Overview

This trial is active, not recruiting.

Conditions acute lymphoblastic leukemia, leukemia
Treatments cyclophosphamide, vincristine, doxorubicin, dexamethasone, dasatinib, methotrexate, ara-c
Phase phase 2
Target BCR-ABL
Sponsor M.D. Anderson Cancer Center
Collaborator Bristol-Myers Squibb
Start date September 2006
End date August 2017
Trial size 115 participants
Trial identifier NCT00390793, 2006-0478, NCI-2010-00518

Summary

The goal of this clinical research study is to find out if intensive chemotherapy combined with dasatinib, 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.

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Allocation non-randomized
Endpoint classification safety/efficacy study
Intervention model single group assignment
Masking open label
Primary purpose treatment
Arm
(Experimental)
Odd-numbered courses (1, 3, 5, and 7), Cyclophosphamide intravenous (IV) Days 1-3, every 12 hours for 6 doses with MESNA CVC over 24 hours until 12 hours after last dose cyclophosphamide; Vincristine IV Days 4 and 11, over 30 minutes during hyper-CVAD therapy; Doxorubicin CVC Day 4 over 24-48 hours after last dose of Cyclophosphamide; Dexamethasone Days 1-4 & Days 11-14 PO or IV over 30 minutes during hyper-CVAD therapy.
cyclophosphamide Cytoxan
300 mg/m2 IV over 3 hours every 12 hours x 6 doses days 1, 2 & 3
vincristine Vincasar
2 mg IV on day 4 +/- 2 days and day 11 +/- 2 days
doxorubicin Adriamycin
50 mg/m^2 IV over 24 hours on day 4
dexamethasone Decadron
40 mg IV or by mouth days 1-4 +/- 2 days and days 11-14 +/- 2 days
dasatinib Sprycel
100 mg by mouth (PO) daily on days 1-14; 70 mg PO daily continuously for Course 2 - 8.
ara-c Cytarabine
3 g/m^2 IV over 2 hours every 12 hours for 4 doses on days 2, 3.
(Experimental)
Even-numbered courses (2, 4, 6, and 8), Methotrexate IV Day 1; Ara-C IV Days 2 and 3 (over 2 hours every 12 hours for total of 4 doses each time)
dasatinib Sprycel
100 mg by mouth (PO) daily on days 1-14; 70 mg PO daily continuously for Course 2 - 8.
methotrexate
200 mg/m^2 over 2 hours followed by 800 mg/m^2 over 22 hours on day 1.
ara-c Cytarabine
3 g/m^2 IV over 2 hours every 12 hours for 4 doses on days 2, 3.

Primary Outcomes

Measure
Event-Free Survival (CR rates and disease-free survivals)
time frame: 2 Years

Eligibility Criteria

Male or female participants at least 18 years old.

Inclusion Criteria: 1. 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) These groups will be analyzed separately. After 1-2 courses of chemotherapy with or without imatinib mesylate (Gleevec) · If they achieved 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. Patients with relapsed Ph-positive ALL or lymphoid blast phase of CML. 2. Age greater than or equal to 18 years 3. ECOG performance status less than or equal to 2 4. Adequate liver function (bilirubin less than or equal to 3.0 mg/dl, unless considered due to tumor), and renal function (creatinine less than or equal to 3.0 mg/dl, unless considered due to tumor) 5. Adequate cardiac function as assessed clinically. 6. Signed informed consent Exclusion Criteria: 1. Active serious infection not controlled by oral or intravenous antibiotics 2. 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 3. 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 4. Active Grade III-V cardiac failure as defined by the New York Heart Association Criteria. Uncontrolled angina, or MI within 6 months. Diagnosed or suspected congenital long QT syndrome. Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes). Prolonged QTc interval on pre-entry electrocardiogram (> 470 msec). 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) 5. Prior history of treatment with dasatinib 6. 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. 7. 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) 8. Patients with documented significant pleural or pericardial effusions unless they are thought to be secondary to their leukemia

Additional Information

Official title Phase II Study of Combination of Hyper-CVAD and Dasatinib in Patients With Philadelphia (Ph) Chromosome Positive and/or BCR-ABL Positive Acute Lymphoblastic Leukemia (ALL)
Principal investigator Farhad Ravandi-Kashani, MD
Description The intensive chemotherapy used in this study includes a combination of 7 chemotherapy drugs. These drugs include cyclophosphamide, vincristine, Adriamycin (doxorubicin), dexamethasone, methotrexate, cytarabine (Ara-C), and dasatinib and possibly rituximab. The maintenance therapy used in this study includes a combination of 3 chemotherapy drugs. These drugs include vincristine, prednisone, and dasatinib. Ara-C is designed to insert itself into DNA (the genetic material of cells) and stop the DNA from repairing itself. Cyclophosphamide is designed to interfere 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. Dasatinib is designed to block a protein that cancer may need to grow, survive, or spread. Dexamethasone, doxorubicin, methotrexate, and prednisone are each designed to stop or slow the growth of cancer cells, which may cause the cells to die. Vincristine is designed to interfere 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. Rituximab is designed to attach to lymphoma cells, which may cause them to die. If you are found to be eligible to take part in this study, you will receive intensive chemotherapy therapy and dasatinib followed by maintenance therapy. You will receive 2 kinds of intensive chemotherapy regimens (hyper-CVAD therapy and methotrexate plus cytarabine) that will alternate about every 3 weeks for a total of 8 cycles (4 courses of each regimen). You will have further routine blood draws (about 1 tablespoon each time) at different time points throughout this study. You will have blood drawn during Course 1 (about twice weekly); for the remainder 7 courses (about once a week); and during the maintenance phase (about once every 4-6 weeks). You will have further bone marrow biopsies performed at different time points throughout this study. You will have a bone marrow biopsy to see if the treatment is controlling the disease, during Course 1 on Days 14 and 21, as well as whenever the study doctor thinks it is necessary to see if the Ph chromosome and/or BCR-ABL is still present. Intensive Chemotherapy: You may receive up to 8 cycles of intensive chemotherapy in the hospital (about 4 or 5 days). For participants 60 years and older, you will receive the entire first course in the hospital (about 21 days), in a protected environment, until you have healthy recovery of your blood counts. Hyper-CVAD therapy will be given during the odd-numbered courses (1, 3, 5, and 7). You will receive cyclophosphamide by vein on Days 1-3, which will be given every 12 hours for a total of 6 doses. While you are receiving cyclophosphamide, you will also receive MESNA by a central venous catheter (CVC), which will be given over 24 hours until about 12 hours after your last dose of cyclophosphamide. This drug is used to help protect your bladder from the side effects (such as irritation and bleeding in the bladder) of cyclophosphamide. 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. You will receive vincristine by vein on Days 4 and 11, which will be given over 30 minutes during each cycle of hyper-CVAD therapy. You will receive doxorubicin on Day 4 through a large vein by a CVC over 24-48 hours after your last dose of cyclophosphamide. This will depend on your heart function because the drug is being given over such a long period of time. You will receive dexamethasone on Days 1-4 and Days 11-14 by mouth or by vein over 30 minutes during each cycle of hyper-CVAD therapy. Methotrexate plus Ara-C will be given during the even-numbered courses (2, 4, 6, and 8). You will receive methotrexate on Day 1 by vein over 24 hours. You will receive Ara-Con Days 2 and 3 of each cycle, which will be given by vein over 2 hours every 12 hours for a total of 4 doses each time. Your dose of Ara-C may be decreased depending on your age, kidney function, or certain side effects you may experience. You will receive citrovorum or leucovorin after the completion of methotrexate, which will help decrease the side effects (such as mouth sores and kidney damage) of methotrexate. You will also receive a growth factor (G-CSF) after the completion of all cycles of Hyper-CVAD and methotrexate plus cytarabine. You will receive G-CSF as in injection just under your skin every day until you have healthy recovery of your white blood cells, which will be determined by the study doctor. If the doctor thinks it is needed, on Days 1 and 11 of Cycles 1-4, you will also receive rituximab by vein over several hours. You will also receive small doses of methotrexate and Ara-C by a spinal tap to help prevent relapse of the disease in the fluid surrounding your brain. A spinal tap requires the insertion of a needle through the skin and the soft tissues of the lower back to reach a pocket of fluid that is a part of the fluid space that surrounds the brain and the spinal cord. Once the fluid space is reached, a sample of the fluid will be collected. The procedure is done under local anesthesia. It can also be used to give chemotherapy. You may be given treatment with methotrexate and Ara-C, alternately, to the brain by spinal tap during each cycle for a total 6-8 doses. The number of doses you receive will depend on how many doses the study doctor thinks is necessary. If you start with leukemia in the brain, it will be given 2 times a week until there is no leukemia present and then 1 time a week for 4 weeks. Occasionally, a sample of the fluid obtained from the spinal taps may be examined by sensitive tests for presence of leukemia. A sample will also be sent to determine the amount of dasatinib to see if it reaches the fluid around the brain. Dasatinib will be given by mouth on Days 1-14 of Cycle 1 and every day of Cycles 2-8 . If the disease is responding to therapy and you have not experienced any intolerable side effects, you will continue on intensive chemotherapy for up to 8 courses, and you will then proceed to the maintenance therapy phase. You will be taken off this study if the disease gets worse or you experience any intolerable side effects. Maintenance Therapy: Maintenance therapy, which will last for up to 2 years, will be given after you complete all 8 courses of intensive chemotherapy. You will receive vincristine on Day 1 by vein about every 28 days. You will receive prednisone on Days 1-5 by mouth about every 28 days. You will receive dasatinib every day by mouth 2 times a day. During Months 6 and 13, you may receive another course of hyper-CVAD, depending on how you are feeling and if you have presence of disease. You will also receive rituximab during these months if your doctor thinks it is needed. Your doses of all chemotherapy that is given in this study may be increased or decreased depending on your organ function and side effects. Throughout intensive chemotherapy and maintenance therapy, you will also receive other drugs, fluids, or blood products (such as antibiotics, antiemetics, antacids, saline, platelets, and plasma), including allopurinol (by mouth) or rasburicase (by vein), to help protect your body against tumor lysis syndrome. This is a condition brought on by the death of large tumors, which causes damage to kidneys. This is an investigational study. All of the drugs used in this study are FDA approved and commercially available. Their use together in this study is investigational. Up to 115 patients will take part in this study. All will be enrolled at MD Anderson.
Trial information was received from ClinicalTrials.gov and was last updated in March 2016.
Information provided to ClinicalTrials.gov by M.D. Anderson Cancer Center.