosphamide for courses 1, 3, 5, 7
Other Names:
  • Adriamycin
  • Rubex
Drug: Mesna
600 mg/m2 by vein continuous infusion daily for 24 hours days 1-3 for courses 1, 3, 5, 7
Other Names:
MesnexDrug: VSLI
2.25 mg/m2 by vein on day 1 and day 8 for courses 1, 3, 5, 7; and day 1 for courses 2, 4, 6, 8
Other Names:
  • Liposomal Vincristine
  • Vincristine Sulfate Liposomes Injection
  • Marqibo
Drug: Solu-Medrol
40 mg by vein every 12 hours for 6 doses days 1-3 for courses 2, 4, 6, 8.
Other Names:
  • Methylprednisolone
  • Depo-Medrol
  • Medrol
Drug: Methotrexate
200 mg/m2 IV over 2 hrs followed by 800 mg/m2 over 22 hrs on day 1 beginning after the completion of rituximab for Courses 2, 4, 6, and 8.
Drug: Ara-C
3 gm/m2 by vein over 2 hours every 12 hours for 4 doses on days 2, 3 for Courses 2, 4, 6, and 8.
Other Names:
  • Cytarabine
  • Cytosar
  • DepoCyt
  • Cytosine Arabinosine Hydrochloride
Drug: G-CSF
10 mg/kg/day (rounded) given subcutaneously until neutrophil recovery to 1 x 109/L or higher can be substituted or can be added if neutrophils have not recovered to 1 x 109/L by day 21.
Other Names:
  • Filgrastim
  • Neupogen
Drug: Pegfilgrastim
6 mg/kg (rounded) within 72 hrs after completion of chemotherapy.
Other Names:
NeulastaDrug: Dexamethasone
40 mg by vein or by mouth daily days 1-4 and days 11-14 for courses 1, 3, 5, 7
Other Names:
Decadron
Study Arm (s)
  • Experimental: Hyper-CMAD + Rituximab
    Odd Courses 1, 3, 5, 7: Rituximab 375 mg/m2 IV Day 1 & 8 Courses 1 & 3; Imatinib oral 600 mg days 1-14 Course 1 then continuously; Cyclophosphamide 300 mg/m2 IV every; 12 hours for 6 doses; Mesna 600 mg/m2/day IV Days 1-3; Doxorubicin 50 mg/m2 IV CVC Day 4; VSLI 2.25 mg/M2 IV Day 1 & 8; Solu-Medrol 40 mg IV approximately every 12 hours for 6 doses days 1-3; Pegfilgrastim 6 mg/kg after chemotherapy + G-CSF 10 mg/kg/day; Dexamethasone 40 mg IV or P.O. daily days 1-4 and days 11-14 +/- 3 days.
  • Experimental: Hyper-CVAD
    Courses 2, 4, 6, 8: Rituximab 375 mg/m2 IV Day 1 & 8 Courses 2 & 4; Imatinib oral 600 mg; Methotrexate 200 mg/m2 IV over 2 hours followed by 8-0- mg/m2 over 22 hours on Day 1; Decadron 40 mg IV or orally 4 times Days 1-4; VSLI 2.25 mg/M2 IV Day 1; Ara-C 3 gm/m2 IV every 2 hours, 4 doses on Days 2-3; Pegfilgrastim 6 mg/kg after chemotherapy + G-CSF 10 mg/kg/day.

Recruitment Information[ + expand ][ + ]

Recruitment StatusRecruiting
Estimated Enrollment65
Estimated Completion DateNot Provided
Estimated Primary Completion DateMarch 2019
Eligibility Criteria
Inclusion Criteria:

1. Newly diagnosed previously untreated ALL or lymphoblastic lymphoma >/= 18 years old.

2. Zubrod performance status
3. Adequate liver function (bilirubin renal function (creatinine
4. No active co-existing malignancy with life expectancy less than 12 months due to that
malignancy.

5. All men and women of childbearing potential who are participating in the study must
agree to use effective forms of birth control throughout the duration of their
treatment.

6. Adequate cardiac function as assessed clinically

Exclusion Criteria:

1. Pregnant or lactating women. Women of childbearing potential (WOCB) must have a blood
or urine pregnancy test within 7 days prior to administration of the study drug.
(WOCB is defined as a woman who has not undergone hysterectomy or bilateral
oophorectomy and has not been naturally postmenopausal for at least 24 consecutive
months).

2. Active Grade III-IV cardiac failure as defined by the New York Heart Association
criteria, uncontrolled angina or MI within 6 months.

3. Patients with medical conditions that compromise their ability to complete the study
or confound interpretation of study results.
GenderBoth
Ages18 Years
Accepts Healthy VolunteersNo
ContactsContact: Susan O'Brien, MD, BA
713-792-7543
Location CountriesUnited States

Administrative Information[ + expand ][ + ]

NCT Number NCT01319981
Other Study ID Numbers2008-0598
Has Data Monitoring CommitteeNo
Information Provided ByM.D. Anderson Cancer Center
Study SponsorM.D. Anderson Cancer Center
CollaboratorsSpectrum Pharmaceuticals, Inc
Investigators Principal Investigator: Susan O'Brien, MD, BA UT MD Anderson Cancer Center
Verification DateDecember 2013

Locations[ + expand ][ + ]

UT MD Anderson Cancer Center
Houston, Texas, United States, 77030
Contact: , MD,BA
Recruiting